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PharmacologyDrugsthatAffecttheCardiovascularSystemTopics•Electrophysiology•Vaughn-Williamsclassification•Antihypertensives•Hemostatica

gentsCardiacFunction•Dependentupon–AdequateamountsofATP–AdequateamountsofCa++–CoordinatedelectricalstimulusAdequat

eAmountsofATP•Neededto:–Maintainelectrochemicalgradients–Propagateactionpotentials–PowermusclecontractionAdequateAmountsofCalcium•Cal

ciumis‘glue’thatlinkselectricalandmechanicalevents.CoordinatedElectricalStimulation•Heartcapableofautoma

ticity•Twotypesofmyocardialtissue–Contractile–Conductive•Impulsestravelthrough‘actionpotentialsuperhighway’.A.P.SuperHighway•

Sinoatrialnode•Atrioventricularnode•BundleofHis•BundleBranches–Fascicles•PurkinjeNetworkElectrophysiology•Twotypesofacti

onpotentials–Fastpotentials•Foundincontractiletissue–Slowpotentials•FoundinSA,AVnodetissuesFastPotential-80-60-40-200+20RMP-80to90mVPhase1Phase2Phase

3Phase4controlledbyNa+channels=“fastchannels”FastPotential•Phase0:Na+influx“fastsodiumchannels”•Phase1:K+efflux•Phase2:(Plateau)K+efflux–ANDCa+

+influx•Phase3:K+efflux•Phase4:RestingMembranePotentialCardiacConductionCycleSlowPotential-80-60-40-200Phase4Phase3dependentuponCa++channels=“

slowchannels”SlowPotential•Self-depolarizing–Responsibleforautomaticity•Phase4depolarization–‘slowsodium-cal

ciumchannels’–‘leaky’tosodium•Phase3repolarization–K+effluxCardiacPacemakerDominance•Intrinsicfiringrates:–SA=60–1

00–AV=45–60–Purkinje=15-45CardiacPacemakers•SAisprimary–Fasterdepolarizationrate•FasterCa++‘leak’•Othersare‘backups’–Graduateddepolariza

tionrate•GraduatedCa++leakratePotentialTermsAPDERPRRPrelativerefractoryperiodeffectiverefractoryperiodactionpotentialdurationDys

rhythmiaGeneration•Abnormalgenesis–ImbalanceofANSstimuli–Pathologicphase4depolarization•EctopicfociDysrhythmiaGenerati

on•Abnormalconduction•Analogies:–Onewayvalve–BuggiesstuckinmuddyroadsReentrantCircuitsWarning!•Allantidysrhythmicshavearrythmogeni

cproperties•Inotherwords,theyallcanCAUSEdysrhythmiastoo!AHARecommendationClassifications•Describesweightofsupporti

ngevidenceNOTmechanism•ClassI•ClassIIa•ClassIIb•Indeterminant•ClassIII•ViewAHAdefinitionsVaughn-WilliamsClassification•Class1–Ia–I

b–Ic•ClassII•ClassIII•ClassIV•Misc•DescriptionofmechanismNOTevidenceClassI:SodiumChannelBlockers•DecreaseNa+movementinphases0and4•Decreasesrateofpr

opagation(conduction)viatissuewithfastpotential(Purkinje)–Ignoresthosewithslowpotential(SA/AV)•Indications:ventricu

lardysrhythmiasClassIaAgents•Slowconductionthroughventricles•Decreaserepolarizationrate–WidenQRSandQTintervals•Maypromot

eTorsadesdesPointes!•PDQ:–procainamide(Pronestyl®)–disopyramide(Norpace®)–qunidine–(Quinidex®)ClassIbAgents•Slowconductionthroughventr

icles•Increaserateofrepolarization•Reduceautomaticity–Effectiveforectopicfoci•Mayhaveotheruses•LTMD:–lidocaine(Xylocaine®)–tocainide(Tonocard®)–mexil

etine(Mexitil®)–phenytoin(Dilantin®)ClassIcAgents•Slowconductionthroughventricles,atria&conductionsystem•Decreaserepolarizati

onrate•Decreasecontractility•Rarelastchancedrug•flecainide(Tambocor®)•propafenone(Rythmol®)ClassII:B

etaBlockers•Beta1receptorsinheartattachedtoCa++channels–GradualCa++influxresponsibleforautomaticity•Beta1blockadedecreasesCa++influx–

EffectssimilartoClassIV(Ca++channelblockers)•Limited#approvedfortachycardiasClassII:BetaBlockers•propra

nolol(Inderal®)•acebutolol(Sectral®)•esmolol(Brevibloc®)ClassIII:PotassiumChannelBlockers•DecreasesK+effluxduringrepolarizat

ion•Prolongsrepolarization•Extendseffectiverefractoryperiod•Prototype:bretylliumtosylate(Bretylol®)–Initialnorepidischargemaycausetemporary

hypertension/tachycardia–SubsequentnorepidepletionmaycausehypotensionClassIV:CalciumChannelBlockers•Similareffectasßblockers•DecreaseS

A/AVautomaticity•DecreaseAVconductivity•Usefulinbreakingreentrantcircuit•Primesideeffect:hypotension&bradycardia•verapamil

(Calan®)•diltiazem(Cardizem®)•Note:nifedipinedoesn’tworkonheartMisc.Agents•adenosine(Adenocard®)–DecreasesCa++influx&increas

esK+effluxvia2ndmessengerpathway•Hyperpolarizationofmembrane•Decreasedconductionvelocityviaslowpotentials•Noeffectonfastpotentials•Profo

undsideeffectspossible(butshort-lived)Misc.Agents•CardiacGlycocides•digoxin(Lanoxin®)–InhibitsNaKATPpump–Increasesintracel

lularCa++•viaNa+-Ca++exchangepump–Increasescontractility–DecreasesAVconductionvelocityPharmacologyAntihypertensivesAntihyper

tensiveClasses•diuretics•betablockers•angiotensin-convertingenzyme(ACE)inhibitors•calciumchannelblockers•vasodilatorsBloodPressure=COXPVR•

CardiacOutput=SVxHR•PVR=AfterloadBP=COxPVRKey:CCB=calciumchannelblockersCAAdrenergics=central-actingadrener

gicsACEi’s=angiotensin-convertingenzymeinhibitorscardiacfactorscirculatingvolumeheartratecontractility1.BetaBlockers2.CCB’s

3.C.A.AdrenergicssaltaldosteroneACEi’sDiureticsBP=COxPVRHormones1.vasodilators2.ACEI’s3.CCB’sCentralNerv

ousSystem1.CAAdrenergicsPeripheralSympatheticReceptorsalphabeta1.alphablockers2.betablockersLocalActing1.Periph

eral-ActingAdrenergicsAlpha1BlockersStimulatealpha1receptors->hypertensionBlockalpha1receptors->hypotension•doxazosin(Card

ura®)•prazosin(Minipress®)•terazosin(Hytrin®)CentralActingAdrenergics•Stimulatealpha2receptors–inhibit

alpha1stimulation•hypotension•clonidine(Catapress®)•methyldopa(Aldomet®)PeripheralActingAdrenergics•reserpine(Serpalan®)

•inhibitsthereleaseofNE•diminishesNEstores•leadstohypotension•Prominentsideeffectofdepression–alsodiminishesseratoninAdrenergicSideEf

fects•Common–drymouth,drowsiness,sedation&constipation–orthostatichypotension•Lesscommon–headache,sleepdisturbances,nausea,rash&palpi

tationsAngiotensinIACEAngiotensinII1.1.potentvasoconstrictor-increasesBP2.stimulatesAldosterone-Na+&H2Oreabsorbt

ionACEInhibitors.RAASRenin-AngiotensinAldosteroneSystem•AngiotensinII=vasoconstrictor•Constrictsbloodvessels&increasesBP

•IncreasesSVRorafterload•ACE-IblockstheseeffectsdecreasingSVR&afterloadACEInhibitors•Aldosteronesecretedfromadrenalglandsca

usesodium&waterreabsorption•Increasebloodvolume•Increasepreload•ACE-IblocksthisanddecreasespreloadAngiotensinConvertingEnzymeInhibitors•cap

topril(Capoten®)•enalapril(Vasotec®)•lisinopril(Prinivil®&Zestril®)•quinapril(Accupril®)•ramipril(Altace®)•benazepril(Lotensin®)•fosinopril(Mono

pril®)CalciumChannelBlockers•Usedfor:•Angina•Tachycardias•HypertensionCCBSiteofActiondiltiazem&verapamilnifedipine(and

otherdihydropyridines)CCBAction•diltiazem&verapamil•decreaseautomaticity&conductioninSA&AVnodes•decr

easemyocardialcontractility•decreasedsmoothmuscletone•decreasedPVR•nifedipine•decreasedsmoothmuscletone•decreasedPVRSideEffectso

fCCBs•Cardiovascular•hypotension,palpitations&tachycardia•Gastrointestinal•constipation&nausea•Other•

rash,flushing&peripheraledemaCalciumChannelBlockers•diltiazem(Cardizem®)•verapamil(Calan®,Isoptin®)•nifedipine(Procard

ia®,Adalat®)DiureticSiteofAction.loopofHenleproximaltubuleDistaltubuleCollectingductMechanism•Waterf

ollowsNa+•20-25%ofallNa+isreabsorbedintothebloodstreamintheloopofHenle•5-10%indistaltubule&3%incollectingducts•Ifitcannotbeabsorbeditise

xcretedwiththeurine•Bloodvolume=preload!SideEffectsofDiuretics•electrolytelosses[Na+&K+]•fluidlosses[dehydration]•myalgia•N/V/D•dizziness•hyperg

lycemiaDiuretics•Thiazides:•chlorothiazide(Diuril®)&hydrochlorothiazide(HCTZ®,HydroDIURIL®)•LoopDiuretics•furosemide(La

six®),bumetanide(Bumex®)•PotassiumSparingDiuretics•spironolactone(Aldactone®)MechanismofVasodilators•Directlyrelaxesarteriolesmoothmuscle•Decr

easeSVR=decreaseafterloadSideEffectsofVasodilators•hydralazine(Apresoline®)–Reflextachycardia•sodiumnitroprusside(Nipride®)–Cyanidetoxic

ityinrenalfailure–CNStoxicity=agitation,hallucinations,etc.Vasodilators•diazoxide[Hyperstat®]•hydralazine[Apresoline®]•minoxidi

l[Loniten®]•sodiumNitroprusside[Nipride®]PharmacologyDrugsAffectingHemostasisHemostasis•Reproducefigur

e11-9,page359SherwoodPlateletAdhesionCoagulationCascade•Reproducefollowingcomponentsofcascade:–Prothrombin->thrombin•Fibrinogen->fibrin–Plasm

inogen->plasminPlateletInhibitors•Inhibittheaggregationofplatelets•IndicatedinprogressingMI,TIA/CVA•SideEffects:uncontrolledbleedin

g•NoeffectonexistingthrombiAspirin–InhibitsCOX•Arachidonicacid(COX)->TXA2(aggregation)GPIIB/IIIAInhibitorsGPIIb/IIIaInhibitorsFibrinoge

nGPIIb/IIIaReceptorGPIIB/IIIAInhibitors•abciximab(ReoPro®)•eptifibitide(Integrilin®)•tirofiban(Aggrastat®)An

ticoagulants•Interruptclottingcascadeatvariouspoints–Noeffectonplatelets•Heparin&LMWHeparin(Lovenox®)•warfarin(Coumadin®)Heparin•Endogenous–Releasedf

rommastcells/basophils•BindswithantithrombinIII•AntithrombinIIIbindswithandinactivatesexcessthrombintoregiona

lizeclottingactivity.–Mostthrombin(80-95%)capturedinfibrinmesh.•Antithrombin-heparincomplex1000Xaseffectiveas

antithrombinIIIaloneHeparin•MeasuredinUnits,notmilligrams•Indications:–MI,PE,DVT,ischemicCVA•AntidoteforheparinOD:protamine.–MOA:heparinisstrongly

negativelycharged.Protamineisstronglypositivelycharged.warfarin(Coumadin®)•FactorsII,VII,IXandXallvitaminKdependentenzymes•Warfarincompeteswithvit

aminKinthesynthesisoftheseenzymes.•Depletesthereservesofclottingfactors.•Delayedonset(~12hours)duetoexistingfactorsThrombolyti

cs•Directlybreakupclots–Promotenaturalthrombolysis•Enhanceactivationofplasminogen•‘TimeisMuscle’•streptokinase(Streptase®)•altep

lase(tPA®,Activase®)•anistreplase(Eminase®)•reteplase(Retevase®)•tenecteplase(TNKase®)OcclusionMechanismtPAMechanismCholest

erolMetabolism•Cholesterolimportantcomponentinmembranesandashormoneprecursor•Synthesizedinliver–Hydroxymethylg

lutarylcoenzymeAreductase–(HMGCoAreductase)dependant•Storedintissuesforlatteruse•Insolubleinplasma(atypeofl

ipid)–MusthavetransportmechanismLipoproteins•Lipidsaresurroundedbyproteincoatto‘hide’hydrophobicfattycore.•Lipoproteinsdescribedbydensity–VLD

L,LDL,IDL,HDL,VHDL•LDLcontainmostcholesterolinbody–Transportcholesterolfromlivertotissuesforuse(“Bad”)•HDLmovecholesterolbacktoliver–

“Good”b/cremovecholesterolfromcirculationWhyWeFearCholesterol•RiskofCADlinkedtoLDLlevels•LDLsaredepositedunderendothelialsurfaceandoxidizedwh

erethey:–Attractsmonocytes->macrophages–MacrophagesengulfoxidizedLDL•Vacuolationinto‘foamcells’–Foamcellsprotrudeagainstintimallining•Eventual

lyatoughcapisformed–Vasculardiameter&bloodflowdecreasedWhyWeFearCholesterol•Plaquecapcanrupture•Collagenexposed•Clottingcascadeactivated•P

lateletadhesion•Thrombusformation•Embolusformationpossible•OcclusioncausesischemiaLipidDepositionThrombusFormat

ionPlateletAdhesionEmbolusFormationOcclusionCausesInfarctionAntihyperlipidemicAgents•Goal:DecreaseLDL–InhibitionofLDLsynthesis–I

ncreaseLDLreceptorsinliver•Target:<200mg/dl•StatinsareHMGCoAreductaseinhibitors•lovastatin(Mevacor®)•pravastatin(Pravachol®)•simvastatin(Zo

cor®)•atorvastatin(Lipitor®)个人观点供参考，欢迎讨论！