The formation of platelet aggregates and thrombi in arterial blood may precipitate coronary vasospasm and occlusion, myocardial infarction, and stroke and contribute to atherosclerotic plaque development. Drugs that inhibit platelet function are administered for the relatively specific prophylaxis of arterial thrombosis and for the prophylaxis and therapeutic management of myocardial infarction and stroke. After an infarction or stroke, antiplatelet therapy must be initiated within 2 hours to obtain significant benefit. The antiplatelet drugs are administered as adjuncts to thrombolytic therapy, along with heparin, to maintain perfusion and to limit the size of the myocardial infarction. Recently, antiplatelet drugs have found new importance in preventing thrombosis in percutaneous coronary intervention procedures (angioplasty and stent). Administration of an antiplatelet drug increases the risk of bleeding.
Aspirin inhibits platelet aggregation and prolongs bleeding time. It is useful for preventing coronary thrombosis in patients with unstable angina, as an adjunct to thrombolytic therapy, and in reducing recurrence of thrombotic stroke. It acetylates and irreversibly inhibits cyclooxygenase (primarily cyclooxygenase-1) both in platelets, preventing the formation of TxA2, and in endothelial cells, inhibiting the synthesis of PGI2 (see
Chapter 26). While endothelial cells can synthesize cy-clooxygenase, platelets cannot. The goal of therapy with aspirin is to selectively inhibit the synthesis of platelet TxA2 and thereby inhibit platelet aggregation. This is accomplished with a low dose of aspirin (160 to 325 mg per day), which spares the endothelial synthesis of PGI2. If ibuprofen is taken concurrently, it will bind re-versibly to cyclooxygenase and prevent the access of aspirin to its acetylation site and thus antagonize the ability of aspirin to inhibit platelets. Dipyridamole (Persantine), a coronary vasodilator, is a phosphodi-esterase inhibitor that increases platelet cyclic adeno-sine monophosphate (cAMP) concentrations. It also may potentiate the effect of PGI2, which stimulates platelet adenylate cyclase. However, dipyridamole itself has little effect on platelets in vivo. Dipyridamole in combination with warfarin is beneficial in patients with artificial heart valves; it is also useful in combination with aspirin (Aggrenox) for the secondary prevention of stroke.
Ticlopidine (Ticlid) and clopidogrel (Plavix) are structurally related drugs that irreversibly inhibit platelet activation by blocking specific purinergic receptors for ADP on the platelet membrane. This action inhibits ADP-induced expression of platelet membrane GPIIb/IIIa and fibrinogen binding to activated platelets. Ticlopidine and clopidogrel are useful antithrombotic drugs. Oral ticlopidine is indicated for prevention of thrombotic stroke in patients who cannot tolerate aspirin and for patients who have had thrombotic stroke. Inhibition of ADP-induced platelet aggregation occurs within 4 days, and the full effect requires approximately 10 days. Ticlopidine is taken with food, is well absorbed, binds extensively to plasma proteins, and is metabolized by the liver. Gastrointestinal disturbances, neutropenia, and agranulocytosis have been observed. Clopidogrel produces fewer side effects than ticlopidine.
Pharmacological agents, such as abciximab (ReoPro), eptifibatide (Integrillin), and tirofiban (Aggrastat), that interrupt the interaction of fibrinogen and Von Willebrand's factor with the platelet GPIIb/IIIa complex are capable of inhibiting aggregation of platelets activated by a wide variety of stimuli. These drugs are given intravenously. The chimeric monoclonal antibody abcix-imab binds to the GPIIb/IIIa complex, preventing interactions of fibrinogen and Von Willebrand's factor with the integrin receptor. Abciximab is used in conjunction with angioplasty and stent procedures and is an adjunct to fibrinolytic therapy (discussed later). Patients who have murine protein hypersensitivity or who have received abciximab previously may produce an immune response after second administration. Eptifibatide, a cyclic peptide, and tirofiban, a small nonpeptide molecule, both bind reversibly to the GPIIb/IIIa complex and competitively prevent the interaction of the clotting factors with this receptor.
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