第二十四章抗慢性心功能不全药.ppt

24章抗慢性心功能不全药,DrugsUsedintheTreatmentofcongestiveheartfailure“CHF”,objective,掌握强心苷的一般药理，地高辛卡托普利用于CHF作用特点。熟悉利尿药、氨氯地平、米力农及其他非苷类抗CHF的作用及特点、扩血管药的应用根据及选药。了解CHF的病理生理及其他药物的抗CHF作用特点。,心脏的泵血功能,1.心肌收缩的特点“全或无”收缩相邻心肌细胞具有润盘的特殊结构，出生于心室某一处的兴奋，通过润盘迅速传递，引起组成心室的所有心肌细胞几乎同步收缩。不发生完全强直收缩与骨骼肌不同，当刺激频率较高时，后一次刺激引起的骨骼肌收缩可发生在前一次刺激所引起的基础上，发生完全强直收缩。心肌细胞的有效不应期（ERP）特别长，相当于整个心肌细胞的收缩期和舒张早期。自动节律性心肌细胞分为工作细胞和特殊分化细胞，特殊分化细胞分布在窦房结、房室交界、希氏束、浦肯野纤维等，构成特殊的传导系统；特殊分化细胞都具有自动产生节律性兴奋的能力。,心脏的泵血功能,心脏泵血机制心动周期心脏一次收缩和舒张构成一个机械性活动周期，称为心动周期。在一个心动周期内，心房和心室均可以产生收缩和舒张活动，心室肌的收缩和舒张造成室内压力的变化，是导致心房和心室之间以及心室和主动脉之间产生压力梯度的主要原因，而心房的收缩和舒张生产是影响较少。压力梯度是推动血液在相应腔室之间流动的主要动力。室内压力的变化和血液的单方向流动，需要在瓣膜活动的配合下实现。,心脏的泵血功能,影响心排出量的因素每分钟内一侧心室排血的总量，也称每分排出量，CO取决于心率和每搏排出量。前负荷：心室舒张期所承受的压力，用心室舒张期末期容量表示。后负荷：指动脉血压心肌收缩力：收缩蛋白、调节蛋白、物质代谢、能量供应、细胞内钙离子浓度、ATP酶的活性等心率：神经因素（交感神经、迷走神经）、体液因素（循环血液中的肾上腺素、去甲肾上腺素、甲状腺素）、体温等。,1introduction,WhatsCHF?Congestiveheartfailure（CHF）isaclinicalsyndromeofcardiacdysfunction（心功能不全）.Itsalsocalled“overloadedmyocardiopathy”(超负荷心肌病）,1introduction,1introduction-pathologyfeature,leftventricle功能障碍,运动耐力,arhythmia心律失常,congestiveheartfailure心衰,suddendeath猝死,1introduction-prognosis预后,1、CHFmortality死亡率,3year30%5year50%1year50-70%(severe),2、deathreason,50%pumpfailure50%arrhythmia,心功能不全（心缩力）,CO,代偿机制,交感NS活性,激活RAAS,血管收缩水、钠潴留,心前、后负荷,耗氧,久,失代偿,循环衰竭,A灌注不足,V淤血,正性肌力药,心脏负荷药（扩血管药、利尿药等）,ACEI,其他,肾素一血管紧张素一醛固酮系统,Othersargininevasopressin（AVP精氨酸加压素）endothelin（ET，内皮素）tumornecrosisfactor（TNF-，肿瘤坏死因子）atrialnatriureticpeptide（ANP，心房利钠肽）endotheliumderivedrelaxingfactor(EDRF内皮细胞衍生舒张因子，NO)PGI2（前列环素）-Rdown-regulation,1introduction-pathophysiology,Functionalteration1)cardiaccontractility2)heartrate3)heartloadStructurealteration1)myocardialcellapoptosis（凋亡）2)extracellularmatrix（细胞外基质）3）remodeling（重构）,病理生理学,Comparisonofnormalandabnormalheart,Cardiaccontractility（心收缩力）CO，LVEDP左心室舒张末期压,Myocardialhypertrophy(心肌肥厚）andremodeling（重构）,1introduction,Classificationofdrugs1、Positiveinotropicagents（正性肌力药）cardiacglycoside强心苷digoxin，digitoxin；non-cardiacglycosidemilrinone米力农，ibopamine异波帕胺；,1introduction,2、RAASinhibitors肾素一血管紧张素一醛固酮系统1).ACEI:captopril卡托普利,enalapril依那普利2).AT1antagonists血管紧张素受体阻滞药:losartan氯沙坦,valsartan缬沙坦3).Aldosterone醛固酮antagonist:spironolacton安体舒通,1introduction,3、Reduceloadagents(降低负荷药）vasodilators:nitroglycerin硝酸甘油，血管扩张剂diuretics:DCT，furosemide；4、Others-Rblocker：carvedilol卡维地洛;Ca2+antagonists：amlodipine氨氯地平,2usualdrugs,I、强心苷cardiacglycosides【definition】selectiveactontheheartmyocardialcontractility（心肌收缩力）;usedforCHFdigoxinF60%80%(20%80%)；2、distributewidely;3、classificationofCGsaccordingtotheireliminationmode:longeffectdigitoxin洋地黄毒苷moderateeffectdigoxin地高辛shorteffectcedilanide（毛花苷），strophanthinK（毒毛花苷）,【pharmacokineticsofCGs】,2usualdrugs-cardiacglycosides,【pharmacologicalactions】1、positiveinotropicaction（正性肌力作用）Selectivityishigher(选择性高)；themyocardialcontractility,characteristics:,1cardiacmusclecontractpromptly，diastoleprolongreversely（舒张期相对延长）；themaximaltension（最高张力）;themaximalshortingvelocity（最大缩短速率）;,2COinpatientwithCHF;3myocardialoxygenconsumptioninpatientwithCHF（衰竭心脏的耗氧量）.,HowreducemyocardialoxygenconsumptionofCHF？,contractility,HR,Ventricularwalltension,CHF,oxygenconsumption,CGs,心室张力,【mechanismofaction】,Na+-K+-ATPaseNa+-K+exchangeintracellularNa+Na+-Ca2+exchangeintracellularCa2+theforceofcardiaccontraction,NKA,NCE,3Na+,2K+,digoxin,Na+,Ca2+,Ca2+,Na+,2usualdrugs-cardiacglycosides,2、negativechronotropicaction（负性频率作用）1)indirectactionmyocardialcontractilityvagalactivity（迷走N活性）reflex;HR；2)vagalsensitivity（迷走N敏感性）directly.,2usualdrugs-cardiacglycosides,3、influenceonelectrophysiologyofmyocardia(心肌电生理),AutomaticityconductivityERP,SAnode窦房结,Atria心房,AVnode房室结,Purkinje,2usualdrugs-cardiacglycosides,4、ECGTloworreverse，S-Tfishhooktype；P-Rinterphase；P-Pinterphase；Q-Tinterphase.5、diureticeffect;reninactivity,2usualdrugs-cardiacglycosides,【clinicaluses】1.CHFbesteffect:CHFaccompaniedbyatrialfibrillation（房颤）.bettereffect:hypertension、coronaryatheroscleroticcardiopathy（冠脉粥样硬化性心脏病）.,2usualdrugs-cardiacglycosides,noeffect：CHFinducedbypulmonaryheartdisease（肺心病）,activemyocarditis（活动性心肌炎）,seriouspericarditis（心包炎）.,2usualdrugs-cardiacglycosides,2.Somearrhythmias1）Atrialfibrillation（房颤）atrialrate400600time/minventricularrate100200time/minCO;digoxineffectsontheA-Vnodeconcealedconduction（隐匿性传导）ventricularrate（心室率）,2usualdrugs-cardiacglycosides,2）Atrialflutter（房扑）atrialrate320360time/minventricularrate;digoxinERPofatria，AtrialflutterAtrialfibrillation，digoxindepressA-Vconductionventricularrate,【adversereactions】,1.Gastrointestinalanorexia(厌食，theearliestsignoftoxicity),nauseaandvomiting2.CNSheadache,fatigue（疲劳）,dizzy（眩晕）,delirium（谵妄）,visual（视觉）changes3.Cardiactoxicity(theworst),2usualdrugs-cardiacglycosides,Cardiactoxication:(introcellularK+)Prematureventricularbeats（室早）33%AV-block房室阻滞18%AVnodetachycardia17%AVjointingrhythmia12%Atrialtachycardia+AVblock10%Ventriculartachycardia（室性过速）8%Sinousarrest（窦性停搏）2%,【treatmentofuntowardeffects】,1、preventionoftoxicsymptoms1）avoidthefactorsalteredthesensitivitytocardiacglycoside(increase)：serumK+,Mg2+;serumCa2+;LowerpHvalue;Myocardialischemia（心肌缺血）;Druginfluence,2usualdrugs-cardiacglycosides,2)Observetheindicationsforwithdrawalthedrug（停药指征）:Sinusbradycardia（窦性心动过缓）HR60beats/min.VentriculartachycardiaAbnormalcolorperception（色视异常）,2usualdrugs-cardiacglycosides,3）measurationofserumconcentration：digoxin3ng/mlistoxiclevel（中毒水平）；2、Cessationofusingthedrugs（停药）supplyKClpo.orivgtt.,severeA-Vblockisnotgiven!,notice,2usualdrugs-cardiacglycosides,3、usingantiarrhythmicdrugsphenytoinsodium，lidocaineusedtotreatventriculararrhythmia室性心律失常；atropineusedtocontrolbradycardia心动过缓、A-Vblock.4、usingdigoxin-AbFabsegmentSpecificityishigher.,1、newmethod：Dailymaintenancedose(每日维持量)：digoxin:0.25mg.d-1after67d（45t1/2）Css(steady-state)1）toxicityoccur；2）usedinchronicCHF;3）notbegiventoacuteCHFordrugswitht1/2overlong；,【administration】,2、oldmethod：1）Totaleffectivedose（全效量）alsocalled：loadingdose（负荷量）,digitalizingdose（洋地黄化量）2）Maintenancedosewasusedaftertotaleffectivedose.,2usualdrugs-RAASinhibitors,II、RAASinhibitors肾素一血管紧张素一醛固酮系统II-1、血管紧张素I转化酶抑制药（Angiotensin-convertingenzymeinhibitorsACEI）captoprilfosinoprilenalaprilcilazaprilramipril,依那普利,西拉普利,依那普利,雷米普利,1、inhibitACEactivity,AngI,AngII,Bloodvessel（+）Aldosterone醛固酮Myocardialhypertrophy,remodeling,Bp,ACE,（kininaseII）,BK,losealive,NO,PGI2synthesisbloodvesseldilation,ACEI,reverse,2usualdrugs-ACEI,2、inhibitmyocardialhypertrophyandremodelingventricularremodeline(心室重构)InCHF，myocardialhypertrophywithchangesofleftventricularstructure,cardiacefficiency（效能）,【mechanismofreversion】,myocardiaoverload,AngII,activate,Cellgrowth、proliferate,ventriclehypertrophyandremodeling,ACEI,2usualdrugs-ACEI,3、influenceonhemodynamics（血流动力学）dilateperipheralvesselspreloadandafterload,CO；LVEDP左心室舒张末期压,renalblood;aldosteroneNa+,H2Oretention；4、sympatheticnerveactivity,【clinicaluses】onlyonedrugtoprolongthesurvivalofCHFpatients.ACEIisusedincombinationwithdiuretics、digoxin.TheyarebasicdrugstotreatCHF.,2usualdrugs-ACEI,II-2、AT1拮抗药,（AngIIreceptor(AT1)blockers,ARBs)losartan（氯沙坦）valsartan（缬沙坦）directlyblockAT1,effectssameasACEI;adverseeffectsless.,II-3、aldosteroneantagonist,spironolacton(螺内酯）competitiveblockaldosterone-R：Cellgrowth、proliferate;ventricleandvesselsremodeling;aloneused-weaker,usedwithACEI-effects,mortality,III、利尿药diuretics,thiazides（噻嗪类），DCTfurosemide（呋塞米）,spironolactone【actionsanduses】excretionofNa+、H2Oextracellularfluidvolume;vasodilations;,2usualdrugs-diuretics,SelectionofdiureticsmildCHF:DCTpo；middleCHF：poDCT+furosemideseriousCHF：ivfurosemideor+spironolactone;recommend:diuretics+digoxin+ACEI,-Rdrugs,2usualdrugs-others,IV、-Rantagonists美托洛尔metoprolol卡维洛尔carvedilol,2usualdrugs-Rantagonists,【actionsanduses】RAAS，HR，oxygenconsumption（耗氧量）1-Rup-regulationantiproliferation（抗增殖作用）andanti-O2freeradial（氧自由基）,2usualdrugs-Rantagonists,Antiarrhythmicandantimyocardialischemiaactions;carvedilolmainlyusedformyocardialdilatation。(扩张型心肌病）usedwithcardiacglycoside.,V.Others,一、VasodilatorsmechanismofvasodilatorstotreatCHF,Vein,venousrefluence