Antiplatelet and Fibrinolytic Drugs - Medical Lecture Notes PDF

Antiplatelet drugs  The role of platelets Platelets play a critical role in thromboembolic disease like ischemic heart disease and stroke Platelets adhere to the diseased or damaged areas and become activated, exposing phospholipids and GPIIb/IIIa receptors. Platelet...

Antiplatelet drugs  The role of platelets Platelets play a critical role in thromboembolic disease like ischemic heart disease and stroke Platelets adhere to the diseased or damaged areas and become activated, exposing phospholipids and GPIIb/IIIa receptors. Platelet change their shape to stellate form Activate platelets also synthesize and release mediators like TXA2 and ADP, which stimulate other platelets to aggregate and eventually fibrin formation and thrombosis. Platelet aggregation is inhibited by prostaglandin I2  1. Aspirin Mechanism of action: Aspirin inhibit platelet aggregation by: – Irreversible inhibition of COX1 enzyme → ↓ TXA2 → ↓ platelet aggregation. Low doses (75-150 mg/day) ↓ synthesis of platelet TXA2 more than PGI2 in endothelial cells. Pharmacokinetics Absorption of aspirin occurs in the stomach The peak inhibitory effect is one hour post- administration Aspirin produces the irreversible inhibition of platelets for the rest of their lifespan (7 days) Adverse effects: Risk of gastrointestinal ulceration and bleeding Allergic reactions Lack of response in some patients (aspirin resistance) The irreversible platelet inhibition  2. Blockers of platelet ADP receptors (Ticlopedine and clopidogrel) These drugs irreversibly inhibit the binding of ADP (P2Y12 receptor antagonists) to its receptors on platelets and, thereby, inhibit platelet aggregation They are pro-drugs that must be activated in the liver The most serious adverse effects associated with ticlopidine are neutropenia and aplastic anemia. Clopidogrel has fewer incidences of these effects. They bind irreversibly to platelets  3. Blockers of platelet glycoprotein IIb/IIIa receptors: (Abciximab) Abciximab is a monoclonal antibody with Fc region removed to prevent immunogenicity. It bind irreversibly to GPIIb/IIIa receptors and prevent its binding to fibrinogen. These drugs have been approved for use in patients undergoing percutaneous coronary intervention, for unstable angina, and for post-MI.  4. Dipyridamole It is a phosphodiaestrase inhibitor. It increases intracellular cyclic AMP, thus reducing TXA2 synthesizes and also potentiate the prostacyclin effect on platelets (inhibit platelet activity). It is ineffective when used alone; should be used with aspirin It reduces the risk of stroke. Unlike aspirin it does not increase the risk of bleeding  Fibrinolytic (thrombolytic) drugs  Fibrinolytic (thrombolytic) drugs Normally, when a fibrin clot is formed, Plasmin causes lysis of the clot. Fibrinolytic drugs cause rapid activation of plasminogen to form plasmin, but unfortunately, they may activate both fibrin-bound plasminogen and circulating plasminogen thus, both protective hemostatic thrombi and pathogenic thromboembolic are broken down (increase risk of bleeding).  Fibrinolytic (thrombolytic) drugs 1. Streptokinase: – Is a non –enzyme protein extracted from culture of streptococci – It activates plasminogen into plasmin causing nonspecific fibrinolysis – Adverse effects include: Hemorrhage can be treated with traneximic acid. Hypotension and hypersensitivity may also recorded 2. Urokinase: – the drug is now prepared in recombinant form from cultured kidney cells. – Streptokinase and urokinase act on both circulating plasminogen and fibrin-bound plasminogen causing a generalized fibrinolytic state (bleeding). 3. Recombinant tissue plasminogen activators (t-PAs):e. g. Alteplase – They are most specific to fibrin-bound plasminogen. – They can cause hemorrhage but less than streptokinase Therapeutic uses of thrombolytic drugs: Acute myocardial infarction, ischemic stroke, and massive pulmonary embolism. In cases of acute MI, they should be given within 12 h of onset (the maximum benefit is obtained if treatment is given within 90 minutes of the onset of pain). Early ischemic stroke (< 3 hours)  Contraindications to thrombolytic therapy 1. Active internal bleeding 2. Bleeding diatheses 3. Pregnancy 4. Uncontrolled hypertension 5. Recent major surgery or Eye surgery 6. Recent hemorrhagic stroke Good luck