《心力衰竭知识》ppt课件

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Chapter26Anti-congestiveheartfailuredrugsLNMUPharmacology ChronicorCongestiveHeartFailure，CHFCHFoccurswhenthecardiacoutputisinadequatetoprovidetheoxygenneededbythebody.ThekeydefectinCHFisadecreaseincardiaccontractility,resultingininadequatecardiacoutput TheCausesofHeartFailurePopulation-attributablerisk,%010203040506070MaleFemale60393410115864475Hyper-Myo-AnginaDiabetesLVheartValvulartensioncardialhyper-heartinfarctiontrophydisease ThecharacterizationsofCHFDecreaseincardiaccontractility,inadequatecardiacoutput.Intravascularvolumeexpansionandventricularfillingpressures↑,systemicandpulmonaryhypertentension,dyspnea呼吸困难.ActivationofsympatheticnervousandRASMyocardialdysfunction.Ventricularremodeling. VentricularremodelingafteracuteinfarctionVentricularremodelingindiastolic舒张andsystolic收缩heartfailureInitialinfarctExpansionofinfarct(hourstodays)Globalremodeling(daystomonths)NormalheartHypertrophiedheart(diastolicheartfailure)Dilatedheart(systolicheartfailure) MyocardialremodelinginCalcineurintransgenichearts(Cell,Vol93,215-228,1998) HeartfailureReducedcardiacoutputSympatheticnervoussystemactivationVasoconstrictionElevatedcardiacfillingpressureSodiumandwaterretentionAngiotensinⅠReninCardiacremodelingAldosteroneAngiotensinⅡPathophysiologicalmechanismsofheartfailureandmajorsitesofdrugactiondigoxinβ-blockers,digoxinVasodilatorsACEinhibitorsAngiotensin-RblockersDiureticsSpironolactone ClassificationofdrugsusedinCHF1.Renin-angiotensin-aldosteronesysteminhibitors(1)ACEIcaptopril(2)angⅡreceptorblocker(AT1antagonist)losartan(3)aldosteroneantagonistspironolacton2.Diureticsthiazides,furosemide3.-receptorblockerMetoprolol,carvedilol4.positiveinotropicagents(1)Cardiacglycosidesdigoxin,digitoxin(2)non-glycosidepositiveinotropicagentsmilrinone5.vasodilatorsnitroprussidesodium6.calciumsensitizerandcalciumchannelblockersamlodipine SectionIIInhibitorsofrenin-angiotensin-aldosteronesystem(RAAS) Renin-AngiotensinSystem(RAS)angiotensinogenreninAngiotensinⅠ糜酶旁路ACEAngiotensinⅡAT1receptor1.vasoconstriction,aldosterone↑：BP↑2.hypertrophyandproliferationcardiovascularremodelingKallikrein-KininSystem(KKS)kininogenaseBradykinin降解产物AT2receptorNO↑,partfightAT1receptorVasodilation,BP↓ACEI(—)Thecompositionandphysiological roleofRASAT1Blockerspironolactone ①Ⅰangiotensin-convertingenzymeinhibitor，ACEI:captopril,enalapril②Ⅱangiotensinreceptor(AT1)blocker,ARB:losartan氯沙坦③Ⅲantagonistforthealdosteronereceptor:spironolactoneTheclassificationofInhibitorsRAAS 1.ACEI卡托普利（captopril）（开搏通）依那普利（enalapril）（悦宁定）赖诺普利（lisinopril）（帝益洛）苯那普利（benazepril（洛丁新/诺华）福辛普利（fosinopril）（蒙诺/施贵宝）喹那普利（quinapril）（益恒）雷米普利（ramipril）（瑞泰）培哚普利（perindopril）（雅施达）西拉普利（cilazapril）（一平苏） 药物起始剂量目标剂量卡托普利6.25mg，tid50mg，tid依那普利2.5mg，bid10～20mg，bid福辛普利5～10mg/d40mg/d赖诺普利2.5～5mg/d30～35mg/d培哚普利2mg/d4～8mg/d喹那普利5mg，bid20mg，bid雷米普利2.5mg/d5mg，bid或10mg/d西拉普利0.5mg/d1～2.5mg/d苯那普利2.5mg/d5～10mg，bid治疗慢性心衰的ACEI及其剂量 Themechanismforanti-congestiveheartfailureeffect1.↓peripheralvascularresistance,↓cardiacafterload2.↓aldosterone3.↓myocardialandventricularremodeling4.changesofhemodynamics5.↓theactivityofsympatheticnervoussystemACEI 1.↓peripheralvascularresistance,↓cardiacafterloadACEI内皮衍生超极化因子(EndotheliumDerivedHyperpolarizingFactor) 5.antisympatheticeffect↓AT1receptorinpresynapticmembraneofsympatheticnerve→↓NA↓AT1receptorinadrenalmedella→↓NA↓AT1receptorinCNS→↓centralsympatheticimpulsetransmission→↓heartloadanddamageACEI 1)Thesaltandwaterretention↓2)Thepreloadandafterload↓3)Thelong-termremodelingoftheheartandvessels↓﹡Mortalityandmorbidity↓↓TherapeuticapplicationsCHFHypertensionClinicalusing:ACEI AT1blocker,ARB氯沙坦(losartan)缬沙坦(valsartan)厄贝沙坦(irbesartan)坎地沙坦(candesartan)依普沙坦(eprosartan)替米沙坦(telmisartan) Renin-AngiotensinSystem(RAS)angiotensinogenreninAngiotensinⅠ糜酶旁路ACEAngiotensinⅡAT1receptor1.vasoconstriction,aldosterone↑：BP↑2.hypertrophyandproliferationcardiovascularremodelingKallikrein-KininSystem(KKS)kininogenaseBradykinin降解产物AT2receptorNO↑,partfightAT1receptorVasodilation,BP↓Thecompositionandphysiological roleofRASARB↑ SectionIIIDiureticsHigh-efficacydiuretics(loopdiuretics)FurosemideModerate-efficacydiureticsThiazides;Low-efficacydiureticsSpironolactone；Theycanpromotethelossofsodiumandwaterfromthebodyandprovideareductioninpreloadandafterload. CardiogenicedemarelievethesymptomsmildCHF←ThiazidesmoderateCHF←Thiazides+SpironolactoneIfitfailsorfortheseriousCHF←loopdiuretics；ButCautions:Alargedosediuretics↓cardiacoutput;↑sympatheticnerveactivity↑aldosteroneandhypokalemia.←CoadministrationwithspironolactoneDiuretics SectionIV-receptorblocker1.Drugsactingon-receptor(1)Carvedilol—α,-receptorblocker.(2)Metoprolol－1-receptorblocker PharmacologicaleffectsInhibitionofsympatheticactivitycatecholamines↓→Ca2+infux↓→myocardialnecrosis↓myocardialremodeling↓renin↓→angiotensin↓up-regulatingβR↓sensitivityofβRtocatecholaminesAnti-arrhythmicandanti-ischemiceffects-Rblocker TherapeuticapplicationsMildandmoderateCHFDilatedcardiomyopathy心肌病CHF,ischemicCHFImprovesymptomsanddecreasemortalityCombinationwithdiureticsandACEIThemedicationshouldbeinitiatedwithlowdoses.-Rblocker Bronchospasm,bradycardiaandhypotensionOthers:depression,nightmares,fatigue,andsexualdysfunction;asthma;maskinghypoglycemicsymptomsAdverseEffects-Rblocker ClassificationofdrugsusedinCHF1.Renin-angiotensin-aldosteronesysteminhibitors(1)ACEIcaptopril(2)angⅡreceptorblocker(AT1antagonist)losartan(3)aldosteroneantagonistspironolacton2.Diureticsthiazides,furosemide3.-receptorblockerMetoprolol,carvedilol4.positiveinotropicagents(1)Cardiacglycosidesdigoxin,digitoxin(2)non-glycosidepositiveinotropicagentsmilrinone5.vasodilatorsnitroprussidesodium6.calciumsensitizerandcalciumchannelblockersamlodipine HeartfailureReducedcardiacoutputSympatheticnervoussystemactivationVasoconstrictionElevatedcardiacfillingpressureSodiumandwaterretentionAngiotensinⅠReninCardiacremodelingAldosteroneAngiotensinⅡPathophysiologicalmechanismsofheartfailureandmajorsitesofdrugactiondigoxinβ-blockers,digoxinVasodilatorsACEinhibitorsAngiotensin-RblockersDiureticsSpironolactone Digitoxin洋地黄毒苷Digoxin地高辛Deslanoside毛花苷丙StrophantinK毒毛花苷KSectionVCardiacglycosides 甾核Steroid不饱和内酯环Lactonering三分子洋地黄毒糖tri-digitoxose(↑苷元的作用强度和时间）ChemicalstructureofDigoxin苷元aglycone(正性肌力)（C3、C14)–OH；C17具β构型。否则苷元失去强心作用。OOOOHOHCH3HCH3HC18H31O531417BACD Effectsofcardiacglycosidesonheart(ahighlyselectiveforheart)1.Positiveinotropicaction(1)Cardiacglycosides→themaximumforce↑→thecontractilityofcardiacmuscle↑→thevelocityofcardiacmusclecontraction↑→diastolerelativeextension↑强心苷Anti-congestiveheartfailuredrugs CHFpatients:Cardiacglycosides→cardiacoutput↑→cardiacfillingpressures↓→heartsize↓andvenousandcapillarypressures↓.(2)Cardiacoutput↑强心苷Anti-congestiveheartfailuredrugs Innormalindividuals:contractility↑→myocardialminuteoxygenconsumption(MVO2)↑.b.InpatientswithCHF:ventricularvolume↓→MVO2↓.(3)Myocardialoxygenconsumption强心苷Anti-congestiveheartfailuredrugs Myocardialoxygenconsumptionventricularpressure(afterload)ventricularvolume(preload)contractilityheartrateventricularwalltensionO2demand强心苷Anti-congestiveheartfailuredrugs Inhibitthemembrane-boundNa+-K+-ATPase.InhibitionofNa+-K+-ATPaseresultsinintracellularaccumulationofNa+(andlossofintracellularK+).AccumulationofintracellularNa+→slightmovementofextracellularCa2+intothecellsecondarytoactivationofamembraneNa+-Ca2+carrier.Themechanismforpositiveinotropiceffect DigoxinmayinterferewiththeabilityofthesarcoplasmicreticulumtobindCa2+→makingmoreCa2+availableforinteractionwithcontractileproteins→Ca2+↑→positiveinotropiceffect 说教学过程Na+Ca2+K+intracellularextracellularNKANCE×强心苷Anti-congestiveheartfailuredrugsNKA:Na+-K+-ATPaseNCE:Na+-Ca2+exchangerThemechanismforpositiveinotropiceffect 说教学过程强心苷Anti-congestiveheartfailuredrugs×CICR:CalciuminducedcalciumreleaseCa2+[Ca]2+i与AP和心肌收缩的关系Themechanismforpositiveinotropiceffect ThemechanismforpositiveinotropiceffectCardiacglycosidesMLCK:Myosinlightchainkinase肌球蛋白轻链激酶SERCA:Sarco-endoplasmicReticulumCalciumAtpase肌浆网钙泵SOCE:store-operatedcalciumentrychannels钙池操纵钙离子通道RYR:Ryanodinereceptor兰尼碱受体强心苷Anti-congestiveheartfailuredrugs 强心苷↓↓Na+-K+-ATPase↓Na+-K+交换↓Cell内Na+短暂↑C内Na+超负荷，失K+↓↓↓影响Na+-Ca2+交换机制Ca2+超负荷异位节律点↓↓自律性↑Na+外流↑，Ca2+内流↑迟后去极Na+内流↓，Ca2+外流↓↓C内[Ca2+]i↑心律失常↓正性肌力治疗量中毒量CICRCICR:Calciuminducedcalciumrelease 说教法HR↓Mechanism：A：CO↑→activatingvagusnerveB：↑sensitivityofvagusSignificance：负性频率→心动周期↑→舒张期↑→心室充盈好心肌自身供血↑心肌获充分休息心功能改善Effectsofcardiacglycosidesonheart2.Negativechronotropicaction 强心苷Anti-congestiveheartfailuredrugs↓窦房结自律性↓房室传导↓心房ERP↑浦肯野纤维自律性，↓ERP、传导与增加迷走神经活性有关3.Electrophysiologicaleffects抑制Na+-K+-ATP酶0-50If,IkandNa+-Ca2+exchangeCa2+channelK+channel 增加迷走神经活性→Ca2+内流↓→房室传导↓→房扑转为房颤a.therapeuticdose3.Electrophysiologicaleffects强心苷Anti-congestiveheartfailure→窦房结细胞KAch开放频率↑→K+外流↑→静息期膜电位↑（多负）→自律性↓→窦性频率↓→K+外流↑→心房ERP缩短0-50If,IkandNa+-Ca2+exchangeCa2+channelK+channel促K+外流↑→心房肌静息电位加大→零相除极速度↑→心房传导速度↑ (—)Na+-K+-ATP酶→[K+]i↓→最大舒张电位↓（少负）→接近阈电位→自律性↑；c.toxicdoseb.highdose（提高普氏纤维自律性）→Centralsympatheticactivity↑[Ca2+]i↑；ERP↓（中毒时室速或室颤的机制）强心苷Anti-congestiveheartfailuredrugsK+外流↓→ERP↓最大舒张电位↓→除极发生在较小的膜电位 强心苷Anti-congestiveheartfailuredrugs电生理特性窦房结心房房室结浦肯野纤维自律性↓↑传导性↑↓↓ERP↓↓与增加迷走神经活性有关抑制Na+-K+-ATP酶是强心苷引起室早、室性心律失常的原因之一治疗房颤、房扑使房扑转为房颤3.Electrophysiologicaleffects Withmoretoxicconcentration,restingmembranepotentialisreducedasaresultofinhibitionofthesodiumpumpandreducedintracellularpotassium.Glycosidestoxicity:atrioventricularjunctionalrhythm,prematureventriculardepolarization,bigeminalrhythm,andatrioventricularblockade.3.Electrophysiologicaleffects Regulationofneuroendocrineactivity--ParasympathomimeticeffectsAtlowerdose:mainlyaffectsatrialandatrioventricularnodalfunction.--SympathomimeticeffectsAtoverdose,enhancetheactivityofsympatheticnervouscentre.Anorexia厌食,nauseaandvomiting,headache,fatigue,….--RAASreninactivity↓;AgⅡ↓;aldosterone↓强心苷Anti-congestiveheartfailuredrugs 1)EffectsonvascularInnormalindividuals:peripheralvascularresistance(directaction)InpatientswithCHF:peripheralvascularresistance(indirectaction)2)EffectsonkidneyAdiureticeffect.cardiacfunctionimprovementinhibitionofkidneytubularNa+-K+-ATPaseExtracardiaceffects强心苷Anti-congestiveheartfailuredrugs PharmacokineticsSerumPrincipalAbsorptionProteinTherapeuticMetabolicDrugs(Peros)BindingT1/2ConcentrationRouteDigoxin60～85%25%36h0.5～2.0ngKidneyDigitoxin90～100%97%5～7d10～35ng/mlLiver强心苷Anti-congestiveheartfailuredrugs Therapeuticuses—CHF强心苷Anti-congestiveheartfailuredrugs 2.Arrhythmias:1.心房纤颤：350-600次/分（f波）强心苷→迷走兴奋↑→房室传导↓→房室结隐匿性传导↑→心室率↓2.心房扑动：240-430次/分（F波）强心苷→↓心房ERP→扑动变颤动→心室率↓；有些病人在停用强心苷后可恢复为窦性节律3.阵发性室上性心动过速：迷走兴奋↑（现已少用)房扑房颤fff强心苷Anti-congestiveheartfailuredrugs Drugactionsanddoses1.ActionvsEffectorResponse2.Pharmacologicaleffectsanddoseslethaltoxicmax.effectivemin.effectivesubmedicalTherapeuticormedicaldose[ Untowardeffects(1)Cardiaceffects(a)Prematureventricularbeatsandventriculartachycardiaandfibrillation(b)A-Vblock(c)Sinusbradycardia(<60bpm)强心苷Anti-congestiveheartfailuredrugs SomefactorsevokingtoxicityHypokalemiaHypomagnesemiaHypercalcemiaMyocarditis心肌炎Myocardialanoxia缺氧AcidbaseimbalanceRenalinsufficiency TreatmentofuntowardeffectsA.digoxinandpotassium-depletingdiureticsarediscontinued.B.Potassiumchloride;C.Phenytoin.D.Lidocaine.E.Atropine.F.Digoxin-specificantibodyfragment(Fab): (2)Anorexia,nauseaandvomiting(oftentheearliestsign)(3)Headache,visionchange,includingabnormalcolorperception(oftenyelloworgreenvision). 1.明确中毒症状，停药指征;（心电图监测）2.血药浓度监测:地高辛>3ng/ml,洋地黄毒苷>45ng/ml--停药;3.注意药物相互作用：排钾利尿药：低血钾—加重毒性，注意补钾；钙阻滞剂、胺碘酮、普罗帕酮抑制地高辛经肾小管分泌—减量；奎尼丁能自组织置换地高辛肝药酶诱导剂苯妥英钠--清除↑--血药浓度↓拟肾上腺素药--心肌对强心苷敏感性↑【中毒预防措施】强心苷Anti-congestiveheartfailuredrugs Non-CardioglycosidePositiveInotropicDrugs1.PDEinhibitors.♢cAMP↑→Ca2+↑→apositiveinotropiceffect♢vasodilation:directaction1)Milrinone米力农2)Vesnarinone维司力农Theyhavenotbeenshowntoreducesurvivalinplacebo-controlledtrials. 2.1-selectiveadrenoceptoragonistDobutamine多巴酚丁胺Ibopamine异布帕明IncreasemortalityNotforregularuseinCHF SectionVIVasodilatorsEffectiveinCHFbecausetheyprovideareductioninpreload,orreductioninafterload,orboth.Nitroprussidesodium:rapidafterloaddecrease,acutesevereCHF. 3.CalciumchannelblokersAmlodipineFelodipineTheyareeffectivearterialvasodilatorsandreducetheafterloadofheart.ReduceHR,facilitatingdiastolicrelaxationandloweringdiastolicfillingpressures.NotforroutineuseinCHF. PDEIPDEI利尿药 心力衰竭治疗建议概要（2002）不同心功能分级心力衰竭患者的治疗NYHA心功能Ⅰ级：控制危险因素；ACEI。NYHA心功能Ⅱ级：ACEI；利尿剂；β-R阻滞剂；地高辛用或不用。NYHA心功能Ⅲ级：ACEI；利尿剂；β-R阻滞剂；地高辛。NYHA心功能Ⅳ级：ACEI；利尿剂；地高辛；醛固酮受体拮抗剂；病情稳定者，谨慎应用β-R阻滞剂。 Thankyou!! 3