Warfarin is used:
1. in the prophylaxis of systemic embolization in patients with rheumatic heart disease and atrial fibrillation and in patients with prosthetic heart valves and
2. in the prophylaxis and treatment of DVT and pulmonary embolism.
Mode of action
Warfarin prevents the synthesis of the vitamin K-dependent clotting factors (II, VII, IX, and X) in the liver. The formation of fully active clotting factors is dependent on the carboxylation of their precursor proteins; during this reaction, vitamin K is oxidized to vitamin K 2,3-epoxide; warfarin prevents the reduction of this epoxide back to vitamin K. This results in vitamin K depletion and a decrease in the rate of formation of complete clotting factors. The S-enantiomer is 2–5 times more potent than the R-enantiomer.
Routes of administration/doses
The adult oral dose is usually 3–9 mg/day, according to response as measured by the prothrombin time. The maximum anticoagulant effect occurs 18–72 hours after the administration of a loading dose.
Haemorrhage is the most frequent side effect. Hypersensitivity reactions and gastrointestinal upsets may occur. The drug appears to be teratogenic if taken during pregnancy.
The drug is rapidly and completely absorbed from the stomach and upper gastrointestinal tract, and has an oral bioavailability of 100%.
Warfarin is 99% protein-bound in the serum, predominantly to albumin. The VD is 0.1–0.16 l/kg.
Warfarin is virtually completely metabolized in the liver by oxidation (of the L-form) and reduction (of the D-form); these metabolites are then conjugated with glucuronide.
The response to warfarin treatment is monitored in the laboratory by the one-stage prothrombin time which is particularly sensitive to the activity of factors II, VII, and X. The INR should be maintained at 2–4.5 times the control value. Many factors may affect warfarin control; in particular, the drug may exhibit significant interactions with many other drugs. The activity of warfarin may be potentiated by alcohol, amiodarone, cimetidine, sulfonamides, salicylates and other NSAIDs, and many antibiotics, including co-trimoxazole, erythromycin, chloramphenicol, metronidazole, and tetracyclines. The activity of warfarin may be decreased by many drugs, including barbiturates, the oral contraceptive pill, and carbamazepine.
Control of anticoagulation in the perioperative period requires special attention. This is usually achieved by transferring the patient to heparin prior to, and immediately after, surgery; the INR should ideally be <2 for routine surgery. Acute reversal of the effects of warfarin can be achieved by the administration of prothrombin complex, especially in cases of life-threatening haemorrhage. Alternatively, 1 mg of vitamin K will reverse its effects within 12 hours, and 10 mg will prevent re-warfarinization due to the saturation of liver stores.
Spinal and epidural anaesthesia are contraindicated in patients anticoagulated with warfarin.