心血管治疗药物综述课件

PharmacologyDrugsthatAffecttheCardiovascularSystemTopicsElectrophysiologyVaughn-WilliamsclassificationAntihypertensivesHemostaticagentsCardiacFunctionDependentuponAdequateamountsofATPAdequateamountsofCa++CoordinatedelectricalstimulusAdequateAmountsofCalciumCalciumis‘glue’thatlinkselectricalandmechanicalevents.CoordinatedElectricalStimulationHeartcapableofautomaticityTwotypesofmyocardialtissueContractileConductiveImpulsestravelthrough‘actionpotentialsuperhighway’.A.P.SuperHighwaySinoatrialnodeAtrioventricularnodeBundleofHisBundleBranchesFasciclesPurkinjeNetworkFastPotential-80-60-40-200+20RMP-80to90mVPhase1Phase2Phase3Phase4controlledbyNa+channels=“fastchannels”FastPotentialPhase0:Na+influx“fastsodiumchannels”Phase1:K+effluxPhase2:(Plateau)K+effluxANDCa++influxPhase3:K+effluxPhase4:RestingMembranePotentialCardiacConductionCycleSlowPotentialSelf-depolarizingResponsibleforautomaticityPhase4depolarization‘slowsodium-calciumchannels’‘leaky’tosodiumPhase3repolarizationK+effluxCardiacPacemakerDominanceIntrinsicfiringrates:SA=60–100AV=45–60Purkinje=15-45CardiacPacemakersSAisprimaryFasterdepolarizationrateFasterCa++‘leak’Othersare‘backups’GraduateddepolarizationrateGraduatedCa++leakrateDysrhythmiaGenerationAbnormalgenesisImbalanceofANSstimuliPathologicphase4depolarizationEctopicfociDysrhythmiaGenerationAbnormalconductionAnalogies:OnewayvalveBuggiesstuckinmuddyroadsReentrantCircuitsAHARecommendationClassificationsDescribesweightofsupportingevidenceNOTmechanismClassIClassIIaClassIIbIndeterminantClassIIIViewAHAdefinitionsVaughn-WilliamsClassificationClass1IaIbIcClassIIClassIIIClassIVMiscDescriptionofmechanismNOTevidenceClassI:SodiumChannelBlockersDecreaseNa+movementinphases0and4Decreasesrateofpropagation(conduction)viatissuewithfastpotential(Purkinje)Ignoresthosewithslowpotential(SA/AV)Indications:ventriculardysrhythmiasClassIbAgentsSlowconductionthroughventriclesIncreaserateofrepolarizationReduceautomaticityEffectiveforectopicfociMayhaveotherusesLTMD:lidocaine(Xylocaine®)tocainide(Tonocard®)mexiletine(Mexitil®)phenytoin(Dilantin®)ClassIcAgentsSlowconductionthroughventricles,atria&conductionsystemDecreaserepolarizationrateDecreasecontractilityRarelastchancedrugflecainide(Tambocor®)propafenone(Rythmol®)ClassIII:PotassiumChannelBlockersDecreasesK+effluxduringrepolarizationProlongsrepolarizationExtendseffectiverefractoryperiodPrototype:bretylliumtosylate(Bretylol®)Initialnorepidischargemaycausetemporaryhypertension/tachycardiaSubsequentnorepidepletionmaycausehypotensionClassIV:CalciumChannelBlockersSimilareffectasßblockersDecreaseSA/AVautomaticityDecreaseAVconductivityUsefulinbreakingreentrantcircuitPrimesideeffect:hypotension&bradycardiaverapamil(Calan®)diltiazem(Cardizem®)Note:nifedipinedoesn’tworkonheartMisc.Agentsadenosine(Adenocard®)DecreasesCa++influx&increasesK+effluxvia2ndmessengerpathwayHyperpolarizationofmembraneDecreasedconductionvelocityviaslowpotentialsNoeffectonfastpotentialsProfoundsideeffectspossible(butshort-lived)Misc.AgentsCardiacGlycocidesdigoxin(Lanoxin®)InhibitsNaKATPpumpIncreasesintracellularCa++viaNa+-Ca++exchangepumpIncreasescontractilityDecreasesAVconductionvelocityPharmacologyAntihypertensivesAntihypertensiveClassesdiureticsbetablockersangiotensin-convertingenzyme(ACE)inhibitorscalciumchannelblockersvasodilatorsBloodPressure=COXPVRCardiacOutput=SVxHRPVR=AfterloadBP=COxPVRKey:CCB=calciumchannelblockersCAAdrenergics=central-actingadrenergicsACEi’s=angiotensin-convertingenzymeinhibitorscardiacfactorscirculatingvolumeheartratecontractility1.BetaBlockers2.CCB’s3.C.A.AdrenergicssaltaldosteroneACEi’sDiureticsBP=COxPVRHormones1.vasodilators2.ACEI’s3.CCB’sCentralNervousSystem1.CAAdrenergicsPeripheralSympatheticReceptorsalpha

beta1.alphablockers2.betablockersLocalActing1.Peripheral-ActingAdrenergicsAlpha1BlockersStimulatealpha1receptors->hypertensionBlockalpha1receptors->hypotensiondoxazosin(Cardura®)prazosin(Minipress®)terazosin(Hytrin®)CentralActingAdrenergicsStimulatealpha2receptorsinhibitalpha1stimulationhypotensionclonidine(Catapress®)methyldopa(Aldomet®)PeripheralActingAdrenergicsreserpine(Serpalan®)inhibitsthereleaseofNEdiminishesNEstoresleadstohypotensionProminentsideeffectofdepressionalsodiminishesseratoninAdrenergicSideEffectsCommondrymouth,drowsiness,sedation&constipationorthostatichypotensionLesscommonheadache,sleepdisturbances,nausea,rash&palpitationsAngiotensinIACEAngiotensinII1.potentvasoconstrictor-increasesBP2.stimulatesAldosterone-Na+&H2OreabsorbtionACEInhibitors.RAASRenin-AngiotensinAldosteroneSystemAngiotensinII=vasoconstrictorConstrictsbloodvessels&increasesBPIncreasesSVRorafterloadACE-IblockstheseeffectsdecreasingSVR&afterloadACEInhibitorsAldosteronesecretedfromadrenalglandscausesodium&waterreabsorptionIncreasebloodvolumeIncreasepreloadACE-IblocksthisanddecreasespreloadAngiotensinConvertingEnzymeInhibitorscaptopril(Capoten®)enalapril(Vasotec®)lisinopril(Prinivil®&Zestril®)quinapril(Accupril®)ramipril(Altace®)benazepril(Lotensin®)fosinopril(Monopril®)CalciumChannelBlockersUsedfor:AnginaTachycardiasHypertensionCCBSiteofActiondiltiazem&verapamilnifedipine(andotherdihydropyridines)CCBActiondiltiazem&verapamildecreaseautomaticity&conductioninSA&AVnodesdecreasemyocardialcontractilitydecreasedsmoothmuscletonedecreasedPVRnifedipinedecreasedsmoothmuscletonedecreasedPVRSideEffectsofCCBsCardiovascularhypotension,palpitations&tachycardiaGastrointestinalconstipation&nauseaOtherrash,flushing&peripheraledemaCalciumChannelBlockersdiltiazem(Cardizem®)verapamil(Calan®,Isoptin®)nifedipine(Procardia®,Adalat®)DiureticSiteofAction.loopofHenleproximaltubuleDistaltubuleCollectingductMechanismWaterfollowsNa+20-25%ofallNa+isreabsorbedintothebloodstreamintheloopofHenle5-10%indistaltubule&3%incollectingductsIfitcannotbeabsorbeditisexcretedwiththeurineBloodvolume=preload!SideEffectsofDiureticselectrolytelosses[Na+&K+]fluidlosses[dehydration]myalgiaN/V/DdizzinesshyperglycemiaDiureticsThiazides:chlorothiazide(Diuril®)&hydrochlorothiazide(HCTZ®,HydroDIURIL®)LoopDiureticsfurosemide(Lasix®),bumetanide(Bumex®)PotassiumSparingDiureticsspironolactone(Aldactone®)MechanismofVasodilatorsDirectlyrelaxesarteriolesmoothmuscleDecreaseSVR=decreaseafterloadSideEffectsofVasodilatorshydralazine(Apresoline®)Reflextachycardiasodiumnitroprusside(Nipride®)CyanidetoxicityinrenalfailureCNStoxicity=agitation,hallucinations,etc.Vasodilatorsdiazoxide[Hyperstat®]hydralazine[Apresoline®]minoxidil[Loniten®]sodiumNitroprusside[Nipride®]PharmacologyDrugsAffectingHemostasisHemostasisReproducefigure11-9,page359SherwoodPlateletAdhesionCoagulationCascadeReproducefollowingcomponentsofcascade:Prothrombin->thrombinFibrinogen->fibrinPlasminogen->plasminPlateletInhibitorsInhibittheaggregationofplateletsIndicatedinprogressingMI,TIA/CVASideEffects:uncontrolledbleedingNoeffectonexistingthrombiAspirinInhibitsCOXArachidonicacid(COX)->TXA2(aggregation)GPIIB/IIIAInhibitorsGPIIb/IIIaInhibitorsFibrinogenGPIIb/IIIaReceptorGPIIB/IIIAInhibitorsabciximab(ReoPro®)eptifibitide(Integrilin®)tirofiban(Aggrastat®)AnticoagulantsInterruptclottingcascadeatvariouspointsNoeffectonplateletsHeparin&LMWHeparin(Lovenox®)warfarin(Coumadin®)HeparinEndogenousReleasedfrommastcells/basophilsBindswithantithrombinIIIAntithrombinIIIbindswithandinactivatesexcessthrombintoregionalizeclottingactivity.Mostthrombin(80-95%)capturedinfibrinmesh.Antithrombin-heparincomplex1000XaseffectiveasantithrombinIIIaloneHeparinMeasuredinUnits,notmilligramsIndications:MI,PE,DVT,ischemicCVAAntidoteforheparinOD:protamine.MOA:heparinisstronglynegativelycharged.Protamineisstronglypositivelycharged.warfarin(Coumadin®)FactorsII,VII,IXandXallvitaminKdependentenzymesWarfarincompeteswithvitaminKinthesynthesisoftheseenzymes.Depletesthereservesofclottingfactors.Delayedonset(~12hours)duetoexistingfactorsThrombolyticsDirectlybreakupclotsPromotenaturalthrombolysisEnhanceactivationofplasminogen‘TimeisMuscle’streptokinase(Streptase®)alteplase(tPA®,Activase®)anistreplase(Eminase®)reteplase(Retevase®)tenecteplase(TNKase®)OcclusionMechanismtPAMechanismCholesterolMetabolismCholesterolimportantcomponentinmembranesandashormoneprecursorSynthesizedinliverHydroxymethylglutarylcoenzymeAreductase(HMGCoAreductase)dependantStoredintissuesforlatteruseInsolubleinplasma(atypeoflipid)MusthavetransportmechanismLipoproteinsLipidsaresurroundedbyproteincoatto‘hide’hydrophobicfattycore.Lipoproteinsdescribedbydensit