Warfarin is a coumarin anticoagulant, first discovered in spoiled sweet clover silage after causing hemorrhagic disease in cattle.
Warfarin blocks the regeneration of vitamin K by blocking the liver enzyme epoxide reductase. Vitamin K is required for the carboxylation of several glutamate residues in prothrombin, factors VII, IX, and X, as well as anticoagulant proteins S and C. Accordingly, the presence of warfarin results in the incomplete, inactive clotting factors, reducing blood clotting capability.
Treatment should be initiated with small daily doses of 5-10 mg. Initial adjustment of prothrombin time is about 1 week, and PTT should be increased to a level representing 25% of normal activity. If activity is less than 20% dosage should be reduced or omitted until it again rises.
Therapeutic range is now defined by international normalized ratio (INR), which is the PTT ratio of test/control using an international reference.
Warfarin binds to plasma albumin, leading to small space of distribution, long plasma half-life (36 hours), and lack of urinary excretion.
There is an 8-12 hour delay in the action of warfarin, as anticoagulation is dependent on the degradation rate of active clotting factors. Half-lives for factors VII, IX, X, and II are 6, 24, 40, and 60 hours, respectively.