Anti-Thrombotic Agents: Antiplatelets

Anti-Thrombotic Agents Overview

• Anti-thrombotic agents include antiplatelets, anticoagulants, and thrombolytics.
• Antiplatelet drugs include plavix
• Anticoagulants include warfarin
• Thrombolytics include alteplase

Learning Objectives

• Understand the mechanism of action and side effects of anti-platelet agents.
• Differentiate between various classes of anti-platelet drugs, including COX-1 Inhibitors, PDE-3 inhibitors, P2Y (ADP) Antagonists, Glycoprotein IIb/IIIa receptor antagonists, and Thrombin Receptor (PAR-1) Antagonist.
• Identify clinical applications, contraindications, and drug interactions of key anti-platelet medications.

Anti-Thrombotic Drug Classes

• Anti-platelet drugs include Aspirin, Dipyridamole, Cilostazol, Clopidogrel, Prasugrel, Ticagrelor, Cangrelor, Abciximab, Eptifibatide, Tirofiban, Defibrotide, and Vorapaxar.
• Aspirin is a COX-1 inhibitor.
• Dipyridamole and Cilostazol are PDE3 inhibitors.
• Clopidogrel, Prasugrel, Ticagrelor and Cangrelor are ADP (P2Y) receptor antagonists.
• Abciximab, Eptifibatide, Tirofiban and Defibrotide are Glycoprotein IIb/IIIa receptor antagonists
• Vorapaxar is a Thrombin Receptor (PAR-1) antagonist.

Aspirin: COX-1 Inhibitor

• Aspirin reduces TXA2 production.
• Aspirin binds irreversibly to COX-1, an enzyme responsible for TXA2 production.
• Decreased TXA2 results in decreased platelet aggregation.
• The effect is profound because platelets cannot synthesize new enzyme molecules.
• Low doses of aspirin are more selective for COX-1, the main isoform in platelets
• Aspirin also inhibits prostacyclin (PGI2), which reduces platelet aggregation, but this effect is not as strong.

Aspirin - Mechanism of Action and Dose

• PGI2 is secreted by endothelial cells, which can synthesize new COX-1, unlike platelets.
• Low-dose aspirin does not effectively inhibit PGI2 synthesis.
• Low doses of aspirin have a selective effect on TxA2 levels, yielding a more profound effect on platelets than on endothelial cells.
• Aspirin is often used as an antiplatelet agent at a dose of 81 mg once daily to prevent arterial thrombosis, leading to transient ischemic attack, stroke, and myocardial infarction.

Aspirin - Clinical Applications

• Primarily used to prevent arterial thrombosis in patients with ischemic heart disease and stroke.
• Prevents myocardial infarction in patients with unstable angina.
• Prevents enlargement of a coronary thrombus and reduces the severity of cardiac damage in patients with recent myocardial infarction.
• Prevents an initial or subsequent stroke in patients with transient ischemic attacks (TIA).
• Prevents thrombosis in patients with artificial heart valves or undergoing percutaneous coronary angioplasty.
• Treats persons with peripheral arterial occlusive disease and chronic limb ischemia.

Aspirin - Adverse Effects

• Can cause bleeding, especially in the GI tract, due to inhibiting prostaglandin synthesis, which promotes bicarbonate and mucus secretion.
• High doses of aspirin and other salicylates have a direct hypoprothrombinemic effect, increasing the likelihood of overall bleeding.
• Other adverse effects include acute renal insufficiency, thrombocytopenia, hepatitis, angioedema, and Reye's syndrome.

Aspirin - Contraindications

• Bleeding disorders such as hemophilia, von Willebrand's disease, or immune thrombocytopenia.
• NSAID-induced sensitivity reactions.
• Children with chickenpox or flu-like syndromes.
• G6PD deficiency

Aspirin - Drug Interactions

• High doses can increase the risk of bleeding when coadministered with anticoagulant drugs.
• Coadministration with ammonium chloride or other urine acidifiers may lead to aspirin toxicity.
• Aspirin antagonizes the uricosuric effects of probenecid.
• Co-administration with aminoglycosides, cisplatin, erythromycin, vancomycin, and loop diuretics may potentiate ototoxic effects.

Dipyridamole: PDE-3 Inhibitor - Mechanism of Action

• Dipyridamole inhibits platelet aggregation by increasing cAMP formation.
• It also inhibits platelet adhesion to the vessel wall.
• It is a coronary vasodilator and a relatively weak antiplatelet drug.
• Cilostazol has the same mechanism.

Dipyridamole: PDE-3 Inhibitor - Use as Anti-Platelet

• It is used in combination with aspirin to prevent ischemic (thrombotic) stroke in persons who have previously had an athero-thrombotic stroke.
• A combination of aspirin and extended-release dipyridamole (aggrenox) may be superior to aspirin alone for stroke prevention.
• It is used in combination with warfarin for postoperative primary prophylaxis of thromboemboli in patients with a prosthetic heart valve.
• Cilostazole reduces symptoms of intermittent claudication.

ADP (P2Y) Receptor Antagonists - Overview

• Two categories: Thienopyridines and Non-thienopyridines

• Thienopyridines: Contain a sulfur-containing pyridine derivative

  • Bind irreversibly.
  • Duration of action reflects the lifespan of platelets.
  • Examples: Clopidogrel (Plavix) and Prasugrel (Effient)

• Non-thienopyridines (nucleoside analogues):

  • Mimic purine (adenosine).
  • Bind reversibly.
  • Drug effect stops quickly.
  • Faster recovery from side effects.
  • Examples: Ticagrelor (Brilinta) and Cangrelor (Kengreal)

• Mechanism of Action -Antagonists inhibit ADP receptors -Leads to reduced expression of platelet glycoprotein(GPIIb/IIIa) receptors -Leads to reduced fibrinogen binding and platelet aggregation

Clopidogrel - Characteristics and Metabolism

• A thienopyridine prodrug.
• It's an irreversible antagonist.
• Inhibits platelet function for the life of the platelet (longer duration of action: 3-5 days).
• Metabolism is affected by the patient's phenotype
• Effect of polymorphism on expression levels on Cyp 2C19 = Therapeutic levels may vary
• DDIs with PPIs, and other CYP2C19 inhibitors

Prasugrel

• Thienopyridine with similarities to clopidogrel.
• Differences when compared to clopidogrel:
  • More rapid onset of action.
  • Max inhibition achieved in 2-4 hours.
  • More potent.
  • Metabolism not affected by polymorphism.
  • More bleeding risk.
• Potential to cause rashes

Ticagrelor

• A non-thienopyridine.
• Much faster onset than Prasugrel.
• Cyp2C19 is not involved (as compared to clopidogrel).
• Long half-life: Parent drug: ~7 hours; active metabolite: ~9 hours.

Cangrelor

• A non-thienopyridine.
• It is a nucleoside (adenosine) triphosphate analogue.
• Clopidogrel: Cyp2C19 not involved
• Prasugrel: Faster onset
• Ticagrelor: More selective
• Administered intravenously only.
• Short half-life elimination: ~3 to 6 minutes
• Selective with no hangover effect.

ADP (P2Y) Receptor Antagonists - Comparison

Glycoprotein IIb/IIIa Receptor Antagonists - Mechanism of Action

• Includes Abciximab (ReoPro), Tirofiban (Aggrastat), Eptifibatide (Integrilin), and Defibrotide (Defitelio)
  • GP IIb/IIIa antagonists prevent binding and cross-linking of platelets by binding to platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptors.
  • Abciximab:
    • Is a chimeric mouse-human monoclonal antibody.
    • Binds with an irreversible manner.
  • Tirofiban and eptifibatide are competitive, reversible inhibitors

Glycoprotein IIb/IIIa Receptor Antagonists - Therapeutic Uses and Adverse Effects

• Used to prevent platelet aggregation and thrombosis in patients having percutaneous coronary interventions (PCI), including coronary angioplasty and stent placement (administered with aspirin and heparin or LMW heparin).
• Most common adverse effects: Bleeding, thrombocytopenia, hypotension, and bradycardia.
• All given IV

Vorapaxar: Thrombin Receptor (PAR-1) Antagonist

• Pyridine vinyl derivative.
• Antagonist at protease-activated receptor-1 (PAR-1).
• Has a different mechanism than other anti-platelet drugs.
• Inhibits thrombin-related platelet aggregation.

Vorapaxar: Pharmacokinetics

• Has overall good absorption and wide distribution.
• Elimination half-life (T1/2): 3 - 4 days (terminal elimination longer).
• The carbamate ester on the structure has the potential to hydrolyze during storage.
• Storage instructions:
  • Store in the original package.
  • Protect from moisture.
  • Keep the desiccant in the bottle