充血性心衰药物.pptx

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:CHF is a complex clinical syndrome CHF is a complex clinical syndrome characterized by impaired ventricular characterized by impaired ventricular performance,exercise intolerance,a performance,exercise intolerance,a high incidence of ventricular high incidence of ventricular arrhythmias,and shortened life arrhythmias,and shortened life expectancy expectancy The signs and symptomsThe signs and symptoms of heart failure The signs and symptoms of heart failure include tachycardia,decreased exercise include tachycardia,decreased exercise tolerance and shortness of breath,tolerance and shortness of breath,peripheral and pulmonary edema,and peripheral and pulmonary edema,and cardiomegaly.cardiomegaly.动脉系统缺血动脉系统缺血-乏力，气短，头晕乏力，气短，头晕静脉系统淤血静脉系统淤血-水肿，颈静脉怒张，肝脾水肿，颈静脉怒张，肝脾肿大，呼吸困难肿大，呼吸困难静脉淤血所致的症状为主。静脉淤血所致的症状为主。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:Augmented sympathetic activity Augmented sympathetic activity Sodium and water retention Sodium and water retention Myocardial hypertrophy Myocardial hypertrophy Ventricular dilatationVentricular dilatation1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。神经体液系统主要改变神经体液系统主要改变Increased sympathetic nervous system sympathetic nervous system activityactivity(and increased plasma catecholamines,b-receptordownregulation)Increased activity of the renin-renin-angiotensin-aldosterone systemangiotensin-aldosterone system Increased release of arginine-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Diureticspharmacologic intervention pharmacologic intervention in CHFin CHF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。Improving hemodynamics with inotropic drugs does not decrease mortality;（病马加鞭）long-term treatment directed towards neurohormonal factors with ACE inhibitors and beta-blockers can decrease mortality Consensus recommendations for the management of CHFPatients with heart failure should first be evaluated to assess LV ejection fraction.Patients with systolic dysfunction(EF 40%)should then undergo the following treatment: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fluid retention-a fluid retention-a diureticdiuretic.ACE inhibitorACE inhibitor and and beta-blockerbeta-blocker should be should be initiated and maintained unless specifically initiated and maintained unless specifically contraindicated.contraindicated.（Patients with severe heart Patients with severe heart failure should probably not receive a failure should probably not receive a beta-beta-blockerblocker）DigoxinDigoxin-in patients with rapid atrial -in patients with rapid atrial fibrillation.fibrillation.Spironolactone,an aldosterone antagonist,may reduce mortality in patients with severe heart failure ACE inhibitorsfirst-line therapy in all patients with heart failureimprove symptoms,slow progression of the disease,reduce mortality,and decrease the incidence of hospitalization The most common adverse effects of ACE inhibitors are directly related to lowering angiotensin II concentrations(hypotension and renal insufficiency)and increasing concentrations of kinins(cough and angioneurotic edema)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-angiotensin receptor blockersangiotensin receptor blockersangiotensin receptor antagonists(angiotensin receptor antagonists(AT1 Receptor Antagonists)are as effective)are as effective as ACE inhibitors in treating heart as ACE inhibitors in treating heart failure,but it appears that therapeutic failure,but it appears that therapeutic efficacy may be comparable efficacy may be comparable losartan,candesartan,valsartan losartan,candesartan,valsartan Inotropic 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 ActivityThereisevidencethatdigitalismayactdirectlytosensitizationofbaroreceptorresponseandtherebyexertsomeofitsbeneficialeffectsthroughreductionofsympathetictoneThe recent Digitalis Investigation Group The recent Digitalis Investigation Group(DIG)clinical trial indicated digoxin did(DIG)clinical trial indicated digoxin did not reduce overall mortality in patients not reduce overall mortality in patients with heart failure(who were receiving with heart failure(who were receiving diuretics and ACE inhibitors),but did diuretics and ACE inhibitors),but did reduce the rate of hospitalizationreduce the rate of hospitalizationOtherinotropicagents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)Though beta-blockers were widely considered to be contraindicated for patients with heart failure only a decade ago,they are now considered first-line first-line therapy for patients with mild to moderate therapy for patients with mild to moderate heart failure heart failure 现认为脂溶性的效果更好。metoprololcarvedilolbisoprololThe adverse effectsThe adverse effects:worsening of symptoms,hypotension,and bradycardia These symptoms can be minimized by initiating therapy with low doses and gradually increasing dosage until tolerable therapeutic doses are reached Beta-blockersarecontraindicatedinpatientswithasthmaorseverebradycardiaDiureticsMost pateints with heart failure require treatment with diuretics to relieve symptoms of fluid retention(edema and congestion),but their is no evidence that diuretics slow the progression of the disease or decrease mortality.Loop diuretics(furosemide)are the most effective diuretics 多用于严重水钠潴留和肾功能不全时。Thiazide diureticsThiazide diuretics act on the distal loop and are less effective than loop diuretics 用于轻度水钠潴留。Concurrent use of two diuretics with different sites of action may be needed in patients who do not respond well to a single oral diuretic The most common adverse effect of diuretic therapy is potassium depletion which can be prevented by use of supplemental potassium,an ACE inhibitor,or a potassium-sparing diuretic(spironolactone or amiloride)Aldosterone AntagonistsAldosterone AntagonistsRecent clinical trials indicate that adding spironolactone(螺内酯)to standard treatment can significantly decrease mortality in patients with severe heart failure Effectofspironolactoneonsurvivalinpatientswithmoderateorseverecongestiveheartfailureinarandomizeddouble-blindclinicalstudy.(Reproduced,withpermission,fromPittBetal:Theeffectofspironolactoneonmorbidityandmortalityinpatientswithsevereheartfailure.NEnglJMed1999;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-1 AntagonistsEndothelin-1 Antagonists Thevasoconstrictorpeptide,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.JAmCollCardiol2008;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.SummaryOn the basis of several recent large-scale clinical trials it appears that reduction in ventricular volumeventricular volume and perhaps a reduction in reduction in the risk ofthe risk of lethal ventricular arrhythmiaslethal ventricular arrhythmias are the keys to long-term improvement and survival of patients with CHF Emphasis on therapy for heart failure has shifted in the past several years from acute interventions to improve hemodynamics and inotropic state to long-term therapies that might slow or halt the progression of the slow or halt the progression of the disease disease Future therapies will most likely involve therapeutic strategies that prevent or minimize the remodeling processes in the heart and vasculature,and thereby arrest the syndrome at early stages of cardiac dysfunction