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anticoagulants.pptx
- 1. Anticoagulants, Protamine, Antiplatelets and Fibrinolytic drugs
- 2. Hemostasis • Hemostasis is defined as the process of clot formation. • Normal hemostasis ensures blood is maintained in its fluid state within blood vessels and is free from clots.
- 3. Virchows Triad • Rudolf Virchow described 3 factors that are critically important in the development of venous thrombosis. • A) Stasis/Turbulance • B) Activation of blood coagulation-hypercoagulable state • C) Vein damage- vessel wall damage/endothelial injury
- 4. Main components of a blood clot • Platelets • Thrombin • Fibrin
- 5. Prevention of excessive coagulation • Occurs via the naturally occurring inhibitors of clotting factors and the fibrinolytic system.
- 6. Extrinsic and Intrinsic pathway • The Extrinsic Pathway It is activated by the release of thromboplastin (tissue factor) from endothelial cells The Intrinsic Pathway It is activated by exposure of factor XII to subendothelial components exposed during endothelial injury
- 8. Prevention of excessive coagulation Inhibitor MOA Antithrombin Inhibits factors IIa, IXa, Xa Protein S Cofactor for activation of protein C Protein C Inactivates factors Va and VIIIa Tissue factor pathway inhibitor Inhibits activity of factor VIIa Plasminogen Converted to plasmin via tissue plasminogen activator Plasmin Lyses fibrin into fibrin degradation products
- 10. Uses of anticoagulants • Deep vein thrombosis and pulmonary embolism • Myocardial infarction • Unstable angina • Rheumatic heart disease, atrial fibrillation • Cerebrovascular disease • Vascular surgery, prosthetic heart valves, hemodialysis.
- 11. Anticoagulants for prophylaxis in: • For prevention of DVT IN: • Bedridden/ immobilized • Old people • Post-operative • Post-stroke patients • Leg fractures • Elective surgery
- 12. Classification of anticoagulants • Parenteral anticoagulants: Indirect thrombin inhibitors- Heparin, Low molecular weight heparins, Fondaparinux, Danaparoid. Direct thrombin inhibitors- Lepirudin, Bivalirudin, Argatroban
- 13. Classification of anticoagulants • Oral anticoagulants: • Coumarin derivatives: Bishydroxycoumarin(dicoumarol) Warfarin sodium, acenocoumarol, • Indadione derivatives: Phenindione • Direct factor Xa inhibitors: Rivaroxaban • Oral direct thrombin inhibitor: Dabigatran
- 15. Heparin • Not absorbed from GIT • Does not cross BBB or placental barrier. • It is a strongly electronegatively charged acidic polymer.
- 16. Heparin • Low dose: Inactivates factor Xa and inhibits conversion of prothrombin to thrombin. • High dose: Inactivates factors IX, X, XI, XII and thrombin and inhibits conversion of fibrinogen to fibrin. • Onset of action is immediate for IV and takes 20-30mins for Subcutaneous
- 17. Heparin
- 18. Adverse effects • Bleeding • Heparin induced thrombocytopenia • Transient and reversible alopecia • Osteoporosis • Hypersensitivity reactions
- 19. Contraindications of Heparin • Bleeding disorder • Heparin Induced Thrombocytopenia • Severe hypertension(risk of cerebral hemorrhage) • GI ulcers • Aspirin and other antiplatelet drugs should be used cautiously during heparin therapy
- 20. Heparin antagonist • Protamine sulphate. • It is strongly basic • It combines with acidic heparin forming a stable complex and neutralizes the anticoagulant activity of heparin.
- 21. Low molecular weight heparin(Lmwh) • The more important advantages of LMWH are pharmacokinetics. • Better subcutaneous bioavailability 70-90% compared to UFH(20-30%) variability in response is minimized • Once daily SC administration • Since Aptt clotting times are not prolonged,laboratory monitoring is not needed. • Risk of osteoporosis with long term use is much less compared to UFH • Low incidence of hemorrhagic complications
- 22. Examples • Enoxaparin( Clexane) • Dalteparin
- 23. Direct thrombin Inhibitors: Heparinoids • Hirudin • Bivalirudin • Lepirudin • Argatroban
- 24. Lepirudin • Recombinant form of Hirudin • Used in HIT
- 25. Argatroban • Used in patients with Heparin Induced Thrombocytopenia • Clearance is not affected by renal disease.
- 27. Warfarin
- 28. Warfarin • It interferes with synthesis of Vitamin K dependent clotting factors in the liver. • Factors 2, 7, 9 and 10 are inhibited.
- 29. Adverse effects of warfarin • Bleeding • Teratogenic potential-contraindicated in pregnancy • Cutaneous necrosis-decreased protein C activity.
- 30. Warfarin antidote • Vitamin K • Fresh frozen plasma • Prothrombin complex concentrates • Recombinant factor VII
- 31. Factors enhancing effects of oral anticoagulants • Liver disease: Chronic alcoholism, synthesis of clotting factors may be deficient • Newborns have a low level of Vitamin K and clotting factors. • Malnutrition- Decreased Vit K • Hyperthyroidism-Increased degradation of clotting factors.
- 32. Warfarin drug interactions • Agents that inhibit warfarin metabolism: • Cimetidine • Cotrimoxazole • Ciprofloxacine • Amiodarone • Metronidazole
- 33. Warfarin drug interactions • Drugs that increase warfarin metabolism. • Barbiturates • Rifampin • Nsaids displace warfarin from binding sites on plasma albumin • Cholestyramine decreases GIT absorption of warfarin
- 35. New Oral antocoagulants • Traditional anticoagulants have 2 major limitations: • Narrow therapeutic window of anticoagulation without bleeding • Variable dose response-requires monitoring by lab testing • 3 new anticoagulants(NOAC) Dabigatran, rivaroxaban and apixaban
- 36. Oral thrombin inhibitors • Dabigatran: Direct thrombin inhibitor • Rivaroxaban: Factor Xa inhibitor • Apixaban: Factor Xa inhibitor
- 38. Antiplatelet agents: Aspirin and related cyclooxygenase inhibitors: • Aspirin works by irreversibly inhibiting the cyclooxygenase enzyme (COX) activity in the prostaglandin synthesis pathway. • This prostaglandin is a precursor of thromboxane A2 (TXA2) and PGI2. Thromboxane A2 works by inducing platelet aggregation and vasoconstriction, and COX-1 mediates its production, while PGI2 works by inhibiting platelet aggregation and induces vasodilation, and is mediated by COX-2. • Low-dose aspirin (75 mg to 150 mg) can induce complete or near- complete inhibition of COX-1, thus inhibiting the production of TXA2, while larger doses are required to inhibit COX-2
- 39. Antiplatelet agents: Oral thienopyridines • Clopidogrel, ticagrelor, ticlopidine, and prasugrel • They selectively inhibit adenosine diphosphate-induced (ADP- induced) platelet aggregation. • Prasugrel is the most potent of all three drugs with a rapid onset of action • Ticlopidine causes bone marrow toxicity
- 40. Antiplatelet agents:Glycoprotein platelet inhibitors • Examples are: abciximab, eptifibatide, tirofiban • They work by inhibiting glycoprotein IIb/IIIa (GpIIb-IIIa) receptors on platelets, thus decreasing platelet aggregation. • Only available in intravenous form
- 41. Dipyridamole • It inhibits platelet cyclic nucleotide phosphodiesterase. • This enzyme is responsible for the degradation of adenosine monophosphate (AMP) to 5'AMP, which increases intra-platelet cyclic AMP accumulation and inhibits platelet aggregation. • It also blocks the uptake of adenosine by the platelets, which also increases cyclic AMP.
- 43. Indications • Acute myocardial infarction • Pulmonary embolism • DVT • Acute ischaemic stroke • Peripheral arterial disease
- 44. Fibrinolytic agents • They work by converting plasminogen to plasmin • Plasmin lyses clots by beaking down the fibrinogen and fibrin contained in the clot.
- 45. Classification of fibrinolytic agents • Fibrin specific agents • Non fibrin specific agents
- 46. Fibrinolytic agents • Fibrin specific agents: • Alteplase, reteplase and tenecteplase • Non-fibrin specific agents: • Streptokinase-they catalyse systemic fibrosis. • Others: Urokinase