Individual variation and Drug interaction

Pawitra Pulbutr

B.Pharm(Hon.), M.Sc. In Pharm (Pharmacology)

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Individual variationIndividual variation

Different response to the same drugDifferent response to the same drug

Difference between each one in the Difference between each one in the population population

Different situation in same one Different situation in same one

Pharmacokinetic variationPharmacokinetic variation

Pharmacodynamic Pharmacodynamic variationvariation

Different drug concentration at site of action

Different drug action

Major factors affecting drug response

o AgeAge

o Genetic FactorGenetic Factor

o Idiosyncratic Idiosyncratic reactionsreactions

o DiseasesDiseases

o Drug interactionsDrug interactions

Effects of agesPharmacokinetic changes

Pharmacodynamic changes

Pharmacokinetic changes

Changes in drug concentration at site of action

Genetic factors

Pharmacogenetic

Genetically determined variation in drug responseGenetic influences on drug metabolism

Genetic polymorphism of enzymeGenetic polymorphism of enzyme

Gene Same enzymeSame enzyme

Enzyme with different activity

Different drug metabolism

Figure 4.1 Distribution of individual plasma concentration of two drugs in human

A = Salicylate plasma concentration

Normal distribution

B = INH plasma concentration

Bimodal distribution

Slow acetylator level > 2 0mol/L

Rapid acetylator level < 2 0 mol/L

Slow acetylator

Rapid acetylator

Idiosyncratic reactionIdiosyncratic reaction

Idiosyncratic response = Unusual Idiosyncratic response = Unusual responseresponse

Genetic difference Immune response

Enzyme which maintain reduced glutathione (GSH) at RBC membrane

Glucose 6- Phosphate dehydrogenase enz.

Primaquine

Dapsone

Doxorubicin

Reduced GSH level

No effect Hemolysis

Normal response Unusual response

G 6- P D deficiency

Normal subjects

Drug InteractionDrug Interaction

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เปัล��ยนแปัลงไปั เมี*�อได�ร บยาอ�กิชน�ดห้น��งร$วมีไปัด�วยConcomitant use of drug

o Increase potential drug interaction

o Increase efficacy

o Increase toxicity

Drug Interaction

1. Pharmacodynamic drug interaction

2. Pharmacokinetic drug interaction

No drug level changes

Drug level changes

Metabolism

Enzyme induction

Enzyme inducer

Increase enzyme production

Increase drug metabolism

Increase level of metabolite

Decrease drug efficacy

Increase toxicity of metabolites

Mostly affect low extraction ratio drug (metabolism dependent)

Drugo Phenobarbital and other barbiturates

o Rifampin

o Carbamazepine

Other Substance

o Ethanol

o Cigarette smoke

o Charcoal broiled meat

o Pesticides

Enzyme inhibition

o Enzyme inhibitors

o Inhibit drug metabolism

o Longer drug effect

o Increase prone to drug toxicity

o Cimetidine

o Erythromycin

o Disulfiram

o Ketoconazole

Drug

Other substan

ceo Grape fruit juice

o Low protein diet

Drug excretion via kidney

Changes in ……..

Glomerular filtration

Tubular secretion

Urine flow or urine pH

Plasma protein binding

Compete for carrier transport system

Affect drug reabsorption

Other substances which may affect drug metabolism

Cigarette smoking

Ethanol consumption

Cruciferous vegetable

Charcoal broiled meat

Pesticides, Organochlorine compound

Grapefruit juice

Diet

Q&AQ&A

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