Genetic polymorphism

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Genetic polymorphism

• Prepared by
• Prof.Abdulkader El Daibani

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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.

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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 ? Peripheral neuritis
• (INH) Slow acetylator
  (P.N)
• So B6 is given to reduce P.N.

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Genetic polymorphism

• INH ? acute hepatocellular necrosis.
• Rapid acetylator
• ( due to formation of hepato-toxic metabolite
  
• Hydralazine and procainamide ? S.L.E.
• slow
  Acetylators
• Dapsone ? Haemolysis.
• slow acetylators

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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.

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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.

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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.

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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.