Aggrastat Mechanism of Action

Therapeutic Class: Aggrastat (tirofiban hydrochloride), a non-peptide antagonist of the platelet GP IIb/IIIa receptor, is a platelet aggregation inhibitor.
Pharmacology: Mechanism of Action: Platelet activation, adhesion and aggregation represent critical initiating steps in the formation of arterial thrombus overlying disrupted atherosclerotic plaque. Thrombus formation is central to the pathophysiology of the acute coronary ischemic syndromes of unstable angina and myocardial infarction, as well as to cardiac ischemic complications following coronary angioplasty.
Aggrastat is a non-peptide antagonist of the GP IIb/IIIa receptor, the major platelet surface receptor involved in platelet aggregation. Aggrastat prevents binding of fibrinogen to GP IIb/IIIa, thereby blocking the cross-linking of platelets and platelet aggregation.
Pharmacodynamics: Aggrastat causes potent inhibition of platelet function as demonstrated by its ability to inhibit ex vivo adenosine phosphate (ADP)-induced platelet aggregation and prolong bleeding time (BT) in healthy subjects and patients with coronary artery disease. The time course of inhibition parallels the plasma concentration profile of the drug. Following discontinuation of an infusion of Aggrastat, platelet function rapidly returns to baseline.
Coadministration of a 4-hour infusion of 0.15 μg/kg/min of Aggrastat and aspirin results in the anticipated near maximal inhibition of platelet aggregation and a modest additive effect of BT prolongation.
In patients with unstable angina, a two-staged intravenous infusion regimen of Aggrastat (loading infusion of 0.4 μg/kg/min for 30 minutes followed by 0.1 μg/kg/min for up to 48 hours in the presence of heparin and aspirin), produces approximately 90% inhibition of ex vivo ADP-induced platelet aggregation with a 2.9-fold prolongation of bleeding time during the infusion. Inhibition was achieved rapidly with the 30-minute loading infusion and was maintained over the duration of the infusion.
In patients in whom Aggrastat is initiated in the setting of coronary angioplasty, a two-staged intravenous infusion regimen of Aggrastat (loading bolus of 10 μg/kg over 5-minutes followed by a maintenance infusion of 0.15 μg/kg/min for 16 to 24 hours), administered in combination with heparin and aspirin, produces approximately >90% inhibition of ex vivo ADP-induced platelet aggregation in nearly all patients. Near maximal inhibition is achieved rapidly with the 5 minute bolus and is maintained over the duration of the infusion. Following discontinuation of the infusion of Aggrastat, platelet function returns rapidly to baseline.
Pharmacokinetics: Distribution: Tirofiban is not highly bound to plasma proteins and protein binding is concentration independent over the range of 0.01 to 25 μg/mL. Unbound fraction in human plasma is 35%. The steady state volume of distribution of tirofiban ranges from 22 to 42 liters. Tirofiban crosses the placenta in rats and rabbits.
Metabolism: Profiling of ¹⁴C-labeled tirofiban in urine and feces indicates that the radioactivity was accounted for mainly by unchanged tirofiban. Circulating plasma radioactivity is accounted for mainly by unchanged tirofiban (up to 10 hours postdose). These data suggest limited metabolism of tirofiban.
Elimination: Following an intravenous dose of ¹⁴C-labeled tirofiban in healthy subjects, 66% of radioactivity is recovered in the urine and 23% in the feces. Total radioactivity recovery is about 91%. Both urinary and biliary excretion contribute significantly to the elimination of tirofiban.
In healthy subjects, the plasma clearance of tirofiban ranges from 213 to 314 mL/min. Renal clearance accounts for 39 to 69% of plasma clearance. Half-life ranges from 1.4 to 1.8 hours.
In patients with coronary artery disease, the plasma clearance of tirofiban ranges from 152 to 267 mL/min. Renal clearance accounts for 39% of plasma clearance. Half-life ranges from 1.9 to 2.2 hours.
Tirofiban is excreted in rat milk.
Characteristics in Patients: Gender: Plasma clearance of tirofiban in patients with coronary artery disease is similar in males and females.
Elderly: Plasma clearance of tirofiban is about 19 to 26% lower in elderly (>65 years) patients with coronary artery disease compared to younger (≤65 years) patients.
Race: No difference in plasma clearance was detected in patients of different races.
Hepatic Insufficiency: In patients with mild to moderate hepatic insufficiency, plasma clearance of tirofiban is not significantly different compared to healthy subjects.
Renal Insufficiency: Plasma clearance of tirofiban is lower to a clinically significant extent (>50%) in patients with creatinine clearance <30 mL/min, including patients requiring hemodialysis (see Patients with Severe Renal Insufficiency under Dosage & Administration). Tirofiban is removed by hemodialysis.