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Libby Zion’s Lesson: Serotonin Syndrome
and P450 Drug Interactions
Laurence J. Kinsella, MD, FAANSSM St Clare
Neuroscience InstituteSaint Louis University
Disclosures
Dr Kinsella is a consultant for Therapath laboratories and Cross Country Education.
No relationships with pharmaceutical industry Stock ownership in Passnet Air Ambulance 2009 Teacher of the Year,
US Psychiatric Congress
You Should Know
mechanism of drug-drug interactions (DDI)
common DDIs in neurologic practice
how to predict and manage interactions
In 1984, a young woman died from a fatal drug-drug interaction (DDI). Her death was blamed on poor judgment of sleep-deprived house staff, and led to the 80 hour work week restriction for residents. What was the DDI and the name of the syndrome?
Question 1
a. Haloperidol and Chlorpromazine - Neuroleptic malignant Syndrome
b. Penicillamine and Gentamicin - Myasthenic Crisis
c. Phenelzine and meperidine - Serotonin Syndrome
d. Carbamazepine and acetaminophen - Stevens Johnson Syndrome
Case 1: 54 Year-Old Female
Admitted for GI distress, vomiting, chest pain On phenelzine (Nardil®) for depression Given meperidine for chest wall discomfort q6hrs Developed shivering, rigidity, tremor, confusion,
mutism, hyperthermia and tachycardia
Case 1
Meperidine, phenelzine held Given cyproheptadine 12 mg per NG, then 2
mg q 2 hrs Ativan 1 mg IV q 2-4 hours EEG - no seizures, diffuse slowing CPK wnl Gradual resolution after 3 days
Case 2
35 year old woman Admitted with confusion Has baseline mental retardation,
schizophrenia, but is able to live independently
Noted to be confused, less verbal by her mother
No longer able to care for self
Case 2
Meds Trazodone (Desyrel®)
Clonazepam (Klonopin®) Venlafaxine (Effexor®) Citalopram (Celexa®) Risperidone (Risperdal®) Aripiprazole (Abilify®) Olanzapine (Zyprexa®) Chlorpromazine (Thorazine®) Oxcarbazepine (Trileptal®)
Exam - resting tachycardia 104 bpm
Fine tremor in hands MMSE - 12/27
Case 2
Confusion and tremulousness resolved over 3 days when holding just 3 meds - Citalopram, venlafaxine and trazodone
Mental status returned to baseline MMSE - 24/30 HR 81
Serotonin Syndrome: Clinical Features
Mental status changes Agitation, hypervigilence, confusion
Autonomic hyperactivity Tachycardia, fever, hypertension,
diaphoresis
Hyperkinetic motor activity Tremor, clonus, hyperreflexia
New York Hospital, 1984 Libby Zion, an 18 year old college student,
dies in New York Hospital
Rcvd meperidine (Demerol®) and haloperidol (Haldol®) for sedation and pain control.
Home meds included phenelzine (Nardil®), an MAOI
Her father, Sidney Zion, indicts the medical training system, overworked and poorly supervised residents
1995 – Zion vs New York Hospital
Jury assigns partial blame to MDs and Zion
Traces of cocaine found in autopsy sampleshttp://www.courttv.com/archive/casefiles/verdicts/zion.html
Asch DA. “The Libby Zion Case”, New England Journal of Medicine 1988;318:771-775.www.ethicsconsultant.com/system/files/Zion-Case-White3.ppt
The Bell Commission 1987
Indictment of residency work hours and poor supervision
Led to current 80 hour workweek mandate
Adopted by ACGME in 2003 for all US residencies
Recent data supports a link between poor decision making and sleep deprivation Poor attention following sleep
deprivation Poor/dangerous order writing by ICU
residents post-call.
Lockley et al. NEJM 2004;351:1829-1837Landrigan et al. Effect of reducing interns’ work hours on
serious medical errors in intensive care units. NEJM 2004;351:1838-1848.
Libby Zion’s Lesson
Would today’s well-rested resident have recognized the problem that killed Libby Zion?
Serotonin Syndrome: Pathophysiology
Hyperstimulation of post synaptic 5-HT receptors
Brain, GI tract and vessels
Drugs may stimulate receptors directly Tryptophan Sumatriptan Buspirone
Or block reuptake and metabolism SSRIs Meperidine (Demerol®) MAOIs Boyer, E. W. et al. N Engl J Med 2005;352:1112-1120
Serotonin Syndrome
1960: tryptophan and MAOIs
1984: Libby Zion - Demerol and phenelzine (and cocaine?)
15% incidence in patients overdosing SSRIs
Toxic Exposure surveillance system 2002 7349 patients reported in 2002 93 deaths 0.4 cases/1,000 patient-months on SSRIs
Oates JA, Neurology, 1960; Asch DA, NEJM 1988
Boyer, E. W. et al. N Engl J Med 2005;352:1112-1120
Spectrum of Clinical Findings
Akathisia, restlessness
Tremor
Altered mental status
Hypertonicity
Multifocal myoclonus
Coma
Hyperthermia
Drugs Associated With Serotonin Syndrome
SSRIs: sertraline, fluoxetine, fluvoxamine, paroxetine, citalopram
Antidepressants: trazodone, nefazodone, buspirone, clomipramine, venlafaxine
MAOI: phenelzine, isocarboxazid
AEDs: valproate
Analgesics: meperidine, fentanyl, tramadol and pentazocine
Antiemetics: ondansetron, metoclopramide†
Migraine: sumatriptan* ABx: linezolid, ritonavir Dietary supplements:
tryptophan, St John’s Wort, Ginseng
Lithium, dextromethorphan
* FDA warning re. Triptans and SSRIs 2006; http://www.fda.gov/cder/drug/InfoSheets/HCP/venlafaxineHCP.pdf
† FDA boxd warning 2/26/09 – Long-term or high-dose use of metoclopramide has been linked to tardive dyskinesia
The serotonin syndrome and neuroleptic malignant syndrome are distinguished by all of the following EXCEPT:
Question 2
a. Movements are hyperkinetic in SS, bradykinetic in NMS.
b. Bowel sounds are diminished in NMS.
c. Agitation is more likely in SS.
d. Both SS and NMS respond to bromocriptine.
Manifestations of Severe Serotonin Syndrome and Neuroleptic Malignant Syndrome
Condition Medication History
Time Needed
Vital signs Bowel sounds
Serotonin
syndrome
Pro
serotonergic
drug
< 12 hours Hypertension, tachycardia, tachypnea, hyperthermia
Hyperactive
Neuroleptic
malignant
syndrome
Dopamine
antagonist
1-3 days Hypertension, tachycardia, tachypnea, hyperthermia
decreased
SS vs NMS
Condition Mental Status
Pupils Neuromuscular tone
Reflexes
Serotonin
syndrome
Agitation, coma
Mydriasis Increased, mainly in lower extremities
Hyperreflexia, clonus
Neuroleptic
malignant
syndrome
Stupor, alert mutism, coma
normal Lead pipe rigidity, all muscle groups
Hyporeflexia
Treatment
Mild cases - withdraw meds; low doses benzodiazepines
Severe cases - benzos, cyproheptadine, olanzapine, intubation, neuromuscular blockade
Cyproheptadine binds 5-HT receptors Give by NG 12 mg, then 2 mg q 2 hours Avoid
Propranolol (hypotension) Bromocriptine (may worsen serotonin syndrome) Dopamine (rqs conversion to epinephrine)
The following are true statements about drug interactions EXCEPT:
Question 3
a. It is among hospitalized patients’ chief concerns
b. Drug interactions increase exponentially above 4 medications
c. Competition for protein binding sites is a more important mechanism of DDI than P450 interactions.
d. Elderly have a 3 fold risk of drug interactions and adverse effects due to altered metabolism and increased sensitivity.
Drugs withdrawn for excessive Adverse Drug Reactions
terfenadine (Seldane®) - February 1998 mibefradil (Posicor®) - June 1998 astemazole (Hismanal®) - July 1999 cisapride (Propulsid®) - January 2000 Fluvoxamine (Luvox®) - 2005 All relate to P450 enzymatic interactions with
other drugshttp://www.fda.gov/cder/drug/drugReactions/default.htm
Adverse Drug Interactions
2.2 million severe reactions/yr 7000 deaths/yr (institute of medicine) Some claim 100,000+/yr 1.75 billion in increased medical costs Largest reason for malpractice payouts
Lazarou J. JAMA 1998
“Top Ten” Drug Interactions
1. MAOIs, meperidine, and SSRIs → Serotonin Syndrome
2. Chinese w/ HLA B1502 and carbamazepine → SJS/TEN
3. Clopidogrel and omeprazole → poor stroke prophylaxis
4. Phenytoin and topiramate → phenytoin toxicity
5. Valproate and Lamotrigine (1/2 life^x3) → rash
6. AEDs and OCPs → pregnancy
7. AEDs and warfarin → low INR
8. Grapefruit juice and statins → myalgias
9. TPMT deficiency and Azathioprine → toxicity
10. Imitrex and fluoxetine → Serotonin Syndrome (rare)
Why So Many ADRs?
64% of patient visits result in Rx 2.8 billion outpatient Rxs (10/person in U.S.)
in 2000 ADRs increase dramatically over 4 medications
Jacubeit T. Agents Actions 1990
Polypharmacy in the Elderly
Average older person takes 4.5 prescription medications and 2 OTC
Average person aged 65-69 fills 13.6 rx/yr Average person aged 80-84 fills 18.2 rx/yr
GAO, 1996; Senior Care Pharmacist, 2005
Beers CriteriaHgh Severity: Should be avoided in elderly
Amiodarone Amphetamine Anorexants Anticholinergics Antihistamines Antispasmodics Barbiturates Benzodiazepines Indomethacin Bisacodyl Clonidine Dessicated thyroid
Disopyridine Fluoxetine Ketorolac Long acting NSAIDs Meperidine Meprobamate Methyldopa Muscle relaxants Nifedipine Nitrofurantoin Certain Sulfonylureas Typical antipsychotics Tricyclic antidepressants
Fick DM. Arch Intern Med 2003;163:2716
©
What Causes Drug Interactions?
Age - > 65 have 3 fold increase
Polypharmacy
Genetic variability in drug metabolism
Lack of awareness of CYP450 system
Protein binding site competition - not clinically relevant (except in renal failure)
Brown CS, US Pharmacist, 2000
Phase I Drug Oxidation
Majority of drug interactions occur during phase 1 metabolism (oxidation, hydroxylation, methylation)
Phase 2 metabolism prepares the compound for elimination by making it water soluble (i.e. glucuronidation)
NADP +
NADPH Oxidized
Fe
P450
Oxidized
Reductase
Reduced
Reduced Drug-OH+
H2O
Drug+O2
P450 Enzyme System
Located in liver, kidney, intestine, lungs, brain
6 Individual enzymes metabolizing > 95% of all drugs: 1A2, 2B6, 2C9, 2C19, 2D6, 3A4
www.fftc.agnet.org/library/image/tb159f1.html
Pharmacogenetic Effect of Cytochrome Genotypes
http://www.healthanddna.com/professional/pharmacogeneticsofpain.html
A. Poor metabolizer (PM) no functioning alleles
B. Intermediate metabolizer (IM) Heterozygous for normal and reduced activity allele
C. Extensive metabolizer (EM) 2 functioning alleles- normal
D. Ultra Metabolizer (UM)Greatly increased activity dueto 3 or more alleles (2D6 only)
©
Polymorphic Distribution
7-10% of Caucasian population have polymorphisms of CYP2D6 isoform
20-30% Asians CYP2C19 PM - poor metabolizers EM - extensive metabolizers URM - ultrarapid metabolism
Center for Drug Evaluation and Research.
www.fda.gov
Increasing Metabolic Capacity
URMEMPMNu
mb
er
of
Su
bje
cts
Genetic variants increase the likelihood of drug toxicity. Which of the following drugs have clinically relevant genetic variations in metabolism?
Question 4
a) Warfarin
b) Clopidogrel
c) Carbamazepine
d) Azathioprine
e) All of the above
Is Pharmacogenomics Important for Physicians to Know About?
TMPT (thiopurine methyltransferase) and azathioprine >> toxicity Enzyme activity absent in
1/300 Caucasians, 1% reduced
HLA B*1502 and carbamazepine>>Stevens Johnson Syndrome (SJS) Present in 15% of Asians and
South Asian Indians (FDA Alert)
CYP2C9 and VKORC1 warfarin >> hemorrhage 1-14% caucasians poor
metabolizers (FDA Alert)
2-3% on Clopidogrel will lack benefit due to 2C19 inactivity
UGT inhibition – lamotrigine and valproate >> skin rash and SJS
Pharmacogenet. Genomics 2006;16(4):297-306; http://www.fda.gov/CDER/drug/infopage/carbamazepine/default.htm#top;
http://www.fda.gov/cder/drug/infopage/warfarin/qa.htm; Parmacol Ther 1996;60:145-156; Pharmacogenetics 1999;9:37-42. NEJM December 2008
Genetic Testing
Commercial labs offer analysis of whole blood for 1A2, 2D6, 2C9, 2C19 NAT (“slow acetylators” of isoniazid, others) VKORC1
$200-250/test, $1,250 for the entire panel Insurance coverage - ”some do, some don’t” Detailed printout of drugs to avoid based on
patient’s genetic polymorphisms
CYP1A2
15% of all drugs metabolized by CYP1A2 Genetic polymorphism Induced (rapid metabolism) by smoking tobacco
Omeprazole, rifampin, smoking, char grilled meats
Substrates - theophylline, tricyclics, clozapine, other antipsychotics,
caffeine, benzodiazepines, zolmitriptan
Inhibitors - Fluvoxamine, ciprofloxacin, cimetidine
75 Year-Old Male With Seizures
Admitted with COPD exacerbation Meds; theophylline 300 mg BID Begun on levaquin for pneumonia Developed confusion, ataxia, over next two days Seizure, encephalopathy 3 days after admission What caused the seizure?
Levaquin/Theophylline Interaction
Theophylline is substrate of CYP1A2
Fluoroquinolones are inhibitors of CYP1A2
Theo levels 8.9 mg/dl (12/14)
16.2 (12/17)
6.2 (12/18) after levaquin stopped, theo held
02468
1012141618
12/1
4/20
05
12/1
5/20
05
12/1
6/20
05
12/1
7/20
05
12/1
8/20
05
Theo levels
CYP2D6
25% of all drugs metabolized by CYP2D6 Significant genetic polymorphism-copies
of alleles 7-10% of whites are poor metabolizers (≤ 1 allele) 4% of African-Americans, < 1% of Asians 1-7% whites, 25% Ethiopians ultrarapid (> 3 alleles)
Deficient patients cannot metabolize codeine (no analgesic effect)
Phenothiazines cannot metabolize, leading to toxicity at therapeutic doses
CYP2D6
Substrates TCAs, SSRIs,
Venlafaxine, Phenothiazines, Risperidone, codeine, morphine, tramadol
Inhibited by: SSRIs, Haldol,
thioridazine, amiodarone, fluvoxamine
Induced by: None
Codeine intoxication associated with ultrarapid CYP2D6 metabolism
62 yo M w/ cough, pneumonia PMHx-CLL, Epilepsy, on Valproate Begun on ceftriaxone (Rocephin®), clarithromycin
(Biaxin®), voriconazole (Vfend®) codeine 25 mg TID for cough suppression
Gasche Y. NEJM 2004;351:2827-2831.
NEJM 2004
Deteriorating LOC, became unresponsive Glasgow Coma Scale 6/15 pO2 56 mmHg, pCO2 80 mmHg Recovered after 2 doses naloxone
Codeine metabolism
Requires 2D6 (to morphine) and 3A4 (to codeine-6 -phosphate)
Normal ratio of codeine to morphine 10 to 1.
Clarithromycin and voriconazole are potent inhibitors of 3A4, leaving more codeine available for conversion to morphine
Patient had genetic testing showing an additional allele of 2D6 -> ultrarapid conversion to morphine.
Gasche Y. NEJM 2004;351:2827-2831.
68 Year-Old Male With Neuropathic Pain
5 years of severe small fiber neuropathy Gabapentin 5600 mg day Tramadol 300 mg day Acetaminophen 2350 mg day Duloxetine (Cymbalta®) added 60 mg day Pain worsens, why?
Duloxetine and Tramadol
Tramadol converted to morphine by 2D6 Duloxetine is an inhibitor of 2D6 Adding duloxetine reduces the efficacy of
tramadol by inhibiting conversion to morphine
Skinner MH, et al. Duloxetine is both an inhibitor and a substrate of cytochrome P4502D6 in healthy volunteers; Clin Pharmacol
Ther. 2003 Mar;73(3):170-7
Diphenhydramine inhibits metoprolol metabolism, prolonging negative inotropy
Benadryl a potent CYP2D6 inhibitor Inhibits metoprolol metabolism in extensive (rapid)
metabolizers Prolonged the effects of metoprolol due to
inhibited metabolism
Hamelin BA, Bouayad A, Methot J, Significant interaction between the nonprescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clinical pharmacology and therapeutics. 67(5):466-77, 2000.
2C9
5-10% on warfarin experience ADRs Dominant metabolic enzyme pathway for warfarin
17% have polymorphisms Non-significant increase in INRs in excess of 4
VKORC1 (Vitamin K epoxide reductase C1) 14% of whites, no blacks with polymorphisms INRs rise 2.5x as fast, and 19% more time in excess of INR > 4
FDA Alert – VKORC1 and 2C9 mutations need less drug 30-60% of variability due to 2C9 and VKORC1 mutations
Schwarz UI et al. Genetic determinants of response to warfarin during initial anticoagulation; N Engl J Med 2008 Mar 6; 358:999
CYP2C19
Deficient in 15-30% of Asians May lead to benzo
toxicity at usual doses
Primary metabolism of: Diazepam Phenytoin Omeprazole
Inhibited by: Omeprazole Isoniazid Ketoconazole
Induced by Carbamazepine Rifampin
http://www.esrf.fr/UsersAndScience/Publications/Highlights/ 2003 /MX/MX06; Ghoneim MM, Clin Pharmacol Ther 1981.
35 yo F with epilepsy
Topamax 50 BID recently added to regimen of phenytoin 300 mg daily and carbamazepine ER 400 BID
Developed ataxia, tremulousness, malaise Phenytoin level 29. Topiramate is a potent inhibitor of 2C19
metabolism, the primary pathway for phenytoin metabolism
Caution in Asian populations
15-30% 2C19 deficient - watch diazepam, phenobarbital, primidone
15% have HLA B*1502 allele High risk of Stevens-Johnson (SJS) with
carbamazepine FDA Alert 12/12/07 SJS 10x more frequent in Asia
http://www.fda.gov/CDER/drug/InfoSheets/HCP/carbamazepineHCP.htm
Hung, S.I. et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet. Genomics.2006;16(4):297-306.
Cytochrome P450 (CYP) 3A4
Metabolizes 60% of currently available meds Ca channel blockers, benzodiazepines, HIV, statins,
cyclosporin, antihistamines, cisapride
No genetic polymorphisms CYP3A4 is present in intestinal mucosa and liver Accounts of majority of first-pass metabolism Induced by St John’s Wort, carbamazepine Several drugs inhibited by grapefruit juice
(bioflavinoids) Amlodipine, lovastatin, buspirone, benzodiazepines
CYP3A4
Substrates Steroids, TCAs, SSRIs, benzodiazepines,
Ca2+ Channel blockers, warfarin, oral contraceptives
Inhibitors Ketoconazole, metronidazole, AZT,
omeprazole, cimetidine, statins, macrolides, verapamil, grapefruit juice
Inducers Rifampin, AEDs, dexamethasone, isoniazid
The Grapefruit Effect
Furanocoumarins in grapefruit inhibit 3A4 Reduces/eliminates first pass metabolism
Strong Interaction
Moderate Interaction
Weak Interaction
diazepam buspirone lovastatin simvistatin
Nicardipine felodipine atorvastatin vincristine vinblastine
Sertraline fexofenadine omeprazole guaifenesin sildenafil
Center for Food-Drug Research and Education, University of Florida
P-Glycoprotein
Transporter proteins in the small intestine, blood brain barrier,liver, kidney, gonads
Encoded by ABCB1 gene, ethnic polymorphisms ATP-dependent cell membrane transporter Similar substrates, inducers, inhibitors as 3A4 Example- loperamide, an opioid antidiarrheal, does
not cross the BBB due to P-glycoprotein Quinidine inhibits Pgp, leading to respiratory
depression and somnalence from loperamide toxicity
Sirot EJ. Drug Safety 2006; 29 (9): 735-768
Which statement is TRUE of the cytochrome P450 system?
Question 5
a. Drug-drug interactions are likely to occur when a P450 substrate is combined with a P450 inhibitor
b. Anticonvulsants tend to be P450 inhibitors.
c. P450 enzymes are located primarily in the stomach and small intestine.
d. Cigarette smoking has no effect on drug metabolism.
DDI: A Stepwise Approach
1. Take a medication history Mnemonic; avoid mistakes
2. Identify high risk patients > 3 medications Red flag drugs
anticonvulsants, SSRIs, antifungals, quinolones, digoxin, warfarin, amiodarone
3. Check pocket reference card
4. Consult pharmacist/ drug specialist
5. Check computer programs www.epocrates.com Medical letter drug
interaction program
www.fda.gov/cder/drug/drugReactions/default.htm
Mnemonic: Avoid Mistakes
Allergies? Vitamins and dietary supplements
Grapefruit juice, St Johns Wort, tobacco, char-grilled meats
Old drugs and OTC? Interactions risk? Dependence? Mendel: any family history of drug sensitivity
When to suspect a genetic variant
Pt requires very low doses of coumadin (<5 mg daily) for therapeutic INR
Pt receives no analgesia from codeine, tramadol Long drug allergy list High sensitivity to drugs
Websites on DDI, CYP450, and drug transporting proteins
http://medicine.iupui.edu/flockhart www.epocrates.com http://www.themedicalletter.com/ http://www.druginteractioninfo.org/
Conclusions Serotonin syndrome may present with mild
symptoms of tremor confusion, and tachycardia and is frequently missed
Drug interactions are extremely common An understanding of the P450 system is useful in
predicting who is at risk for drug interactions or adverse reactions
Suspect a genetic susceptibility to DDI when Patients have history of multiple drug sensitivities Long drug allergy lists Those who receive no analgesia from codeine Those on > 4 medications Asian descent