心血管治療藥物綜述

心血管治療藥物綜述第1頁(yè)/共83頁(yè)P(yáng)harmacologyDrugsthatAffecttheCardiovascularSystem第2頁(yè)/共83頁(yè)TopicsElectrophysiologyVaughn-WilliamsclassificationAntihypertensivesHemostaticagents第3頁(yè)/共83頁(yè)CardiacFunctionDependentuponAdequateamountsofATPAdequateamountsofCa++Coordinatedelectricalstimulus第4頁(yè)/共83頁(yè)AdequateAmountsofATPNeededto:MaintainelectrochemicalgradientsPropagateactionpotentialsPowermusclecontraction第5頁(yè)/共83頁(yè)AdequateAmountsofCalciumCalciumis‘glue’thatlinkselectricalandmechanicalevents.第6頁(yè)/共83頁(yè)CoordinatedElectricalStimulationHeartcapableofautomaticityTwotypesofmyocardialtissueContractileConductiveImpulsestravelthrough‘a(chǎn)ctionpotentialsuperhighway’.第7頁(yè)/共83頁(yè)A.P.SuperHighwaySinoatrialnodeAtrioventricularnodeBundleofHisBundleBranchesFasciclesPurkinjeNetwork第8頁(yè)/共83頁(yè)ElectrophysiologyTwotypesofactionpotentialsFastpotentialsFoundincontractiletissueSlowpotentialsFoundinSA,AVnodetissues第9頁(yè)/共83頁(yè)FastPotential-80-60-40-200+20RMP-80to90mVPhase1Phase2Phase3Phase4controlledbyNa+channels=“fastchannels”第10頁(yè)/共83頁(yè)FastPotentialPhase0:Na+influx“fastsodiumchannels”Phase1:K+effluxPhase2:(Plateau)K+effluxANDCa++influxPhase3:K+effluxPhase4:RestingMembranePotential第11頁(yè)/共83頁(yè)CardiacConductionCycle第12頁(yè)/共83頁(yè)SlowPotential-80-60-40-200Phase4Phase3dependentuponCa++channels=“slowchannels”第13頁(yè)/共83頁(yè)SlowPotentialSelf-depolarizingResponsibleforautomaticityPhase4depolarization‘slowsodium-calciumchannels’‘leaky’tosodiumPhase3repolarizationK+efflux第14頁(yè)/共83頁(yè)CardiacPacemakerDominanceIntrinsicfiringrates:SA=60–100AV=45–60Purkinje=15-45第15頁(yè)/共83頁(yè)CardiacPacemakersSAisprimaryFasterdepolarizationrateFasterCa++‘leak’Othersare‘backups’GraduateddepolarizationrateGraduatedCa++leakrate第16頁(yè)/共83頁(yè)P(yáng)otentialTermsAPDERPRRPrelativerefractoryperiodeffectiverefractoryperiodactionpotentialduration第17頁(yè)/共83頁(yè)DysrhythmiaGenerationAbnormalgenesisImbalanceofANSstimuliPathologicphase4depolarizationEctopicfoci第18頁(yè)/共83頁(yè)DysrhythmiaGenerationAbnormalconductionAnalogies:OnewayvalveBuggiesstuckinmuddyroads第19頁(yè)/共83頁(yè)ReentrantCircuits第20頁(yè)/共83頁(yè)Warning!AllantidysrhythmicshavearrythmogenicpropertiesInotherwords,theyallcanCAUSEdysrhythmiastoo!第21頁(yè)/共83頁(yè)AHARecommendationClassificationsDescribesweightofsupportingevidenceNOTmechanismClassIClassIIaClassIIbIndeterminantClassIIIViewAHAdefinitions第22頁(yè)/共83頁(yè)Vaughn-WilliamsClassificationClass1IaIbIcClassIIClassIIIClassIVMiscDescriptionofmechanismNOTevidence第23頁(yè)/共83頁(yè)ClassI:SodiumChannelBlockersDecreaseNa+movementinphases0and4Decreasesrateofpropagation(conduction)viatissuewithfastpotential(Purkinje)Ignoresthosewithslowpotential(SA/AV)Indications:ventriculardysrhythmias第24頁(yè)/共83頁(yè)ClassIaAgentsSlowconductionthroughventriclesDecreaserepolarizationrateWidenQRSandQTintervalsMaypromoteTorsadesdesPointes!PDQ:procainamide(Pronestyl?)disopyramide(Norpace?)qunidine(Quinidex?)第25頁(yè)/共83頁(yè)ClassIbAgentsSlowconductionthroughventriclesIncreaserateofrepolarizationReduceautomaticityEffectiveforectopicfociMayhaveotherusesLTMD:lidocaine(Xylocaine?)tocainide(Tonocard?)mexiletine(Mexitil?)phenytoin(Dilantin?)第26頁(yè)/共83頁(yè)ClassIcAgentsSlowconductionthroughventricles,atria&conductionsystemDecreaserepolarizationrateDecreasecontractilityRarelastchancedrugflecainide(Tambocor?)propafenone(Rythmol?)第27頁(yè)/共83頁(yè)ClassII:BetaBlockersBeta1receptorsinheartattachedtoCa++channelsGradualCa++influxresponsibleforautomaticity Beta1blockadedecreasesCa++influxEffectssimilartoClassIV(Ca++channelblockers)Limited#approvedfortachycardias第28頁(yè)/共83頁(yè)ClassII:BetaBlockerspropranolol(Inderal?)acebutolol(Sectral?)esmolol(Brevibloc?)第29頁(yè)/共83頁(yè)ClassIII:PotassiumChannelBlockersDecreasesK+effluxduringrepolarizationProlongsrepolarizationExtendseffectiverefractoryperiodPrototype:bretylliumtosylate(Bretylol?)Initialnorepidischargemaycausetemporaryhypertension/tachycardiaSubsequentnorepidepletionmaycausehypotension第30頁(yè)/共83頁(yè)ClassIV:CalciumChannelBlockersSimilareffectas?blockersDecreaseSA/AVautomaticityDecreaseAVconductivityUsefulinbreakingreentrantcircuitPrimesideeffect:hypotension&bradycardiaverapamil(Calan?)diltiazem(Cardizem?)Note:nifedipinedoesn’tworkonheart第31頁(yè)/共83頁(yè)Misc.Agentsadenosine(Adenocard?)DecreasesCa++influx&increasesK+effluxvia2ndmessengerpathwayHyperpolarizationofmembraneDecreasedconductionvelocityviaslowpotentialsNoeffectonfastpotentialsProfoundsideeffectspossible(butshort-lived)第32頁(yè)/共83頁(yè)Misc.AgentsCardiacGlycocidesdigoxin(Lanoxin?)InhibitsNaKATPpumpIncreasesintracellularCa++viaNa+-Ca++exchangepumpIncreasescontractilityDecreasesAVconductionvelocity第33頁(yè)/共83頁(yè)P(yáng)harmacologyAntihypertensives第34頁(yè)/共83頁(yè)AntihypertensiveClassesdiureticsbetablockersangiotensin-convertingenzyme(ACE)inhibitorscalciumchannelblockersvasodilators第35頁(yè)/共83頁(yè)BloodPressure=COXPVRCardiacOutput=SVxHRPVR=Afterload第36頁(yè)/共83頁(yè)BP=COxPVRKey:CCB=calciumchannelblockersCAAdrenergics=central-actingadrenergicsACEi’s=angiotensin-convertingenzymeinhibitorscardiacfactorscirculatingvolumeheartratecontractility1.BetaBlockers2.CCB’s3.C.A.AdrenergicssaltaldosteroneACEi’sDiuretics第37頁(yè)/共83頁(yè)BP=COxPVRHormones1.vasodilators2.ACEI’s3.CCB’sCentralNervousSystem1.CAAdrenergicsPeripheralSympatheticReceptorsalpha

beta1.alphablockers2.betablockersLocalActing1.Peripheral-ActingAdrenergics第38頁(yè)/共83頁(yè)Alpha1BlockersStimulatealpha1receptors->hypertensionBlockalpha1receptors->hypotensiondoxazosin(Cardura?)prazosin(Minipress?)terazosin(Hytrin?)第39頁(yè)/共83頁(yè)CentralActingAdrenergicsStimulatealpha2receptorsinhibitalpha1stimulationhypotensionclonidine(Catapress?)methyldopa(Aldomet?)第40頁(yè)/共83頁(yè)P(yáng)eripheralActingAdrenergicsreserpine(Serpalan?)inhibitsthereleaseofNEdiminishesNEstoresleadstohypotensionProminentsideeffectofdepressionalsodiminishesseratonin第41頁(yè)/共83頁(yè)AdrenergicSideEffectsCommondrymouth,drowsiness,sedation&constipationorthostatichypotensionLesscommonheadache,sleepdisturbances,nausea,rash&palpitations第42頁(yè)/共83頁(yè)AngiotensinIACEAngiotensinII1.potentvasoconstrictor-increasesBP2.stimulatesAldosterone-Na+&H2OreabsorbtionACEInhibitors.RAAS第43頁(yè)/共83頁(yè)Renin-AngiotensinAldosteroneSystemAngiotensinII=vasoconstrictorConstrictsbloodvessels&increasesBPIncreasesSVRorafterloadACE-IblockstheseeffectsdecreasingSVR&afterload第44頁(yè)/共83頁(yè)ACEInhibitorsAldosteronesecretedfromadrenalglandscausesodium&waterreabsorptionIncreasebloodvolumeIncreasepreloadACE-Iblocksthisanddecreasespreload第45頁(yè)/共83頁(yè)AngiotensinConvertingEnzymeInhibitorscaptopril(Capoten?)enalapril(Vasotec?)lisinopril(Prinivil?&Zestril?)quinapril(Accupril?)ramipril(Altace?)benazepril(Lotensin?)fosinopril(Monopril?)第46頁(yè)/共83頁(yè)CalciumChannelBlockersUsedfor:AnginaTachycardiasHypertension第47頁(yè)/共83頁(yè)CCBSiteofActiondiltiazem&verapamilnifedipine(andotherdihydropyridines)第48頁(yè)/共83頁(yè)CCBActiondiltiazem&verapamildecreaseautomaticity&conductioninSA&AVnodesdecreasemyocardialcontractilitydecreasedsmoothmuscletonedecreasedPVRnifedipinedecreasedsmoothmuscletonedecreasedPVR第49頁(yè)/共83頁(yè)SideEffectsofCCBsCardiovascularhypotension,palpitations&tachycardiaGastrointestinalconstipation&nauseaOtherrash,flushing&peripheraledema第50頁(yè)/共83頁(yè)CalciumChannelBlockersdiltiazem(Cardizem?)verapamil(Calan?,Isoptin?)nifedipine(Procardia?,Adalat?)第51頁(yè)/共83頁(yè)DiureticSiteofAction.loopofHenleproximaltubuleDistaltubuleCollectingduct第52頁(yè)/共83頁(yè)MechanismWaterfollowsNa+20-25%ofallNa+isreabsorbedintothebloodstreamintheloopofHenle5-10%indistaltubule&3%incollectingductsIfitcannotbeabsorbeditisexcretedwiththeurineBloodvolume=preload!第53頁(yè)/共83頁(yè)SideEffectsofDiureticselectrolytelosses[Na+&K+]fluidlosses[dehydration]myalgiaN/V/Ddizzinesshyperglycemia第54頁(yè)/共83頁(yè)DiureticsThiazides:chlorothiazide(Diuril?)&hydrochlorothiazide(HCTZ?,HydroDIURIL?)LoopDiureticsfurosemide(Lasix?),bumetanide(Bumex?)PotassiumSparingDiureticsspironolactone(Aldactone?)第55頁(yè)/共83頁(yè)MechanismofVasodilatorsDirectlyrelaxesarteriolesmoothmuscleDecreaseSVR=decreaseafterload第56頁(yè)/共83頁(yè)SideEffectsofVasodilatorshydralazine(Apresoline?)Reflextachycardiasodiumnitroprusside(Nipride?)CyanidetoxicityinrenalfailureCNStoxicity=agitation,hallucinations,etc.第57頁(yè)/共83頁(yè)Vasodilatorsdiazoxide[Hyperstat?]hydralazine[Apresoline?]minoxidil[Loniten?]sodiumNitroprusside[Nipride?]第58頁(yè)/共83頁(yè)P(yáng)harmacologyDrugsAffectingHemostasis第59頁(yè)/共83頁(yè)HemostasisReproducefigure11-9,page359Sherwood第60頁(yè)/共83頁(yè)P(yáng)lateletAdhesion第61頁(yè)/共83頁(yè)CoagulationCascadeReproducefollowingcomponentsofcascade:Prothrombin->thrombinFibrinogen->fibrinPlasminogen->plasmin第62頁(yè)/共83頁(yè)P(yáng)lateletInhibitorsInhibittheaggregationofplateletsIndicatedinprogressingMI,TIA/CVASideEffects:uncontrolledbleedingNoeffectonexistingthrombi第63頁(yè)/共83頁(yè)AspirinInhibitsCOXArachidonicacid(COX)->TXA2(aggregation)第64頁(yè)/共83頁(yè)GPIIB/IIIAInhibitorsGPIIb/IIIaInhibitorsFibrinogenGPIIb/IIIaReceptor第65頁(yè)/共83頁(yè)GPIIB/IIIAInhibitorsabciximab(ReoPro?)eptifibitide(Integrilin?)tirofiban(Aggrastat?)第66頁(yè)/共83頁(yè)AnticoagulantsInterruptclottingcascadeatvariouspointsNoeffectonplateletsHeparin&LMWHeparin(Lovenox?)warfarin(Coumadin?)第67頁(yè)/共83頁(yè)HeparinEndogenousReleasedfrommastcells/basophilsBindswithantithrombinIIIAntithrombinIIIbindswithandinactivatesexcessthrombintoregionalizeclottingactivity.Mostthrombin(80-95%)capturedinfibrinmesh.Antithrombin-heparincomplex1000XaseffectiveasantithrombinIIIalone第68頁(yè)/共83頁(yè)HeparinMeasuredinUnits,notmilligramsIndications:MI,PE,DVT,ischemicCVAAntidoteforheparinOD:protamine.MOA:heparinisstronglynegativelycharged.Protamineisstronglypositivelycharged.第69頁(yè)/共83頁(yè)warfarin(Coumadin?)FactorsII,VII,IXandXallvitaminKdependentenzymesWarfarincompeteswithvitaminKinthesynthesisoftheseenzymes.Depletesthereservesofclottingfactors.Delayedonset(~12hours)duetoexistingfactors第70頁(yè)/共83頁(yè)ThrombolyticsDirectlybreakupclotsPromotenaturalthrombolysisEnhanceactivationofplasminogen‘TimeisMuscle’streptokinase(Streptase?)alteplase(tPA?,Activase?)anistreplase(Eminase?)reteplase(Retevase?)tenecteplase(TNKase?)第71頁(yè)/共83頁(yè)OcclusionMechanism第72頁(yè)/共83頁(yè)tPAMechanism第73頁(yè)/共83頁(yè)CholesterolMetabolismCholesterolimportantcomponentinmembranesandashormonepr