Warfarin indirectly alters the synthesis of functional coagulation factors by interfering with vitamin K activity, which is required for t-carboxylation of factors II, VII, IX, and X.
Prophylaxis and treatment of deep venous thrombosis, hypercoagulable states, and anti-phospholipid syndrome, and care after cerebrovascular accident. Metabolism
Warfarin is generally well absorbed by the gastrointestinal tract, but the rate of absorption can be highly dependent on individual variability and the commercial source of the drug. Although peak levels of warfarin occur within hours after ingestion, its antithrombogenic activity does not depend on plasma levels but rather on levels of vitamin K-dependent factors, which may not be affected until at least 2 days after administration. IV administration of warfarin does not hasten the onset of activity. The effects of warfarin may be potentiated or diminished by innumerable foods and medications, all of which should be taken into careful consideration during treatment. Warfarin is inactivated in the liver, and the metabolites are excreted in urine.
Hemorrhage is the most common adverse effect of warfarin. Potentially fatal necrosis of the skin or other tissue is a rare complication, most commonly seen in patients with defects or deficiencies in the antithrombotic factors protein C or protein S. This is usually seen early after initiation of therapy and is thought to be caused the rapid depletion of the vitamin K-dependent protein C, which results in a transient prothrombotic state. Another rare complication is cholesterol microembolization syndrome, which can result in systemic microvascular ischemia. Although the PT/INR is most sensitive to warfarin, the PTT can also be elevated at high doses.
Close monitoring of the PT/INR is required for appropriate dosing of warfarin, especially at the start of therapy or when changes in concurrent medications are made. Familiarity with drugs that may enhance or reduce the anticoagulant effects of warfarin is advised. Warfarin is contraindicated during pregnancy and in nursing women. IM injections should not be given to patients in an anticoagulated state. Patients with anti-phospholipid syndrome present an additional problem in that circulating antibodies may cause artifacts in the INR, which makes monitoring of anticoagulation difficult.
Tablets, 1, 2, 2.5, 4, 5, 7.5, and 10 mg. Injectable solution, 5 mg.
Daily dosing as dictated by desired INR. For most indications (e.g., treatment of deep venous thrombosis, atrial fibrillation), an INR of 2.0 to 3.0 is generally recommended. For patients with mechanical heart valves, an INR of 2.5 to 3.5 should be maintained. Patients with anti-phospholipid syndrome may require an INR of 3.0 to 4.0 or higher.
Vasoactive agents are useful in the management of systemic and pulmonary hypertension, Raynaud's phenomenon, and congestive heart failure. Vascular tone may be relaxed by (a) inhibition of sympathetic function (e.g., prazocin), (b) direct relaxation of smooth muscle (e.g., hydralazine), (c) calcium channel blockade (e.g., amlodipine, diltiazem, nifedipine, verapamil), and (d) inhibition of ACE (e.g., captopril, enalapril). The use of ACE inhibitors, in particular, has drastically changed the outcome in diffuse systemic sclerosis. Included below is a small sampling of available agents.
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