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Pharmacokinetic interaction
Dr.Datten Bangun MSc,SpFK & Dr.Zulkarnain Rangkuty
of pharmacological effect at standard drug concentrations or of pharmacological effect resulting from altered pharmacokinetic exposures
All drugs known to humans are poisons, only the amount or dose determine the effects.
Paracelsus, 1490 - 1541
2
Pharmacokinetics
Movement of drugs in the body Four Processes
Absorption Distribution Metabolism Excretion
a) Altered pH;
The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does.
Ex1.,
antiacids
Decrease the pH
Ex2.,
H2 antagonists
pH
Therefore, these drugs must be separated by at least 2h in the time of administration of both .
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
c) Complexation or chelation;
or
Milk (Ca2+ ) Unabsorpable complex
Ex2., Antacid (aluminum or magnesium) hydroxide Decrease absorption of ciprofloxacin by 85% due to chelation
OATP (azoles, echinocandins?) Phase I metabolism (CYP P450) (itraconazole, voriconazole) Phase II metabolism (glucoronidation) (posaconazole)
Extraction?
10
Metabolism
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
Plasma
Drug A protein bound
Tissue
Drug A free
Drug A free
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 drug with higher affinity.
Phenytoin is a highly bound to plasma protein (90%), Tolbutamide (96%), and warfarin (99%)
CYP450 Nomenclature
Family
CYP2D6
Sub-Family Individual Gene CYP = Cytochrome P450
2E1
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.
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
Antibiotics and Oral Contraceptives Antibiotics, Phenytoin, Carbemazepine, Barbiturates induce hepatic Phase I enzymes Synthetic Estrogens & Progesterones are metabolised by Phase I enzymes
Enzyme Inhibition
Often rapid, reversible and relatively short acting. E.g. erythromycin and cyclosporin NB :erythromycin is a substrate and an inhibitor of CYP 3A4 May be prolonged due to long half- life of drug. E.g. amiodarone and S-Warfarin NB: amiodarone is an inhibitor of CYP2C9 but not a substrate for this CYP
Time
P. B. Watkins 2003
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.
Excretion Interactions
Mechanisms of urinary excretion: - Simple filtration - Active secretion Mechanisms for active secretion - Acids - Bases
Excretion interactions
Active secretion mechanisms have limited capacity.
e.g. One acid drug may saturate the acid drug active secretion mechanism. Another acid drug will then be secreted less efficiently
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.
DRUG METABOLISM
ENZYME INDUCTION
OR ENZYME INHIBITION ENZYME INDUCTION BY INCREASING DRUG INACTIVATION MAY PRODUCE TOLERANCE OR COMPLETELY NULLIFY DRUG ACTION.
ENZYME INDUCTION
EXAMPLES INCLUDE:
PRIMARY DRUG ORAL ANTICOAGULANTS e.g. WARFARIN TOLBUTAMIDE PHENYTOIN CHLORPROMAZINE ORAL CONTRACEPTIVES PREDNISONE DEXAMETHASONE DOXYCYCLINE BARBITURATES BARBITURATES PHENOBARBITONE DECREASED HYPOGLYCAEMIA FAILURE OF CONTRCEPTION REDUCED STEROID LEVELS REDUCED DOXYCYCLINE LEVELS QUINIDINE PHENYTOIN BARBITURATES REDUCED QUINIDINE LEVELS INDUCING DRUG BARBITURATES RIFAMPICIN EFFECT OF INTERACTION DECREASED ANTI-COAGULATION
ALTERNATIVELY: SOME DRUGS MAY ACT AS ENZYME INHIBITORS AND RAISE THE CONCENTRATION OF SIMULTANEOUSLY ADMINISTERED DRUGS.
PRIMARY DRUG
PHENYTOIN
INHIBITING DRUG
ISONIZID AZAPROPAZONE CHLORAMPHENICOL
INTERACTION
PHENYTOIN INTOXICATION
6-MERCAPTOPURINE AZATHIOPRINE
ALLOPURINOL
DRUG SPIRONOLACTONE
FERRIC CHLORIDE
CHLORPROMAZINE NA VALPROATE
INVALIDATE TEST