Warfarin
Coumadin®

Description: Warfarin is an oral coumarin anticoagulant. The original discovery in 1939 that spoiled sweet clover possessed anticoagulant properties is a classic story in pharmacology. It is also the active ingredient in various rodenticides and insecticides. Warfarin is a racemic mixture of roughly equal amounts of two active isomers; the S-form is roughly 5 times as potent as a vitamin K antagonist than the R-form. Clinically, warfarin is used to prevent and treat thromboembolic disease. Some clinicians believe that warfarin, despite its higher associated risk of bleeding, is preferable to aspirin for prevention of stroke in patients with nonvalvular atrial fibrillation.[1076] Warfarin is currently being actively studied to determine its role in acute myocardial infarction. Warfarin was originally approved by the FDA in 1954.

Mechanism of Action: Warfarin interferes with the action of vitamin K, a cofactor essential for converting precursor proteins into the active coagulation factors II, VII, IX, and X. As a result, the vitamin K-dependent factors that have been affected by warfarin during synthesis are dysfunctional. Warfarin does not affect the activity of coagulation factors in which synthesis was complete before exposure to warfarin. Thus, depletion of these mature factors through normal catabolism must occur before therapeutic effects of warfarin are seen. Each factor differs in its degradation half-life, ranging from as short as 5 hours (factor VII) to as long as 60 hours (factor II). As a result, several days of therapy are required before a clinical response is seen. Exogenous vitamin K as well as transfusions of plasma proteins will overcome the effects of warfarin. In contrast to heparin, warfarin has no anticoagulant effect in vitro. Warfarin has little effect on preexisting thrombi and does not affect prostaglandin-mediated platelet aggregation. The drug prolongs both prothrombin time (PT) and thromboplastin time (APTT), but prothrombin time is used clinically to guide therapy.

Pharmacokinetics: Warfarin is well absorbed from the GI tract, but individual brands of warfarin can exhibit different rates or degrees of absorption. Administration with food can delay the rate but not the extent of absorption. Warfarin also can be readily absorbed through the skin, and systemic manifestations are possible with significant exposure to rodenticides. Although warfarin plasma concentrations are detectable within 1 hour of administration, antithrombogenic effects are dependent on the gradual catabolism of circulating activated factors. A similar delay in return to normal blood coagulation time occurs following discontinuation of the drug.

Warfarin is highly bound (about 97%) to plasma protein, mainly albumin, and this is one of several mechanisms whereby other drugs interact with warfarin. It is distributed to the liver, lungs, spleen, and kidneys but does not appear to be distributed into breast milk in significant amounts. It crosses the placenta and is a known teratogen.

Warfarin is hydroxylated in the liver by hepatic microsomal enzymes to produce inactive metabolites. This mechanism is the basis for other significant drug interactions. There is considerable patient variation in the rate of metabolism of specific preparations. Plasma half-life of warfarin is highly variable and may be less important to the duration of action than the rate of catabolism of activated clotting factors. Inactive metabolites of warfarin are excreted in the bile and are reabsorbed and excreted in the urine.