Antiplatelets and Fibrinolytics PDF

Antiplatelets By Neimat Yassin  Blockers of platelet ADP receptors: (Ticlopedine, clopidogrel, prasugrel) ▪ These drugs irreversibly inhibit the binding of ADP to its receptors on platelets and, thereby, inhibit the activation of the glycoprotein IIb/IIIa receptors required f...

Antiplatelets By Neimat Yassin  Blockers of platelet ADP receptors: (Ticlopedine, clopidogrel, prasugrel) ▪ These drugs irreversibly inhibit the binding of ADP to its receptors on platelets and, thereby, inhibit the activation of the glycoprotein IIb/IIIa receptors required for platelets to bind to fibrinogen and to each other. ▪ Clopidogrel is approved for prophylaxis of thrombosis in both cerebrovascular and cardiovascular disease (e.g. coronary artery disease, coronary angioplasty, peripheral vascular disease, etc.). ▪ The maintenance dose is 75 mg/d orally. ▪ Clopidogrel is a prodrug, and its therapeutic efficacy relies entirely on its active metabolite. ▪ Ticlopedine has been largely replaced by clopedogrel because of serious adverse effects (neutropenia and bleeding). Clopidogrel has fewer incidence of these effects.  Blockers of platelet glycoprotein IIb/IIIa receptors: (Abciximab, eptifibatide, tirofiban) ▪ Activation of this receptor complex is the “final common pathway” for platelet aggregation and binding with fibrinogen. ▪ Abciximab a monoclonal antibody that binds to gpIIb/IIIa and blocks binding of platelets to fibrinogen. ▪ Eptifibatide, Tirofiban peptides that competitively blocks gpIIb/IIIa receptor.  Dipyridamole ▪ Dipyridamole inhibits phosphodiesterase (PDE) enzyme → ↑ cGMP → VD and inhibition of platelet activity. It also inhibits uptake of adenosine into platelets and RBCs leading to extracellular accumulation and prolongation of its action. ▪ The use of dipyridamole as an antithrombotic agent is limited to prophylaxis (combined with warfarin) in patients with prosthetic (mechanical) heart valves.  Aspirin ▪ Aspirin inhibit platelet aggregation by: – Irreversible inhibition of COX enzyme → ↓ TXA2 → ↓ platelet aggregation. – Irreversible acetylation of platelet cell membranes → ↓ platelet adhesions. ▪ At higher doses (> 325 mg/day), aspirin may decrease endothelial synthesis of PGI2, which inhibits platelet activity. Low doses (75-150 mg/day) ↓ synthesis of platelet TXA2 more than PGI2 in endothelial cells and avoid this effect. ▪ Other NSAIDs do not have comparable antithrombotic activity.  Fibrinolytic drugs ▪ Normally, when a fibrin clot is formed, plasminogen gets in contact with this clot and becomes activated into plasmin by the help of naturally occurring tissue plasminogen activators (t-PAs). Plasmin causes lysis of the clot. ▪ These endogenous activators preferentially activate plasminogen that is bound to fibrin, which (in theory) confines fibrinolysis to the formed thrombus and avoids systemic activation. ▪ 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 thromboemboli are broken down (→ risk of bleeding).  Streptokinase ▪ Streptokinase is a protein (not an enzyme) that is isolated from streptococci; it activates plasminogen into plasmin. ▪ It may be antigenic (causes allergy) in some people. Urokinase ▪ Urokinase is a protease originally isolated from urine; the drug is now prepared in recombinant form from cultured kidney cells. ▪ It is less antigenic than streptokinase. Recombinant tissue plasminogen activators (t-PAs): (Alteplase, reteplase, and tenecteplase) ▪ They are most specific to fibrin-bound plasminogen; local activation of plasmin at the thrombus site reduces the incidence of systemic bleeding. ▪ Reteplase and tenecteplase have long half-life. ▪ The long half-life permits administration as a bolus i.v. injection rather than by continuous infusion. (two injections i.v. separated by 30 minutes for reteplase, one single i.v. injection for tenecteplase). ▪ https://youtu.be/a_eikNB9Bf4?si=w5d6Zw4NKN91YDEO  Therapeutic uses of thrombolytic drugs ▪ Acute myocardial infarction, ischemic stroke, pulmonary embolism, and arterial thrombosis. ▪ 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. Adverse effects of thrombolytic drugs – Systemic bleeding is the major adverse effect. The risk is low with recombinant tissue plasminogen activators. – Streptokinase can cause allergy, fever, and hypotension.  DRUGS USED IN BLEEDING DISORDERS (HEMOSTATIC AGENTS) Systemic agents – Vitamin K: essential for synthesis of factors II, VII, IX, X by the liver. – Vitamin C and rutin: preserve the integrity of the vascular wall. – Fresh blood or plasma transfusion: as sources of coagulation factors. – Plasma fractions: – Thromboplastin (factor III): prepared from mammalian tissues. – Antihemophilic globulin (factor VIII): given in hemophilia A. – Calcium (factor IV): as a coagulation factor. – Aminocaproic acid and tranexamic acid: inhibitors of fibrinolytic system. – Ethamsylate (Dicynone): given i.m. to reduce capillary bleeding.  Local agents – Physical methods: application of pressure, cooling or heat coagulation. – Vasoconstrictor drugs: e.g. adrenaline nasal pack in epistaxis. – Thrombin and thromboplastin: as powders. – Fibrin and fibrinogen: available as dried sheets and used in surgery. – Sclerosing agents: chemicals that cause thrombosis in veins and permanent obliteration, e.g. ethanolamine oleate (given i.v. for varicose veins).