Significance behind anti-platelet drugs:
- 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:
- 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).
- MI & stroke prophylaxis – Aspirin most commonly used – Prevents arterial thrombosis.
- CVS diseases & in artificial heart valves – Dipyridamole + warfarin preferred.
Individual drug description:
- 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.
- For PDA treatment.
- Adverse effects:
- Therapeutic doses cause hyperuricemia.
- High doses cause uricosuria.
- Aspirin inhibits only thromboxane synthesis (but not enzyme thromboxane synthetase)
- Dazoxiben – Thromboxane synthetase enzyme inhibitor.
2. Irreversible antagonists of P2 Y12 receptors of ADP:
- Ticlopidine, clopidogrel & Prasugrel.
- 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.
- Ticlopidine causes severe neutropenia.
- 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.
- Strong antiplatelet drug.
- Faster acting than clopidogrel.
3. Gp IIb/IIIa antagonists:
- Strongest antiplatelet drugs – Abciximab, eptifibatide & tirofiban.
- Blocks platelet aggregation induced by all agonists.
- Non-antigenic monoclonal antibody.
- Platelet-bound abciximab has long half-life.
- 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.
- In PTCA & cardiac transplants.
- Eptifibatide & tirofiban:
- Specific for GpIIb/IIIa.
4. Phosphodiesterase-3 inhibitors:
- Acts byinhibiting phosphodiesterase (which breaks down cAMP) –> Increased cAMP –> potentiating prostacyclins –> anti-aggregation.
- Drug effects: Increases platelet survival time.
- 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:
- Inhibits thrombin receptors on platelets called protease-activated receptor 1 (PAR-1).
- 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.
- 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 valves, Dipyridamole + 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 & αMβ2 receptor.
- αvβ3 receptor binds vitronectin.
- αMβ2 receptor is a leucocyte integrin.
- Abciximab is used in PTCA & cardiac transplants.
- Phosphodiesterase-3 inhibitors includes dipyridamole & cilastazole.
- Dipyridamole acts by inhibiting phosphodiesterase, increasing cAMP & potentiating anti-aggregation factor like prostacyclin.
- Cilostazol is useful in treatment 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.