Irreversible cyclooxygenase inhibitors

Agents

Acetylsalicylic acid (ASA, aspirin)

Mechanism of action

ASA covalently attaches an acetyl group to COX.

• Irreversible COX-1 inhibition → inhibition of thromboxane (TXA2) synthesis in platelets → inhibition of platelet aggregation (antithrombotic effect)
  • Onset of antiplatelet action: within minutes
  • Duration of antiplatelet action: 7–10 days
• Irreversible COX-1 and COX-2 inhibition → inhibition of prostacyclin and prostaglandin synthesis → antipyretic, anti-inflammatory, and analgesic effect
  • COX-2 is more resistant to inhibition than COX-1. Therefore, higher doses of aspirin are required to achieve the antipyretic, anti-inflammatory, and analgesic effects.

Effects

• Low dose (below 300 mg/day): inhibition of platelet aggregation
• Intermediate dose (300-2400 mg/day): antipyretic and analgesic effect
• High dose (2400-4000 mg/day): antiinflammatory effect

P2Y12 receptor antagonists

Agents

• Clopidogrel
  • Pro-drug
  • Activation is dependent on hepatic cytochrome P enzymes.
  • Not effective in individuals with genetic polymorphisms of CYP enzymes or drug-induced inhibition of CYP enzymes (e.g., cimetidine, amiodarone, omeprazole, etc.)
• Prasugrel
  • Pro-drug
  • Faster acting and more potent than clopidogrel
• Ticagrelor
  • Not a pro-drug
  • Orally administered direct antagonist of P2Y12 platelet receptor
  • Faster acting and more potent than clopidogrel
• Ticlopidine: irreversible P2Y12 receptor antagonist

Mechanism of action

• Inhibition of P2Y12 receptor on platelets (ADP receptor) → ↓ expression of Gp IIb/IIIa receptors on platelets → inhibition of platelet aggregation
  • ADP usually binds to P2Y12 receptors, leading to activation of Gp IIb/IIIa receptors and subsequent platelet aggregation.
  • Irreversible inhibition: clopidogrel, prasugrel, ticlopidine
  • Reversible inhibition: ticagrelor

Glycoprotein IIb/IIIa inhibitors

Agents

• Abciximab (Fab region fragments of monoclonal antibodies against glycoprotein IIb/IIIa receptors)
• Eptifibatide
• Tirofiban

Mechanism of action

• Gp IIb/IIIa inhibitors bind to and block glycoprotein IIb/IIIa receptors (fibrinogen receptor) on the surface of activated platelets → prevention of platelets binding to fibrinogen → inhibition of platelet aggregation and thrombus formation

Indication

• Prevention of thrombotic complications in high-risk patients with unstable angina/NSTEMI planned for PCI within 24 hours

Others

• Cilostazol
  • See Phosphodiesterase inhibitors#Phosphodiesterase type 3 inhibitor (PDE3 inhibitor)