Glycoprotein IIb/IIIa Inhibitors (Abciximab / Tirofiban)

Mechanism

Mechanism of Action

Abciximab and tirofiban block the abundant platelet GPIIb/IIIa surface receptor, a heterodimeric integrin also called α_IIbβ₃).

Molecular Mechanism of GP IIb/IIIa Integrin Blockade

1. Platelet activation by agonists such as collagen, thrombin, ADP or TXA2 initiates an inside-out conformational change that activates integrin receptors GPIIb/IIIa exposed on the platelet surface.
2. Active GPIIb/IIIa binds the Arg-Gly-Asp (RGD) tripeptide sequence of soluble fibrinogen or plasma von Willebrand factor.
3. This cross-links adjacent platelets and consolidates the platelet thrombus.
4. Abciximab: A chimeric monoclonal antibody Fab fragment that binds strongly to the platelet receptor and sterically prevents adhesion-ligand binding.
5. Tirofiban: A synthetic non-peptide tyrosine derivative that acts as a competitive, reversible inhibitor at the active integrin RGD-binding site.

Pharmacokinetics

Pharmacokinetics

• Route of administration: Exclusively intravenous by initial bolus followed by closely regulated continuous intravenous infusion.
• Abciximab: After IV bolus, the free plasma concentration decreases rapidly due to selective binding to peripheral platelet receptors. It has an initial plasma half-life of 10 to 30 minutes, but the platelet-bound drug remains active, allowing the residual antiplatelet function to continue being altered up to 48 hours after completing the infusion.
• Tirofiban: Short plasma half-life of approximately 1.5 to 2 hours. Its plasma clearance is mainly unchanged renal (65%). Basal platelet function recovers almost completely within a short period of 4 to 8 hours after stopping the continuous infusion.

Indicators and dose

Indications

• Prevention of myocardial ischemia in high-risk patients with acute coronary syndromes undergoing PCI.
• Prevention of recurrent thrombotic events in NSTEMI patients with high coronary risk anatomy.

Dosage and Adjustment

• Abciximab: IV bolus of 0.25 mg/kg given 10–60 minutes before PCI, followed by continuous IV infusion of 0.125 µg/kg/min (maximum 10 µg/min) for 12 hours after the procedure.
• Tirofiban: Initial infusion of 25 µg/kg over 3 minutes, followed by maintenance infusion of 0.15 µg/kg/min for up to 18 to 24 hours. Kidney adjustment: Reduce the infusion rate by half (0.075 µg/kg/min) when CrCl_Cr < 30 mL/min.

Pregnancy and Breastfeeding

FDA Category C. Pregnancy safety data are insufficient. Avoid unless the expected maternal benefit justifies the risk.

Security

Contraindications

Absolute

• Demonstrated active internal bleeding.
• History of stroke of any etiology within a period of less than 2 years.
• Active intracranial hemorrhage or documented history of cerebral arteriovenous malformation or aneurysm.
• Recent major surgery or serious trauma in the last 6 weeks.
• Pre-existing severe thrombocytopenia (platelets < 100,000/µL).

Relative

• Severe chronic renal failure (for Tirofiban requires a mandatory 50% reduction in infusion clearance).
• Severe uncontrolled hypertension.
• Recent non-compressible arterial puncture in major vessels.

Adverse effects (ADRs)

• Hemorrhage: High risk of inducing major gastrointestinal bleeding or massive hematomas in the femoral arterial catheterization access.
• Severe Acute Thrombocytopenia (Immune): Abciximab induces a sharp decrease in platelets (< 20,000/µL) in 1 - 2% of patients in the first 2 to 24 hours of infusion due to the development of antibodies directed against antigenic conformations of the Fab fragment linked to the integrin. Requires immediate platelet counts in the first hour after starting the continuous infusion.
• Transient hypotension and reflex bradycardia.