抗凝和溶栓2课件

1、Anticoagulants and ThrombolyticsS. RamakrishnanObjectives To learn how Blood Clots are formed. How the blood clots are broken down ? What drugs can be used to regulate clotting ? How to rectify clotting deficienciesBlood clots - ThrombusThrombus dislodge from arteries and veins and become an embolus

2、.Venous emboli can block arterioles in the lung and pulmonary circulationThromboembolism Classes of Drugs Prevent coagulation Dissolve clots Prevent bleeding and hemorrhage - Hemostatic Overcome clotting deficiencies ( replacement therapies)Blood Clotting Vascular Phase Platelet Phase Coagulation Ph

3、ase Fibrinolytic PhasePlatelet phase Non-nucleated - arise from magakaryocytes blood vessel wall (endothelial cells) prevent platelet adhesion and aggregation platelets contain receptors for fibrinogen and von Willebrand factor after vessel injury Platelets adhere and aggregate. Release permeability

4、 increasing factors (e.g. vascular permeability factor, VPF) Loose their membrane and form a viscous plug Platelets and ThromboemolismArteries : White ThrombusPlatelets adhereRelease ADPMore adhesion/ aggregation Reduced blood flow (stasis)Fibrin clotVeins low pressure : Red thrombus is formedEspeci

5、ally in valve pocketsContains a long tail of fibrinCan detach and form emboliIntrinsic PathwayAll clotting factors are within the blood vesselsClotting slower Activated partial thromboplastin test (aPTT) Extrinsic PathwayInitiating factor is outside the blood vessels - tissue factorClotting - faster

6、 - in SecondsProthrombin test (PT)Prothrombin time (PT)Tissue Thromboplastin factor IIIMix with phospholipid extractAdd calcium and blood sampleDetermine clotting timeGenerally 12 - 14 secondsUsed to detect defects in extrinsic pathwayActivated partial thromboplastin time (APTT)Blood sample + EDTA o

7、r CitrateNo clot ( recalcification will result in clot in about 2 - 4 min)Add calciumMix with negatively charged phospholipidKaoline (aluminum silicate)Determine clotting time Generally clotting occurs in 26 to 33 secondsUsed to detect defects in the intrinsic pathwayBlood Vessel InjuryIX IXaXI XIaX

8、 XaXII XIIaTissue InjuryTissue FactorThromboplastinVIIa VIIX ProthrombinThrombinFibrinogenFribrin monomerFibrin polymerXIIIIntrinsic PathwayExtrinsic PathwayFactors affectedBy HeparinVit. K dependent FactorsAffected by Oral Anticoagulants ActivationInactive XIActive XIaXIIa+Anticoagulant drugs to tr

9、eat thromboembolismDrug ClassPrototypeActionEffectAnticoagulantParenteralHeparinInactivation of clottingFactorsPrevent venousThrombosisAnticoagulantOralWarfarinDecrease synthesis ofClotting factors Prevent venousThrombosisAntiplateletdrugsAspirinDecrease plateletaggregationPrevent arterialThrombosis

10、Thrombolytic DrugsStreptokinaseFibinolysisBreakdown ofthrombiHeparinSulphated carbohydratePurified from bovine lungsDifferent sizeActive in vitro and in vivoAdministration - parenteral- Do not inject IM - only IV or deep s.c. Half-life 1 - 5 hrs - monitor aPTTAdverse effect - hemorrhage - antidote -

11、 protamine sulphateHeparin mechanism of actionHeparinAntithrombin IIIThrombinOral anticoagulants : warfarin, dicumarolCoumarins - warfarin, dicumarolIsolated from clover leavesStructurally related to vitamin KInhibits production of active clotting factorsAbsorption rapid - binds to albuminClearance

12、is slow - 36 hrs Delayed onset 8 - 12 hrsOverdose - reversed by vitamin K infusionCan cross placenta - do not use during late pregnanciesMechanism of actionDescarboxy ProthrombinProthrombinReduced Vitamin KOxidized Vitamin KNADHNADWarfarinAntiplatelet drugsAspirinPrevents platelet aggregation /adhes

13、ionClinical use - prevents arterial thrombusMyocardial infarction (MI), stroke, heart valve replacement and shunts Other antiplatelet drugs are - Dipyridamole, sulfinpyrazone and TiclopidineProphylactic use of AspirinLow dose daily ( 180 mg/day)Prevents ischemic attack (ministroke) and MI335 mg/day

14、reduced the risk of heart attack in patients over 50More than 1000 mg/day NO EFFECTHigh dose inhibits prostacyclin synthesis in cells surrounding vessels. PS normally prevents platelet aggregation. Therefore, inhibition of PS leads to abrogation of the prophylactic benefit of Aspirin Contraindicatio

15、n - DO NOT give to patients with glucose 6-PO4 dehydrogenase deficiency Drug interaction- prototype Warfarin Drugs that Increase Warfarin ActivityDecrease binding toAlbuminInhibit DegradationDecrease synthesis ofClotting FactorsAspirin, SulfonamidesCimetidine, Disulfiram Antibiotics (oral)Category M

16、echanism Representative DrugsFibrinolysis Enhance degradation of clotsActivation of endogenous proteasePlasminogen (inactive form) is converted to Plasmin (active form)Plasmin breaks down fibrin clotsFibrinolysisExogenously administered drugsStreptokinase - bacterial product - continuous use - immun

17、e reaction Urokinase - human tissue derived - no immune responseTissue plasminogen activator (tPA) - genetically cloned - no immune reaction - EXPENSIVE Inhibitors of fibrinolysis - aminocaproic acidLysine analog- inhibits proteasesDrug preparations : To reduce clottingHeparin (generic, Liquaemin so

18、dium)Parenteral - 1000 - 40,000 U/ml Warfarin (generic , Coumadin)Oral : 2 - 20 mg tablets Dipyridamole (Persantine)Oral : 25,50,75 mg tabletsDrug preparations : to lyse clotsAlteplase recombinant (tPA, Activase) 20, 50 mg Lyophilized powder - reconstitute for iv streptokinase (Kabikinase, streptase)Parenteral : 250000 - 1.5 million units per vial . Lyophilized powder. Reconstitute for iv Urokinase ( Abbokinase)Parenteral : 250000 units per vial. Powder to reconstitute to 5000 u/ml for in