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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.