The platelet integrin receptor αIIbβ3 (GPIIb/IIIa) plays a critical role in thrombosis and hemostasis by mediating interactions between platelets and several ligands, primarily fibrinogen. This receptor is the most abundant integrin found on the surface of platelets and is composed of two separate subunits, αIIb (GPIIb) and β3 (GPIIIa). On unstimulated platelets, GPIIb/IIIa is present in a closed conformation that prevents ligand binding. Upon platelet activation, the receptor undergoes conformational changes and several binding sites for fibrinogen and other ligands are exposed. Fibrinogen binding to the activated GPIIb/IIIa mediates platelet aggregation by crosslinking adjacent platelets. The ligand binding to GPIIb/IIIa is mediated through Arg–Gly–Asp (RGD) sequences in these ligands, as well as through the 12-peptide HHLGGAKQAGDV sequence located at the c-terminus of the γ-chain of fibrinogen. Since fibrinogen binding to the activated receptor GPIIb/IIIa constitutes the final common pathway of platelet aggregation, GPIIb/IIIa antagonists inhibit platelet aggregation independently of the type of platelet agonist. Currently, three GPIIb/IIIa antagonists are available: abciximab, eptifibatide and tirofiban.
Abciximab is a noncompetitive irreversible inhibitor of GPIIb/IIIa. It is the humanized chimeric Fab fragment of the monoclonal mouse antibody 7E3. Eptifibatide and tirofiban are low-molecular-weight competitive and reversible GPIIb/IIIa antagonists that act specifically on the αIIb-subunit of GPIIb/IIIa. Eptifibatide is a cyclic heptapeptide whereas tirofiban is a nonpeptide (peptidomimetic) antagonist. Tirofiban contains the RGD sequence, whereas in eptifibatide the arginine residue of RGD is replaced by lysine.
Unlike abciximab, which crossreacts with other integrins on the surface of various cell types, eptifibatide and tirofiban specifically act on GPIIb/IIIa receptors. Furthermore, eptifibatide and tirofiban, unlike abciximab, cannot induce immune response given their small molecular weights and low affinities to GPIIb/IIIa receptors. Their effect on platelet aggregation is closely linked to plasma concentrations. Owing to their short plasma half-lives, continuous infusion is needed for sustained platelet inhibition.
Abciximab, eptifibatide and tirofiban are all intravenously injected. Large-scale clinical trials have demonstrated the clear clinical effects and safety of these drugs in decreasing the ischemic events in ACS. Their uses in adjunctive therapy during PCI have also been revealed. However, the available data suggest that the most common adverse events are episodes of bleeding, mostly minor and essentially at the vascular access site, without an excess of intracranial hemorrhage.
Expert Rev Clin Pharmacol. 2012;5(3):319-336. © 2012 Expert Reviews Ltd.