1Dr. Stephen LamDepartment of PharmacologyCollege of Medicine East, Room [email protected] Drugs• Hemostasis: physiological process toarrest the blood loss from injured bloodvessels• Thrombosis: pathological complicationsresulting in the formation of occludingthrombi2Platelet Aggregation Blood CoagulationThrombus Formation3The Coagulation Pathways• Serine proteases• Zymogens• Cascades ofpreoteolytic reactions• Thrombin generation• Fibrinogen → Fibrin• Extrinsic• IntrinsicThrombosis• Formation of occluding thrombi• Heart – myocardial infarction• Brain – stroke• Leading cause of death• High incidence groups – prevention4Anti-thrombotic therapyAnti-coagulant and anti-platelet therapy:• Prevent thrombus formation• Prevent propagationThrombolytic therapy:• Lysis of existing thrombiAnticoagulants• Heparin• Coumarins (oral anticoagulants)5Heparin• Anionic mucopolysaccharide• Glycosaminoglycans• Activate anti-thrombin III (AT III)Anti-thrombin III6Heparin Action on Anti-thrombin IIIHeparin• Highly charged, crosses membranes poorly• Administered parenterally• Does not cross placenta, given during pregnancy• Cleared by the reticuloendothelial system• Metabolized by the liver• Half-life (0.5-2.5 h) depends on dosage• Non-toxic• Minor side effects: allergy, alopecia, osteoporosis• Major side effects: hemorrhage, thrombocytopenia• Alternate therapy: Danaparoid, Lepirudin• Antidote: protamine sulfate7Heparin-induced Thrombocytopenia (HIT)• Platelet Factor 4 (PF4) released by activatedplatelets• Heparin binds to PF4• Antibodies against the Heparin-PF4 complex aregenerated• Anti-Heparin-PF4 antibodies activate plateletsthrough platelet Fc receptors• Spontaneous thrombus formationHeparin Dosage• Full dosetreatment of venous thromboembolismintravenous: bolus injection 5,000 units followedby 700-2,000 units/h by infusion pump deliverysubcutaneous: 7,500-15,000 units/12 hmonitored by aPTT – intrinsic coagulation26-30 sec → 50-70 sec• Low doseprevent deep vein thombosis, thromboembolismsubcutaneously 5,000 units/8-12 hdoes not affect aPTT8Oral Anticoagulants (Coumarins)The Coagulation Pathways• Serine proteases• Zymogens• Cascades ofpreoteolytic reactions• Thrombin generation• Fibrinogen → Fibrin• Extrinsic• Intrinsic9The Gla Domain of Clotting FactorsCoagulation Complexes on Phospholipids10Mode of Action of WarfarinWarfarin• Given orally for prevention of thromboembolism• Peak concentrations reached within 1 h• A lag phase for effectiveness• In plasma, 99% bound to albumin• Drugs competes warfarin binding to proteins arecontradictive• Metabolized by liver; half-life ~ 36 h• Crosses placenta, NOT given during pregnancy• Major side effect is hemorrhage• Dosage for adults: 10-15 mg/day for 2-4 daysfollowed by 2-15 mg/day depending on PT time• Antidote: vitamin K, Plasma
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