Anti-Platelet Drugs

ANTI-PLATELET DRUGS


ANTI-PLATELET DRUGS

Significance behind anti-platelet drugs:

Mechanism:

  • In arterial thrombi, platelets are main constituents.
  • 1st 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 prophylaxisAspirin most commonly used – Prevents arterial thrombosis.
  • CVS diseases & in artificial heart valvesDipyridamole + 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 αvβ3 receptor & αMβ2 receptor.
    • αvβ3 receptor binds vitronectin
    • αMβ2 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.
    • 1st 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.

Exam Important

ANTI-PLATELET DRUGS

  • Aspirin is a TXA2 synthesis inhibitor, used as anti-platelet drugs.
  • Clopidogrel & ticlopidine are irreversible antagonists of P2 Y12 receptors of ADP, used as anti-platelet drugs.
  • Abciximab, tirofiban, eptifibatide are Gp IIb/IIIa antagonists used as anti-platelet drugs.
  • For all anti-platelet drugs, bleeding is due to prolonged bleeding time, which is most common adverse effect.
  • Most serious adverse effect of antiplatelet drugs is Thrombocytopenia.
  • Aspirin is most commonly used for prophylaxis of MI & stroke, mainly prevents arterial thrombosis.
  • For CVS diseases & in artificial heart valvesDipyridamole + warfarin preferred.
  • Antiplatelet action of aspirin is exhibited only at its low doses (40-325mg).
  • Aspirin irreversibly inhibits COX enzyme, thus inhibits COX, resulting in inhibition of TXA2 & PGI2 synthesis.
  • Aspirin has nil effect on platelet survival time.
  • Aspirin inhibits only thromboxane synthesis but does not inhibit enzyme thromboxane synthetase.
  • Dazoxiben is a thromboxane synthetase enzyme inhibitor.
  • Irreversible antagonists of P2 Y12 receptors of ADP interfere with platelet activation by ADP & fibrinogen.
  • Drugs like ticlopidine, clopidogrel & prasugrel increase platelet survival time.
  • Ticlopidine causes severe neutropenia with absolute neutrophil count < 500/mL & thrombocytopenia.
  • Clopidogrel better tolerated than ticlopidine.
  • Ticlopidine & clopidogrel are prodrugs, activated by CYP2C19 enzyme in liver.
  • Prasugrel is a strong antiplatelet drug, which is faster acting than clopidogrel.
  • Gp IIb/IIIa antagonists like Abciximab, eptifibatide & tirofiban are strongest antiplatelet drugs.
  • Abciximab is a non-antigenic monoclonal antibody, which is an anti-platelet drug inhibiting Gp IIb/IIIa receptor.
  • Abciximab also inhibits  αvβ3 receptor & αMβreceptor.
  • αvβ3 receptor binds vitronectin.
  • αMβreceptor is a leucocyte integrin.
  • Abciximab is used in PTCA & cardiac transplants.
  • Phosphodiesterase-3 inhibitors includes dipyridamole & cilastazole.
  • Dipyridamole acts by inhibiting phosphodiesteraseincreasing cAMP & potentiating anti-aggregation factor like prostacyclin.
  • Cilostazol is useful itreatment of intermittent claudication.
  • Direct-acting & reversible P2 Y12 receptor antagonists like Ticagrelor & cangrelor are used as antiplatelet drugs.
  • Ticagrelor is orally effective antiplatelet drug.
  • Ticagrelor & cangrelor are more rapid onset & offset of action, provides greater & more predictable antiplatelet action.
  • Ticagrelor & cangrelor are the 1st new antiplatelet drug demonstrating greater reduction in CVS death in patients with acute coronary syndromes.
  • PAR-1 inhibitors act by inhibiting thrombin receptors on platelets called protease-activated receptor 1 (PAR-1).
  • Vorapaxar is a PAR-1 inhibitor used as an antiplatelet drug.
Don’t Forget to Solve all the previous Year Question asked on ANTI-PLATELET DRUGS

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