ANTIPLATELETDRUGS

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 While endothelial cells can synthesize cyclooxygenase, 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 reversibly 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 phosphodiesterase inhibitor that increases platelet cyclic adenosine 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.

Most of the current available antiplatelet drugs, such as aspirin, dipyridamole, ticlopidine, and sulfinpyrazone, exert their actions by affecting only the secondary platelet aggregation pathways (87). For example, aspirin and sulfinpyrazone work by inhibiting the biosynthesis of TXA2 in the platelets. Aspirin works by irreversibly and permanently inactivating cyclooxygenase (COX) through covalent acetylation of a serine residue in close proximity to the active site of the enzyme. A cumulative inactivation effect occurs on platelets with long-term therapy, because platelets do not synthesize new COX (i.e., platelets are unable to synthesize, via de novo pathway, COX-1, because they are anucleated cells). Therefore, the effects of aspirin last for the lifetime of the platelet (7–10 days). Sulfinpyrazone also is a potent but reversible COX inhibitor that does not affect PGI2 synthesis in endothelial cells. Like nonsteroidal anti-inflammatory agents (NSAIDs), such as aspirin, this action inhibits the aggregation of platelets into thrombi. Dipyridamole interrupts platelet function through its effect of increasing cellular concentration of cAMP by inhibiting phosphodiesterase, an enzyme needed for degradation of cAMP. Dipyridamole also may stimulate PGI2 release and inhibits TXA2 formation. Ticlopidine and clopidogrel selectively inhibit ADP-induced platelet aggregation with no direct action on prostaglandin production. New and more selective antiplatelet drugs, such as integrin αIIbβ3 receptor antagonists (GPIIa/IIIb blockers), thromboxane synthase inhibitor, and TXA2 receptor antagonists, are currently being developed.