1 Pharmacokinetics of Psychotropic Drugs Terence A. Ketter, M.D. Stanford University School of Medicine
Transcript
1
Pharmacokinetics of Psychotropic Drugs
Terence A Ketter MDStanford University School of Medicine
2
Teaching Pointsbull Key pharmacokinetic parameters include volume of
distribution half life and clearance
bull Most drugs undergo hepatic metabolism and are thus at risk for drug interactions related to hepatic metabolism but a few drugs (such as lithium) have renal excretion and are thus at risk for drug interactions related to renal excretion
bull Characterizing medications as substrates inducers and inhibitors of specific cytochrome p450 metabolic enzymes can help predict and prevent adverse events related to drug interactions
bull The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are CYP2D6 and CYP3A34
3
Pre Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
4
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
5
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
6
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
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Nuacutemero de diapositiva 20
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Nuacutemero de diapositiva 29
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Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
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Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
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Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
2
Teaching Pointsbull Key pharmacokinetic parameters include volume of
distribution half life and clearance
bull Most drugs undergo hepatic metabolism and are thus at risk for drug interactions related to hepatic metabolism but a few drugs (such as lithium) have renal excretion and are thus at risk for drug interactions related to renal excretion
bull Characterizing medications as substrates inducers and inhibitors of specific cytochrome p450 metabolic enzymes can help predict and prevent adverse events related to drug interactions
bull The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are CYP2D6 and CYP3A34
3
Pre Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
4
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
5
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
6
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
3
Pre Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
4
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
5
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
6
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
4
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
5
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
6
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
5
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
6
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
6
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
7
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
8
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
9
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
10
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
11
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
12
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
14
PHARMACOKINETICS
bullTime course of drug absorption distribution metabolism amp excretion
bullDrug transport to amp from receptors
bullWhat the body does to the drug
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
15
PHARMACODYNAMICS
bull Relationships between drug concentrations amp responses
bull Drug activity at receptors
bull What the drug does to the body
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
16
CONCEPT DEFINITION
V (vol of distrib) Volume needed to contain drug at concentration same as plasma
t12 Time for [drug] to darr 50(half life)
Cl Volume of blood cleared(clearance) of drug per unit time
PHARMACOKINETIC CONCEPTS
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
17
CONCEPT RELEVANCE
V (vol of distrib) Extracirculatory distribution(binding lipophilicity)
Loading dose(Load with V x[desired conc change])
t12 Time to steady state = 5 x t12 (half life)(t12 = 7 x V Cl)
Cl Steady state concentration (clearance) (Css = dose x dosing interval x F Cl)
PHARMACOKINETIC CONCEPTS
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
18
CONCEPT EXAMPLE
V Li - 1 L kg TCAs - 10 L kg(vol of dist) (dialysis effective dialysis ineffective)
VPA - 02 L kg(Load with 02 Lkg x 100 mgL = 20 mgkg)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
19
ABSORPTION
bull Bioavailability = reaching circulation as compared to IV (F = absorption - first pass metabolism)
bull Affected by food(uarr sertraline ziprasidone darr nefazodone absorption)
bull Affected by enterichepatic metabolism(tyramine - MAO terfenadine - CYP3A4)
bull Speed affected by enteric motility(uarr with metoclopramide darr with TCAs)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
20
DISTRIBUTION
bull Lipophilicity amp binding
bull Many drugs 80 - 95 protein boundndash Albumin - acidsndash α 1-acid glycoprotein - bases neutral ndash Lipoproteins - bases neutral
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
21
EXCRETION
Rate = filtration + secretion - reabsorption
bull Filtration (glomerulus)ndash Affected by binding interactionsndash darr in renal disease
bull Secretion (proximal tubule)ndash Drugs compete for active transport
bull Reabsorption (proximal gt distal tubule)ndash Passive (high for lipophilic drugs)ndash Thiazides rarruarr Li amp Na reabsorptionndash Acidifying urine rarrdarr base reabsorption
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
22
METABOLISM
PHASE I - Introduce functional groupsbull Oxidation
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
23
bull Longer t12
bull More water soluble
bull Generally less active but can be more active (hydroxylated demethylated)
bull Pharmacodynamics may be - Similar (CBZ-E cf CBZ) - Different (m-CPP anxiogenic cf
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
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Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
26
CONCEPT DEFINITION RELEVANCE
Therapeutic index Efficacy relative to toxicity
Dose-response curve Linear sigmoidal curvilinear relationships
Tolerance darr therapeutic or adverse responses with time
Withdrawal Discontinuation effects
Response latency Delay to onset of effects
PHARMACODYNAMIC CONCEPTS
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
27
CONCEPT EXAMPLE
Therapeutic index High for SSRIs low for Li
Dose-response curve Curvilinear for nortriptyline(therapeutic window)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
29
INTERACTION POTENTIAL
bull Low therapeutic indexbull Long half-lifebull Nonlinear kineticsbull Active metabolitesbull Potent metabolic inhibition
inductionbull Single metabolic route bull CYP2D6 CYP3A457
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
30
CYP2D6
P450 NOTATION
CYP - CYtochrome P (protein) 450 (wave length CO absorption)
2 - family (gt 40 homology) D - subfamily (gt 55 homology)6 - gene
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
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Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
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Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
37
SPECIAL POPULATIONS
Group Protein Hepatic Renalbinding elimination elimination
Prebubes (=) (uarr) (uarr)
Elderly (=) (= darr) darr
Pregnant (=darr) (= darr uarr) uarr
Manic (=) (=) (uarr)
Renal d darr darr darr
Liver d (= darr) darr (= darr)
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
38
DRUG
lithiumcarbamazepine
valproate
phenytoinbarbiturateslamotriginegabapentin
SUBSTRATE OF
renal excretion3A4 3A5-7conjugation
β-hydroxylationP450 oxidation
2C910 plusmn 2C192C19
UGT1A4renal excretion
INDUCES INHIBITS
-induces 3A457 weak inhibitor
induces 3A457 induce 3A457
mildly self-
MOOD STABILIZER ANDANTICONVULSANT METABOLISM
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
39
LITHIUMbull 100 absorbed F = 100 bull 0 bound V = 1 L kgbull t12 = 24 h Cl = 10 - 40 mL min bull Cl = 25 x creatinine Cl bull 900 - 2400 mg d 6 - 12 mEq Lbull No metabolitesbull No metabolic interactionsbull 100 renal excretionbull Renal excretion interactions bull Low therapeutic index -gt neurotoxicity
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
40
LITHIUM CLEARANCE
Decreased by
thiazides
NSAIDs
ACE inhibitors
dehydrationelderlyrenal disease
Increased by
acetazolamide mannitol
aminophyllinecaffeine theophylline
pregnancymania
Not changed by
amiloride furosemide
ASAsulindac
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
41
CARBAMAZEPINE
bull Erratic absorption F = 80bull 75 bound V = 1 L kgbull t12 = 24 h Cl = 25 mL min (pre-induction)
t12 = 8 h Cl = 75 mL min (post-induction)bull 400 - 1600 mg d 4 - 12 mcg mLbull Active CBZ-1011-epoxide metabolite (t12 6h)bull Complex kinetics amp multiple interactionsbull gt 40 1011-epoxidation [mostly 3A43A5-7]bull Autoinduction heteroinductionbull Low therapeutic index (neurotoxicity)
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
Antidepressants
AnxiolyticsSedatives
Anticonvulsants
Antimicrobials
Steroids
Bupropion
Alprazolam ()
Carbamazepine
Caspofungin
Hormonal contraceptives
Citalopram
Buspirone
Ethosuximide
Doxycycline
Dexamethasone
Mirtazapine ()
Clonazepam
Felbamate
Mifepristone
Tricyclics
Midazolam
Lamotrigine
Antivirals
Prednisolone
Zopiclone
Oxcarbazepine
Delavirdine
Antipsychotics
Phenytoin
Protease inhibitors
Others
Aripiprazole
Stimulants
Primidone
Bepridil
Clozapine
Methylphenidate
Tiagabine
Immunosuppressants
Dihydropyridine CCBs
Fluphenazine ()
Modafinil
Topiramate
Cyclosporine ()
Oxiracetam ()
Haloperidol
Valproate
Sirolimus
Paclitaxel
Olanzapine
Analgesics
Zonisamide
Tacrolimus
Quinidine
Quetiapine ()
Alfentanil
Remacemide ()
Risperidone
Buprenorphine
Anticoagulants
Muscle Relaxants
Repaglinide
Thiothixene ()
Fentanyl ()
Dicumarol ()
Doxacurium
Theophylline ()
Ziprasidone
Levobupivacaine
Phenprocoumon
Pancuronium
Thoraloralyroid hormones
Methadone
Warfarin
Rapacuronium
Tramadol
Rocuronium
Vecuronium
42Ketter TA et al J Clin Psychopharmacol 199111198-203306-313
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Selected Drugs that Increase Levels ofCarbamazepine
(A Partial List)
Ketter TA et al In Schatzberg AF Nemeroff CB (eds) The American Psychiatric Press Textbook of Psychopharmacology (3rd ed) American Psychiatric Press Washington DC 2003581-606
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
Antidepressants
Calcium Channel Blockers
Fluoxetine
Diltiazem
Fluvoxamine
Verapamil
Nefazodone
Hypolipidemics
Antimicrobials
Gemfibrozil
Isoniazid
Nicotinamide
Quinupristindalfopristin
Others
Macrolide Antibiotics
Acetazolamide
Clarithromycin
Cimetidine
Erythromycin
Danazol
Flurithromycin
Omeprazole
Josamycin
d-Propoxyphene
Ponsinomycin
Ritonovir ()
Ticlopidine ()
VPA (increases CBZ-E)
45
CYP3A4-MEDIATED CBZ DRUG INTERACTIONS
CBZ rarrdarr DRUG
3deg tricyclics (demethylation)
Ca blockers CBZ
benzodiazepines
dexamethasone oral contraceptives
prednisolone local anesthetics
ethosuximide
DRUG rarruarr CBZ
Fluoxetinefluvoxamine Nefazodone
Ca blockers
danazol
cimetidine
clarithromycin erythromycin
DRUG rarrdarr CBZ
CBZphenobarbitalphenytoin ()
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
46
VALPROATEbull 100 absorbed F = 100bull 80 - 90 bound (saturable) V = 01 - 02 L kgbull t12 = 12 h Cl = 10 mL min bull 750 - 4000 mg d 50 - 125 mcg mLbull Binding saturation-lower bound at hi levelsbull ldquoSublinearrdquo kinetics binding interactionsbull 3 elimination routes metabolites
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
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Nuacutemero de diapositiva 18
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Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
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Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
47Potter WZ Ketter TA Can J Psychiatry 199338S51-S56
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
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Nuacutemero de diapositiva 24
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Nuacutemero de diapositiva 26
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Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
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Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
51
TRICYCLIC ANTIDEPRESSANTS
bull 100 absorbed F = 20 - 70 bull 90 bound V = 10 - 30 L kgbull t12 = 24 h Cl = 300 - 1700 mL min bull 150 - 300 mgd 150 - 300 ngmL (AMIIMIDMI)
75 - 150 mg d 75 - 150 ngmL (NORT)bull Active demethylated amp hydroxylated metabs
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
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Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
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Nuacutemero de diapositiva 21
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Nuacutemero de diapositiva 28
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Nuacutemero de diapositiva 30
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Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bulldarr side effects uarr therapeutic index cf TCAs
(es)Citalopramplusmn(1A22C192D6)
(3A42C19)plusmn
Paroxetine (2D6)(2D6)
-
Fluoxetine (2D63A4) (2D63A4)
+
Sertraline(plusmn2D6) (3A4)
plusmn
Fluvoxamine(1A22C93A4)
-
Venlafaxine-
(2D6) +
Duloxetine- substrate of CYP1A2 and CYP2D6 and modest inhibitor CYP2D6
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
56
FLUOXETINE
bull Well absorbed F gt 60bull 95 bound V = 20 - 45 L kgbull t12 = 4 d Cl = 300 mL min bull 20 - 80 mg d bull Norfluoxetine metabolite
(active t12 = 7-14 d)bull 5 week wait for MAOIsbull CYP2D6 substrate (40)bull CYP2D6 gt CYP3A4 inhibitorbull Nonlinear kinetics (saturation)bull High therapeutic index
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
57
FLUOXETINE INTERACTIONS
VIA 2D6AMI IMI
NORT DMIfluphenazinehaloperidolclozapine
dextromethorphanoxycodone
atomoxetineduloxetinevenlafaxine
VIA 2C19moclobemide
diazepamplusmn phenytoin
VIA valproate
VIA 3A4 3A5-7alprazolamdiazepam
+-carbamazepine
FLUOXETINE rarruarr DRUG
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
58
PAROXETINE
bull 100 absorbed bull Large first pass F dose dependentbull 95 bound V = 17 L kgbull t12 = 21 h 10 - 50 mg d bull Inactive metabolitesbull 2 week wait for MAOIsbull CYP2D6 inhibitor amp substratebull Nonlinear kinetics (saturation)bull Increases TCA levelsbull High therapeutic index
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
60
FLUVOXAMINE
bull 94 absorbed F = 53bull 80 bound V = 20 L kgbull t12 = 16 h Cl = 1600 mL min bull 50 - 300 mg dbull Inactive metabolitesbull Novel interaction profilebull High therapeutic index
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
61
FLUVOXAMINE INTERACTIONS
VIA 1A2
AMI IMI CMImaprotilineclozapine
olanzapinemethadone
caffeinephenacetinpropranololtheophylline
FLUVOXAMINE rarruarr DRUG
VIA 3A457
alprazolamdiazepam
carbamazepine
VIA 2C910
phenytoinwarfarin
VIA 2D6
haloperidol
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
62
SERTRALINEbull Absorption uarr with foodbull 98 bound V = 20 L kgbull t12 = 26 h 50 - 200 mg dbull Desmethylsertraline metabolite
(plusmn active t12 = 3 d)bull 2 week wait for MAOIsbull CYP3A457 substratebull CYP2D6 gt CYP3A457 inhibitorbull At 50 mg day less effect on TCA
levels than fluoxetine paroxetine but more significant at 200mgday
bull High therapeutic index
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
63
VENLAFAXINE
bull 92 absorbed F = 10bull 27 bound V = 8 L kgbull t12 = 5 h Cl = 1400 mL min bull 75 - 375 mg dbull Desmethylvenlafaxine metabolite
(active t12 = 11 h)bull 2 week wait for MAOIsbull CYP2D6 substratebull Modest inhibition on CYP2D6bull High therapeutic index
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
64
DULOXETINE
bull t12= 12 hrs similar in men amp womenbull Vd = 23 L kgbull 90 bound to albumin and alpha1-acid proteinbull Metabolized by CYP1A2 and CYP2D6
bull Cmax = 6 h (am administration)ndash pm administration delays Cmax 3 h increases AUC 10ndash food delays Cmax 6-10 h
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
65
CITALOPRAM-racemic mixtureescitalopram-enantiomer
bull Rapidly absorbed F = 80bull Absorption not affected by foodbull 80 bound V = 12 L kgbull t12 = 35 h Cl = 330 mL min bull 10 - 60 mg dbull Desmethylcitalopram metabolite
(plusmn active via 2C19 3A4 plusmn 2D6)bull Didemethylcitalopram metabolite
(plusmn active via 2D6)bull Contraindicated-canine acral lick syndromebull 2 week wait for MAOIsbull Weak 1A2 2C19 2D6 inhibitorbull High therapeutic index
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
68
BUPROPION
bull 90 absorbed bull 85 bound V = 20 L kgbull t12 = 20 h Cl = 2300 mL min bull 150 - 400 mg d gt 10 ng mL ()bull Extensive CBZ-inducible metabolismbull Hydroxy-BUP (morpholinol) via CYP2B6
ndash Threohydro-BUP via carbonyl reductase ndash Erythrohydro-BUP via carbonyl reductase
bull 3 main active metabolites t12 AUCss cf BUPndash hydroxy-BUP (morpholinol) 20 h 17 x BUP ndash threohydro-BUP 37 h 7 x BUPndash erythrohydro-BUP 33 h 15 x BUP
bull High H-BUP levels in poor response ()bull CYP2D6 potent inhibitor
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
69
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
70
DRUG rarruarr BUPVIA 2B6
orphenadrineifosfamide cimetidine
DRUG rarrdarr BUPVIA
carbamazepinephenobarbital
phenytoin
BUPROPION INTERACTIONS
BUP rarrdarr DRUGno evidence thus far
BUP rarruarr DRUGVIA 2D6
Desipraminevenlafaxine
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
71
MAO INHIBITORS
bull t12 brief amp not directly related to effects(irreversible MAO inhibition)
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
73
MAO INHIBITOR INTERACTIONS
DRUGSdecongestants
opiatesSSRIs SNRIs CMI
stimulants
nefazodone bupropion
(Li VPA okay)(CBZ okay)
FOODShigh tyramine
cheesechianti
fava
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
74
TRAZODONE
bull 100 absorbed F = 80bull 90 bound V = 1 L kgbull t12 = 4 h Cl = 120 - 200 mL min bull 150 - 600 mg d 500 - 1500 ng mLbull Active m-CPP metabolite
(anxiogenic 5HT-1 agonist t12 = 6 h) bull May give with MAOIsbull CYP3A4 substratebull Few metabolic interactionsbull Low therapeutic index (sedation)
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
75
NEFAZODONEbull 100 absorbed (darr with food) F = 20bull 99 bound V = 05 L kgbull t12 = 3 h Cl = 500 - 2000 mL min bull 300 - 600 mg dbull Active m-CPP metabolite
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
78
MIRTAZAPINE
bull F = 50 85 bound V = 4 L kgbull t12 = 30 h men 26 h women 37 hbull Cl = 500 mL min bull 15 - 45 mg d 40 - 120 ng mL bull 2D6 gt 1A2 rarr 8-hydroxy-MIRT
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
79
CLASS DRUG
2-KETOclorazepatediazepam
flurazepam
TRIAZOLOalprazolamtriazolam
7-NITRO clonazepam nitrazepam
3-HYDROXYlorazepamoxazepam
temazepam
SUBSTRATE OF
2C19 3A4
3A4
N-reduction(3A4)
ConjugationUGTs
INHIBITED BY
fluoxetinefluvoxamine
fluoxetinefluvoxaminenefazodone
-
-
ANXIOLYTIC METABOLISM
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
80
BENZODIAZEPINESbull 100 absorbed (darr with antacid)bull 95 bound V = 1 L kgbull t12 short (lt 6 h) triaz cloraz fluraz
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
81
BENZODIAZEPINES
TRIAZOLO
alprazolamtriazolam
4-hydrox [3A4]α-hydrox [3A4]
activeshort t12metab (alpraz)
+ kinetic ints
2-KETO
clorazepatediazepam
flurazepam
N-dealk [2C19] -3-hydrox [3A4]
activelong t12metabs
+ kinetic ints
3-HYDROX
lorazepamoxazepam
temazepam
directconjugation
inactivemetabs
plusmn kinetic ints
7-NITRO
clonazepamnitrazepam
N-reduction
inactivemetabs
plusmn kinetic ints
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
82
DRUG rarruarr 2-KETO BZclorazepate diazepam flurazepam
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
87
TYPCIAL ANTIPSYCHOTICSbull F = 20 - 80bull absorption darr with antacidbull 80 - 95 bound V = 10 - 40 L kgbull t12 = 12 - 24 h Cl = 70 - 600 mL min bull Low potency 200 - 600 mg d
High potency 5 - 20 mg d
bull Active metaboliteschlorpromazine 7-hydroxy-CPZthioridazine mesoridazinehaloperidol reduced haloperidolloxapine amoxapine
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
89
CLOZAPINE
bull 100 absorbed F = 70bull 97 bound V = 5 L kgbull t12 = 12 h Cl = 750 mL min bull 50 - 900 mg d 100 - 600 ng mLbull Desmethyclozapine metabolite
(active)bull CYP1A2 gt CYP2D6 substrate or CYP3A4bull Low therapeutic index (sedation seizures)
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
90
DRUG rarruarr CLOZfluoxetine
fluvoxaminecimetidinerisperidoneplusmn valproate
CLOZAPINE INTERACTIONS
DRUG rarrdarr CLOZCigarette smokecarbamazepine
phenytoin
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
91
RISPERIDONE
bull 90 - 100 absorbed F = 70bull 90 bound V = 1 L kgbull t12 = 3 h Cl = 400 mL min bull 4 - 16 mg dbull 9-hydroxy-risperidone metabolite(active t12 = 21 h)
is substrate CYP3A4bull Risperidone is CYP2D6 substratebull Carbamazepine rarr darr risperidone bull Fluoxetine rarr uarr risperidonebull Mod therapeutic index (neurotoxicity)
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
92
OLANZAPINE
bull Well absorbedbull 93 bound V = 15 L kgbull t12 = 30 h Cl = 400 mL min bull 5 - 20 mg dbull Substrate of UGTs and CYP1A2bull Metabolites
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
93
QUETIAPINE
bull 100 absorbed F = 100bull 83 bound V = 10 L kgbull t12 = 6 h Cl darr 40 in elderly bull 50 - 800 mg d (in divided doses)bull Inactive sulfoxide metabolite via CYP3A4bull PHT thioridazine rarr darr quetiapine bull Quetiapine rarruarr warfarin bull Well tolerated with lithiumbull No effect on lithium levels
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
94
bull 60 absorbed with food (30 unfed)bull 99 bound V = 15 L kgbull t12 = 66 h Cl = 525 mL min bull 40 - 160 mg d po 20 - 40 mg d im
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
95
bull F = 87bull 99 bound V = 49 L kgbull t12 = 75 hbull 10 - 30 mg dbull Metabolized by CYP2D6 CYP3A4bull Active dehydro-aripiprazole metabolite
(t12 = 94 h) bull carbamazepine rarr darr aripiprazole bull ketoconazole rarr uarr aripiprazole bull quinidine rarr uarr aripiprazole bull Not affected by lithium or VPA
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
97
GABAPENTIN
bull F = 60bull Absorption less with doses gt 900 mgbull 0 bound V = 1 L kgbull t12 = 6 h Cl = 120 mL min = GFRbull 900 - 4800 mg d gt 2 mgmLbull Excreted unchanged in urinebull No metabolic drug interactionsbull Clearance increased with exercise (Borchert 96)
bull Does not alter Li kinetics (Frye 98)
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
98
LAMOTRIGINE
bull F = 98 55 bound V = 1 L kgbull Rx t12 (h) Cl (mLmin) dose (mgd)
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
99
Lamotrigine Titration Influenced by Valproate and Carbamazepine
1 Guberman et al Epilepsia 1999 2 Physiciansrsquo Desk Reference 2006
bull Double lamotrigine dose with carbamazepinebull Halve lamotrigine dose with valproate
Lamotrigine Titration in Adults12
Week Daily Dose1 25 mg2 25 mg3 50 mg4 50 mg
Week 5 Add 50-100 mgwkonward as clinically indicated
Maintenance 100-400 mg
Moderador
Notas de la presentacioacuten
Slide 44 Reducing the Risk of Rash With Lamotrigine13Lamotrigine (LTG) is used ldquooff-labelrdquo for treating bipolar disorder so specific dosage guidelines are not provided in the package insert The usual regimen is to start patients on 25 mg once daily for weeks 1 and 2 increase to 50 mg for weeks 3 and 4 and then titrate by 50 to 100 mg daily every 1 to 2 weeks after the fifth week The maintenance dosage for LTG monotherapy is 100 to 400 mg daily Retitrate if 5 or more days elapse without drug administration113If the patient is already receiving carbamazepine then the initial titration and maintenance doses of LTG should be increased Use 50 mg once daily for weeks 1 and 2 follow with 50 mg twice daily for weeks 3 and 4 and then titrate by 100 mg daily every 1 to 2 weeks to a maintenance dose of 300 to 500 mg daily2 13Because valproate (VPA) can increase LTG steady-state concentrations 2-fold in healthy volunteers the recommended titration schedule for LTG in combination with VPA should be ldquolow and slowrdquo In this case LTG dosing is 25 mg every other day for weeks 1 and 2 followed by 25 mg daily for weeks 3 and 4 then titrate by 25 to 50 mg daily every 1 to 2 weeks afterward The maintenance dose for LTG with concomitant VPA is usually 100 to 200 mg daily in 1 to 2 divided doses213The safest approach to LTG dosing in general is to ldquostart low go slowrdquo High initial doses and rapid dose escalation significantly increase the risk of rash A serious rash is most likely to occur in the first 2 to 8 weeks of therapy but isolated cases have been reported after prolonged treatment (approximately 6 months) Therefore the patient should be monitored for the duration of LTG therapy113The risk of discontinuation of drug therapy due to rash in patients with epilepsy taking LTG is 28-fold higher in patients with any history of drug allergy and 38-fold higher in patients with a history of allergy to an antiepileptic drug
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
100
bull F = 80 15 bound V = 08 L kgbull t12 = 24 h Cl = 25 mL minbull 70 excreted unchanged monoRx 50 excreted
unchanged with inducersbull Inactive hydroxylation hydrolysis amp conjugation
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
101
TIAGABINE
bull F = 90 96 bound bull t12 = 8 h with monoRxt12 = 4 h with inducers bull Cl = 109 mL minbull TGB is a CYP3A4 substratebull Inactive 5-oxo-tiagabine amp glucuronide metabolitesbull 4 mgd rarruarr 4 - 8 mgd q wk rarr up to 56 mgdbull CBZ PHT PB rarrdarr TGB VPA rarruarr free TGBbull TGB rarr plusmn darr VPA (10)
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
102
OXCARBAZEPINEbull 100 absorptionbull MHD 40 bound MHD V = 07 L kgbull OXC t12 = 2 h MHD t12 = 9 hbull 900 - 2400 mg d 10 - 35 mcg mLbull Metabolized by cytosol reductasebull Active 10-monohydroxyderivative (MHD)bull Fewer interactions than CBZ
ndash No autoinduction less heteroinductionbull OXC rarr darr ethinyl estradiol (CYP3A4 modest
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
104
LEVETIRACETAM
bull F = 100 lt 10 boundbull 66 excreted unchangedbull 24 hydrolyzed to inactive metabolite (ucb L057) bull t12 = 8 hbull Cl = 40 mL minbull 1000 mgd rarr uarr 1000 mgd q 2wks -up to 3000 mgdbull CBZ PHT PB VPA do not alter levels
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
105
Ca CHANNEL BLOCKERSbull 90 - 100 absorbed F = 10 - 50bull 80 - 90 bound V = 1 - 5 L kgbull t12 = 1 - 6 h Cl = 70 - 140 mL minbull verapamil (phenylalkylamine) 120 - 480 mg d
bull Active norverapamil metabolite (t12 = 10 h)bull 3A4 substrates (metabolism darr with cimetidine)bull verapamil diltiazem (not dihydropyridines)
ndash 3A4 inhibitors (darr cyclosporin CBZ metab)
bull Varying therapeutic indices (cardiovascular)
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
106
CONCLUSIONS
bull Combination Rx often needed
bull Extensive observational clinical data
bull Evolving characterization of substrates inhibitors amp inducers
bull Understanding of drug metabolism
bull Prediction of drug interactions
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
107
REFERENCES
bull Ciraulo DA et al Drug Interactions in Psychiatry 2nd ed Williams amp Wilkins Baltimore 1995
bull DeVane CL Fundamentals of Monitoring Psychoactive Drug Therapy Williams amp Wilkins Baltimore 1990
bull Evans WE et al Applied Pharmacokinetics Principles of Therapeutic Drug Monitoring 3rd ed Applied Therapeutics Vancouver WA 1992
bull Ketter TA et al Metabolism and excretion of mood stabilizers and new anticonvulsants Cell Mol Neurobiol 199919(4)511-32
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
108
Post Lecture ExamQuestion 1
1 Key pharmacokinetic parameters include (choose one)
A Volume of distribution (V)B Half life (t12)C Clearance (Cl)D Therapeutic indexE All of the aboveF A B and C
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
109
Question 2
2 After discontinuation how long does it take to completely clear a drug (choose one)
A Clearance x half-lifeB 2 x half-lifeC 5 x half-lifeD Volume of distribution x clearance
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
110
Question 3
3 The two most important cytochrome P450 isoforms mediating drug interactions in psychiatric patients receiving combination therapies are (choose two)
A 1A2B 2C910C 2C19D 2D6E 2E1F 3A34
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
111
Question 4
4 Which of the following drugs is NOT an enzyme inducer (choose one)
A CarbamazepineB ValproateC OxcarbazepineD PhenytoinE PhenobarbitalF Primidone
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
112
Question 5
5 Which of the following drugs decrease plasma concentrations of hormonal contraceptives (choose one)
A CarbamazepineB OxcarbazepineC TopiramateD PhenytoinE PhenobarbitalF All of the above
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
113
Question 6
6 Which of the following drugs is NOT an enzyme inhibitor (choose one)
A LithiumB BupropionC FluoxetineD ValproateE CimetidineF Erythromycin
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
114
Question 7
7 Which of the following drugs robustly increases plasma concentrations of lamotrigine (choose one)
A CarbamazepineB ValproateC CimetidineD GabapentinE Phenytoin
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
115
Question 8
8 Which of the following drugs have exclusively renal excretion (choose one)
A GabapentinB ValproateC LithiumD CarbamazepineE A and C
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
116
Question 9
9 Monoamine oxidase inhibitor combination therapy is limited by
A Side effects (low to low-moderate therapeutic index)B Serious pharmacodynamic drug interactionsC Allergic reactions (rashes)D Their exclusively renal excretionE A and BF None of the above
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
117
Question 10
10Which of the following benzodiazepines has least potential for drug interactions
A Diazepam (a 2-keto-benzodiazepine)B Alprazolam (a triazolo-benzodiazepine)C Flurazepam (a 2-keto-benzodiazepine)D Lorazepam (a 3-hydroxy-benzodiazepine)
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine
Nuacutemero de diapositiva 100
Nuacutemero de diapositiva 101
OXCARBAZEPINE
Nuacutemero de diapositiva 103
Nuacutemero de diapositiva 104
Nuacutemero de diapositiva 105
CONCLUSIONS
Nuacutemero de diapositiva 107
Post Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Answers to Pre amp PostCompetency Exams
118
Answers to Pre amp PostCompetency Exams
1 F2 C3 D amp F4 B5 F
6 A7 B8 E9 E10D
Nuacutemero de diapositiva 1
Teaching Points
Pre Lecture ExamQuestion 1
Question 2
Question 3
Question 4
Question 5
Question 6
Question 7
Question 8
Question 9
Question 10
Outline
Nuacutemero de diapositiva 14
Nuacutemero de diapositiva 15
Nuacutemero de diapositiva 16
Nuacutemero de diapositiva 17
Nuacutemero de diapositiva 18
Nuacutemero de diapositiva 19
Nuacutemero de diapositiva 20
Nuacutemero de diapositiva 21
Nuacutemero de diapositiva 22
Nuacutemero de diapositiva 23
Nuacutemero de diapositiva 24
Nuacutemero de diapositiva 25
Nuacutemero de diapositiva 26
Nuacutemero de diapositiva 27
Nuacutemero de diapositiva 28
Nuacutemero de diapositiva 29
Nuacutemero de diapositiva 30
Nuacutemero de diapositiva 31
Nuacutemero de diapositiva 32
Nuacutemero de diapositiva 33
Nuacutemero de diapositiva 34
Nuacutemero de diapositiva 35
Nuacutemero de diapositiva 36
Nuacutemero de diapositiva 37
Nuacutemero de diapositiva 38
LITHIUM
Nuacutemero de diapositiva 40
CARBAMAZEPINE
Nuacutemero de diapositiva 42
Nuacutemero de diapositiva 43
Nuacutemero de diapositiva 44
Nuacutemero de diapositiva 45
VALPROATE
Nuacutemero de diapositiva 47
Nuacutemero de diapositiva 48
Nuacutemero de diapositiva 49
Nuacutemero de diapositiva 50
Nuacutemero de diapositiva 51
Nuacutemero de diapositiva 52
Nuacutemero de diapositiva 53
Nuacutemero de diapositiva 54
SSRIs amp SNRIs
FLUOXETINE
Nuacutemero de diapositiva 57
PAROXETINE
Nuacutemero de diapositiva 59
Nuacutemero de diapositiva 60
Nuacutemero de diapositiva 61
SERTRALINE
VENLAFAXINE
DULOXETINE
CITALOPRAM-racemic mixtureescitalopram-enantiomer
Nuacutemero de diapositiva 66
PHARMACOKINETICS OFSSRIs AND SNRIs
BUPROPION
Nuacutemero de diapositiva 69
Nuacutemero de diapositiva 70
Nuacutemero de diapositiva 71
MAO INHIBITORS
MAO INHIBITOR INTERACTIONS
Nuacutemero de diapositiva 74
Nuacutemero de diapositiva 75
Nuacutemero de diapositiva 76
Nuacutemero de diapositiva 77
Nuacutemero de diapositiva 78
Nuacutemero de diapositiva 79
BENZODIAZEPINES
Nuacutemero de diapositiva 81
Nuacutemero de diapositiva 82
Nuacutemero de diapositiva 83
Nuacutemero de diapositiva 84
Nuacutemero de diapositiva 85
Nuacutemero de diapositiva 86
TYPCIAL ANTIPSYCHOTICS
Nuacutemero de diapositiva 88
Nuacutemero de diapositiva 89
Nuacutemero de diapositiva 90
Nuacutemero de diapositiva 91
Nuacutemero de diapositiva 92
Nuacutemero de diapositiva 93
Nuacutemero de diapositiva 94
Nuacutemero de diapositiva 95
Nuacutemero de diapositiva 96
Nuacutemero de diapositiva 97
Nuacutemero de diapositiva 98
Lamotrigine Titration Influenced by Valproate and Carbamazepine