Platelet Glycoprotein IIb/IIIa Receptor Antagonists
The glycoprotein (GP) IIb/IIIa (αIIb/β3) receptor totalling 50,000 to 70,000 copies per platelet represents a common pathway for platelet aggregation in response to a wide variety of biochemical and mechanical stimuli. Accordingly, it represents an attractive target for pharmacologic inhibition that can be applied to patients with acute coronary syndromes. The evolution of GPIIb/IIIa receptor antagonists began with murine monoclonal antibodies and subsequently expanded to include small peptide or nonpeptide molecules with structural similarities to fibrinogen. There are three intravenous GPIIb/IIIa receptor antagonists that have been approved by the U.S. Food and Drug Administration: . . . • Abciximab (ReoPro) . . . . . . • Tirofiban (Aggrastat) . . . . . . • Eptifibatide (Integrilin) . . . Abciximab (ReoPro) is the Fab fragment of the chimeric human–murine monoclonal antibody c7E3. Following an intravenous bolus, free plasma concentrations of abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second-phase half-life of 30 minutes, representing rapid binding to the platelet GPIIb/IIIa receptor. Abciximab remains in the circulation for 10 or more days in the platelet-bound state. Intravenous administration of abciximab in doses ranging from 0.15 mg/kg to 0.3 mg/kg produces a rapid dose-dependent inhibition of platelet aggregation in response to adenosine diphosphate (ADP). At the highest dose, 80% of platelet GPIIb/IIIa receptors are occupied within 2 hours and platelet aggregation, even with 20 μM ADP, is completely inhibited. Sustained inhibition is achieved with prolonged infusions (12 to 24 hours) and low-level receptor blockade is present for up to 10 days following cessation of the infusion; however, platelet inhibition during infusions beyond 24 hours has not been well characterized. Platelet aggregation in response to 5 μM ADP returns to greater than or equal to 50% of baseline within 24 hours of drug cessation. In nearly 2,100 patients undergoing either balloon coronary angioplasty or atherectomy at high risk for ischemic (thrombotic) complications, a bolus of abciximab (0.25 mg/kg) followed by a 12-hour continuous infusion (10 μg/min) reduced the occurrence of death, the occurrence myocardial infarction (MI), or the need for an urgent intervention (repeat angioplasty, stent placement, balloon pump insertion, or bypass grafting) by 35% (EPIC Investigators, 1994).