临床药理--治疗充血性心力衰竭药物课件资料

治疗充血性心力衰竭药物治疗充血性心力衰竭药物 Drugs for Congestive Heart FailureDrugs for Congestive Heart Failure 心心力力衰衰竭竭（heart failure）是是各各种种原原因因引引起起的的心心肌肌舒舒缩缩障障碍碍，导导致致心心输输出出量量不不能能满满足足机机体体需需求求的的一一组组临床综合征。充血性心衰是其中最主要的一种。临床综合征。充血性心衰是其中最主要的一种。慢慢 性性 或或 充充 血血 性性 心心 力力 衰衰 竭竭（congestive congestive heart heart failure,failure,CHFCHF）是是各各种种病病因因所所引引起起的的多多种种心心脏脏疾疾病病（冠冠心心、高高心心、肺肺心心、风风心心、心心肌肌病病等等）的的终终末末阶阶段段，当当静静脉脉回回流流足足够够的的情情况况下下，心心脏脏排排出出量量绝绝对对或或相相对对减减少少，不不能能满满足足机机体体组组织织需需求求的的一一种种临临床床或或病病理综合征理综合征。心衰病人运动耐量下降，寿命缩短。心衰病人运动耐量下降，寿命缩短。Concept:Concept:CHFisacomplexclinicalsyndromeCHFisacomplexclinicalsyndromecharacterizedbyimpairedventricularcharacterizedbyimpairedventricularperformance,exerciseintolerance,aperformance,exerciseintolerance,ahighincidenceofventricularhighincidenceofventriculararrhythmias,andshortenedlifearrhythmias,andshortenedlifeexpectancyexpectancyThesignsandsymptomsThesignsandsymptomsofheartfailureThesignsandsymptomsofheartfailureincludetachycardia,decreasedexerciseincludetachycardia,decreasedexercisetoleranceandshortnessofbreath,toleranceandshortnessofbreath,peripheralandpulmonaryedema,andperipheralandpulmonaryedema,andcardiomegaly.cardiomegaly.动脉系脉系统缺血缺血-乏力，气短，乏力，气短，头晕静脉系静脉系统淤血淤血-水水肿，颈静脉怒静脉怒张，肝脾，肝脾肿大，呼吸困大，呼吸困难静脉淤血所致的症状静脉淤血所致的症状为主。主。心衰的分级（心衰的分级（NYHA标准）标准）级级：心心功功能能代代偿偿完完全全，体体力力活活动动不不受受限限，日日常活动无乏力，心悸，呼吸困难等症状；常活动无乏力，心悸，呼吸困难等症状；级级：轻轻度度代代偿偿不不全全，活活动动轻轻度度受受限限，休休息息时无症状；时无症状；级级：中中度度代代偿偿不不全全，体体力力活活动动明明显显受受限限，日常活动即可产生症状。限于室内活动；日常活动即可产生症状。限于室内活动；级级：严严重重代代偿偿不不全全，休休息息时时亦亦有有症症状状，不不能从事任何体力活动。能从事任何体力活动。心力衰竭不是一种独立的疾病，而是由多心力衰竭不是一种独立的疾病，而是由多种原因引起的心肌收缩和种原因引起的心肌收缩和/或舒张功能障碍或舒张功能障碍的综合征。近年来的研究发现，心力衰竭的综合征。近年来的研究发现，心力衰竭虽然主要表现为心肌收缩和舒张功能障碍，虽然主要表现为心肌收缩和舒张功能障碍，但神经内分泌的改变对其恶性循环的形成但神经内分泌的改变对其恶性循环的形成和维持有重要的作用。这些变化导致心脏和维持有重要的作用。这些变化导致心脏出现不可逆的重构出现不可逆的重构(remodeling)，使衰竭的，使衰竭的心脏一步步恶化。心脏一步步恶化。Pathophysiology心力衰竭时机体的代偿机制心力衰竭时机体的代偿机制:AugmentedsympatheticactivityAugmentedsympatheticactivitySodiumandwaterretentionSodiumandwaterretentionMyocardialhypertrophyMyocardialhypertrophyVentriculardilatationVentriculardilatation1心脏本身的代偿心脏本身的代偿心率加快、心肌收缩加强心率加快、心肌收缩加强-快速发生快速发生心脏扩大和肥大心脏扩大和肥大缓慢发生缓慢发生是心脏本身储备功能的动员。是心脏本身储备功能的动员。2 心脏外的代偿心脏外的代偿血容量增加血容量增加血液重分配及红细胞增多血液重分配及红细胞增多等几方面的心脏外代偿作用。等几方面的心脏外代偿作用。机机体体的的代代偿偿机机制制虽虽然然有有助助于于维维持持机机体体所所需需的的心心输输出出量量要要求求，但但长长时时间间代代偿偿机机制制的的激激活活可可加加重重心脏的负担。心脏的负担。在在CHF的的长长期期发发病病过过程程中中，各各种种代代偿偿机机制制对对心心脏脏和和动动脉脉血血管管等等的的影影响响可可产产生生恶恶性性循循环环，加加重重心脏负担，最终加重心力衰竭。心脏负担，最终加重心力衰竭。实际上慢性心衰的发展过程就是在实际上慢性心衰的发展过程就是在心肌氧供不心肌氧供不足和维持机体循环血供需求之间不断平衡的矛足和维持机体循环血供需求之间不断平衡的矛盾发展过程盾发展过程。神神经体液系体液系统主要改主要改变Increasedsympatheticnervoussystemsympatheticnervoussystemactivityactivity(andincreasedplasmacatecholamines,b-receptordownregulation)Increasedactivityoftherenin-angiotensin-renin-angiotensin-aldosteronesystemaldosteronesystemIncreasedreleaseofarginine-vasopressinarginine-vasopressin心衰的一些代偿机制Inadditiontotheeffectsshown,angiotensinIIincreasessympatheticeffectsbyfacilitatingnorepinephrinerelease.慢性心衰的药物治疗：应应减减轻轻负负荷荷，降降低低能能耗耗，保保护护心心脏脏。达到改改善善血血流流动动力力学学；改改善善运运动动耐耐量量；延延长生命。长生命。而不是病马加鞭，只增强心肌收缩力心衰的血流动力学指标：压力指标：LVEDP，dP/dtmax；容积指标：SV，CO，CI，EF（正常0.67,心衰0.45,严重心衰0.3）时间指标：PEP，LVET，T-dP/dtmax抗心衰药物的发展和演变抗心衰药物的发展和演变洋地黄时代（从民间的治疗水肿药物而来）利尿药（噻嗪类、汞撒利）非苷类强心药（儿茶酚胺类，磷酸二酯酶抑制剂-氨力农、米力农）扩血管药物血管紧张素转化酶抑制剂ACEIs，ARBs受体阻断剂醛固酮受体阻断剂使用抗心衰药物后心功能曲线的改变使用抗心衰药物后心功能曲线的改变(I)正性肌力药物positiveinotropicagents(V)舒血管药Vasodilators(D)利尿药DiureticspharmacologicinterventionpharmacologicinterventioninCHFinCHF抗心衰药物是主要用于治疗CHF的药物，主要有强心苷、非甙类正性肌力药、利尿药、强心苷、非甙类正性肌力药、利尿药、ACEI和和受体阻断药受体阻断药等。Improvinghemodynamicswithinotropicdrugsdoesnotdecreasemortality;（病马加鞭）long-termtreatmentdirectedtowardsneurohormonalfactorswithACEinhibitorsandbeta-blockerscandecreasemortalityConsensusrecommendationsforthemanagementofCHFPatientswithheartfailureshouldfirstbeevaluatedtoassessLVejectionfraction.Patientswithsystolicdysfunction(EF40%)shouldthenundergothefollowingtreatment:水钠潴留：利尿药ACEIs，ARBs和/或beta-blocker室率快的房颤：强心苷（地高辛）重症患者延长寿命：醛固酮受体拮抗剂fluidretention-afluidretention-adiureticdiuretic.ACEinhibitorACEinhibitorandandbeta-blockerbeta-blockershouldbeshouldbeinitiatedandmaintainedunlessspecificallyinitiatedandmaintainedunlessspecificallycontraindicated.contraindicated.（PatientswithsevereheartPatientswithsevereheartfailureshouldprobablynotreceiveafailureshouldprobablynotreceiveabeta-beta-blockerblocker）DigoxinDigoxin-inpatientswithrapidatrialfibrillation.-inpatientswithrapidatrialfibrillation.Spironolactone,an aldosterone antagonist,may reduce mortality in patients with severe heart failure ACE inhibitorsfirst-line therapy in all patients with heart failureimprovesymptoms,slowprogressionofthedisease,reducemortality,anddecreasetheincidenceofhospitalizationThemostcommonadverseeffectsofACEinhibitorsaredirectlyrelatedtoloweringangiotensinIIconcentrations(hypotensionandrenalinsufficiency)andincreasingconcentrationsofkinins(coughandangioneuroticedema)血管紧张素原血管紧张素原Angiotensin收缩血管肾素激肽原激肽原缓激肽缓激肽降解失活AngACEACEIsAng分泌醛固酮NOPGI(-)ACE和ACEIs作用示意图舒张血管Captopril第1个在临床上广泛应用的ACEI。含巯基，可致味觉异常。Enalapril前体药，不含巯基。药效和作用时间比cartopril强。ARBs-angiotensinreceptorblockersangiotensinreceptorblockersangiotensinreceptorantagonists(angiotensinreceptorantagonists(AT1 Receptor Antagonists)areaseffectiveas)areaseffectiveasACEinhibitorsintreatingheartfailure,butACEinhibitorsintreatingheartfailure,butitappearsthattherapeuticefficacymayitappearsthattherapeuticefficacymaybecomparablebecomparablelosartan,candesartan,valsartanlosartan,candesartan,valsartanInotropic Drugs-digitalisThebeneficialeffectsofcardiacglycosidesinthetreatmentofheartfailurehavebeenattributedtoapositiveinotropiceffectonfailingmyocardiumandefficacyincontrollingtheventricularrateresponsetoatrialfibrillation.Thecardiacglycosidesalsomodulateautonomicnervoussystemactivity,anditislikelythatthismechanismcontributessubstantiallytotheirefficacyinthemanagementofheartfailure.Positive Inotropic Effect（抑制Na+,K+-ATPase）Electrophysiological Actions（加上增强迷走）Regulation of Sympathetic Nervous System ActivityThereisevidencethatdigitalismayactdirectlytosensitizationofbaroreceptorresponseandtherebyexertsomeofitsbeneficialeffectsthroughreductionofsympathetictoneTherecentDigitalisInvestigationGroupTherecentDigitalisInvestigationGroup(DIG)clinicaltrialindicateddigoxindidnot(DIG)clinicaltrialindicateddigoxindidnotreduceoverallmortalityinpatientswithreduceoverallmortalityinpatientswithheartfailure(whowerereceivingdiureticsheartfailure(whowerereceivingdiureticsandACEinhibitors),butdidreducetheandACEinhibitors),butdidreducetherateofhospitalizationrateofhospitalizationOtherinotropicagents只适用于急性心衰，长期应用于慢性心衰后，病人死亡率增加。Beta-AdrenergicAgonistsdopamine,dobutamine,prenalterolLevodopaandibopamineCyclicNucleotidePhosphodiesterase(PDE-III,cGMP-inhibitablePDE)InhibitorsBipyridines-amrinoneandmilrinoneimidazolonederivatives-enoximoneandpiroximoneBeta-Blockers and CHFAnumberofstudiesbeginninginthe1970shaveshownthatbeta-blockerscanimprovesymptomsandventricularfunctioninpatientswithmoderatetosevereheartfailure,andmayslowtheprogressionofheartfailureinsomepatients(reviewedinBristow,Circulation101:558(2000)Thoughbeta-blockerswerewidelyconsideredtobecontraindicatedforpatientswithheartfailureonlyadecadeago,theyarenowconsideredfirst-linetherapyfirst-linetherapyforpatientswithmildtomoderateheartforpatientswithmildtomoderateheartfailurefailure现认为脂溶性的效果更好。metoprololcarvedilolbisoprololTheadverseeffectsTheadverseeffects:worseningofsymptoms,hypotension,andbradycardiaThesesymptomscanbeminimizedbyinitiatingtherapywithlowdosesandgraduallyincreasingdosageuntiltolerabletherapeuticdosesarereachedBeta-blockersarecontraindicatedinpatientswithasthmaorseverebradycardiaDiureticsMostpateintswithheartfailurerequiretreatmentwithdiureticstorelievesymptomsoffluidretention(edemaandcongestion),buttheirisnoevidencethatdiureticsslowtheprogressionofthediseaseordecreasemortality.Loopdiuretics(furosemide)arethemosteffectivediuretics多用于严重水钠潴留和肾功能不全时。ThiazidediureticsThiazidediureticsactonthedistalloopandarelesseffectivethanloopdiuretics用于轻度水钠潴留。ConcurrentuseoftwodiureticswithdifferentsitesofactionmaybeneededinpatientswhodonotrespondwelltoasingleoraldiureticThemostcommonadverseeffectofdiuretictherapyispotassiumdepletionwhichcanbepreventedbyuseofsupplementalpotassium,anACEinhibitor,orapotassium-sparingdiuretic(spironolactoneoramiloride)AldosteroneAntagonistsAldosteroneAntagonistsRecentclinicaltrialsindicatethataddingspironolactone(螺内酯)tostandardtreatmentcansignificantlydecreasemortalityinpatientswithsevereheartfailureEffectofspironolactoneonsurvivalinpatientswithmoderateorseverecongestiveheartfailureinarandomizeddouble-blindclinicalstudy.(Reproduced,withpermission,fromPittBetal:Theeffectofspironolactoneonmorbidityandmortalityinpatientswithsevereheartfailure.NEnglJMed2019;341:709醛醛固固酮酮受受体体拮拮抗抗剂剂螺螺内内酯酯降降低低充充血血性性心心衰衰病病人人死死亡亡率率OtherAgentswithTherapaeuticPotentialEndothelin-1AntagonistsEndothelin-1AntagonistsThevasoconstrictorpeptide,endothelin-1,isknowntobeelevatedinheartfailureandisapredictorofmortalityinpatientswithheartfailure.Animalmodelsofheartfailureindicateendothelinreceptorantagonistssuchasbosentanmayhavelong-termbenefitsinreversingmyocardialremodelingandimprovingsurvival.Short-term,small-scaletrialsinhumansindicatepossiblebeneficialeffectsonsystemicandpulmonaryhemodynamicsxanthine oxidase inhibitorBackground:Highserumuricacid(SUA)levelsareastrong,independentmarkerofimpairedprognosisinpatientswithmoderatetosevereCHF.Resultsandconclusion:Oxypurinoldidnotproduceclinicalimprovementsinunselectedpatientswithmoderate-to-severeheartfailure.However,post-hocanalysissuggeststhatbenefitsoccurinpatientswithelevatedSUAinamannercorrelatingwiththedegreeofSUAreduction.Impactofoxypurinolinpatientswithsymptomaticheartfailure.ResultsoftheOPT-CHFstudy.JAmCollCardiol2019;51(24):2301-9.Steps in the treatment of chronic heart failure._1.Reduceworkloadofthehearta.Limitactivitylevelb.Reduceweightc.Controlhypertension2.Restrictsodium3.Restrictwater(rarelyrequired)4.Givediuretics5.GiveACEinhibitoranddigitalis16.Giveb-blockerstopatientswithstableclassII-IIIheartfailure7.Givevasodilators_1Manycliniciansuseangiotensin-convertingenzymeinhibitorsbeforedigitalis.SummaryOnthebasisofseveralrecentlarge-scaleclinicaltrialsitappearsthatreductioninventricularvolumeventricularvolumeandperhapsareductioninreductionintheriskoftheriskoflethalventriculararrhythmiaslethalventriculararrhythmiasarethekeystolong-termimprovementandsurvivalofpatientswithCHFEmphasisontherapyforheartfailurehasshiftedinthepastseveralyearsfromacuteinterventionstoimprovehemodynamicsandinotropicstatetolong-termtherapiesthatmightsloworhalttheprogressionofthediseasesloworhalttheprogressionofthediseaseFuturetherapieswillmostlikelyinvolvetherapeuticstrategiesthatpreventorminimizetheremodelingprocessesintheheartandvasculature,andtherebyarrestthesyndromeatearlystagesofcardiacdysfunction