Individual variation and Drug interaction Pawitra Pulbutr B.Pharm(Hon.), M.Sc. In Pharm (Pharmacology)

Objectives อธิบายถึงปัจจัยของอายุที่มีผลทำให้เกิดความผันแปรในการตอบสนองต่อยา อธิบายถึงปัจจัยของพันธุกรรมที่มีผลทำให้เกิดความผันแปรในการตอบสนองต่อยา อธิบายถึงการตอบสนองต่อยาแบบ Idiosyncratic reaction อธิบายถึงปัจจัยของโรคที่มีผลทำให้เกิดความผันแปรในการตอบสนองต่อยา อธิบายปฏิกิริยาระหว่างยาที่มีผลทำให้เกิดความผันแปรในการตอบสนองต่อยา

Pharmacokinetic variation Pharmacodynamic variation Individual variation Different response to the same drug Difference between each one in the population Different situation in same one Pharmacokinetic variation Different drug concentration at site of action Pharmacodynamic variation Different drug action

Major factors affecting drug response Age Genetic Factor Idiosyncratic reactions Diseases Drug interactions

Pharmacodynamic changes Pharmacokinetic changes Effects of ages Pharmacodynamic changes Pharmacokinetic changes Changes in drug concentration at site of action

Genetic polymorphism of enzyme Genetic factors Pharmacogenetic Genetically determined variation in drug response Genetic influences on drug metabolism Genetic polymorphism of enzyme Same enzyme Gene Enzyme with different activity Different drug metabolism

A = Salicylate plasma concentration Normal distribution Rapid acetylator Slow acetylator 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 > 20 mol/L Rapid acetylator level < 20 mol/L

Idiosyncratic reaction Idiosyncratic response = Unusual response Genetic difference Immune response Glucose 6- Phosphate dehydrogenase enz. Enzyme which maintain reduced glutathione (GSH) at RBC membrane

Normal subjects Hemolysis Unusual response Primaquine Dapsone Doxorubicin Reduced GSH level Normal subjects G 6- P D deficiency No effect Hemolysis Normal response Unusual response

Concomitant use of drug Increase potential drug interaction ปฏิกิริยาระหว่างยา(อันตรกิริยา) ที่ทำให้ผล หรือฤทธิ์ทางเภสัชวิทยาของยาชนิดหนึ่งเปลี่ยนแปลงไป เมื่อได้รับยาอีกชนิดหนึ่งร่วมไปด้วย Concomitant use of drug Increase potential drug interaction Increase efficacy Increase toxicity

Drug Interaction 1. Pharmacodynamic drug interaction No drug level changes 2. Pharmacokinetic drug interaction 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)

Drug Other Substance Phenobarbital and other barbiturates Rifampin Carbamazepine Drug Other Substance Ethanol Cigarette smoke Charcoal broiled meat Pesticides

Enzyme inhibition Enzyme inhibitors Inhibit drug metabolism Longer drug effect Increase prone to drug toxicity

Drug Other substance Cimetidine Erythromycin Disulfiram Ketoconazole Grape fruit juice 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

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