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Transcript
Fibrinolytics, anticoagulants and antiplatelets Anticoagulants Drugs that coagulation anticoagulant interfere cascade with are blood called COAGULATION CASCADE Key Clotting Factor is THROMBIN COAGULATION CASCADE ANTICOAGULANTS & COAGULATION CASCADE Classification of anticoagulants 1. Parenteral anticoagulants 2. Oral anticoagulants Parenteral Anticoagulants (THROMBIN INHIBITORS) Indirect thrombin inhibitors High molecular weight (HMW) heparin or unfractionated (UFH) heparin. Low molecular weight (LMW) heparin. Direct thrombin inhibitors Indirect Thrombin Inhibitors antithrombin III –dependent thrombin inhibitors High molecular weight (HMW) heparin or unfractionated (UFH) heparin. Low molecular weight (LMW) heparin. are unfractionated (UFH) heparin. Heterogeneous mixture of sulfated mucopolysaccharides (glycosaminoglycan). Strongly acidic nature. Extraction of unfractionated (UFH) heparin. Extracted from porcine intestinal mucosa & bovine lung. Mechanism of Action of UFH Has anticoagulant effect that depends upon antithrombin III Antithrombin III: is a natural anticoagulant that inhibits activated clotting factors especially (IIa, IXa, Xa, XIa). This inhibition is slow but increased 1000 fold in presence of heparin. Heparin inhibits activated clotting factors in blood by activity of antithrombin III against activated clotting factors as (IIa, IXa, Xa, XIIa) inhibits blood clotting. LMWH acts via increasing activity of antithrombin III against activated clotting factor Xa . MECHANISM OF ACTION OF UFH MECHANISM OF ACTION OF UFH & LMWH Heparin Free Heparin Pharmacokinetics of UFH Given only parenerally (S.C. or I.V) Not I.M (hematoma). Immediate anticoagulant effect (t ½ = 60 - 90 min). Metabolized in the liver (80 %) - 20 % excreted unchanged in urine (not by microsomes). Does not cross placenta & not excreted in milk. Low Molecular Weight Heparin (LMWH) Enoxaparin – Dalteparin -Danaproid. prepared by chemical or enzymatic depolymerization of UFH LMWHs are antithrombin III-dependent Administration: S.C. in- & out-hospital LMW heparins 1. Increased bioavailability 2. Longer biological half life. 3. Less frequent dosing requirements 4. Doses are specified in milligrams 5. Favorable pharmacokinetic characters. 6. predictable anticoagulant effect 7. No dose adjustment or monitoring 8. Less incidence of bleeding and thrombocytopenia. Pharmacological Actions 1. Heparin& LMWH have anticoagulant activity in vivo & in vitro. Control of Therapy Unfractionated heparin (UFH) 1. Activated partial thromboplastin time (aPTT) 1.5 - 2.5 times that of the normal value (30 sec). 2. Whole blood clotting time (WBCT): 2 - 3 times the normal value (5 - 7 min). LMWH estimation of plasma factor Xa. Side Effects of Heparin 1. 2. 3. 4. Bleeding Thrombocytopenia & Thrombosis Hypersensitivity reactions: (Antigenicity due to animal source) rarely occurring reactions include urticaria, rash, rhinitis. Reversible alopecia & osteoporosis (long term, for 6 months or longer). Heparin-induced thrombocytopenia (HIT) is an immune reaction that occurs in up to 3% of patients on heparin therapy for 5-14 days due to formation of IgM & IgG against heparin-PF4 complex Platelet count is required. Lower risk with LMWH Treated by 1. 2. Heparin discontinuation Direct thrombin inhibitor is used Heparin antidote Protamine sulphate Basic peptide Given I.V. slowly (1 mg / 100 U heparin). Excess protamine should be avoided since it has anticoagulant effect. Uses of heparin for the prevention of 1. Pulmonary embolism. 2. Deep vein thrombosis. 3. Post-operative venous thrombosis. 4. Stroke. 5. Myocardial infarction. 6. Hemodialysis. 7. Reduction of coronary artery thrombosis after thrombolytic treatment 8. Anticoagulant of choice in pregnant women Contraindications of heparin 1. 2. 3. 4. 5. 6. 7. 8. 9. Hemophilia, thrombocytopenia. Severe hypertension. Intra cranial hemorrhage. Threatened abortion Ulcerative lesions of GIT. Threatened abortion. Advanced hepatic or renal disease. Hypersensitivity to heparin. Patients who have had surgery of CNS, eye or spinal cord. Differences HMWH LMWH activity of a antithrombin III against active factor II, IX, X, XI, and XII. activity of antithrombin III against Xa High Low thrombocytopenia High Low T½ Short Long ( double ) Bioavailability Low High Control of dose aPTT, WBC. Plasma factor Xa Administration 3 - 4 dose / day ( I.V. or S.C ) 1 - 2 dose / day S.C. only Efficacy Equal Equal MW 5000 - 30.000 2000 - 9000 Bleeding tendency Direct Thrombin Inhibitor anticoagulants Lepirudin-Bivalirudin acts via direct binding to active site on activated factor II (thrombin) is antithrombin III- independent. Prepared by recombinant DNA technology Given I.V. Has short duration of action (1 hr) Used for treatment of thrombosis in HIT patients. Lepirudin Is accumulated in renal insufficiency. It is monitored by aPTT No antagonists are available. ORAL ANTICOAGULANTS Coumarin anticoagulants e.g. warfarin Warfarin Mechanism of action Warfarin is vitamin K antagonist (vitamin K epoxide reductase inhibitor). Reduced vitamin K is required for γ-carboxylation of glutamate residues in clotting factors. Warfarin acts by inhibiting the activation of several clotting factors (II, VII, IX, X ) by blocking γ-carboxylation of glutamate residues in clotting factors in the liver. This results in the production of inactive clotting factors lacking ɣ-carboxyglutamyl residues vitamin K reductase The reduced vit K is converted into vitamin K epoxide which is reduced back by vitamin K reductase the target enzyme which warfarin inhibits Pharmacokinetics Taken orally. Highly bound to plasma protein (low Vd). Long plasma half life (36 h). Cross placenta (# pregnancy). Metabolized in the liver by cytochrome P450 Excreted in urine and stool. Delayed onset of action (8-12 h). Acts in vivo only. Side effects 1. 2. 3. 4. 5. slow onset of action Hemorrhage : treated by vitamin K 1 Soft tissue necrosis Drug interactions Teratogenicity: hemorrhagic disorder abnormal bone formation in the fetus. Warfarin Drug interactions Warfarin action is increased by: Broad spectrum antibiotics Cyt P450 inhibitors: Cimetidine, erythromycin Aspirin Diseases Hyperthyroidism & liver disease Warfarin Drug interactions Warfarin action is decreased by Cyt P450 inducers: Phenobarbitone, rifampicin, phenytoin Contraindications Pregnancy Hypoprothrombinemia (Liver disease). Overdose of warfarin Treated by vitamin K Control of warfarin Therapy Prothrombin time (PT) Time required for plasma clotting with calcium and thromboplastin (10-12 seconds) 2-4 times expressed as INR International normalized ratio (INR) Ratio between patients PT and standard PT (2-4). Uses for Maintenance of anticoagulant activity. Uses of anticoagulants for the prevention of 1. 2. 3. 4. 5. Pulmonary embolism recurrence Deep vein thrombosis Post - operative venous thrombosis Stroke Myocardial infarction 6. During hemodialysis 7. Unstable angina Heparin (LMW) for short term action Warfarin is used for prolonged therapy Contraindications of anticoagulants 1. 2. 3. 4. 5. 6. 7. 8. 9. Hemophilia, thrombocytopenia. Severe hypertension. Intra cranial hemorrhage. Threatened abortion Ulcerative lesions of GIT. Threatened abortion. Advanced hepatic or renal disease. Hypersensitivity to heparin. Patients who have had surgery of CNS, eye or spinal cord.