Anticoagulant drugs

Anticoagulant drugs prevent the formation of thrombi by inhibiting the coagulation phase. They are used to prevent the formation and spread of venous and arterial thrombi; however, they are ineffective against existing thrombi. Anticoagulant therapy is used to treat deep-vein thrombosis and pulmonary embolism arising after immobilization or surgery; systemic or coronary arterial embolism caused by heart diseases or replacement of the prosthetic valve; and disseminated intravascular coagulation, which is a systemic activation of the system that leads to consumption of coagulation factors and hemorrhage.

Heparin, used primarily in hospitalized patients, is a mixture of negatively charged mucopolysaccharides. An endogenous substance whose physiological role is not understood, heparin blocks the coagulation cascade by promoting the interaction of a circulating inhibitor of thrombin (antithrombin III) with activated clotting factors. Because it is not well-absorbed when taken orally, heparin is given intravenously to inhibit coagulation immediately; the onset of the drug's effect is delayed after subcutaneous administration. Heparin is not bound to plasma proteins, it is not secreted into breast milk, and it does not cross the placenta. The drug's action is terminated by metabolism in the liver and excretion by the kidney. The major side effect associated with heparin is hemorrhage; thrombocytopenia (reduced number of circulating platelets) and hypersensitivity reactions also occur. Oral anticoagulants and heparin have additional anticoagulant effects. Heparin-induced hemorrhage may be reversed with the antagonist protamine, a positively charged protein that has a high affinity for heparin's negatively charged molecules, thus neutralizing the drug's anticoagulant effect. When given in combination with heparin, dihydroergotamine, which constricts veins and increases blood flow, increases heparin's antithrombotic effect.

Oral anticoagulants are derivatives of 4-hydroxycoumarin (coumarin) or indan-l, 3-dione (indandione). Structurally the coumarin derivatives resemble vitamin K, an important element in the synthesis of a number of clotting factors. Interference in the metabolism of vitamin K in the liver by coumarin derivatives gives rise to clotting factors that are defective and incapable of binding calcium ions (another important element in the activation of coagulation factors at several steps in the coagulation cascade). When anticoagulants are taken orally, several hours are required for the onset of the anticoagulant effect because time is required both for their absorption from the gastrointestinal tract and for the clearance of biologically active clotting factors from the blood. Warfarin, the most commonly used oral anticoagulant, is rapidly and almost completely absorbed; the absorption of dicumarol and other anticoagulant agents, however, is slower and less consistent.

Oral anticoagulants bind extensively to plasma proteins, have relatively long plasma half-lives, and are metabolized by the liver and excreted in the urine and feces. They may cross the placenta to cause fetal abnormalities or hemorrhages in neonates; their appearance in breast milk apparently has no adverse effect on nursing infants. Hemorrhage is the principal toxic effect during oral anticoagulant therapy, but each of the coumarin derivatives causes its own idiosyncratic side effects. Vitamin K, when given intravenously to promote the synthesis of functional clotting factors, stops bleeding after several hours. Plasma that contains normal clotting factors is given to control serious bleeding. Oral anticoagulants may interact adversely with other drugs that bind to plasma proteins or are metabolized by the liver.