Platelet Action and Aspirin Mechanism

• Platelets play a critical role in thromboembolic diseases such as ischemic heart disease and stroke.
• Platelets stick to diseased or damaged areas, become activated, and expose phospholipids and GPIIb/IIIa receptors.

Platelet Action

• Platelets change to a stellate form when activated.
• Activated platelets synthesize and release TXA2 and ADP, which stimulate other platelets to aggregate, leading to fibrin formation and thrombosis.
• Platelet aggregation is inhibited by prostaglandin I₂.

Aspirin Mechanism

• Aspirin inhibits platelet aggregation by irreversibly inhibiting the COX1 enzyme, which reduces TXA2 production, resulting in decreased platelet aggregation.
• Low doses of aspirin (75-150 mg/day) reduce platelet TXA2 synthesis more than PGI2 in endothelial cells.

Aspirin Pharmacokinetics

• Aspirin is absorbed in the stomach.
• Aspirin's peak inhibitory effect occurs one hour after administration.
• Aspirin causes irreversible platelet inhibition for the remainder of their 7-day lifespan.

Aspirin Adverse Effects

• Aspirin can cause gastrointestinal ulceration and bleeding.
• Aspirin may cause allergic reactions.
• Some patients do not respond to aspirin (aspirin resistance).
• Aspirin causes irreversible platelet inhibition

Platelet ADP Receptor Blockers

• Ticlopedine and clopidogrel block platelet ADP.
• These drugs irreversibly block ADP (P2Y12 receptor antagonists) from binding to platelet receptors, preventing platelet aggregation.
• These drugs are pro-drugs that require activation in the liver.
• Ticlopidine has been linked to neutropenia and aplastic anemia as significant side effects; clopidogrel has a lower incidence of these effects.
• These drugs bind platelets irreversibly.

Platelet Glycoprotein IIb/IIIa Receptor Blockers

• Abciximab is a monoclonal antibody with the Fc region removed to avoid immunogenicity.
• Abciximab binds irreversibly to GPIIb/IIIa receptors, preventing fibrinogen from binding.
• These drugs are approved for use in patients undergoing percutaneous coronary intervention, unstable angina, and post-MI.

Dipyridamole

• Dipyridamole is a phosphodiesterase inhibitor.
• It boosts intracellular cyclic AMP, which reduces TXA2 synthesis and enhances prostacyclin's effect on platelets, inhibiting platelet activity.
• It is not effective when used alone and should be used with aspirin.
• Dipyridamole decreases the risk of stroke.
• Dipyridamole, unlike aspirin, does not increase the risk of bleeding.

Fibrinolytic (Thrombolytic) Drugs

• Plasmin usually causes clot lysis when a fibrin clot forms.
• Fibrinolytic drugs rapidly activate plasminogen to form plasmin, but may also activate circulating and fibrin-bound plasminogen, breaking down protective hemostatic thrombi and pathogenic thromboembolic.

Streptokinase

• Streptokinase is a non-enzyme protein derived from streptococci cultures.
• It activates plasminogen to plasmin, resulting in nonspecific fibrinolysis.
• Hemorrhage, hypotension, and hypersensitivity are all possible side effects. Hemorrhage can be treated with tranexamic acid.

Urokinase

• Urokinase is now made in recombinant form from cultured kidney cells.
• Streptokinase and urokinase act on both circulating and fibrin-bound plasminogen, causing a generalized fibrinolytic state and bleeding.

Recombinant Tissue Plasminogen Activators (t-PAs)

• Includes Alteplase.
• These are the most specific for fibrin-bound plasminogen.
• They can cause hemorrhage, but it is less common than with streptokinase.

Therapeutic uses of thrombolytic drugs:

• These drugs treat acute myocardial infarction, ischemic stroke, and massive pulmonary embolism.
• In cases of acute MI, administer within 12 hours of onset, with maximum benefit obtained within 90 minutes of pain onset.
• They also treat strokes.

Contraindications to thrombolytic therapy

• Active internal bleeding
• Bleeding diatheses
• Pregnancy
• Uncontrolled hypertension
• Recent major surgery or eye surgery
• Recent hemorrhagic stroke

Platelets are crucial in thromboembolic diseases. Aspirin inhibits platelet aggregation by irreversibly inhibiting the COX1 enzyme, reducing TXA2 production. This leads to decreased platelet aggregation, making aspirin a key medication.