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Genetic polymorphism Prepared by Prof.Abdulkader El Daibani Genetic polymorphism Genetic polymorphism Variation in drug response due to genetic differences, most genetic polymorphism involves differences in drug metabolism such as 1) acetyation 2) slow acetylators: low activity of acetyltransferase. 3) Rapid acetylators : normal activity of acetyltransferase. Genetic polymorphism Eskimos and Japanese are rapid acetylators (90%), while Egyptians are slow acetylators. Drugs subject to acetylation polymorphism include INH, procainamide, hydralazine, dapsone. Isoniazid → (INH) Slow acetylator Peripheral neuritis So B6 is given to reduce P.N. (P.N) Genetic polymorphism INH → acute hepatocellular necrosis. Rapid acetylator ( due to formation of hepato-toxic metabolite Hydralazine and procainamide → slow Acetylators Dapsone → slow acetylators Haemolysis. S.L.E. Genetic polymorphism 2) hydolysis of succinyl chlorine (S.C) Normally pseudocholinesterase hydrolysis S.C.,but some patients have abnormal plasma pseudocholinesterase which result in reduced metabolism of S.C and causes marked respiratory muscle paralysis and apnea. 3) Glucose-6-phosphate dehydogenase deficiency Subject who deficient in G-6-DP may suffer acute Haemolysis if they take oxidizing drugs e.g. Primaquine ,Sulfonamides,Quinolones e.g. Ciprofloxacin and nitrofurantoin. The defect is coming among Jews,Indians,Africans and Mediterraneans. Genetic polymorphism ↓ G6PD →↓formation of reduced glutathione(GSH) → methaemoglobinemia→haemolysis. Oxidizing drugs increase conversion of hemoglobin into methaemoglbin. 4) Porphyrias Deficiency in enzymes which convert porphyrin to haem. This result in ↑acumulation of prophyrins leading to porphyria characterized by sever neurological disorders and death . Inducing agents e.g. Phenobarbitone, Phenytoin ↑ activity of aminolaevulinic acid (ALA) synthetase causing increase synthesis of porphyrins leading to porphyria. Genetic polymorphism 5) Malignant hyperthermia Due to release of calcium from sarcoplasmic reticulum in skeletal muscle due to administration of succinyl choline or halothane.Fatal and characterized by: I) Hyperthermia II) Muscle rigidity III) Tachycardia IV) cyanosis. dantrolene is used in treatment of malignant hyperthermia and acts by inhibiting release of Ca++ from sarcuplasmic reticulum. Genetic polymorphism 5) Coumarin resistance Genetic insensitivity to coumarin anticoagulants e.g. Warfarin . due to abnormality of enzyme which converts vit. K to redueced vit. K (active form). Coumarine acts by inhibiting reduced vit. K. Steroid induced ↑ intraocular pressure leading to glaucoma.