Clopidogrel: a review of its mechanism of action

Abstract

The search for active antiplatelet drugs within the original chemical class of the thienopyridines, led to the discovery of clopidogrel, a novel ADP-selective agent whose antiaggregating properties are several times higher than those of ticlopidine. The antiaggregating properties of this compound are well known and, very recently, new results have clarified its mechanism of action. Clopidogrel is active only after intravenous or oral administration, and no circulating activity has been found in the plasma of treated animals or human volunteers. Experiments in rats have demonstrated that the antiaggregating activity was caused by a shortlasting metabolite generated in the liver by a cytochrome P450-dependent pathway. The antiaggregating property of clopidogrel is caused by an inhibition of the binding of ADP to its platelet receptors, and more specifically to the low affinity receptors, the high affinity binding sites being unaffected by clopidogrel. Several events in the ADP activation process, including adenylyl cyclase down-regulation, protein tyrosine phosphorylation, activation of the GPIIb-IIIa complex, fibrinogen binding, aggregation and release, were inhibited by clopidogrel and indicate their close relationship with the activation of a low affinity receptor by ADP. In contrast, binding of ADP to its high affinity binding sites (clopidogrel-resistant receptors) induced shape change, cytosolic calcium increase and phosphorylations of several other proteins, some events which were clopidogrel-sensitive. Thus, clopidogrel not only constitutes a potent antithrombotic drug in humans but also a good tool to study the effect of ADP on platelets.

Platelet Microvesicles (Microparticles) in Cardiac Surgery

“…ADP produced from activated platelets triggers G-protein coupled receptors to increase cytosolic calcium to cause PMV production. 43 Clopidogrel use in the 24 hours prior to cardiac surgery has an odds ratio of 2.4 for excessive bleeding compared to patients not receiving clopidogrel. 40 The plasma concentration of clopidogrel is inversely proportional to the number of PMV in patients with stable coronary artery disease, suggesting clopidogrel reduces the production of PMV.…”

Colonoscopy with Polypectomy in Patients Taking Clopidogrel

“…Clopidogrel is a thienopyridine derivative that irreversibly inhibits platelet activation and aggregation [1]. It is commonly used to reduce thrombotic events, particularly in patients who have undergone coronary stent placement [2,3].…”

Conventional and Novel Pharmacotherapy of Angina Pectoris

“…Clopidogrel is a selective adenosine diphosphate (ADP) antagonist. It irreversibly blocks the ADP receptor on the platelet cell membrane and consequently the glycoprotein IIb/IIIa cannot be activated and so platelet aggregation will be avoided (Savi, Nurden et al 1998). …”