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Anticoagulant, antithrombotic and anti platelet drugs


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Anticoagulant, antithrombotic and anti platelet drugs

  1. 1. Anticoagulant, Antithrombotic and Anti-Platelet Drugs
  2. 2. Clinical Thrombosis <ul><li>>2.5 million cases of deep venous thrombosis (DVT) per year </li></ul><ul><li>>600,000 cases of pulmonary embolism (PE) per year </li></ul><ul><li>>50,000 deaths per year from PE </li></ul><ul><li>PE contributes to another 150,000 deaths per year </li></ul><ul><li>> 11,000 postsurgical PE deaths per year </li></ul>
  3. 3. Indications For Antithrombotic Therapy <ul><li>Venous thromboembolic disease </li></ul><ul><ul><li>Deep venous thrombosis (DVT) </li></ul></ul><ul><ul><li>Pulmonary embolism (PE) </li></ul></ul><ul><ul><li>Primary prophylaxis of DVT or PE </li></ul></ul><ul><li>Arterial thromboembolic disease </li></ul><ul><ul><li>Prosthetic heart valves </li></ul></ul><ul><ul><li>Mitral valve disease, especially with atrial fibrillation </li></ul></ul><ul><ul><li>Congestive cardiomyopathies, especially with atrial fibrillatio </li></ul></ul><ul><ul><li>Atrial fibrillation </li></ul></ul><ul><ul><li>Mural cardiac thrombi </li></ul></ul><ul><ul><li>Transient ischemic attacks </li></ul></ul><ul><ul><li>Stroke in evolution </li></ul></ul><ul><li>Disseminated intravascular coagulation </li></ul><ul><li>Maintenance of patency of vascular grafts, shunts, bypasses </li></ul>
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  11. 11. Recombinant Human Activated Protein C <ul><li>Drotrecogin alfa (activated)- Xigris </li></ul><ul><li>Indicated for Severe Sepsis in Adults with Acute Organ Dysfunction with High Risk of Death </li></ul><ul><li>Reduction in Death as Primary End Point </li></ul><ul><li>Antithrombotic, Antiinfammatory, Profibrinolytic Properties </li></ul><ul><li>Serious Bleeding is Major Side Effect </li></ul>
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  20. 20. Antithrombin III Inhibits the Following Serine Proteases <ul><li>Coagulation </li></ul><ul><li>Factor XIIa </li></ul><ul><li>Factor XIa </li></ul><ul><li>Factor IXa </li></ul><ul><li>Factor Xa </li></ul><ul><li>Thrombin </li></ul><ul><li>Fibrinolysis </li></ul><ul><li>Plasmin </li></ul>Inhibitory activity against all these enzymes is substantially accelerated by heparin
  21. 21. Heparin <ul><li>Heterogeneous; 3,000-30,000 d </li></ul><ul><li>Average=15,000 d (~45monosaccharide chains) </li></ul><ul><li>About 1/3 of dose binds to AT III </li></ul><ul><li>To form the AT III:Heparin:Clotting Factor Complex- requires at least 18 saccarides except </li></ul><ul><li>Unique high affinity pentasaccaride heparin sequences catalyze inhibition of Xa by AT </li></ul>
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  23. 23. Anticoagulant Properties of Heparin <ul><li>Inhibits the thrombin-mediated conversion of fibrinogen to fibrin </li></ul><ul><li>Inhibits the aggregation of platelets by thrombin </li></ul><ul><li>Inhibits activation of fibrin stabilizing enzyme </li></ul><ul><li>Inhibits activated factors XII, XI, IX, X and II </li></ul>
  24. 24. Heparin <ul><li>Biologic Sources </li></ul><ul><li>Bioavailability </li></ul><ul><li>Metabolism </li></ul><ul><li>Elimination </li></ul><ul><li>Side Effects </li></ul><ul><li>Overdose </li></ul><ul><li>Contraindications </li></ul><ul><li>Pregnancy- YES </li></ul>
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  26. 26. Unfractionated Heparin <ul><li>High Dose </li></ul><ul><ul><li>Treatment of venous/arterial thrombi </li></ul></ul><ul><ul><li>Requires monitoring </li></ul></ul><ul><ul><li>IV- 5,000 Units bolus, then 30,000-35,000 units/24 hrs </li></ul></ul><ul><ul><li>80 Units/kg bolus, then 18 Units/kg/hr to maintain aPTT in therapeutic range </li></ul></ul>
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  28. 28. Monitoring of Anticoagulant Therapy <ul><li>Heparin </li></ul><ul><li>s.q. – no monitoring required </li></ul><ul><li>i.v. - partial thromboplastin time (P.T.T.) </li></ul><ul><li>*daily or more frequent if PTT varies </li></ul><ul><li>mechanism – measures intrinsic pathway </li></ul><ul><li>therapeutic goal – 2-2.5 times normal control value (-30 sec) </li></ul>
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  30. 30. Low Dose Unfractionated Heparin <ul><li>Surgical Prophylaxis </li></ul><ul><ul><li>5,000 Units SQ 2 hr preop </li></ul></ul><ul><ul><li>5,000 Units SQ every 12 hours </li></ul></ul><ul><li>Medical Prophylaxis </li></ul><ul><ul><li>5,000 Units SQ every 12 hours </li></ul></ul><ul><li>No monitoring required </li></ul>
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  34. 34. Indications for and Contraindications to Parenteral Anticoagulant Agents Anticoagulant Agent Class Approved & Appropriate Indications Contraindication Unfractionated heparin Enoxaparin ( Lovenox ) Dalteparin ( Fragmin ) Tinzaparin ( Innohep ) Antithrombin III inhibitor Low-molecular-weight heparin Low-molecular-weight heparin Low-molecular-weight heparin Treatment of venous thromboembolism or unstable angina; used when rapid reversal is important Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism ? Prophylactic treatment Regional anesthesia Pregnancy Prosthetic Heart Valves Regional anesthesia Regional anesthesia
  35. 35. Indications for and Contraindications to Parenteral Anticoagulant Agents (cont’d) Ardeparin Lepirudin Argatroban Danaparoid Bivalirudin Fondaparinux ( Arixtra ) Low-molecular-weight heparin Hirudin derivative Direct thrombin inhibitor Heparinoid Hirudin derivative Synthetic factor Xa inhibitor Approved; not being marketed Heparin-induced thrombocytopenia with thrombosis Heparin-induced thrombocytopenia with thrombosis Prophylaxis against thrombosis in heparin-induced thrombocytopenia Unstable angina or angioplasty Prophylaxis in high-risk patients? Regional anesthesia Thrombocytopenia other than heparin-induced thrombocytopenia Thrombocytopenia other than heparin-induced thrombocytopenia Thrombocytopenia other than heparin-induced thrombocytopenia Unknown Unknown
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  37. 37. Heparin-Antibiotic Interactions <ul><li>The second-generation cephalosporins- cefamandole, cefotetan, and cefoperazone, contain an N-methylthiotetrazole (NMTT) side chain. This NMTT group can: </li></ul><ul><li>- Dissociate from the parent antibiotic in solution or in vivo and competitively inhibit vitamin K action, leading to prolongation of the prothrombin time and bleeding. </li></ul><ul><li>- This side chain is also associated with a disulfiram-like reaction to alcohol. </li></ul><ul><li>- Clinical bleeding has been less frequently reported with Cefotetan than with cefoperazone or cefamandole. </li></ul>
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  39. 39. Mechanisms of HIT <ul><li>Type 1: In most of these cases, the fall in platelet count occurs within the first two days after heparin initiation, often returns to normal with continued heparin administration, and is of no clinical consequence. The mechanism of the thrombocytopenia is non-immune and appears to be due to a direct effect of heparin on platelet activation. </li></ul><ul><li>    Type 2: Approximately 0.3 to 3 percent of patients receiving heparin develop an immune thrombocytopenia, mediated by antibodies to a heparin-platelet factor 4 complex. One study, for example, randomly assigned 665 patients to therapy with unfractionated heparin or LMW heparin. Type 2 HIT developed in 2.7 percent of patients treated with unfractionated heparin but in none of those receiving LMW heparin. </li></ul>
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  41. 41. Therapy of HIT <ul><li>There are two recommended approaches: </li></ul><ul><ul><li>Use of the heparinoid danaparoid </li></ul></ul><ul><ul><li>The direct thrombin inhibitor lepirudin (recombinant hirudin) </li></ul></ul><ul><ul><li>Based upon the data published to date, either danaparoid or lepirudin should be used to treat HIT that is complicated by thrombosis; these agents should also be considered for prophylactic therapy in patients with HIT without thrombosis until the platelet count has recovered </li></ul></ul>
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  49. 49. Warfarin <ul><li>Bioavailability </li></ul><ul><li>Metabolism </li></ul><ul><li>Serum Protein Binding </li></ul><ul><li>Vitamin K Status </li></ul><ul><li>Protein C Effects </li></ul><ul><li>Elimination </li></ul><ul><li>Side Effects </li></ul><ul><li>Overdose </li></ul><ul><li>Contraindications </li></ul><ul><li>Pregnancy- NO </li></ul>
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  59. 59. Contraindications to Antithrombotic Therapy <ul><li>General risk factors </li></ul><ul><li>-Pre-existing coagulation or platelet defect, thrombocytopenia, or other bleeding abnormality </li></ul><ul><li>-Inaccessible ulcerative lesion (e.g., gastrointestinal tract lesion) </li></ul><ul><li>-Central nervous system lesion (e.g., caused by stroke, surgery, trauma) </li></ul><ul><li>-Spinal anesthesia or lumbar puncture </li></ul><ul><li>-Malignant hypertension </li></ul><ul><li>-Bacterial endocarditis </li></ul><ul><li>-Advanced retinopathy </li></ul><ul><li>-Old age (relative) </li></ul><ul><li>-Aspirin or other antiplatelet drugs </li></ul><ul><li>-Neoplastic disease </li></ul>
  60. 60. Contraindications to Antithrombotic Therapy <ul><li>Specific to warfarin (ambulatory patients) </li></ul><ul><li>-Early and late pregnancy </li></ul><ul><li>-Poor patient cooperation, understanding, reliability </li></ul><ul><li>-Unsatisfactory laboratory or patient follow-up </li></ul><ul><li>-Occupational risk to trauma </li></ul>
  61. 61. Contraindications to Antithrombotic Therapy <ul><li>Specific to thrombolytic agents </li></ul><ul><li>-Recent thoracic, abdominal, or central nervous system surgery </li></ul><ul><li>-Recent cerebrovascular accident, trauma, or neoplasm </li></ul><ul><li>-Bleeding ulcer </li></ul><ul><li>-Hypertension </li></ul><ul><li>-Anticipated invasive procedures (arterial punctures, biopsies, central lines) </li></ul><ul><li>-Concurrent hemostatic dysfunction </li></ul>
  62. 62. Platelet Receptor Mediated Pathways: Drugs Arachidonic Acid ASA NSAIDs ADP Ticlopidine Clopidogrel Thrombin -Final Common Pathway -Promotes Platelet Adhesion (Fibrinogen, vWF) GP IIB/IIIA Inhibitors Abciximab (ReoPro) Eptifibatide (Integrilin) Tirofiban
  63. 63. Anti Platelet Drugs Drug Mechanism Uses Aspirin Permanently inhibits COX-1 and COX-2 CAD Stroke-TIAs NSAIDs Reversibly inhibits COX-1 Limited Dipyridamole Inhibits PDE; increases cAMP TIAs Ticlopidine Clopidrgrel Inhibits ADP PlatAg;active metabolite TIAs;Stroke CAD;PVD