Compare and contrast warfarin with heparin.

Outline:

·        Mechanism of action.

·        Mode of administration.

·        Adverse effects and drug interactions.

·        Combined use in anticoagulation.

Suggested Answer:

Warfarin and heparin are two anticoagulants commonly used in clinical practice to prevent thrombus formation in occlusive vascular disease, pulmonary embolism and after surgery.

Warfarin is an indirect-acting oral anticoagulant. During the gamma-carboxylation of factors II, VII, IX and X as well as proteins C and S, active vitamin K is oxidized to an epoxide and must be reduced by the enzyme vitamin K epoxide reductase to become active again. Warfarin is structurally similar to vitamin K and competitively inhibit epoxide reductase, so limiting availability of the active form of the vitamin to form coagulant proteins. The overall result is a shift in haemostatic balance in favor of anticoagulation because of the accumulation of clotting proteins with absent or decreased gamma-carboxylation sites. Due to this indirect mode of action, anticoagulation is delayed until the functioning clotting factors already present in the circulation have been used up; the net result is that anticoagulant protection is not effective until about 72h after the first dose.

Heparin is a mixture of sulfated mucopolysacchardie. It binds to endothelial cell surface, activating antithrombin III, which is a naturally occurring inhibitor of thrombin and of activated factor X. In the presence of heparin antithrombin becomes vastly more active. Factor Xa is involved in both the intrinsic and extrinsic coagulation systems and its inhibition put a premature halt to the coagulation pathway, thereby preventing the formation of blood clots. The onset of action is 20 – 60 min.

Heparin hence exerts its anticoagulant effect directly by activating antithrombin III which accounts for its fast onset of action while warfarin takes 72h for anticoagulation to occur. This is the chief advantage that heparin has over warfarin. The different mechanisms of action between heparin and warfarin is responsible for their different onset of anticoagulant action which in turn affects their clinical usage. For example, heparin is usually used to initiate anticoagulation in for example, patients after surgery, while warfarin is used a few hours or days later to maintain the anticoagulation.

Heparin is poorly absorbed from the GI tract and is given i.v. or s.c. It binds to several plasma proteins and to sites on endothelial cells. It is metabolized chiefly in the liver. Control of heparin therapy is by the kaolin-cephalin clotting time (KCCT). On the other hand, warfarin is readily absorbed from the GI tract and more than 90% bound to plasma proteins. It has a half-life of 36h and its action is terminated by metabolism in the liver. Monitoring of therapy is by the prothrombin time. The advantage offered by warfarin is that it can be taken orally and therefore can be used to maintain anticoagulant therapy at home long after the patient has been discharged while heparin can only be administered in a hospital. Oral anticoagulation is commonly undertaken in patients who are already receiving heparin.

Bleeding is the serious acute complication of heparin therapy. It is uncommon, but patients with impaired hepatic or renal function, with carcinoma, and those over 60 years appear to be most at risk. A further serious complication is the syndrome of thrombocytopenia with arterial thromboemboli and haemorrhage which occurs in about 2 – 3% of patients who receive heparin for a week or more. Osteoporosis may occur and is dose-related. Hypersensitivity reactions and skin necrosis occur but are rare.

Bleeding is also the commonest side effects of warfarin and is most likely to occur in the alimentary and renal tracts, and in the brain in those with cerebrovascular disease. Cutaneous reactions, apart from purpura and ecchymoses in those who are excessively anticoagulated, include pruritic lesions. Warfarin used in early pregnancy may cause skeletal disorder (bossed forehead, sunken nose, foci of calcification in the epiphyses) and absence of the spleen. CNS abnormalities (microcephaly, cranial nerve palsies) are reported with warfarin use at any stage of pregnancy. Women on long-term warfarin therapy should be advised not to become pregnant while taking the drug. Heparin should be substituted prior to conception and continued throughout the first trimester, after which warfarin should replace heparin, as continued exposure to heparin may cause osteoporosis. Hence, as warfarin is teratogenic, heparin is preferred as the anticoagulant during pregnancy.

Heparin is used in established venous thromboembolism to prevent extension of an existing thrombus, to recanalize veins and to clear vein valves of thrombus. The site and extent of thrombosis can be determined by venous ultrasound or venography. Heparin is used initially because of its rapid onset of effect and continued until the signs of thrombosis have settled which may take 5 – 7 days. Warfarin is usually started on the third to fifth day to maintain anticoagulant therapy.

Warfarin and low-dose heparin are used to prevent deep vein thrombosis and pulmonary embolism in patients after surgery and those immobilized with strokes, cardiac failure or malignant disease.

Anticoagulation with heparin is used to reduce the risk of venous thromboembolism, and the risk and size of emboli from mural thrombi following acute myocardial infarction. Long-term anticoagulation with warfarin to prevent arterial thromboembolism is indicated for patients who has a large left atrium, low cardiac output or paroxysmal or established atrial fibrillation.

Contraindications to warfarin and heparin relate mostly to conditions in which there is a tendency to bleed such as stroke within 3 weeks, surgery to the brain or eye, active peptic ulcer, active inflammatory disease, esophageal varices, severe hypertension and pre-existing bleeding disorder.