Pathophysiological role of thromboxane A2 and pharmacological approaches to its inhibition.

The formation of the proischemic and prothrombotic thromboxane A2 (TXA2) and of its functional antagonist prostacyclin is increased in patients with unstable angina and myocardial infarction. Therefore, pharmacological interventions aim at an inhibition of the synthesis or action of TXA2 without interference with the desirable effects of prostacyclin. Clinical studies currently evaluate low-dose aspirin, thromboxane synthase inhibitors, TXA2/PGH2 receptor antagonists, and a combination of the latter two principles of action. The major advantages and disadvantages of these drugs are: 1. Aspirin irreversibly inhibits TXA2 and PGH2 synthesis in platelets, but also reduces the formation of the platelet-inhibiting PGD2 and prostacyclin--even under a low-dose regimen. 2. Thromboxane synthase inhibitors increase the formation of PGD2 and prostacyclin, but also enhance the accumulation of the potent platelet agonist PGH2. 3. Competitive TXA2/PGH2 receptor antagonists selectively inhibit the action of TXA2 and PGH2 and do not interfere with the eicosanoid metabolism, but their inhibitory effect can be overcome by very high local TXA2 or PGH2 concentrations. 4. Non-competitive TXA2/PGH2 receptor antagonists do not share this drawback. Therefore, they might combine the advantage of aspirin to exert an irreversible inhibition with the specificity of a TXA2/PGH2 receptor antagonist. However, these antagonists are in the stage of experimental studies. 5. The most potent of the clinically available principles of a platelet inhibition is the combination of a thromboxane synthase inhibitor with a competitive TXA2/PGH2 receptor antagonist. Agents that combine both principles of action in one compound are also under clinical investigation.