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PharmacologyDrugsthatAffecttheCardiovascularSystemTopics•Electrophysiology•Vaughn-Williamsclassification•Antihyper

tensives•HemostaticagentsCardiacFunction•Dependentupon–AdequateamountsofATP–AdequateamountsofCa++–CoordinatedelectricalstimulusA

dequateAmountsofATP•Neededto:–Maintainelectrochemicalgradients–Propagateactionpotentials–Powermuscle

contractionAdequateAmountsofCalcium•Calciumis‘glue’thatlinkselectricalandmechanicalevents.CoordinatedElectricalStimulation•Heartcapableofautomatici

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

trioventricularnode•BundleofHis•BundleBranches–Fascicles•PurkinjeNetworkElectrophysiology•Twotypesofactionp

otentials–Fastpotentials•Foundincontractiletissue–Slowpotentials•FoundinSA,AVnodetissuesFastPotential-80-60-40-200+20RMP-80to90mVPhase1Phase2Phase3P

hase4controlledbyNa+channels=“fastchannels”FastPotential•Phase0:Na+influx“fastsodiumchannels”•Phase1:K+efflux•Phase2:(Plateau

)K+efflux–ANDCa++influx•Phase3:K+efflux•Phase4:RestingMembranePotentialCardiacConductionCycleSlowPotential-80-60-40-200Phase4Phase3d

ependentuponCa++channels=“slowchannels”SlowPotential•Self-depolarizing–Responsibleforautomaticity•Phase4depolarization–‘slowsodium-calci

umchannels’–‘leaky’tosodium•Phase3repolarization–K+effluxCardiacPacemakerDominance•Intrinsicfiringrates:–SA=60–100–AV=45–60–Pu

rkinje=15-45CardiacPacemakers•SAisprimary–Fasterdepolarizationrate•FasterCa++‘leak’•Othersare‘backups’–Graduateddepolarizationrate•GraduatedCa++leak

ratePotentialTermsAPDERPRRPrelativerefractoryperiodeffectiverefractoryperiodactionpotentialdurationDysrhythmiaGeneration•Abnormalgene

sis–ImbalanceofANSstimuli–Pathologicphase4depolarization•EctopicfociDysrhythmiaGeneration•Abnormalconduction

•Analogies:–Onewayvalve–BuggiesstuckinmuddyroadsReentrantCircuitsWarning!•Allantidysrhythmicshavearrythmog

enicproperties•Inotherwords,theyallcanCAUSEdysrhythmiastoo!AHARecommendationClassifications•DescribesweightofsupportingevidenceNOTmechanism•Clas

sI•ClassIIa•ClassIIb•Indeterminant•ClassIII•ViewAHAdefinitionsVaughn-WilliamsClassification•Class1–Ia

–Ib–Ic•ClassII•ClassIII•ClassIV•Misc•DescriptionofmechanismNOTevidenceClassI:SodiumChannelBlockers•DecreaseNa+mo

vementinphases0and4•Decreasesrateofpropagation(conduction)viatissuewithfastpotential(Purkinje)–Ignoresthosewithslowpotential(SA/AV)•I

ndications:ventriculardysrhythmiasClassIaAgents•Slowconductionthroughventricles•Decreaserepolarizationrate–WidenQRSandQTinterv

als•MaypromoteTorsadesdesPointes!•PDQ:–procainamide(Pronestyl®)–disopyramide(Norpace®)–qunidine–(Quinidex®)ClassIbAgents•S

lowconductionthroughventricles•Increaserateofrepolarization•Reduceautomaticity–Effectiveforectopicfoci•Ma

yhaveotheruses•LTMD:–lidocaine(Xylocaine®)–tocainide(Tonocard®)–mexiletine(Mexitil®)–phenytoin(Dilantin®)ClassIcAgents•Sl

owconductionthroughventricles,atria&conductionsystem•Decreaserepolarizationrate•Decreasecontractility•Rarelastchancedrug

•flecainide(Tambocor®)•propafenone(Rythmol®)ClassII:BetaBlockers•Beta1receptorsinheartattachedtoCa++channels–GradualCa++influxresponsibleforautoma

ticity•Beta1blockadedecreasesCa++influx–EffectssimilartoClassIV(Ca++channelblockers)•Limited#approvedfortachycardiasClassI

I:BetaBlockers•propranolol(Inderal®)•acebutolol(Sectral®)•esmolol(Brevibloc®)ClassIII:PotassiumChannelBlockers•DecreasesK+efflu

xduringrepolarization•Prolongsrepolarization•Extendseffectiverefractoryperiod•Prototype:bretylliumtosylate(Bretylol®)–Initialnorepid

ischargemaycausetemporaryhypertension/tachycardia–SubsequentnorepidepletionmaycausehypotensionClassI

V:CalciumChannelBlockers•Similareffectasßblockers•DecreaseSA/AVautomaticity•DecreaseAVconductivity•Usefulinbreakingreen

trantcircuit•Primesideeffect:hypotension&bradycardia•verapamil(Calan®)•diltiazem(Cardizem®)•Note:nifed

ipinedoesn’tworkonheartMisc.Agents•adenosine(Adenocard®)–DecreasesCa++influx&increasesK+effluxvia2ndmesse

ngerpathway•Hyperpolarizationofmembrane•Decreasedconductionvelocityviaslowpotentials•Noeffectonfastpote

ntials•Profoundsideeffectspossible(butshort-lived)Misc.Agents•CardiacGlycocides•digoxin(Lanoxin®)–InhibitsNaKATPpump–IncreasesintracellularCa++•v

iaNa+-Ca++exchangepump–Increasescontractility–DecreasesAVconductionvelocityPharmacologyAntihypertensivesAntihypertensiveClass

es•diuretics•betablockers•angiotensin-convertingenzyme(ACE)inhibitors•calciumchannelblockers•vasodilatorsBloodPressure=COX

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

rgicsACEi’s=angiotensin-convertingenzymeinhibitorscardiacfactorscirculatingvolumeheartratecontractility1.B

etaBlockers2.CCB’s3.C.A.AdrenergicssaltaldosteroneACEi’sDiureticsBP=COxPVRHormones1.vasodilators2.ACEI’s3.CCB’sCentralNervousSys

tem1.CAAdrenergicsPeripheralSympatheticReceptorsalphabeta1.alphablockers2.betablockersLocalActing1.Peripheral-ActingAdrenergicsAlpha1Blockers

Stimulatealpha1receptors->hypertensionBlockalpha1receptors->hypotension•doxazosin(Cardura®)•prazosin(Minipres

s®)•terazosin(Hytrin®)CentralActingAdrenergics•Stimulatealpha2receptors–inhibitalpha1stimulation•hypote

nsion•clonidine(Catapress®)•methyldopa(Aldomet®)PeripheralActingAdrenergics•reserpine(Serpalan®)•inhibitsthereleaseofNE•diminishesNEstores•leadst

ohypotension•Prominentsideeffectofdepression–alsodiminishesseratoninAdrenergicSideEffects•Common–drymouth,drowsiness,sedation&constipati

on–orthostatichypotension•Lesscommon–headache,sleepdisturbances,nausea,rash&palpitationsAngiotensinIACEAngiotensinII1.1.pote

ntvasoconstrictor-increasesBP2.stimulatesAldosterone-Na+&H2OreabsorbtionACEInhibitors.RAASRenin-AngiotensinAldosteroneSystem•Angiote

nsinII=vasoconstrictor•Constrictsbloodvessels&increasesBP•IncreasesSVRorafterload•ACE-Iblockstheseeffectsdecreasi

ngSVR&afterloadACEInhibitors•Aldosteronesecretedfromadrenalglandscausesodium&waterreabsorption•Increasebloodvolume•Increasepreload•ACE-Iblo

cksthisanddecreasespreloadAngiotensinConvertingEnzymeInhibitors•captopril(Capoten®)•enalapril(Vasotec®)•li

sinopril(Prinivil®&Zestril®)•quinapril(Accupril®)•ramipril(Altace®)•benazepril(Lotensin®)•fosinopril(Monopril

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

ndotherdihydropyridines)CCBAction•diltiazem&verapamil•decreaseautomaticity&conductioninSA&AVnodes•decreasemyocardialcontract

ility•decreasedsmoothmuscletone•decreasedPVR•nifedipine•decreasedsmoothmuscletone•decreasedPVRSideEffectsofCCBs•Cardiovascular•

hypotension,palpitations&tachycardia•Gastrointestinal•constipation&nausea•Other•rash,flushing&peripheraledemaCalciumChannelBlockers•diltiazem(Cardize

m®)•verapamil(Calan®,Isoptin®)•nifedipine(Procardia®,Adalat®)DiureticSiteofAction.loopofHenleproximaltubuleDist

altubuleCollectingductMechanism•WaterfollowsNa+•20-25%ofallNa+isreabsorbedintothebloodstreamintheloopofHenle•5-10%i

ndistaltubule&3%incollectingducts•Ifitcannotbeabsorbeditisexcretedwiththeurine•Bloodvolume=preload!SideEffectsofDiuretics•electrolytelosses[Na+&K+

]•fluidlosses[dehydration]•myalgia•N/V/D•dizziness•hyperglycemiaDiuretics•Thiazides:•chlorothiazide(Diuril®)&hydrochlorothiazide(H

CTZ®,HydroDIURIL®)•LoopDiuretics•furosemide(Lasix®),bumetanide(Bumex®)•PotassiumSparingDiuretics•spironolactone(Aldactone®)Mechan

ismofVasodilators•Directlyrelaxesarteriolesmoothmuscle•DecreaseSVR=decreaseafterloadSideEffectsofVasodilators•hydralazine(Apresoline®)–

Reflextachycardia•sodiumnitroprusside(Nipride®)–Cyanidetoxicityinrenalfailure–CNStoxicity=agitation,hallucinations,etc.Vasodilators•diazoxide[Hy

perstat®]•hydralazine[Apresoline®]•minoxidil[Loniten®]•sodiumNitroprusside[Nipride®]PharmacologyDrugsAffectingH

emostasisHemostasis•Reproducefigure11-9,page359SherwoodPlateletAdhesionCoagulationCascade•Reproducefollowingcompo

nentsofcascade:–Prothrombin->thrombin•Fibrinogen->fibrin–Plasminogen->plasminPlateletInhibitors•Inhibittheaggrega

tionofplatelets•IndicatedinprogressingMI,TIA/CVA•SideEffects:uncontrolledbleeding•NoeffectonexistingthrombiAspirin–InhibitsCOX•Arachidonicacid(COX)

->TXA2(aggregation)GPIIB/IIIAInhibitorsGPIIb/IIIaInhibitorsFibrinogenGPIIb/IIIaReceptorGPIIB/IIIAInhibitors•abcix

imab(ReoPro®)•eptifibitide(Integrilin®)•tirofiban(Aggrastat®)Anticoagulants•Interruptclottingcascadeatvariouspoints–Noeffect

onplatelets•Heparin&LMWHeparin(Lovenox®)•warfarin(Coumadin®)Heparin•Endogenous–Releasedfrommastcells/basophils•

BindswithantithrombinIII•AntithrombinIIIbindswithandinactivatesexcessthrombintoregionalizeclottingactivity.–Mostthrombin(

80-95%)capturedinfibrinmesh.•Antithrombin-heparincomplex1000XaseffectiveasantithrombinIIIaloneHeparin•MeasuredinUnits,notmilligrams•Ind

ications:–MI,PE,DVT,ischemicCVA•AntidoteforheparinOD:protamine.–MOA:heparinisstronglynegativelycharged.Protamineisstronglypositivelycharged.w

arfarin(Coumadin®)•FactorsII,VII,IXandXallvitaminKdependentenzymes•WarfarincompeteswithvitaminKinthesynthesisoftheseenzymes.

•Depletesthereservesofclottingfactors.•Delayedonset(~12hours)duetoexistingfactorsThrombolytics•Directlybreakupclots–Promotenaturalt

hrombolysis•Enhanceactivationofplasminogen•‘TimeisMuscle’•streptokinase(Streptase®)•alteplase(tPA®,Acti

vase®)•anistreplase(Eminase®)•reteplase(Retevase®)•tenecteplase(TNKase®)OcclusionMechanismtPAMechanismCholesterolMetab

olism•Cholesterolimportantcomponentinmembranesandashormoneprecursor•Synthesizedinliver–Hydroxymethylglutarylcoenzy

meAreductase–(HMGCoAreductase)dependant•Storedintissuesforlatteruse•Insolubleinplasma(atypeoflipid)–MusthavetransportmechanismLipo

proteins•Lipidsaresurroundedbyproteincoatto‘hide’hydrophobicfattycore.•Lipoproteinsdescribedbydensity–VLDL,LDL,IDL,HDL,VHD

L•LDLcontainmostcholesterolinbody–Transportcholesterolfromlivertotissuesforuse(“Bad”)•HDLmovecholesterolbacktolive

r–“Good”b/cremovecholesterolfromcirculationWhyWeFearCholesterol•RiskofCADlinkedtoLDLlevels•LDLsaredepositedunderendothelialsurfaceando

xidizedwherethey:–Attractsmonocytes->macrophages–MacrophagesengulfoxidizedLDL•Vacuolationinto‘foamcells’–Foamcellsprotrudeagainstintimallini

ng•Eventuallyatoughcapisformed–Vasculardiameter&bloodflowdecreasedWhyWeFearCholesterol•Plaquecapcanruptur

e•Collagenexposed•Clottingcascadeactivated•Plateletadhesion•Thrombusformation•Embolusformationpossible•Oc

clusioncausesischemiaLipidDepositionThrombusFormationPlateletAdhesionEmbolusFormationOcclusionCausesInfarctionAntihyperl

ipidemicAgents•Goal:DecreaseLDL–InhibitionofLDLsynthesis–IncreaseLDLreceptorsinliver•Target:<200mg/dl•StatinsareHMGCoAreductaseinhibitors•lo

vastatin(Mevacor®)•pravastatin(Pravachol®)•simvastatin(Zocor®)•atorvastatin(Lipitor®)个人观点供参考，欢迎讨论！