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Anticoagulants.pptx00000000000000000000000
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- 6. • Antiplatelets- prevention/treatmentof heart attack, ischemic stroke Peripheral artery disease • Anticoagulants- Deep vein thrombosis, thromboembolism
- 8. Endogenous inhibitors ofcoagulation • Protein C, protein S, antithrombin III, and tissue factor pathway inhibitor • Antithrombin III is an α globulin that inhibits serine proteases of thrombin (factor IIa) and factor Xa.
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- 10. Heparin and lowmolecular weight heparins • Heparin • LMWH- Enoxaparin, Dalteparin, • heparin is about 15 kDa and LMWH is about 4.5 kDa • Fondaparinux- Synthetic molecule- Chemically similar to Penta saccharide of heparin/LMWH- No extra chain
- 11. • Heparin, aglycosaminoglycan found in the secretory granules of mast cells • Commonly extracted from porcine intestinal mucosa • 1 unit - quantity of heparin that prevents 1 mL of citrated sheep plasma from clotting for 1 h after calcium addition Mechanism of Action • Heparin, LMWH, and fondaparinux have no intrinsic anticoagulant activity • They bind to antithrombin and accelerate the rate at which it inhibits various coagulation proteases
- 12. Pentasaccharide binding toantithrombin induces a conformational change in antithrombin that renders its reactive site more accessible to the target
- 14. Therapeutic uses • Heparinand the LMWHs limit the expansion of thrombi by preventing fibrin formation. • These agents are used for the treatment of acute venous thromboembolism (Deep Vein Thromboembolism or Pulmonary Embolism). • Heparin and LMWHs are also used for prophylaxis of postoperative venous thrombosis in patients undergoing surgery (for example, hip replacement) • Acute MI, unstable angina • Anticoagulants of choice for treating pregnant women, because they do not cross the placenta, due to their large size and negative charge.
- 15. • Heparin mustbe administered subcutaneously or intravenously • LMWHs are usually administered subcutaneously • Heparin requires activated partial thromboplastin time (APTT) monitoring- to titrate dose or to prevent bleeding. • Heparin is taken up by the monocyte/macrophage system, and it undergoes depolymerization and desulfation to inactive products • LMWHs are primarily eliminated in the urine
- 16. Adverse effects • Bleedingrisk • Allergic reactions with heparin- chills, fever, urticaria, and anaphylactic shock • Heparin-induced thrombocytopenia (HIT) • Reversible abnormalities of hepatic function tests • Osteoporosis (risk of osteoporosis is lower with LMWH or fondaparinux than it is with heparin • Heparin can inhibit the synthesis of aldosterone by the adrenal glands and occasionally causes hyperkalemia
- 17. • Anticoagulant effectof heparin disappears within hours of discontinuation of the drug • Mild bleeding due to heparin usually can be controlled without administration of an antagonist • If life-threatening hemorrhage occurs, heparin can rapidly be reversed by the intravenous infusion of protamine sulfate (a mixture of basic polypeptides isolated from salmon sperm) • Protamine binds tightly to heparin and neutralizes its anticoagulant effect. • Protamine also interacts with platelets, fibrinogen, and other plasma proteins and may cause an anticoagulant effect of its own. Therefore, one should give the minimal amount of protamine required to neutralize the heparin present in the plasma
- 18. • 1 mgof protamine for every 100 units of heparin remaining in the patient; • Protamine is given intravenously at a slow rate (up to a maximum of 50 mg over 10 min). • Protamine binds only long heparin molecules. • Protamine only partially reverses the anticoagulant activity of LMWH • No effect on fondaparinux
- 19. • Protamine cancause severe hypotension, noncardiogenic pulmonary edema, and catastrophic pulmonary vasoconstriction when given rapidly and at high doses. • Risk factors include previous administration of protamine-containing drugs (e.g., NPH insulin, protamine zinc insulin, and certain β blockers), allergy to fish, severe left
- 20. HIT • Platelet count<150,000/μL or a 50% decrease from the pretreatment value • Immunogenic- development of IgG antibodies against complexes of heparin with platelet factor 4 • Occurs in about 0.5% of medical patients 5 to 10 days after initiation of therapy with heparin • Incidence is lower with LMWH and rarely with fondaparinux.
- 21. HIT • Heparin orLMWH should be discontinued immediately if unexplained thrombocytopenia occurs • Alternative anticoagulant such as bivalirudin, argatroban, or rivaroxaban should be administered to patients with heparin-induced thrombocytopenia. • Fondaparinux is another alternative, although fondaparinux-induced thrombocytopenia rarely occurs • LMWH should be avoided because it cross-reacts with heparin antibodies.
- 22. Differences b/w Heparin& LMWH • Average molecular weight: heparin is about 15 kDa and LMWH is about 4.5 kDa. • Less frequent subcutaneous dosing than for heparin • Once or twice daily subcutaneous injection for treatment of venous thromboembolism and in unstable angina instead of intravenous infusion of high dose heparin. • No need for monitoring of the APTT coagulation parameter as required for high dose heparin. • Possibly a smaller risk of bleeding. • Smaller risk of osteoporosis in long-term use. • Smaller risk of heparin-induced thrombocytopenia • The anticoagulant effects of heparin are typically reversible with protamine sulfate, while protamine's effect on LMWH is limited. • LMWH has less of an effect on thrombin compared to heparin, but about the same effect on Factor Xa. • Due to its renal clearance, LMWH is contraindicated in patients with kidney disease in whom unfractionated heparin can be used safely.
- 24. Administration and Monitoringof heparin • Full-dose heparin usually is administered by continuous intravenous infusion • 5000 units bolus, followed by 800 to 1600 units/h delivered by an infusion pump • aPTT - two or three times the normal mean aPTT value - therapeutic • Extremely high doses of heparin are required to prevent clotting in patients undergoing percutaneous coronary intervention or cardiac surgery with cardiopulmonary bypass • Activated clotting time (ACT), is employed to monitor therapy in this situation
- 25. • Heparin alsocan be administered subcutaneously on a twice-daily basis. • A total daily dose of about 35,000 units administered as divided doses every 8 to 12 h usually is sufficient to achieve an aPTT of twice the control value (measured midway between doses) • For low-dose heparin therapy (to prevent venous thromboembolism in hospitalized medical or surgical patients), a subcutaneous dose of 5000 units is given two or three times daily
- 26. Other Parenteral Anticoagulants •Desirudin and Lepirudin Recombinant forms of hirudin- thrombin inhibitor derived from saliva of the medicinal leech • Bivalirudine- synthetic analogue of hirudin • Argatroban Synthetic compound based on the structure of l-arginine- binds reversibly to the active site of thrombin. • Can be Used in patients with renal impairment (metabolized in the liver) Licensed for the prophylaxis or treatment of patients with, or at risk of developing, heparin- induced thrombocytopenia
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- 28. Coumarin anticoagulants • Discoveryof an anticoagulant substance formed in spoiled sweet clover silage, which caused hemorrhagic disease in cattle. • At the behest of local farmers, a chemist at the University of Wisconsin identified the toxic agent as bishydroxycoumarin. • Dicumarol, a synthesized derivative, and its congeners, most notably warfarin (Wisconsin Alumni Research Foundation, with “-arin” from coumarin added), were initially used as rodenticides. • In the 1950s, warfarin (under the brand name Coumadin) was introduced as an antithrombotic agent in humans.
- 30. Warfarin • Vitamin kantagonist • Antagonize the cofactor functions of vitamin K. • Factors II, VII, IX, and X require vitamin K as a cofactor for their synthesis by the liver • Warfarin treatment results in the production of clotting factors with diminished activity (10% to 40% of normal), due to the lack of sufficient γ-carboxyglutamyl side chains.
- 32. • Anticoagulant effectsof warfarin are not observed immediately after drug administration • Peak effects may be delayed for 72 to 96 hours • Time required to deplete the pool of circulating clotting factors. • Anticoagulant effects of warfarin can be overcome by the administration of vitamin K. • Reversal takes 24 hours (the time necessary for degradation of already synthesized clotting factors).
- 33. PK • Oral bioavailabilityof warfarin is nearly complete • The t1/2 varies (25–60 h), but the duration of action of warfarin is 2 to 5 days • Polymorphisms in genes (eg. CYP2C9 and VKORC1), account for genetic variability in warfarin response- dose adjustments required • 99% of racemic warfarin is bound to plasma albumin
- 34. Warfarin uses • Preventionand treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)- following an initial course of heparin, LMWH, or fondaparinux • Stroke prevention or prevention of systemic embolization in patients with atrial fibrillation, mechanical heart valves, or ventricular assist devices • Protein C and S deficiency • Antiphospholipid syndrome.
- 35. • Monitoring- PT/INRtest • For most indications, an INR range of 2 to 3 is used. • A higher INR range (2.5–3.5) is recommended for patients with mechanical heart valves in the mitral position or for patients with mechanical valves in another position who have concomitant atrial fibrillation or a prior history of stroke. • For treatment of acute venous thromboembolism, heparin, LMWH, or fondaparinux usually is continued for at least 5 days after warfarin therapy is begun. • The parenteral agent is stopped when the INR is in the therapeutic range on 2 consecutive days. • Once a stable dose of warfarin has been identified, the INR can be monitored every 3 to 4 weeks.
- 37. Adverse effects: • Bleeding(more risk if INR > 4) • Minor bleeding may be treated by withdrawal of the drug or administration of oral vitamin K • Severe bleeding - higher doses of vitamin K given intravenously. • Whole blood, frozen plasma, and plasma concentrates of blood factors may also be used for rapid reversal of warfarin. • Skin lesions and necrosis are rare complications of warfarin therapy. • Warfarin is teratogenic and is contraindicated in pregnancy. (risk of abortion, CNS abnormalities, Fetal or neonatal hemorrhage and intrauterine death)
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- 39. Dabigatran • Direct thrombininhibitor (blocks the active site of free and clot-bound thrombin) • Predictable anticoagulant response- routine coagulation monitoring not necessary • Prevention of stroke and systemic embolism • Prophylaxis to prevent or reduce the risk of recurrence of DVT and PE • Contraindicated in patients with mechanical prosthetic heart valves and is not recommended in patients with bioprosthetic heart valves • Risk of GI bleeding more, but less risk of intracranial bleeding compared with warfarin • Idarucizumab- monoclonal antibody binds to dabigatran and reverses the anticoagulant effect- antidote for dabigatran induced bleeding
- 40. Direct oral factorXa inhibitors • Rivaroxaban, Apixaban, Edoxaban • Inhibit free and clot-associated factor Xa • Results in reduced thrombin generation. • Platelet aggregation and fibrin formation are suppressed • Prevention of stroke in nonvalvular atrial fibrillation, • Prevention and treatment of DVT and PE • Contraindicated for stroke prevention in patients with mechanical heart valves.
- 41. • Low-dose rivaroxaban(2.5 mg twice daily) in combination with aspirin (81 or 100 mg daily) is licensed for prevention of major adverse cardiac and limb events in patients with coronary or peripheral artery disease • Despite the increased risk of GI bleeding, rates of life-threatening and fatal bleeding are lower with all the oral factor Xa inhibitors than with warfarin Reversal Agent • Andexanet Alfa- coagulation factor Xa (recombinant), inactivated-zhzo • Decoy for the oral factor Xa inhibitors • Rapidly reverses the anti–factor Xa activity produced by these agents and restores thrombin generation
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Editor's Notes
- #36 Prothrombin Time and International Normalized Ratio