Warfarin

Overview

Warfarin (Coumadin) is an orally-available anticoagulant that functions by disrupting hepatic synthesis of Vitamin K-dependent coagulation factors, specifically Factors II, VII, IX, and X. Warfarin has a relatively narrow therapeutic range and can lead to bleeding disorders at high levels. Because metabolism of warfarin can be affected by a number of drugs and foods, frequent monitoring its anticoagulant effect is necessary with long-term use.

Mechanism of Action

For proper functioning, coagulation Factor II (Thrombin), Factor VII, Factor IX, and Factor X, Protein C, and Protein S must undergo gamma-carboxylation of their glutamate residues. The enzyme that performs this reaction requires the presence of Vitamin K as a cofactor. During this enzymatic modification, Vitamin K is oxidized and must be regenerated. The enzyme which regenerates Vitamin K is competitively antagonized by warfarin, resulting in accumulation of oxidized Vitamin K and ultimately an inability to properly modify Factors II, VII, XI, X as well as Protein C/S. The end result is reduced hepatic synthesis of these coagulation factors and their gradual decline within the plasma.
Over the long term, the absence of coagulation-promoting factors II, VII, IX, and X outweigh the absence of coagulation-inhibiting factors Protein C/S, yielding an inhibition of coagulation. However, in the early stages of treatment the effects on coagulation depend on the plasma half-lives of the individual factors. Factor VII and Protein C have the shortest half lives. In some cases, this early fall in Protein C can lead to a hypercoagulable state and thus most patients are "bridged" during the first 3-5 days of Warfarin therapy with heparins to avoid enhancing the clot burden.

Laboratory Monitoring of Anticoagulation

Because Factor VII has the shortest half-life of the pro-coagulant factors affected by warfarin, its effective concentration declines the fastest upon administration of warfarin. Consequently, the PT and INR are the first coagulation parameters which will begin to lengthen and these are used to monitor the anticoagulant effect of warfarin.

Pharmacokinetics

Warfarin is orally available and thus it is frequently used for chronic, outpatient purposes. Warfarin is metabolized by the hepatic Cytochrome P450 system. A long list of drugs can interact with this system, either by inducing increased synthesis of P450 and thus enhanced metabolism of warfarin, or by interfering with P450 metabolism of warfarin and thus increasing its blood concentration. It is important to know some of the most common interacting drugs given the common use of warfarin and the potentially disastrous adverse effects of supra-therapeutic levels.

Acute Alcohol Intoxication, Cimetidine, Chloramphenicol, Disulfiram, Metronidazole

Reversal

The anticoagulant effect of warfarin can be reversed by the parenteral administration of Vitamin K; however, improved coagulation requires the synthesis of new coagulation factors and thus takes several days to occur. If immediate reversal is clinically necessary then this can be done solely by parenteral supplementation with exogenous coagulation factors. In general, this is done by administration of Fresh Frozen Plasma (FFP)

Adverse Effects

Predictably, supra-therapeutic doses of warfarin can result in abnormal or excessive bleeding, a potentially fatal complication

Warfarin should never be administered during pregnancy as it can cross the placenta and act as a potent teratogen

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