Antiplatelet Drugs

Antiplatelet Drugs - Setting the Stage

• Hemostasis & Thrombosis: Platelets crucial for primary hemostasis; dysregulation leads to thrombosis.
• Platelet Plug Formation:
  • Adhesion (GPIb-vWF to collagen)
  • Activation & Release (TXA2, ADP)
  • Aggregation (GPIIb/IIIa crosslinking)
• Primary Drug Targets:
  • COX-1 (TXA2 synthesis)
  • P2Y12 Receptors (ADP action)
  • GPIIb/IIIa Receptors (Aggregation)

⭐ Thromboxane A2 (TXA2) is a potent platelet aggregator and vasoconstrictor, synthesized from arachidonic acid by COX-1 in platelets.

Antiplatelet Drugs - Aspirin's Reign

• Mechanism: Irreversibly acetylates & inhibits COX-1 → ↓ Thromboxane A2 (TXA2) → ↓ platelet aggregation.
• Duration: Effect lasts for platelet lifespan (7-10 days).
• Dose (Antiplatelet): Low dose, 75-150 mg daily.
• Key Uses:
  • MI & stroke prophylaxis/treatment.
  • TIA prevention.
• Adverse Effects:
  • GI upset/bleeding.
  • Aspirin-induced asthma.
  • ⚠️ Reye's syndrome (children with viral illness).

⭐ Aspirin's antiplatelet effect is due to irreversible acetylation of a serine residue on COX-1, lasting for the platelet's lifespan (7-10 days).

Antiplatelet Drugs - P2Y12 Blockers

Block ADP binding to P2Y12 platelet receptor → ↓platelet activation/aggregation. Crucial in DAPT with Aspirin.

• Thienopyridines (Irreversible, Prodrugs)
  • Clopidogrel: CYP2C19 activation needed. Load: 300-600 mg; Maint: 75 mg OD. 📌 "ClOPidogrel needs Cytochrome P enzymes."
  • Prasugrel: Potent, faster onset. Contra: TIA/stroke. Load: 60 mg; Maint: 10 mg OD.
  • Ticlopidine: Older, more SE (neutropenia, TTP).
• Non-Thienopyridines (Reversible)
  • Ticagrelor: Direct-acting. Load: 180 mg; Maint: 90 mg BD. Dyspnea common.

    ⭐ Ticagrelor is a reversible, direct-acting P2Y12 inhibitor that does not require metabolic activation, unlike clopidogrel and prasugrel.

  • Cangrelor: IV, rapid on/off. PCI use.

Uses: ACS, PCI, stroke prevention. Main AE: Bleeding; TTP (rare).

Antiplatelet Drugs - Final Pathway Blockers

• Glycoprotein (GP) IIb/IIIa inhibitors: Block the final common pathway of platelet aggregation, preventing fibrinogen binding.
• Agents (IV only):
  • Abciximab (monoclonal antibody)
  • Eptifibatide (peptide)
  • Tirofiban (non-peptide)
• Use: High-risk acute coronary syndromes (ACS), percutaneous coronary intervention (PCI).
• Side Effects: Bleeding, thrombocytopenia.

⭐ Abciximab, a chimeric monoclonal antibody against GP IIb/IIIa, can cause profound and long-lasting platelet inhibition and carries a risk of thrombocytopenia.

• 📌 Abciximab, Eptifibatide, Tirofiban = AETiology of no clots!

Antiplatelet Drugs - Diverse Mechanisms

• Dipyridamole: PDE inhibitor (↑cAMP); inhibits adenosine uptake. Used with aspirin.
• Cilostazol: Selective PDE3 inhibitor (↑cAMP). For intermittent claudication.

  ⭐ Cilostazol, a PDE3 inhibitor used for intermittent claudication, is contraindicated in patients with heart failure of any severity due to increased mortality risk.

• Epoprostenol (PGI₂): Prostacyclin analog (↑cAMP). Potent vasodilator; for PAH, dialysis.
• Vorapaxar: PAR-1 antagonist (thrombin receptor). Blocks thrombin-induced platelet activation.

High‑Yield Points - ⚡ Biggest Takeaways

• Aspirin irreversibly inhibits COX-1, reducing Thromboxane A2 (TXA2) and platelet aggregation.
• P2Y12 inhibitors: Clopidogrel & Prasugrel (prodrugs, irreversible), Ticagrelor (not prodrug, reversible).
• Clopidogrel efficacy reduced by CYP2C19 polymorphisms; Prasugrel contraindicated in TIA/stroke.
• GPIIb/IIIa inhibitors (e.g., Abciximab) are most potent, blocking the final aggregation step.
• Cilostazol, a PDE3 inhibitor, treats intermittent claudication via vasodilation and antiplatelet effects.
• Primary risk for all antiplatelets: Increased bleeding.