1LamAnti-thrombotic DrugsHemostasis - spontaneous arrest of blood loss from injured blood vessels.Thrombosis - a pathological process in which thrombi occlude blood flow to vital organs.Activation of: 1). Platelets 2). Blood coagulation factorsThe coagulation pathways: S Coagulation factors are plasma glycoproteins produced by hepatocytes. S Most are serine proteases in an inactive zymogen form that is converted to the active formby proteolytic cleavage of a specific peptide bond. S In the coagulation cascade, an active coagulation factor cleaves and activates its substrate.The goal of the coagulation cascades is to convert soluble fibrinogen to insoluble fibrin. S Extrinsic pathway - activated by tissue factor expression. S Intrinsic pathway - activated by contact of Factor XII with an anionic surface (collagen). S Platelet procoagulant activity is required for efficient blood clotting. Platelets provide aphospholipid surface for the assembly of Ca2+-dependent coagulation complexes. S Thrombin in turn activates platelets to aggregate. S Platelet activation and blood coagulation are inter-dependent events for clot formation.Platelet Aggregation Coagulation2Thrombosis S The formation of occluding blood clots in blood vessels. S The leading cause of death in developed countries (e.g., myocardial infarction, stroke,pulmonary embolism). S High incidence in patients over 40 especially after hip, knee and prostate surgery. S In veins, red thrombi due to trapped red cells. S In arteries, white thrombi with no trapped red cells.Therapeutic aims of thrombosis:1). prevent propagation if already present2). prevent thrombus formation in high risk group3). Lyse existing thrombiAnti-coagulation and anti-platelet therapy are directed towards aims 1 and 2.Thrombolytic therapy with plasminogen activators is directed towards aim 3.Anticoagulants: 1). Heparin32). Coumarins (oral anticoagulants)HeparinHeparin is a heterogeneous group of anionic mucopolysaccharide called glycosaminoglycans withmolecular weight ranging from 3-100 kDa (average 15 kDa).Modeof action: Once the coagulation pathways are activated, FactorIXa, Xa, XIa, XIIa, and thrombin need to beneutralized by anti-thrombin III (AT III). Heparinaccelerates the interaction of the active clottingfactors with AT III. The negatively charged heparinmolecule binds to the positively charged lysine siteson AT III, causing a conformational change of AT IIIand exposing its reactive arginine site. The serineactive sites of the active clotting factors bind to thereactive arginine site of AT III, and the complex isremoved by the reticuloendothelial system.4Absorption and clearance: S Heparin is highly charged, crosses membranes poorly, given parenterally. S low dose: subcutaneous or intrafat injection S high dose: intravenous or subcutaneous injection, monitored by aPTT (2x increase) S Heparin does not cross placenta, given during pregnancy.: S taken up by the reticuloendothelial system, metabolized by the liver. S Half-life (0.5 - 2.5 h) depends on dosage. S Patients with high titre of active clotting factor require high dose given by continuous orintermittent injection.Side effect: S Non toxic, mild allergic reaction may be encountered. S Alopecia S Osteoporosis upon prolonged use. S Hemorrhage. Use protamine sulfate (a highly basic peptide) as antidote. S Do not use with anti-platelet drugs. S Heparin-induced thrombocytopenia. Monitored platelet counts and discontinue use ifencountered. Incidence is lower with LMW heparin. S Thrombotic complications - venous thromboembolism and arterial thrombosis. Heparinbinds to platelet factor 4 released by platelets. IgG antibodies against the heparin-plateletfactor 4 complex activates platelets to aggregate through Fc receptors.Oral Anticoagulants (coumarins)5Mode of action:Several coagulation factors (Factor II, VII, IX and X) and two anti-clotting proteins in blood (proteinC and S) contain γ-carboxylglutamic acid (Gla) which is formed by post-translational modificationof glutamic acid (Gla) involving a vitamin K-dependent reaction. The Gla residues on these clottingfactors interact with Ca2+ to promote the formation of coagulation complexes on phospholipid (PL)surfaces. Activated platelets provide the PL surfaces in the form of microparticles (see handout onplatelet lecture). As a result, the activation of Factor X by Factor IXa in the presence of Ca2+, PLand Factor VIII, and the activation of prothrombin to thrombin by Factor X in the presence of Ca2+,PL and Factor V are greatly accelerated.Vitamin K exists in two forms, the reduced KH2 and theoxidized KO forms. KH2 is the active coenzyme formodification of Glu to Gla in the clotting factors, and KH2 isconverted to KO in this reaction. The reductases responsiblefor the reduction of KO back to KH2 are inhibited bycoumarins, thus trapping the vitamin K in the inactive KOform. Newly synthesized clotting factors will beundercarboxylated.Absorption and clearance:6 S Given orally. S Warfarin sodium is rapidly and completely absorbed. Peak concentration in plasma isreached within 1 h of ingestion. Food decreases the rate but not extent of adsorption. S After drug ingestion, there is a lag phase depending on the turnover of existing clottingfactors in blood. S In plasma, 99% is bound to albumin. Only the free form is active. Drugs (e.g.,phenylbutazone) that compete with warfarin binding to proteins are dangerous because atransient increase of free warfarin may occur. S Warfarin is metabolized by the liver with an average half life of 36 h, but there are largevariations among individuals.Side effects S Uricosuria S Increased SGOT and LDH enzymes in blood S Anorexia S Nausea S Decrease in osteocalcin (also a vitamin K-dependent protein) S Most serious side effect is hemorrhage - treated with vitamin K and plasma infusion. S Usually not given with anti-platelet drugs, except with dipyridamole to preventthromboembolism in patients with prosthetic heat
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