Mechanical Heart Valves. Atrial Fibrillation. Deep Vein Thrombosis and Pulmonary Embolism. Myocardial infarction. Acute Ischemic Stroke.
Warfarin is a [vitamin K] antagonist which acts to inhibit the production of vitamin K by vitamin K epoxide reductase. The reduced form of vitamin K, vitamin KH2 is a cofactor used in the γ-carboxylation of coagulation factors VII, IX, X, and thrombin. Carboxylation induces a conformational change allowing the factors to bind Ca2+ and to phospholipid surfaces. Uncarboxylated factors VII, IX, X, and thrombin are biologically inactive and therefore serve to interrupt the coagulation cascade. The endogenous anticoagulation proteins C and S also require γ-carboxylation to function. This is particularly true in the case of thrombin which must be activated in order to form a thrombus. vitamin KH2 is converted to vitamin K epoxide as part of the γ-carboxylation reaction catalyzed by γ-glutamyl carboxylase. Vitamin K epoxide is then converted to vitamin K1 by vitamin K epoxide reductase then back to vitamin KH2 by vitamin K reductase. Warfarin binds to vitamin K epoxide reductase complex subunit 1 and irreversibly inhibits the enzyme thereby stopping the recycling of vitamin K by preventing the conversion of vitamin K epoxide to vitamin K1. This process creates a hypercoagulable state for a short time as proteins C and S degrade first with half lives of 8 and 24 hours, with the exception of factor VII which has a half life of 6 hours. Factors IX, X, and finally thrombin degrade later with half lives of 24, 36, and 50 hours resulting in a dominant anticoagulation effect. In order to reverse this anticoagulation vitamin K must be supplied, either exogenously or by removal of the vitamin K epoxide reductase inhibition, and time allowed for new coagulation factors to be synthesized. It takes approximately 2 days for new coagulation factors to be synthesized in the liver. Vitamin K2, functionally identical to vitamin K1, is synthesized by gut bacteria leading to interactions with antibiotics as elimination of these bacteria can reduce vitamin K2
Treatment & prophylaxis of venous thromboembolism: Adult: Initially, 5 mg daily. Rapid anti-coagulation: Initially, 10 mg daily for 2 days. Adjust subsequent doses based on PT/INR. Usual maintenance dose: 2-10 mg daily. Elderly: Lower initial dose. INTRAVENOUS Treatment & prophylaxis of venous thromboembolism: Adult: Given as slow bolus lnj over 1-2 min into peripheral vein. Initially, 5 mg daily. Rapid anti-coagulation:Initially, 10 mg daily for 2 days. Adjust subsequent doses based on PT/INR. Usual maintenance dose: 2-10 mg daily. Elderly: Lower initial dose.
Oral anticoagulants have a greater potential for clinically significant drug interactions. Warn all patients about potential hazards and instruct against taking or withdrawing any drug, including non-prescription products, without the advice of a physician.
Hypersensitivity; haemorrhagic tendencies or blood dyscrasia; recent surgery; peptic ulcer; severe hypertension; bacterial endocarditis; cerebrovascular disorders; psychosis; senility; aneurysms; pericarditis; pericardial effusion; eclampsia; pre-eclampsia; threatened abortion; alcoholism; severe renal & hepatic impairment; pregnancy. Heparin induced thrombocytopenia, DVT, infectious disease, disturbances of intestinal flora, surgery or trauma, indwelling catheters, hypertension, Vit C, Vit K, protein C or S deficiency. Elderly, lactation, alcoholics. Purple toes syndrome (due to cholesterol microembolisation) may occur between 3-10 wk after start of therapy. Discontinue therapy if necrosis develops. Periodic determination of PT/INR. Patient to report any signs of bleeding, symptoms of blood clot & avoid activities or sports that can cause injuries. An INR <2 generally represents insufficient anticoagulation while INR>4 represents higher risk of bleeding.
Hypersensitivity, rash, alopecia, diarrhoea, drop in haematocrit, purple toes syndrome, skin necrosis, jaundice, nausea, vomiting, hepatic dysfunction, pancreatitis, increased LFT. Haemorrhage (narrow therapeutic index).
Warfarin is known to pass the placental barrier during pregnancy and to cause birth defects as well as fetal and maternal coagulopathy. However, warfarin is considered safe in lactation as it does not pass into breast milk to any measurable degree.
If hemorrhage occurs or a potential bleeding state arises, excessive depression of the coagulation activity can be corrected by temporary withdrawal of warfarin accompanied, if necessary, by infusion of fresh-frozen plasma or whole blood. Vitamin K, 5 mg to 10 mg orally or intravenously, may be required to supplement specific treatment with co-factor concentrates.
Do not store above 30°C. Keep away from light and out of the reach of children.
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