Glycoprotein IIb/IIIa Inhibitors (Abciximab / Tirofiban)

Mechanism

Mechanism of Action

Abciximab and Tirofiban act by competitively blocking the most abundant platelet surface receptor: the heterodimeric integrin GPIIb/IIIa (also called α_IIbβ₃).

Molecular Mechanism of GP IIb/IIIa Integrin Blockade

1. After platelet cell activation triggered by any physiological agonist (collagen, thrombin, ADP, TXA2), an intracellular conformational change ("inside out") occurs that activates the integrin GPIIb/IIIa receptor molecules exposed on the platelet surface.
2. The active GPIIb/IIIa receptor binds specifically to the Arg-Gly-Asp (RGD) tripeptide sequence of plasma soluble fibrinogen or von Willebrand factor molecules.
3. This serves as a physical cross-linking link between adjacent platelets to consolidate the platelet thrombus.
4. Abciximab: It is a chimeric monoclonal antibody Fab fragment that binds almost irreversibly to the platelet receptor, sterically preventing the binding of potent adhesion ligands.
5. Tirofiban: It is a non-peptide synthetic derivative mimicking the amino acid tyrosine that acts as a competitive reversible inhibitor by reversibly occupying the RGD site of the active integrin.

Pharmacokinetics

Pharmacokinetics

• Rout 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 administered 10-60 minutes before initiating PCI, followed by continuous IV infusion of 0.125 µg/kg/min (maximum 10 µg/min) for a period of 12 hours post-procedure.
• Tirofiban: Rapid initial infusion of 25 µg/kg over 3 minutes, followed by a continuous maintenance infusion of 0.15 µg/kg/min for up to 18 to 24 hours. Renal adjustment: Reduce infusion clearance by half (0.075 µg/kg/min) if CrCl < 30 mL/min.

Pregnancy and Breastfeeding

FDA Category C. Safety data in pregnant women is lacking. Avoid use unless there is an incontrovertible direct clinical benefit to the mother.

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 (ADR)

• Hemorrhage: High risk of inducing major digestive 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.