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Download PowerPoint Presentation - Anticoagulants and Thrombolytics
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At the end of session students should be able to: Know the normal hemostatic pathway Know Parenteral anticoagulant drugs Know pharmacokinetics, dynamics of heparin Know the oral anticoagulants Know pharmacokinetics and pharmacodynamics of warfarin Maintaining fluidity of blood Repairing vascular injury Limiting blood loss Break down of hemostasis lead to Excessive bleeding and thrombosis Vascular Phase Platelet Phase Coagulation Phase Fibrinolytic Phase Vasoconstriction Exposure to tissues activate Tissue factor and initiate coagulation Tissue Factor Blood vessel wall (endothelial cells) prevent platelet adhesion and aggregation In vascular injury, sub endothelial matrix proteins, collagen and von Willebrand factor Platelets contain receptors for fibrinogen and von Willebrand factor After vessel injury Platelets adhere and aggregate Thromboxane A2 is synthesized from Arachidonic acid ADP released from platelet granules cause platelet aggregation and formation of platelet plug Activation of platelets result in conformational change in the IIb/IIIa receptor, enabling it to bind fibrinogen, which cross link adjacent platelets Two major pathways Intrinsic pathway Extrinsic pathway Both converge at a common point Biosynthesis of these factors are dependent on Vitamin K1 and K2 Hereditary lack of clotting factors lead to hemophilia -A Intrinsic Pathway Extrinsic Pathway Tissue Injury Blood Vessel Injury Tissue Factor XIIa XII Thromboplastin XIa XI IXa IX Xa X Factors affected By Heparin VIIa Prothrombin Vit. K dependent Factors Affected by Oral Anticoagulants Fibrinogen XIII VII X Thrombin Fribrin monomer Fibrin polymer Prevent coagulation Dissolve clots Prevent bleeding and hemorrhage Hemostatic Overcome clotting deficiencies (replacement therapies) A. Reduce the formation of fibrin clots. 1. INDIRECT THROMBIN INHIBITORS UFH: Heparin LMWH: Enoxaparin, dalteparin, tinzaparin SYNTHETIC: Fondaparinux 2. DIRECT THROMBIN INHIBITORS Parenteral: Hirudin, lepirudin Oral: Ximelagatran, dabigatran 3. ORAL ANTICOAGULANT DRUGS Coumarin anticoagulants ▪ warfarin – dicumarol B. Lyse thrombi already formed Streptokinase, Urokinase, Anistreplase Tissue Plasminogen Activator: Alteplase, Reteplase, Tenecteplase C. Antiplatelet drugs Aspirin, clopidogrel, ticlopidine Platelet glycoprotein IIa/IIIb Receptor blockers Others: dipyridamole, cilostazol It is heterogeneous mixture of sulfated mucopolysaccharides It is glycosaminoglycan found in secretory granules of mast cells, polymer of alternating D-glucronic acid and Nacetyl-D-glucosamine residues These are D-glucosamine-L-iduronic acid and Dglucosamine-D-glucuronic acid Source: commonly extracted from porcine intestinal mucosa or bovine lung and preparations contain small amount of other glycosaminoglycans. Not absorbed through GI mucosa Heparin is given as continuous intravenous infusion Immediate onset of action when given intravenously Half life depend on the dose administered Destroyed in liver by heparinase Drug can accumulate in patients with renal impairment I/M can lead to hematoma Unit of Heparin The USP unit of Heparin is defined as the quantity of Heparin that prevents 1.0 ml of citrated sheep plasma from clotting for 1 hour after the addition of 0.2 ml of 1% Calcium chloride (CaCl2) solution Standard Heparin or Unfractioned Heparin (UFH) MW 5000-30000 Low MW Forms of Heparin preparations (20006000 MW) Enoxaparin Tinzaparin Dalteparin Danaparoid Fondaparinux Heparin Antithrombin III Thrombin Heparin binds to endothelial blood surface It activates ant thrombin III It inhibits thrombin IIa , IXa and Xa In the absence of heparin these reactions are slow LMW heparin and fondaparinux have same mechanism of action PTT or a PTT Level of UFH determined by protamine titration or anti Xa units Weight based dosing of LMW heparin is important in renal insufficiency, obesity and pregnancy Initiate treatment of venous thrombosis and pulmonary embolism Inherited and acquired (atrial fibrillation, prolonged bed rest, high risk surgical procedures and cancer) Prevention as well as treatment Oral anticoagulant is started concurrently Heparin is continued for at least 5 days to allow warfarin to achieve full therapeutic effect Initial management of unstable angina Acute myocardial infarction Venous thrombosis and pulmonary embolism Bleeding Major bleeding occur in 1-5% of patients Less bleeding with LMWH Mild bleeding can be controlled without antagonist Protamine sulfate is the antidote (highly basic positively charged peptide, combine with negatively charged heparin 1 mg of protamine neutralize 100 units of heparin Thrombocytopenia platelet count <150,000/ml This also occur with LMWH and fondaparinux Mild elevation of hepatic transaminases Osteoporosis Inhibit the synthesis of aldosterone Hypersensitivity to drug Active bleeding Hemophilia Significant thrombocytopenia Purpura Severe hypertension Intracranial hemorrhage Infective endocarditis Active tuberculosis Ulcerative lesion of GIT Threatened abortion Visceral carcinoma Advanced hepatic or renal disease Recent surgery of brain, spinal cord or eye Careful use in pregnancy Features Heparin LMWH Fondaparinux Source Biological Biological Synthetic Molecular weight 15,000 5000 1500 Target X a and II a X a and II a Xa Bioavailability % 30 90 100 Half life 1 4 17 Antidote effect Complete Partial None Features Heparin LMWH Fondaparinux Administration I/V infusion Subcutaneous Monitoring a PTT Adverse effect Thrombocytopenia Osteoporosis Effect on platelet High dose of heparin interfere with platelets aggregation In units Subcutaneous administration Do not require monitoring Less incidence of thrombocytopenia and osteoporosis Little effect on platelets In mg In mg Dose Do not require monitoring Less incidence Little effect on platelets Exert their anticoagulant effect by directly binding to active site of thrombin Hirudin and bivalirudin Agatroban and melagatran Lepirudin (leech saliva) It inactivate fibrin-bound thrombin in thrombi Monitored by aPTT Clinical use: thrombosis related to heparin induced thrombocytopenia Excreted by kidney Anaphylactic reaction Predictable pharmacokinetics and bioavailability Debigatran etexilate mesylate Debigatran is the active form Clinical use: prevention of stroke and systemic embolism in non valvular atrial fibrillation Prolong PTT and thrombin time Bleeding More in patients >75 years No antidote Coumarins - warfarin, dicumarol used as rodenticide Administered as sodium salt and has 100% bioavailability Structurally related to vitamin K Delayed onset 8 - 12 hrs Block γ-carboxylation of glutamate residues in prothrombin and factor VII, IX and X Proteins C and S Incomplete coagulation factor molecules that are inactive Vitamin k epoxide reductase is inhibited by warfarin Descarboxy Prothrombin Prothrombin Reduced Vitamin K Oxidized Vitamin K NAD NADH Warfarin Normally, vitamin K is converted to vitamin K epoxide in the liver. →This epoxide is then reduced by the enzyme epoxide reductase. →The reduced form of vitamin K epoxide is necessary for the synthesis of many coagulation factors (II, VII, IX and X, as well as protein C and protein S). →Warfarin inhibits the enzyme epoxide reductase in the liver, thereby inhibiting coagulation. )(عبدهللا المطيري Absorption: complete after oral, I/V or rectal route Distribution: 99 % bound to plasma protein Can reach fetus through placenta Used clinically as racemic mixture S and R warfarin Levorotatory S-warfarin is four times potent Prevent the progression or recurrence of acute DVT or pulmonary embolism following an initial course of heparin Prevent venous thromboembolism in patients undergoing orthopedic or gyneocological surgery Recurrent coronary ischemia in acute MI patients Systemic embolization in patients with prosthetic heart valves or chronic atrial fibrillation Bleeding Minor bleeding: withdrawal of the drug and administer vitamin K1 (PHYTONADIONE) Severe bleeding: fresh frozen plasma or factor IX concentrate Cutaneous necrosis Infarction of fatty tissues, breast, intestine Cross the placenta: Hemorrhagic disorder in the fetus Teratogenic – abnormal bone formation Must not be given to pregnant women. INR Ratio of PT of patient PT of normal person plasma INR = PTpt PT ref Category Drugs that Increase Warfarin Activity Mechanism Representative Drugs Decrease binding to Albumin Aspirin, Sulfonamides Inhibit Degradation Cimetidine, Disulfiram Decrease synthesis of Clotting Factors Antibiotics (oral) Drugs that promote bleeding Inhibition of platelets Aspirin Inhibition of clotting Factors heparin antimetabolites Induction of metabolizing Enzymes Drugs that decrease Promote clotting factor Warfarin activity Synthesis Reduced absorption Hypoproteinemia Barbiturates Phenytoin,rifampin Vitamin K cholestyramine colestipol Nephrotic syndrome Example: Aspirin Prevents platelet aggregation /adhesion Clinical use - prevents arterial thrombus Myocardial infarction (MI), stroke, heart valve replacement and shunts Other antiplatelet drugs are - Dipyridamole, sulfinpyrazone and Ticlopidine Aspirin inhibits cyclooxygenase (COX) COX is a key enzyme involved in the synthesis of thromboxane 2 (prostaglandins) Inhibits platelet aggregation Low dose daily. Prevents ischemic attack (ministroke) and MI 335 mg/day reduced the risk of heart attack in patients over 50 More than 1000 mg/day NO EFFECT Contraindication - DO NOT give to patients with glucose 6-PO4 dehydrogenase deficiency Enhance degradation of clots Activation of endogenous protease Plasminogen (inactive form) is converted to Plasmin (active form) Plasmin breaks down fibrin clots Exogenously administered drugs Streptokinase - bacterial product ▪ - continuous use - immune reaction Urokinase - human tissue derived – ▪ no immune response Tissue plasminogen activator (tPA) - genetically cloned ▪ no immune reaction ▪ EXPENSIVE Heparin (generic, Liquaemin sodium) Parenteral - 1000 - 40,000 U/ml Warfarin (generic , Coumadin) Oral : 2 - 20 mg tablets Dipyridamole (Persantine) Oral : 25,50,75 mg tablets Alteplase recombinant (tPA, Activase) 20, 50 mg Lyophilized powder - reconstitute for iv streptokinase (Kabikinase, streptase) Parenteral : 250000 - 1.5 million units per vial . Lyophilized powder. Reconstitute for iv Urokinase ( Abbokinase) Parenteral : 250000 units per vial. Powder to reconstitute to 5000 u/ml for injection Vitamin K ( Phytonadione (K1), Mephyton Oral : 5 mg tablets Plasma fractions - for hemophilia Antihemophilic factor ( VIII, AHF) Parenteral Factor IX complex (konyne HT, proplex T) Parenteral : in vials Systemic use : aminocaproic acid (Amicar); Tranexamic acid (cyclokapron),Vitamin K Local adsorbable drugs Gelatin sponge (Gelfoam) Gelatin film Oxidized cellulose ( Oxycel) Microfibrillar collagen (Avitene) Thrombin Drug Class Anticoagulant Parenteral Prototype Heparin Action Inactivation of clotting Factors Effect Prevent venous Thrombosis Anticoagulant Warfarin Decrease synthesis of Oral Clotting factors Prevent venous Thrombosis Antiplatelet drugs Prevent arterial Thrombosis Aspirin Decrease platelet aggregation Thrombolytic Streptokinase Fibinolysis Drugs Breakdown of thrombi Intrinsic Pathway All clotting factors are Extrinsic Pathway Initiating factor is outside within the blood vessels the blood vessels - tissue Clotting slower factor Activated partial thromboplastin test (aPTT) Clotting - faster - in Seconds Prothrombin test (PT)
