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Warfarin
- indication:For the treatment of retinal vascular occlusion, pulmonary embolism, cardiomyopathy, atrial fibrillation and flutter, cerebral embolism, transient cerebral ischaemia, arterial embolism and thrombosis.
- pharmacologypharmacology:
- mechanism: Warfarin inhibits vitamin K reductase, resulting in depletion of the reduced form of vitamin K (vitamin KH2). As vitamin K is a cofactor for the carboxylation of glutamate residues on the N-terminal regions of vitamin K-dependent proteins, this limits the gamma-carboxylation and subsequent activation of the vitamin K-dependent coagulant proteins. The synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X and anticoagulant proteins C and S is inhibited. Depression of three of the four vitamin K-dependent coagulation factors (factors II, VII, and X) results in decresed prothrombin levels and a decrease in the amount of thrombin generated and bound to fibrin. This reduces the thrombogenicity of clots.
- toxicity: LD<sub>50</sub>=374 (orally in mice)
- absorprion: Rapidly absorbed following oral administration with consider interindividual variations. Also absorbed percutaneously.
- halflife: R-warfarin t<sub>1/2</sub>=37-89 hours; S-warfarin t<sub>1/2</sub>=21-43 hours.
- roouteelimination: The elimination of warfarin is almost entirely by metabolism. Very little warfarin is excreted unchanged in urine. The metabolites are principally excreted into the urine; and to a lesser extent into the bile.
- volumedistribution: * 0.14 L/kg
- clearance: * 0.065 +/- 0.025 mL/min/kg [CYP2C9 Genotype *1/*1] * 0.041 +/- 0.021 [CYP2C9 Genotype *1/*2 or *1/*3] * 0.020 +/- 0.011 [CYP2C9 Genotype *2/*2, *2/*3, or *3/*3]