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032012Pharmacokinetic interaction
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2
All drugs known to humans are poisons, only the
amount or dose determine the effects.Paracelsus, 1490 - 1541
Classification of Drug Interactions
Pharmacokinetic
in drug absorption,
distribution, metabolism
or excretion
Pharmacodynamic
of pharmacological effect at standarddrug
concentrations
or
of pharmacological effect resulting from
alteredpharmacokinetic exposures
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Pharmacokinetics
Movement of drugs in the body
Four Processes Absorption
Distribution
Metabolism
Excretion
Drug concentration at sites of action influencedby several factors, such as:
Route of administration Dose
Characteristics of drug molecules (e.g., lipid solubility)
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Altered Absorption (Availability)
Change in gastrointestinal pH
Ketoconazole needs acidic conditions in gut
Drug binding in GI tract
E.g. tetracycline and calcium
Change in gastrointestinal flora
Antibiotics with OCs
Change in gastrointestinal motility
Metoclopramide and digoxin
Malabsorption caused by other drugs
Orlistat (Xenical) and fat soluble vitamins
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Pharmacokinetic interactions
1) Altered GIT absorption.
Altered pH, Altered bacterial flora, formation of drug
chelates or complexes, drug induced mucosal damage
and altered GIT motility.
a) Altered pH;The non-ionized form of a drug is more lipid
soluble and more readily absorbed from GIT than theionized form does.
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Ex1., antiacidsDecrease the pH Decreasethe tablet
dissolution
ofKetoconazole (acidic)
Ex2., H2 antagonists pH
Therefore, these drugs must be separated by at least 2h
in the time of administration of both .
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b) Altered intestinal bacterial flora ;
EX., In 10% 0f patients receive digoxin..40% or more
of the administered dose is metabolized by the intestinal flora
Antibiotics kill a large number of the normal
flora of the intestine
Increase digoxin conc.
and increase its toxicity
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c) Complexation or chelation;
EX1., Tetracycline interacts with iron preparations
or
Milk (Ca2+
) Unabsorpable complex
Ex2., Antacid (aluminum or magnesium) hydroxide
Decrease absorption of
ciprofloxacin by 85%
due to chelation
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d) Drug-induced mucosal damage.
Antineoplastic agents e.g., cyclophosphamide
vincristineprocarbazine
Inhibit absorption
of several drugs
eg., digoxin
e) Altered motility
Metoclopramide (antiemitic)
Increase absorption of cyclosporine due
to the increase of stomach empting time
Increase the toxicity
of cyclosporine
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10
Hepatic Drug Interactions
OATP (azoles, echinocandins?)
Phase I metabolism (CYP P450)(itraconazole, voriconazole)
Phase II metabolism (glucoronidation)
(posaconazole)
Genetic Disease Diet Drugs Infection
Extraction? Metabolism
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DRUG DISTRIBUTION
DISPLACEMENT FROM PLASMA PROTEIN
BINDING SITES
e.g. AZAPROPAZONE + WARFARIN
INTERACTION(BUT INHIBITION OF WARFARIN
METABOLISM SEEMS MORE LIKELY)
DISPLACEMENT OF ORAL
HYPOGLYCAEMICS BY ASPIRIN
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Protein Binding
Drug Displacement
Plasma Tissue
Drug A
protein bound
Drug A
free
Drug A
free
Drug B
Drugs A and B both bind to the same plasma protein
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f) Displaced protein binding
It depends on the affinity of the drug to plasma protein.
The most likely bound drugs is capable to displace others.
The free drug is increased by displacement by another drugwith higher affinity.
Phenytoin is a highly bound to plasma protein (90%),Tolbutamide (96%), and warfarin (99%)
Drugs that displace these agents are Aspirin
Sulfonamidesphenylbutazone
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CYP450 Nomenclature
CYP2D6
Family
Sub-FamilyIndividual Gene
CYP = Cytochrome P450
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Enzyme characteristics
% drugs metabolised by enzyme
3A4 60%
2D6 25%
1A2 15%
2C9 Small no. but significant interactions
2C19 Small no. but significant interactions
2E1 ?
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CYP 450 System
Definitions
Substrate:Drug is metabolised by the enzyme system
Inducer:Drug that will increase the synthesis of CYP450enzymes
InhibitorDrug that will decrease the metabolism of asubstrate
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Enzyme Induction 1
Leads to production of more enzyme,
usually after 3-4 days of exposure to
inducer
Most CYPs are inducible but not CYP2D6
Time course of interaction depends on
half-life of inducer.
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Enzyme Induction 2
Rifampicin has short half-life and induction
apparent with 24 hours
Phenobarbitone has longer half life so time
to complete induction takes longer
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Enzyme Inducers
Examples
Rifampicin
Phenobarbitone
Carbamazepine
Cigarette smoke
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Antibiotics and Oral Contraceptives
Antibiotics, Phenytoin, Carbemazepine,
Barbiturates induce hepatic Phase I enzymes
Synthetic Estrogens & Progesterones are
metabolised by Phase I enzymes
Increased metabolism of Oral contraceptives
Decreased effectiveness of Oral contraceptive
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Enzyme Inhibition
Often rapid, reversible and relatively shortacting.E.g. erythromycin and cyclosporinNB :erythromycin is a substrate and an inhibitorof CYP 3A4
May be prolonged due to long half- life of drug.
E.g. amiodarone and S-WarfarinNB: amiodarone is an inhibitor of CYP2C9 butnot a substrate for this CYP
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Grapefruit Juice-Drug Interaction
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Time
DrugBlood
Co
ncentration(AUC
)
Drug Taken with GJ
Drug Taken without GJ
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P. B. Watkins 2003
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EXCRETION
Drug A increases or reduces the excretion
(usually renal) of Drug B.
Blood levels of B fall below or rise above
normal therapeutic range.
Becomes either ineffective or toxic.
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Excretion Interactions
Mechanisms of urinary excretion:
- Simple filtration
- Active secretion
Mechanisms for active secretion
- Acids- Bases
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Excretion interactions
Active secretion mechanisms have limited capacity.
e.g. One acid drug may saturate the acid drugactive secretion mechanism. Another acid drug
will then be secreted less efficiently
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Excretion Interaction
Lithium + Thiazides
Probable mechanism:
Thiazides cause diuresis and initial sodium loss. Compensatory sodium retention in proximal
tubules.
Proximal tubules do not distinguish sodium
from lithium.
Lithium also retained and accumulates.
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Excretion Interaction
Change in renal blood flow
Methotrexate and NSAIDs
NSAIDS can decrease renal blood flow byinhibition of renal prostaglandins.
Reduced clearance of MTX and active
(toxic) metabolite
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Some enzyme Inducers
Barbiturates (3A)
Carbamazepine
(2C19, 3A)
Phenytoin (3A)
Rifampicin
(2C19, 2C9, 3A)
St Johns Wort (3A)
Ethanol (2E1)
Troglitazone (3A)
Tobacco (1A2)
Omeprazole (1A2)
Nevirapine (3A)
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Where are these enzymes ?
Most cells
Predominantly in endoplasmic reticulum of
hepatocytes
Also present in gut wall
Kidney lungs and brain
Liver is main site of drug metabolism
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DRUG METABOLISM
ENZYME INDUCTION
OR
ENZYME INHIBITION
ENZYME INDUCTION
BY INCREASING DRUG INACTIVATIONMAY PRODUCE TOLERANCE OR
COMPLETELY NULLIFY DRUG ACTION.
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ENZYME INDUCTIONEXAMPLES INCLUDE:
PRIMARY DRUG INDUCING DRUG EFFECT OF INTERACTION
ORAL
ANTICOAGULANTS
e.g. WARFARIN
BARBITURATES
RIFAMPICIN
DECREASED
ANTI-COAGULATION
TOLBUTAMIDE PHENYTOIN
CHLORPROMAZINE
DECREASED
HYPOGLYCAEMIA
ORAL CONTRA-
CEPTIVES
PHENOBARBITONE FAILURE OF
CONTRCEPTION
PREDNISONE
DEXAMETHASONE
BARBITURATES REDUCED STEROID
LEVELS
DOXYCYCLINE BARBITURATES REDUCED DOXYCYCLINE
LEVELS
QUINIDINE PHENYTOIN
BARBITURATES
REDUCED
QUINIDINE LEVELS
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ALTERNATIVELY:
SOME DRUGS MAY ACT AS ENZYME
INHIBITORS AND RAISE THE
CONCENTRATION OF SIMULTANEOUSLY
ADMINISTERED DRUGS.
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INTERACTIONS OF LIVER ENZYME INHIBITORS
PRIMARY DRUG INHIBITING DRUG INTERACTION
PHENYTOIN ISONIZID
AZAPROPAZONE
CHLORAMPHENICOL
PHENYTOIN
INTOXICATION
ORAL
ANTICOAGULANTS
e.g. WARFARIN
ALLOPURINOL
NORTRIPTYLINE
QUINIDINE
HAEMORRHAGE
TOLBUTAMIDE
CHLORPROPAMIDE
PHENYLBUTAZONE
CHLORAMPHENICOL
DISCOUMAROL
HYPOGLYCAEMIA
6-MERCAPTOPURINE
AZATHIOPRINE
ALLOPURINOL BONE MARROW
SUPPRESSION
ANY DRUG
CIMETIDINE
KETOCONAZOLE
FLUOXETINE
RAISED PLASMA
LEVEL OF DRUG
DRUG EXCRETION
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DRUG EXCRETION
EXAMPLES
PRIMARY DRUG COMPETING DRUG EFFECT OF INTERACTION
PENICILLIN PROBENECID INCREASED
PENCILLIN LEVELS
METHOTREXATE SALICYLATES
SULPHONAMIDES
BONE MARROW
DEPRESSIONLITHIUM THIAZIDES LITHIUM TOXICITY
HYPERNATRAEMIA
DIGOXIN SPIRONOLACTONE INCREASED PLASMA
DIGOXIN LEVELS
SALICYLATES
INDOMETHACIN
PROBENECID INDOMETHACIN OR
SALICYLATES TOXICITY.
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INTERACTIONS WITH DIAGNOSTIC LAB. TEST
TEST DRUG EFFECT ON TEST
DIGOXIN (RIA)
(FAB. VE)
SPIRONOLACTONE REDUCE (FALSE-VE)
URATE (SPECTO) PARACETAMOL RAISED RAISED (FALSE +VE)
KETONES IN URINE SALICYLATES INVALIDATE TEST
FERRIC CHLORIDE CHLORPROMAZINE
NA VALPROATE
INVALIDATE TEST
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