Pharmacodynamic Properties of Antiplatelet Agents

GPIIb/IIIa Antagonists

The platelet integrin receptor α_IIbβ₃ (GPIIb/IIIa) plays a critical role in thrombosis and hemostasis by mediating interactions between platelets and several ligands, primarily fibrinogen.^[72] This receptor is the most abundant integrin found on the surface of platelets and is composed of two separate subunits, α_IIb (GPIIb) and β₃ (GPIIIa).^[73] 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.^[74] 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,^[74] as well as through the 12-peptide HHLGGAKQAGDV sequence located at the c-terminus of the γ-chain of fibrinogen.^[75] 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.^[76] Eptifibatide and tirofiban are low-molecular-weight competitive and reversible GPIIb/IIIa antagonists that act specifically on the α_IIb-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.^[77] 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.^[78]

Table 1. Characteristics of P2Y ₁₂ antagonists.
P2Y₁₂ antagonist	Type	Administration	Action	Time to peak IPA	Plasma half-life	Loading dose/maintenance	Drug interactions	Resistance
Clopidogrel	Thienopyridine	Oral	Hepatic activation, irreversible inhibition	6–12 h	7–8 h	300–600 mg/75 mg/day	Yes	Yes
Prasugrel	Thienopyridine	Oral	Hepatic activation, irreversible inhibition	2 h	7–8 h	60 mg/10 mg/day	Yes	Yes/no^†
Ticagrelor	Cyclopentyl-triazolo-pyrimidine	Oral	Direct, noncompetitive, reversible inhibition	2 h	6–8 h	180 mg/90 mg twice-daily	Not reported	No
Cangrelor	ATP analog	iv.	Direct competitive reversible inhibition	Seconds	3–9 min	30 µg/kg bolus, 4 µg/kg/min, continuous infusion	Not reported	No
Elinogrel	N-[(5-chlorothioph n-2-yl)sulfonyl]N'-{4-[6-fluoro-7(methylamino)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]phenyl}urea	Oral/iv.	Direct competitive reversible inhibition	4–6 h	12 h	80–120 mg bolus infusion/50–150 mg oral twice-daily	Not reported	No

†There are controversial data concerning prasugrel resistance, and there is a need for larger studies to confirm prasugrel resistance. IPA: Inhibition of platelet aggregation; iv.: Intravenous.

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

My Alerts

Add to Email Alerts

Your Name is required.

Subject is required.

Please enter a Recipient Address and/or check the Send me a copy checkbox.

Your email has been sent.

is an Invalid Email Address.

Pharmacodynamic Properties of Antiplatelet Agents

Current Knowledge and Future Perspectives

GPIIb/IIIa Antagonists

Tables

References

Authors and Disclosures

Authors and Disclosures

Sidebar

Sidebar

Key Issues

Comments

Email This

Feedback