• Overview: antithrombotic agents
  • Regulation of platelet function -- Three types of substances:
    1. Substances developed outside the platelet but interacts with platelet membrane receptors:
       •   catecholamines
       •   collagen
       •   thrombin
       •   prostacyclin
    2. Agents generated internal to the platelet and interact with membrane receptors:
       •   ADP
       •   prostaglandin D₂
       •   prostaglandin E₂
       •   serotonin
    3. Agents generated internal to the platelet and interact within the platelet:
       • prostaglandin endoperoxidases
       • thromboxane A₂
       •   cAMP
       •   cGMP
       •   Ca²⁺

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  • Pharmacological Targets:antithrombotic agents
    • Inhibition of prostaglandin metabolism: aspirin
    • inhibition of ADP-induced platelet aggregation: ticlopidine
    • blockade of GP IIb/IIIa platelet membrane glycoprotein receptors: abciximab(ReoPro)& integrelin

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• Aspirin:
  • Mechanism of Action:aspirin
    • Prostaglandin thromboxane A2 (arachidonate product) causes:
      • platelet aggregation
      • platelet shape changing
      • platelet degranulation
    • nhibition of this process inhibits platelet aggregation, prolonging in vivo bleeding time
    • Aspirin inhibits thromboxane A₂ synthesis by:
      • irreversible acetylation of cyclooxygenase
      • new cyclooxygenase cannot be synthesize during the 10-day lifespan of the platelet
      • Other cyclooxygenase inhibitors are reversible and therefore have shorter duration of action, e.g. other salicylates & other nonsteroidal anti-inflammatory drugs

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  • Clinical Use --antithrombotic effects
    • Possible primary prophylaxis of myocardial infarction
    • FDA approval for this indication
  •  Adverse Effects:aspirin
    • increased gastrointestinal bleeding
    • increased frequency of peptic ulcer disease.
• Dietary:antithrombotic effects
  • unsaturated fatty acid eicosapentaenoic acid -- generates prostaglandin I₃ and thromboxane A₃, anti-aggregation agents

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• Ticlopidine:
  • Inhibits ADP platelet pathway: reduces platelet aggregation
  • no effect on prostaglandin metabolism
  • Clinical Use-Ticlopidine: Efficacy in prevention:
    •   completed strokes
    •   unstable angina
    •   transient ischemic attacks
  •  Adverse Effect:ticlopidine
    •   gastrointestinal disturbance: frequency = 20%
    • hemorrhage: frequency = 5%
    •  leukopenia (serious): frequency: = 1%
      • requires blood testing during first three months of ticlopidine treatment

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• Blockade of GP IIb/IIIa platelet membrane glycoprotein receptors: abciximab, integrelin
  • Abciximab:(ReoPro)
    • mouse/human chimeric monoclonal antibody blocking IIb/IIIa receptors
    • Clinical Use:abciximab
      • adjunctive treatment in high-risk angioplasty and atherectomy

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