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Tuesday, August 19, 2025

Antiplatelet agents


Introduction

Antiplatelet agents are drugs that reduce platelet activation and aggregation, thereby inhibiting thrombus formation in the arterial circulation. Unlike anticoagulants, which primarily interfere with the coagulation cascade, antiplatelets work on the platelet phase of hemostasis.

They are essential in the prevention and treatment of cardiovascular and cerebrovascular diseases, particularly myocardial infarction (MI), stroke, peripheral arterial disease (PAD), and after percutaneous coronary interventions (PCI) with stent placement.

The development of antiplatelet therapy has been pivotal in reducing morbidity and mortality from atherothrombotic events.

Classification of Antiplatelet Agents

1. Cyclooxygenase (COX) Inhibitors

  • Aspirin (acetylsalicylic acid)

2. P2Y12 Receptor Inhibitors (ADP Receptor Blockers)

  • Thienopyridines (irreversible inhibitors): Clopidogrel, Prasugrel, Ticlopidine

  • Cyclopentyltriazolopyrimidines (reversible inhibitors): Ticagrelor, Cangrelor (IV)

3. Glycoprotein IIb/IIIa (GPIIb/IIIa) Receptor Antagonists

  • Abciximab

  • Eptifibatide

  • Tirofiban

4. Phosphodiesterase (PDE) Inhibitors

  • Dipyridamole

  • Cilostazol

5. Thromboxane A2 Receptor Antagonists (under research)

  • Terutroban (experimental, not in routine use)

Mechanisms of Action

  • Aspirin: Irreversibly inhibits COX-1 in platelets → prevents thromboxane A2 synthesis → reduced platelet aggregation.

  • P2Y12 inhibitors: Block ADP-mediated activation of P2Y12 receptors on platelets → inhibit GPIIb/IIIa receptor activation → prevent platelet cross-linking by fibrinogen.

  • GPIIb/IIIa antagonists: Directly block the final common pathway of platelet aggregation by preventing fibrinogen binding.

  • PDE inhibitors: Increase cAMP and cGMP levels in platelets → reduce platelet activation; also cause vasodilation.

Clinical Uses

1. Primary prevention

  • Selected high-risk patients (diabetes, high cardiovascular risk, but not universally recommended).

2. Secondary prevention

  • After myocardial infarction (aspirin, clopidogrel, dual therapy in some cases).

  • After ischemic stroke or transient ischemic attack (TIA).

  • After PCI with stent placement (dual antiplatelet therapy with aspirin + a P2Y12 inhibitor).

3. Acute coronary syndromes (ACS)

  • Aspirin + clopidogrel/prasugrel/ticagrelor for unstable angina, NSTEMI, STEMI.

  • GPIIb/IIIa inhibitors used as adjuncts in PCI for high-risk cases.

4. Peripheral arterial disease (PAD)

  • Cilostazol for claudication.

  • Aspirin or clopidogrel to prevent ischemic events.

5. Stroke prevention

  • Aspirin or clopidogrel for ischemic stroke and TIA.

  • Aspirin + dipyridamole combination in some cases.

Dosage Examples

  • Aspirin: 75–325 mg orally once daily (most commonly 81–100 mg daily for cardiovascular prevention).

  • Clopidogrel: Loading dose 300–600 mg orally, then 75 mg daily.

  • Prasugrel: Loading dose 60 mg orally, then 10 mg daily.

  • Ticagrelor: Loading dose 180 mg orally, then 90 mg twice daily.

  • Cangrelor: IV infusion, 30 µg/kg bolus followed by 4 µg/kg/min during PCI.

  • Abciximab: IV bolus 0.25 mg/kg, followed by 0.125 µg/kg/min infusion during PCI.

  • Eptifibatide: IV bolus 180 µg/kg, followed by 2 µg/kg/min infusion.

  • Tirofiban: IV bolus 25 µg/kg, followed by 0.15 µg/kg/min infusion.

  • Dipyridamole: 200 mg extended-release orally twice daily (often combined with aspirin).

  • Cilostazol: 100 mg orally twice daily.

Contraindications

  • Aspirin: Hypersensitivity, active peptic ulcer, bleeding disorders, children (Reye’s syndrome risk).

  • Clopidogrel/Prasugrel/Ticagrelor: Active bleeding, history of intracranial hemorrhage, severe hepatic impairment.

  • Prasugrel: Contraindicated in patients with history of stroke or TIA.

  • GPIIb/IIIa inhibitors: Severe thrombocytopenia, active bleeding, history of hemorrhagic stroke.

  • Dipyridamole: Severe hypotension, unstable angina.

  • Cilostazol: Heart failure (contraindicated due to increased mortality risk).

Adverse Effects

  • Aspirin: Dyspepsia, gastric ulcer, GI bleeding, hypersensitivity reactions, tinnitus (high doses).

  • Clopidogrel: Bleeding, diarrhea, rare thrombotic thrombocytopenic purpura (TTP).

  • Prasugrel: Higher bleeding risk than clopidogrel.

  • Ticagrelor: Dyspnea, ventricular pauses, bleeding.

  • Cangrelor: Bleeding, transient dyspnea.

  • GPIIb/IIIa inhibitors: Severe bleeding, thrombocytopenia, hypotension.

  • Dipyridamole: Headache, dizziness, hypotension.

  • Cilostazol: Headache, palpitations, diarrhea, contraindicated in heart failure.

Precautions

  • Bleeding risk: Monitor for GI bleeding, intracranial hemorrhage, especially when combined with anticoagulants.

  • Drug metabolism: Clopidogrel is a prodrug requiring CYP2C19 activation—poor metabolizers may have reduced efficacy.

  • Renal impairment: Adjust doses for eptifibatide and tirofiban.

  • Elderly patients: Higher bleeding risk with prasugrel; avoid if ≥75 years unless high thrombotic risk.

  • Perioperative management: Discontinue clopidogrel, prasugrel, ticagrelor 5–7 days before elective surgery (unless stent-dependent).

Drug Interactions

  • Aspirin: Additive bleeding risk with NSAIDs, anticoagulants, SSRIs.

  • Clopidogrel: Reduced effect with proton pump inhibitors (omeprazole, esomeprazole) due to CYP2C19 inhibition.

  • Ticagrelor: Increased bleeding risk with strong CYP3A4 inhibitors (ketoconazole, clarithromycin).

  • GPIIb/IIIa inhibitors: Increased bleeding risk with heparin, thrombolytics, or warfarin.

  • Dipyridamole: Enhances effects of other antiplatelets and anticoagulants.

  • Cilostazol: Metabolized by CYP3A4 and CYP2C19; interactions with inhibitors (e.g., diltiazem, omeprazole).

Combination Therapy (Dual and Triple Therapy)

  • Dual Antiplatelet Therapy (DAPT): Aspirin + a P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor). Standard after PCI and in ACS.

  • Triple Therapy: Aspirin + P2Y12 inhibitor + oral anticoagulant (for atrial fibrillation patients with stents). Must be balanced due to high bleeding risk.

Monitoring

  • CBC and platelet counts (with GPIIb/IIIa inhibitors).

  • Bleeding signs (GI, intracranial, mucosal).

  • Drug-specific testing: VerifyNow P2Y12 assay can measure clopidogrel responsiveness in selected cases.

Comparative Efficacy

  • Aspirin: First-line, cornerstone of therapy for secondary prevention.

  • Clopidogrel: Standard alternative or adjunct to aspirin; variable response due to genetics.

  • Prasugrel: More potent, faster onset than clopidogrel, but higher bleeding risk.

  • Ticagrelor: Reversible, rapid effect, superior to clopidogrel in ACS but associated with dyspnea.

  • GPIIb/IIIa inhibitors: Powerful IV therapy for PCI, but reserved for high-risk cases due to bleeding.

  • Dipyridamole + aspirin: Stroke prevention combination.

  • Cilostazol: Best for PAD symptom relief (claudication).




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