Leonard J. Czuba

Chapter 7. Platelet Aggregation Inhibitors

Publisher Summary This chapter presents an overview of the platelet aggregation inhibitors. The therapeutic approach to thromboembolic disease is based on the inhibition of platelet aggregation. The use of fibrinolytic agents for the dissolution of thrombi and the prophylactic use of anticoagulants for their prevention has been known for some time, but success with these agents has been significant only in the management of venous thrombosis in which coagulation factors, not platelets, play an important role. Arterial thrombi, which are essentially composed of aggregated platelets and are not blood clots, are not affected by anticoagulants. The activities of prostaglandins as inhibitors of platelet aggregation have been reviewed. The most conspicuously active member of this group of compounds is PGE l , which is at least 100 times more potent as an inhibitor of human platelet aggregation than the next most active member, PGE 2 . The platelet inhibitory properties of aspirin appear to be due to its ability to acetylate proteins and thereby cause an irreversible change in the platelet membrane that inhibits aggregation. Therefore, the duration of inhibitory action roughly parallels platelet survival time and is much longer than expected, based on the short serum half-life of this drug.

Chapter 8. Antithrombotic Agents

Publisher Summary This chapter describes the development and clinical studies of antithrombotic agents. The therapeutic approaches to the treatment of thrombosis include inhibition of platelet aggregation, inhibition of blood coagulation, and enhancement of the fibrinolytic process. The agents involved affect platelet function or act on the blood coagulation mechanisms either by inhibiting the formation or enhancing the breakdown of fibrin. In this regard, it is important to differentiate between a clot and a thrombus. The effects of natural prostaglandins (PG) on platelet function have been studied extensively. As a group, they are generally inhibitors of ADP-induced platelet aggregation. PGE 1 is by far the most potent by at least two orders of magnitude. PGE 2 differs in that it exhibits a biphasic activity; at concentrations less than those required for inhibition, it potentiates platelet aggregation. Evidence continues to support the hypothesis that platelet aggregation and the release reaction are inhibited by raised levels of intracellular cyclic AMP. The inhibitory effects on platelet function of such diverse agents as PGE 1 , dipyridamole, the methylxanthines and papaverine all appear to be mediated by this cyclic nucleotide.