Comparative Pharmacology of GP IIb/IIIa Antagonists

Abstract

GP IIb/IIIa antagonists are qualitatively different from classical antiplatelet agents, such as aspirin or clopidogrel. They do not inhibit platelet activation, i.e. intraplatelet signal generation or conduction but primarily act outside the platelet by competing with ligand (e.g. fibrinogen) binding that is essential for platelet bridging and aggregate formation. Three compounds are in clinical use: abciximab, an antibody fragment and two low-molecular weight compounds, tirofiban and eptifibatide. In comparison to the low-molecular weight compounds, abciximab has a substantially longer platelet half-life (4 h), i.e. slow off-rate and a short plasma half-life (20–30 min) without significant distribution into the extravascular space. The plasma half-life of tirofiban and eptifibatide is about 2 h and parallels the antiplatelet effect. The off-rate from the platelet GP IIb/IIIa receptor is much faster and there is a significant distribution into the extravascular space. These pharmacokinetic variables might influence the competition between the antagonists and fibrinogen for GP IIb/IIIa binding. Other pharmacological variables are a partial agonistic activity, facilitation of thrombolysis, modification of other integrin-related actions, including inflammatory responses, effects on vascular cells and apoptosis. Importantly, GP IIb/IIIa antagonists might also interfere with prothrombin binding to the platelet surface and, thus, might influence the coagulation pathway. There is no clear evidence that the biological activity of the agents is modified by gene polymorphism (HPA-1). All three compounds may cause thrombocytopenia, possibly related to drug-induced antibodies.

There is no clear data suggesting that these pharmacological differences transfer into significant differences in clinical outcome, for example in patients with acute coronary syndromes (ACS) subjected to acute percutaneous coronary interventions (PCI). The only head-to-head comparison of all three clinically used parenteral compounds did not demonstrate differences in major adverse cardiac effects (MACE) at 30 days although those have been described in particular with long-term use of oral antagonists. The inherent problems with all GP IIb/IIIa antagonists are the narrow therapeutic range because the same mechanisms are involved in hemostasis and thrombosis and their inability to inhibit platelet activation.