Platelet adenosine diphosphate receptor antagonists: ticlopidine to ticagrelor—a long continuing journey

Abstract

Platelet aggregation plays a central role in the pathogenesis of atherothrombosis. Platelet adenosine diphosphate (ADP) receptor antagonists (ticlopidine, clopidogrel, prasugrel, and ticagrelor) are a major advance in the treatment of atherothrombotic diseases, especially acute coronary syndromes (ACS). Ticlopidine was the first thienopyridine introduced into clinical practice, but its potentially serious haematological side-effects limited its use and it was quickly eclipsed by clopidogrel. Clinical trials established aspirin plus clopidogrel as the standard dual anti-platelet therapy in patients with ACS and patients undergoing percutaneous coronary intervention (PCI) with stenting. Clopidogrel was found to have pharmacokinetic and pharmacodynamic limitations. Prasugrel is the next approved thienopyridine that has shown superior efficacy in ACS patients undergoing PCI in comparison to clopidogrel, although at the cost of a higher bleeding risk. Ticagrelor is the latest non-thienopyridine ADP receptor blocker that is potent, effective, reversible, and relatively safer as compared to clopidogrel.Both prasugrel and ticagrelor are more potent than clopidogrel. The data so far suggests that ticagrelor has a wider applicability in usage in patients with ACS as compared to prasugrel. Prasugrel however seems to be better tolerated. Search is on for newer more potent but safer anti-platelet agents.

Ticagrelor, a molecular breakthrough to modulate cytokine network in the treatment of acute myocardial infarction "perspective and prospective"

“…Clopidogrel and prasugrel are the most successful thienopyridines that are selective in action which inhibits ADP mediated platelet activation irreversibly. Clopidogrel is a prodrug that needs cytochrome P 450 (CYP) 3A4 and 3A5 enzymes of the liver, with contributions from 2C19, 2C9, and 1A2 enzymes [56][57][58][59] to convert to active drug molecule that inhibits platelet aggregation through P2Y 12 receptor action. Since it depends on CYP system the efficacy also varies with individual patients Kannan/Makeen/Albarraq/Meraya/Sanhouri/Moni due to the variability of enzyme activity developed by genetic polymorphism.…”

Hematoma Expansion Following Intracerebral Hemorrhage: Mechanisms Targeting the Coagulation Cascade and Platelet Activation

“…It is metabolized by the hepatic CYP450 enzymes, resulting in the formation of the active metabolite that irreversibly inhibits the P2Y12 receptor [155]. Ticlopidine was the first thienopyridine to be introduced to the clinic, but due to its unfavorable side effects, was replaced by clopidogrel [156].…”