充血性心衰药物

治疗充血性心力衰竭药物DrugsforCongestiveHeartFailure心力衰竭（heartfailure）是各种原因引起的心肌舒缩障碍，导致心输出量不能满足机体需求的一组临床综合征。充血性心衰是其中最主要的一种。慢性或充血性心力衰竭（congestiveheartfailure,CHF）是各种病因所引起的多种心脏疾病（冠心、高心、肺心、风心、心肌病等）的终末阶段，当静脉回流足够的情况下，心脏排出量绝对或相对减少，不能满足机体组织需求的一种临床或病理综合征。心衰病人运动耐量下降，寿命缩短。Concept:CHFisacomplexclinicalsyndromecharacterizedbyimpairedventricularperformance,exerciseintolerance,ahighincidenceofventriculararrhythmias,andshortenedlifeexpectancyThesignsandsymptomsThesignsandsymptomsofheartfailureincludetachycardia,decreasedexercisetoleranceandshortnessofbreath,peripheralandpulmonaryedema,andcardiomegaly.动脉系统缺血-乏力，气短，头晕静脉系统淤血-水肿，颈静脉怒张，肝脾肿大，呼吸困难静脉淤血所致的症状为主。心衰的分级（NYHA标准）Ⅰ级：心功能代偿完全，体力活动不受限，日常活动无乏力，心悸，呼吸困难等症状；Ⅱ级：轻度代偿不全，活动轻度受限，休息时无症状；Ⅲ级：中度代偿不全，体力活动明显受限，日常活动即可产生症状。限于室内活动；Ⅳ级：严重代偿不全，休息时亦有症状，不能从事任何体力活动。心力衰竭不是一种独立的疾病，而是由多种原因引起的心肌收缩和/或舒张功能障碍的综合征。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，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。这些变化导致心脏出现不可逆的重构(remodeling)，使衰竭的心脏一步步恶化。Pathophysiology心力衰竭时机体的代偿机制:•Augmentedsympatheticactivity•Sodiumandwaterretention•Myocardialhypertrophy•Ventriculardilatation1．心脏本身的代偿心率加快、心肌收缩加强--快速发生心脏扩大和肥大—缓慢发生是心脏本身储备功能的动员。2．心脏外的代偿血容量增加血液重分配及红细胞增多等几方面的心脏外代偿作用。机体的代偿机制虽然有助于维持机体所需的心输出量要求，但长时间代偿机制的激活可加重心脏的负担。在CHF的长期发病过程中，各种代偿机制对心脏和动脉血管等的影响可产生恶性循环，加重心脏负担，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盾发展过程。神经体液系统主要改变•Increasedsympatheticnervoussystemactivity(andincreasedplasmacatecholamines,b-receptordownregulation)•Increasedactivityoftherenin-angiotensin-aldosteronesystem•Increasedreleaseofarginine-vasopressin心衰的一些代偿机制Inadditiontotheeffectsshown,angiotensinIIincreasessympatheticeffectsbyfacilitatingnorepinephrinerelease.慢性心衰的药物治疗：应减轻负荷，降低能耗，保护心脏。达到改善血流动力学；改善运动耐量；延长生命。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•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•β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(I)正性肌力药物positiveinotropicagents(V)舒血管药Vasodilators(D)利尿药DiureticspharmacologicinterventioninCHF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、ACEI和β受体阻断药等。•Improvinghemodynamicswithinotropicdrugsdoesnotdecreasemortality;（病马加鞭）•long-termtreatmentdirectedtowardsneurohormonalfactorswithACEinhibitorsandbeta-blockerscandecreasemortalityConsensusrecommendationsforthemanagementofCHF•PatientswithheartfailureshouldfirstbeevaluatedtoassessLVejectionfraction.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-adiuretic.•ACEinhibitorandbeta-blockershouldbeinitiatedandmaintainedunlessspecificallycontraindicated.（Patientswithsevereheartfailureshouldprobablynotreceiveabeta-blocker）•Digoxin-inpatientswithrapidatrialfibrillation.•Spironolactone,analdosteroneantagonist,mayreducemortalityinpatientswithsevereheartfailureACEinhibitors•first-linetherapyinallpatientswithheartfailure•improvesymptoms,slowprogressionofthedisease,reducemortality,anddecreasetheincidenceofhospitalization•ThemostcommonadverseeffectsofACEinhibitorsaredirectlyrelatedtoloweringangiotensinIIconcentrations(hypotensionandrenalinsufficiency)andincreasingconcentrationsofkinins(coughandangioneuroticedema)血管紧张素原AngiotensinⅠ收缩血管肾素激肽原缓激肽↑降解失活AngⅢACEACEIsAngⅡ↓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-angiotensinreceptorblockers•angiotensinreceptorantagonists(AT1ReceptorAntagonists)areaseffectiveasACEinhibitorsintreatingheartfailure,butitappearsthattherapeuticefficacymaybecomparable•losartan,candesartan,valsartanInotropicDrugs-digitalis•Thebeneficialeffectsofcardiacglycosidesinthetreatmentofheartfailurehavebeenattributedtoapositiveinotropiceffectonfailingmyocardiumandefficacyincontrollingtheventricularrateresponsetoatrialfibrillation.Thecardiacglycosidesalsomodulateautonomicnervoussystemactivity,anditislikelythatthismechanismcontributessubstantiallytotheirefficacyinthemanagementofheartfailure.•PositiveInotropicEffect（抑制Na+,K+-ATPase）•ElectrophysiologicalActions（加上增强迷走）•RegulationofSympatheticNervousSystemActivity–Thereisevidencethatdigitalismayactdirectlytosensitizationofbaroreceptorresponseandtherebyexertsomeofitsbeneficialeffectsthroughreductionofsympathetictone•TherecentDigitalisInvestigationGroup(DIG)clinicaltrialindicateddigoxindidnotreduceoverallmortalityinpatientswithheartfailure(whowerereceivingdiureticsandACEinhibitors),butdidreducetherateofhospitalizationOtherinotropicagents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-AdrenergicAgonists–dopamine,dobutamine,prenalterol–Levodopaandibopamine•CyclicNucleotidePhosphodiesterase(PDE-III,cGMP-inhibitablePDE)Inhibitors–Bipyridines-amrinoneandmilrinone–imidazolonederivatives-enoximoneandpiroximoneBeta-BlockersandCHF•Anumberofstudiesbeginninginthe1970shaveshownthatbeta-blockerscanimprovesymptomsandventricularfunctioninpatientswithmoderatetosevereheartfailure,andmayslowtheprogressionofheartfailureinsomepatients(reviewedinBristow,Circulation101:558(2000))•Thoughbeta-blockerswerewidelyconsideredtobec