Pharmacology of thienopyridines: rationale for dual pathway inhibition

Atherothrombotic disease is the result of atherosclerosis progression, and its clinical manifestations, mostly secondary to atherosclerotic plaque disruption and subsequent thrombus formation. At the site of vascular lesions, platelets adhere to the exposed matrix proteins, prompting platelet activation, resulting in the secretion of multiple platelet agonists, mostly modulated by intracellular calcium release. Among them, ADP, thromboxane A2, thrombin, and others play a critical role in maintaining a ‘pro-platelet-activating’ environment. Aspirin has been considered the gold standard of antithrombotic therapy. Its antiplatelet activity is achieved mainly by inhibiting arachidonic acid pathway (blocking thromboxane A2 release from platelets). ADP binds to platelet P2Y12 receptor, although this receptor is important in platelet aggregation induced by other agonists. Thienopyridines (ticlopidine and clopidogrel) exert their antiplatelet activity by binding to the P2Y12 receptor, irreversibly modifying it. Oral clopidogrel loading dose of 300–600 mg clopidogrel produces significant inhibition of ADP-induced platelet aggregation 2 hours after administration, which becomes maximal after 6 hours. Both aspirin and clopidogrel are ‘selective platelet-receptor’ inhibitors, and therefore are weak and safe antiplatelet agents. The co-administration aspirin-clopidogrel results in enhancement of platelet inhibition, since the act via different platelet receptors. Current research is focused in reversible or more potent ADP antagonists.