Anti-Platelet Drugs

ANTI-PLATELET DRUGS

Significance behind anti-platelet drugs:

Mechanism:

• In arterial thrombi, platelets are main constituents.
• 1^st platelets stick to damaged blood vessel wall → causing aggregation → Mainly releases ADP, TXA₂, serotonin → Activates Gp IIb/IIIa receptors on platelet surface → Promotes further aggregation.
• Every step of these can be inhibited to achieve anti-platelet properties.      

Important drug groups:

• TXA₂ synthesis inhibitor:
  • Aspirin
• Irreversible antagonists of P₂ Y₁₂ receptors of ADP:
  • Clopidogrel & ticlopidine.
• Gp IIb/IIIa antagonists:
  • Abciximab, tirofiban, eptifibatide.

General adverse effects:

• Bleeding (all antiplatelet drugs) – Due to prolonged bleeding time.
• Thrombocytopenia (most serious).

General indications:

• MI & stroke prophylaxis – Aspirin most commonly used – Prevents arterial thrombosis.
• CVS diseases & in artificial heart valves – Dipyridamole + warfarin preferred.

Individual drug description:

1. Aspirin:

• Antiplatelet action – 
  • Only exhibited at lower doses (40-325mg).
  • Due to irreversible inhibition of COX enzyme –> Thus, inhibition of COX –> Causes inhibition of TXA₂ & PGI₂ synthesis.
  • PGI₂: Anti-aggregatory properties.
  • TXA₂: Platelet aggregator.
  • No effect on platelet survival time & their adhesion to vessel wall.
• Uses: 
  • For PDA treatment.
• Adverse effects:
  • Therapeutic doses cause hyperuricemia.
  • High doses cause uricosuria.

Note:

• Aspirin inhibits only thromboxane synthesis (but not enzyme thromboxane synthetase)
• Dazoxiben – Thromboxane synthetase enzyme inhibitor.

2. Irreversible antagonists of P₂ Y₁₂ receptors of ADP:

• Drugs:
  • Ticlopidine, clopidogrel & Prasugrel.
• MOA:
  • Interferes with platelet activation by ADP & fibrinogen.
• Drug effects (overall):
  • Increases platelet survival time.
• Adverse effect:
  • Ticlopidine causes severe neutropenia.
    • Absolute neutrophil count < 500/mL & thrombocytopenia.
    • Hence, less commonly used.
  • Gastrointestinal effects (Most common).  
  • Clopidogrel better tolerated.
• Contraindications:
  • Avoided in elderly patients (>75 years old) – Higher risk of fatal bleeding.
  • In stroke.
• Ticlopidine & clopidogrel:
  • Are prodrugs.
  • Converted to active metabolites in liver by CYP₂C₁₉.
• Note on CYP₂C₁₉:
  • Genetic polymorphisms in CYP₂C₁₉ enzyme affects antiplatelet action of these drugs.
  • Proton pump inhibitors (omeprazole) inhibits CYP2C19.
  • Prevents drug activation -=> Decreases antiplatelet effect.
• Prasugrel:
  • Strong antiplatelet drug.
  • Faster acting than clopidogrel.

3. Gp IIb/IIIa antagonists:

• Strongest antiplatelet drugs – Abciximab, eptifibatide & tirofiban.
• MOA:
  • Blocks platelet aggregation induced by all agonists.
• Abciximab:
  • Non-antigenic monoclonal antibody.
  • Platelet-bound abciximab has long half-life.
• MOA:
  • Inhibits Gp IIb/IIIa receptor.
  • Also inhibits α_vβ₃ receptor & α_Mβ₂ receptor.
  • α_vβ₃ receptor binds vitronectin
  • α_Mβ₂ receptor – A leucocyte integrin.
  • This results in anti-inflammatory & anti-proliferative properties.
• Uses:
  • In PTCA & cardiac transplants.
• Eptifibatide & tirofiban:
  • Specific for GpIIb/IIIa.

4. Phosphodiesterase-3 inhibitors:

• Dipyridamole:
• MOA: 
  • Acts byinhibiting phosphodiesterase (which breaks down cAMP) –> Increased cAMP –> potentiating prostacyclins –> anti-aggregation.
  • Drug effects: Increases platelet survival time.
• Cilastazol:
• MOA: 
  • Inhibits phosphodiesterase-3 –> Elevates cAMP levels –> Reduces platelet aggregation.
  • Possess peripheral vasodilatory action.
  • Useful in treatment of intermittent claudication.

NEWER ANTI-PLATELET DRUGS:

• Used in advanced stages of development.
• Two groups –

1. Direct-acting & reversible P₂ Y₁₂ receptor antagonists:

• Ticagrelor & cangrelor.
  • Ticagrelor – Orally effective.
  • Cangrelor – Intravenous.
• Effectiveness on comparison to clopidogrel:
  • Produces greater & more predictable antiplatelet action.
  • More rapid onset & offset of action.
  • 1^st new antiplatelet drug demonstrating greater reduction in CVS death in patients with acute coronary syndromes.

2. PAR-1 inhibitors:

• MOA: 
  • Inhibits thrombin receptors on platelets called protease-activated receptor 1 (PAR-1).
• Drugs:
  • Vorapaxar – Orally active.
  • Used in patients with history of MI or peripheral artery disease.

OTHER ANTI-PLATELET DRUGS:

• Gliclazide – Anti-diabetic drug with mild anti-platelet action.

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