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12anticoagulants 12anticoagulants Presentation Transcript

  • • • • • • Indications of anticoagulant therapy Established venous thromboembolism Prophylaxis of venous thrombosis and pulmonary embolism Prosthetic heart valve Rheumatoid mitral valvular disease Myocardial infarction Contraindications • Pre existing bleeding disorder • Stroke within 3 weeks or neural / ocular surgery • Severe uncontrolled hypertension • Active peptic ulcer , IBS • Renal failure • Liver cirrhosis • Pregnancy ( warfarin)
  • • Mucopolysachharide Heparin Heparin is a powerful and instantaneously acting anticoagulant ,effective both invivo and in vitro.It is not absorbed by mouth and is usually given by intravenous or sometimes by subcutaneous injection. MECHANISM OF ACTIONS Heparin acts indirectly by binding to antithrombin III(AT III ,a serine proteinase inhibitors).The heparin AT III complex then binds to clotting factors and inactivates them ,thus by inhibits coagulation. • Inhibits factor II, VII, IX, X, XI, XII • Prevents conversion of prothrombin to thrombin • Prevents conversion of fibrinogen to fibrin • Decrease platelet aggregation at high dose Effects: • Anticoagulant • Antiplatelet • Lipemia clearing ( releasing lipoprotein lipase)
  • • Pharmacokinetics • Route : IV/SC • Onset of action : immediate ( within 10-15 mins ) • Plasma half life : 40-90 mins • Metabolism : liver • Excretion : kidney
  • USES • Disseminated intravascular coagulation • Deep vein thrombosis • Pulmonary embolism • Postoperative or after myocardial surgery • Cardipulmonary bypass machines ( extra corporeal devices eg dialysis) • Thrombophlebitis • To reduce frequency of arterial embolism in patient with atrial fibrillation, mitral stenosis or prosthetic heart valves • Prevention of clotting during – Blood transfusion – Hemodialysis – Blood sampling for lab analysis Safe drug during pregnancy
  • ADVERSE EFFECTS • Hemorrhage • Hypersensitivity : Chills,fever,urticaria,anaphylactic shock • Thrombocytopenia • Transeint but reversible alopecia • Osteoporosis • Neuropathy • Inhibition of aldosterone secretion • Slowing of wound healing • Depression of cell mediated immunity CONTRAINDICATIONS • Hypersensitive patients • Patients having bleeding disorders ( thrombocytopenia, hemophilia) • Intracranial hemorrhage • Ulcerative lesions of GIT • Threatened abortion • Active tuberculosis • Alcoholics • Ocular and neurosurgery, • lumbar puncture
  • DOSES • IV bolus dose : 5,000-10,000 U every 4-6 hours • Child dose : 50-100U/kg • Infusion is best given via a syringe pump at the rate of 25000-30000 units in 24hrs following an initial bolus of 5000 units.If a pump is not available the heparin can be added to 1litre of saline or 5% dextrose and given as an infusion. • To prevent thrombosis :5000 units in 0.2ml subcutaneously twice daily. UNITS 1 Unit = amount of heparin that prevents 1 ml of citrated sheep plasma from clotting for 1 hour after additon of 0.2 ml of 1% calcium chloride solution. Heparin sodium 1 mg = 120-140U Monitoring of heparin dose : Blood partial thromboplastin time with kaolin (PTTK) or aPTT . It should increase by 2.5 -3.5 times with heparin
  • Heparinisation 1) Continuous intravenous infusion via an infusion pump: – Initial loading dose : 5000-10000 units – Continuous infusion : 900 units / hour – PTTK should be maintained at 2.5-3.5 times control 2) Intermittent intravenous administration: – Heparin : 75-100 units /kg every 4 hours 3) Subcutaneous administration ( low dose ) – Heparin : 5000 units every 8 or 12 hours
  • Low molecular weight heparins • Selectively inhibit factor Xa with little effect on IIa • Better subcutaneous bioavailability • Advantages – – – – more predictable pharmacokinetic profile. therapy may be provided in the outpatient setting lower incidence of heparin-induced thrombocytopenia lower risks of bleeding and osteopenia • Once daily sc – – – – – – Enoxaparin Reviparin Nadroparin Dalteparin Pamparin Ardeparin
  • Heparin antagonist: protamine sulfate • Strongly basic , low molecular weight protein • 1 mg needed for every 100 U of heparin • Rapid iv injection but rate should not exceed 50 mg in any 10 min period .
  • Other parenteral anticoagulants • • • • • Lepirudin Bivalirudin Argatroban Danaparoid Drotrecogin Alfa
  • Oral anticoagulants Warfarin and its congeners acts as anticoagulant only in vivo not in vitro.it is an oral anticoagulant.Unlike heparin, the anticoagulant effects of warfarin are not observed until 8-12 hours of drug administration.the anticoagulants effects of warfarin can be overcome by the administration of vitamin K. MECHANISM OF ACTION It acts indirectly by interfering with the synthesis of vitamin K dependent clotting factors in the liver. They interfere with regeneration of active hydroquinone which carries out gamma carboxylation of glutamate residues of prothrombin and factors VII, IX, and X. • Inhibits Vit K epoxide reductase
  • • USES – – – – – – – – Deep vein thrombosis Pulmonary embolism Myocardial infarction Unstable angina Frost bite Acute gangrene Cerebrovascular disease Atrial fibrillation ADVERSE EFFECTS – – – – – – – – – Bleeding Hematuria Bleeding in GIT Intracranial or other internal hemorrhages Skin rashes / transient purpura Drug fever Jaundice Purple toe syndrome Congenital bony abnormality in children ( if given in pregnancy )
  • Effects of warfarin on pregnancy • Teratogenecity – Bony deformity – Nasal hypoplasia – CNS abnormality • Abortion • Foetal and neonatal hemorrhage • Intrauterine death of the foetus
  • CONTRAINDICATIONS • Should not be used during pregnancy • Recent trauma , head injury • Active internal bleeding ( eg active ulceration) • Severe hyeprtension • Major surgery • Pre-existing bleeding disorders • Severe renal and hepatic disease DOSE Warfarin sodium Initial dose is 10-15mg ,maintenance dose 2-10mg daily for 4-7days
  • • Factors enhancing effect: – Malnutrition, malabsorption, prolonged antibiotic therapy – Liver diseases – Chronic alcoholism – Hyperthyroidism – newborn • Factors decreasing effect – Pregnancy – Nephrotic syndrome – Genetic warfarin resistance – Drugs : enzyme inducers (OCP)
  • Monitoring of oral anticoagulant therapy INR ( international normalised ratio) : Prothrombin time ratio ( test/ control) based on human thromboplastin . Optimum range should be 2.5-3.5 times normal for effective anticoagulant effect. i) A coagulation screen and platelet count is done before starting treatment ii) Transfusion with fresh blood is required if blood loss has been excessive. ii) The dose of oral anticoagulant must be individualized by repeated measure of prothrombin time
  • • Antidote: – Immediate antagonism : plasma concentrated with vit K dependent clotting factors ( II, VII, IX , X) – Delayed antagonism by Inj Vitamin K ( I/ V)
  • Hemostatic agents / coagulants 1) Fresh whole blood or fresh frozen plasma 2) Vit K – K1 (from plants, fat soluble ) : phytonadione ( phylloquinone ) K2 ( produced by bacteria ) : menaquinone K3 ( synthetic) – – • • Fat soluble : menadione , acetomenapthone Water soluble : menadione sodium bisulfite , menadione sod diphosphate 3) Miscellaneous : – – – – – – Fibrinogen Antihemophilic factor Adrenochrome Monosemi carbazone Rutin Ethamsylate 4) Local hemostatics (styptics): – – – – – – Thrombin Fibrin Gelatin foam Russel viper venom Vasoconstrictors Astringents
  • Vitamin K • normal physiological function: to promote the biosynthesis of the gcarboxy-glutamate (Gla) forms of factors II (prothrombin), VII, IX, and X, anticoagulant proteins C and S. • Vitamin K, as KH2, the reduced vitamin K hydroquinone, is an essential cofactor for gglutamyl carboxylase
  • minimum daily requirement • 0.03 mg/kg of body weight DEFICIENCY • can result from inadequate intake, absorption, or utilization of the vitamin, • or action of a vitamin K antagonist • increased tendency to bleed • Ecchymoses, epistaxis, hematuria, gastrointestinal bleeding, and postoperative hemorrhage are common • intracranial hemorrhage may occur. Hemoptysis is uncommon. • fetal warfarin syndrome may be related to a deficiency of the vitamin. • deficits in bone mineral density and fractures;
  • • menadione and its derivatives cause hemolytic anemia and kernicterus in neonates, especially in premature infants Uses • correct the bleeding tendency or hemorrhage associated with its deficiency. • Oral Anticoagulant overdose • Hypoprothombinemia prophylaxis
  • Toxicity • Rapid iv injection : flushing ,breathlessness , hypotension, and chest constriction • Menadione can cause hemolysis , so not used
  • Fibrinolytics / thrombolytics • Urokinase • Streptokinase • Alteplase – Recombinant tissue plasminogen activator)
  • Streptokinase • It is a streptococcal exotoxin ( beta hemolytic streptococci group C) MECHANISM OF ACTIONS – It combines with circulating–plasminogen-liberating plasmin which breaks down fibrin – No intrinsic enzymatic activity but forms a stable complex with plasminogen . This complex then converts uncomplexed plasminogen to active plasmin which causes hydrolysis of fibrin plugs . – Plasmin catalyses degradation of fibrinogen as well as clotting factors V and VII USES – – – – – Pulmonary embolism Peripheral arterial occlusion Venous thrombosis Lysis of coronary thrombosis(present use) in acute myocardial infarction Clear occluded arterio venous cannula
  • • ADVERSE EFFECTS – – – – – – Bleeding particularly at the sites of recent trauma. Hypersensitive reactions Anaphylaxis(especially when used second time in a patient) Fever Hypotension Arrhythmias. • PRECAUTIONS – It should not be used if patient has had previous streptokinase within the last 12 months – Blood pressure should be monitored.
  • • CONTRAINDICATIONS – Surgery within 10 days including : • Organ biopsy • Serious trauma – – – – Serious GIT bleeding within 3 months History of hypertension Hemorrhagic disorders Cerebrovascular accident • DOSE – For coronary thrombosis: 1.5 million units infused over 1hr this may be preceded by chlorpheniramine 10mg and hydrocortisone 100mg to reduce allergic reactions. This is combined with 300mg aspirin ,which should be chewed before swallowing and followed by 150mg daily.
  • FIBRINOLYTIC INHIBITORS: • • • • AMINOCAPROIC ACID TRANEXAMIC ACID PHYTOMENADIONE APROTININ • Aminocaproic acid (EACA)- chemically similar to the amino acid lysine • It competitively inhibits plasminogen activation It is rapidly absorbed orally and is cleared from the body by the kidney. The usual oral dosage of EACA is 6 g four times a day. When the drug is administered intravenously, a 5 g loading dose should be infused over 30 minutes to avoid hypotension. • Tranexamic acid is an analog of aminocaproic acid and has the same properties. It is administered orally with a 15 mg/kg loading dose followed by 30 mg/kg every 6 hours
  • Anti thrombotic drugs / antiplatelet drugs • Drugs interfering with platelet function: – – – – – – – – – – – – – Aspirin Sulfinpyrazole Ticlopidine Eptifibatide Tirofiban Dextran-70 Dazaxiben Dipyridamole Epoprostenol Clofibrate Clopidogrel Abciximab Glycoprotein IIb/IIIa Inhibitors
  • Aspirin • In platelets, the major cyclooxygenase product is thromboxane A2, a labile inducer of platelet aggregation and a potent vasoconstrictor. • Aspirin blocks production of thromboxane A2 by acetylating a serine residue near the active site of platelet cyclooxygenase (COX-1), the enzyme that produces the cyclic endoperoxide precursor of thromboxane A2. • 50 to 320 mg per day
  • Ticlopidine. • Platelets contain two purinergic receptors, P2Y1 and P2Y12; both are GPCRs for ADP. The ADP-activated platelet P2Y1 receptor couples to the Gq-PLC-IP3-Ca2+ pathway and induces a shape change and aggregation. The P2Y12 receptor couples to Gi and, when activated by ADP, inhibits adenylyl cyclase, resulting in lower levels of cyclic AMP and thereby less cyclic AMPdependent inhibition of platelet that inhibits the P2Y12 receptor • dose is 250 mg twice per day • common side effects are nausea, vomiting, and diarrhea. The most serious is severe neutropenia .
  • Blood and plasma Volume expanders • High molecular weight substances that exert colloidal osmotic pressure and when infused iv retain fluid in the vascular compartment. • Substances: – Human albumin – Dextran – Degraded gelatin polymer – Hydroxyethyl starch ( HES) , hetastarch – Polyvinyl pyrrolidone (PVP)
  • • Desirable properties of plasma expanders : – Should exert osmotic pressure comparable to plasma – Should remain in circulation and not leak out in tissues or be too rapidly disposed – Should be pharmacodynamically inert – Should be non pyrogenic or antigenic – Should not interfere with grouping or cross matching of blood – Should be stable , easily sterilizable , and cheap
  • Human albumin • Obtained from human pooled plasma • 100 ml of 20% human albumin equivalent to 400 ml of fresh frozen plasma or 800 ml of whole blood . • Uses: – – – – – – Dehydration Burns , hypovolemia Shock Acute hypoproteinemia Acute liver failure Dialysis • Febrile reaction may occur • Expensive
  • Dextran • Polysachharide obtained from sugar beat. • Dextran-70 ( MW- 70,000)- 6% solution in dextrose or saline • Expands plasma volume for 24 hours and is excreted through kidney and oxidation. • May interfere with blood grouping • May cause allergic reactions : urticaria , itching , bronchospasm, hypotension and anaphylactic reaction. • Can prolong bleeding time , so should not be given in hypofibrinogenemia, or thrombocytopenia • Dextran-40 ( MW- 40,000) – 10% solution I dextrose or saline • Reduces blood viscosity • Acts for a shorter period and quickly eliminated through kidney • Used in stroke , and for prophylaxis of deep vein thrombosis and pulmonary infarction.