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.