臨床藥理治療充血性心力衰竭藥物課件Concept: CHFisacomplexclinicalsyndromecharacterizedbyimpairedventricularperformance,exerciseintolerance,ahighincidenceofventriculararrhythmias,andshortenedlifeexpectancy2021/1/122Thesignsandsymptoms Thesignsandsymptomsofheartfailureincludetachycardia,decreasedexercisetoleranceandshortnessofbreath,peripheralandpulmonaryedema,andcardiomegaly. 動脈系統(tǒng)缺血-乏力，氣短，頭暈 靜脈系統(tǒng)淤血-水腫，頸靜脈怒張，肝脾腫大，呼吸困難靜脈淤血所致的病癥為主。2021/1/123心衰的分級〔NYHA標準〕Ⅰ級：心功能代償完全，體力活動不受限，日?；顒訜o乏力，心悸，呼吸困難等病癥；Ⅱ級：輕度代償不全，活動輕度受限，休息時無病癥；Ⅲ級：中度代償不全，體力活動明顯受限，日常活動即可產(chǎn)生病癥。限于室內(nèi)活動；Ⅳ級：嚴重代償不全，休息時亦有病癥，不能從事任何體力活動。2021/1/124 心力衰竭不是一種獨立的疾病，而是由多種原因引起的心肌收縮和/或舒張功能障礙的綜合征。近年來的研究發(fā)現(xiàn)，心力衰竭雖然主要表現(xiàn)為心肌收縮和舒張功能障礙，但神經(jīng)內(nèi)分泌的改變對其惡性循環(huán)的形成和維持有重要的作用。這些變化導(dǎo)致心臟出現(xiàn)不可逆的重構(gòu)(remodeling)，使衰竭的心臟一步步惡化。Pathophysiology2021/1/125心力衰竭時機體的代償機制:AugmentedsympatheticactivitySodiumandwaterretentionMyocardialhypertrophyVentriculardilatation1．心臟本身的代償 心率加快、心肌收縮加強--快速發(fā)生 心臟擴大和肥大—緩慢發(fā)生 是心臟本身儲藏功能的發(fā)動。2．心臟外的代償 血容量增加 血液重分配及紅細胞增多 等幾方面的心臟外代償作用。2021/1/126 機體的代償機制雖然有助于維持機體所需的心輸出量要求，但長時間代償機制的激活可加重心臟的負擔(dān)。 在CHF的長期發(fā)病過程中，各種代償機制對心臟和動脈血管等的影響可產(chǎn)生惡性循環(huán)，加重心臟負擔(dān)，最終加重心力衰竭。實際上慢性心衰的開展過程就是在心肌氧供缺乏和維持機體循環(huán)血供需求之間不斷平衡的矛盾開展過程。2021/1/127神經(jīng)體液系統(tǒng)主要改變Increasedsympatheticnervoussystemactivity(andincreasedplasmacatecholamines,b-receptordownregulation)Increasedactivityoftherenin-angiotensin-aldosteronesystem

Increasedreleaseofarginine-vasopressin

2021/1/128心衰的一些代償機制Inadditiontotheeffectsshown,angiotensinIIincreasessympatheticeffectsbyfacilitatingnorepinephrinerelease.

2021/1/129慢性心衰的藥物治療： 應(yīng)減輕負荷，降低能耗，保護心臟。到達改善血流動力學(xué)；改善運動耐量；延長生命。

而不是病馬加鞭，只增強心肌收縮力心衰的血流動力學(xué)指標：壓力指標：LVEDP，±dP/dtmax；容積指標：SV，CO，CI，EF〔正常0.67,心衰<0.45,嚴重心衰<0.3〕時間指標：PEP，LVET，T-dP/dtmax2021/1/1210抗心衰藥物的開展和演變洋地黃時代〔從民間的治療水腫藥物而來〕利尿藥〔噻嗪類、汞撒利〕非苷類強心藥〔兒茶酚胺類，磷酸二酯酶抑制劑-氨力農(nóng)、米力農(nóng)〕擴血管藥物血管緊張素轉(zhuǎn)化酶抑制劑ACEIs，ARBsβ受體阻斷劑醛固酮受體阻斷劑2021/1/1211使用抗心衰藥物后心功能曲線的改變(I)正性肌力藥物positiveinotropicagents(V)舒血管藥Vasodilators(D)利尿藥Diuretics2021/1/1212pharmacologicintervention

inCHF 抗心衰藥物是主要用于治療CHF的藥物，主要有強心苷、非甙類正性肌力藥、利尿藥、ACEI和β受體阻斷藥等。Improvinghemodynamicswithinotropicdrugsdoesnotdecreasemortality;〔病馬加鞭〕long-termtreatmentdirectedtowardsneurohormonalfactorswithACEinhibitorsandbeta-blockerscandecreasemortality2021/1/1213ConsensusrecommendationsforthemanagementofCHFPatientswithheartfailureshouldfirstbeevaluatedtoassessLVejectionfraction.Patientswithsystolicdysfunction(EF<40%)shouldthenundergothefollowingtreatment:水鈉潴留：利尿藥ACEIs，ARBs和/或beta-blocker室率快的房顫：強心苷〔地高辛〕重癥患者延長壽命：醛固酮受體拮抗劑2021/1/1214fluidretention-adiuretic.ACEinhibitorandbeta-blockershouldbeinitiatedandmaintainedunlessspecificallycontraindicated.〔Patientswithsevereheartfailureshouldprobablynotreceiveabeta-blocker〕Digoxin-inpatientswithrapidatrialfibrillation.Spironolactone,analdosteroneantagonist,mayreducemortalityinpatientswithsevereheartfailure2021/1/1215ACEinhibitorsfirst-linetherapyinallpatientswithheartfailure

improvesymptoms,slowprogressionofthedisease,reducemortality,anddecreasetheincidenceofhospitalizationThemostcommonadverseeffectsofACEinhibitorsaredirectlyrelatedtoloweringangiotensinIIconcentrations(hypotensionandrenalinsufficiency)andincreasingconcentrationsofkinins(coughandangioneuroticedema)2021/1/1216血管緊張素原AngiotensinⅠ收縮血管腎素激肽原緩激肽↑降解失活A(yù)ngⅢACEACEIsAngⅡ

↓

分泌醛固酮NOPGI(-)ACE和ACEIs作用示意圖舒張血管2021/1/1217Captopril第1個在臨床上廣泛應(yīng)用的ACEI。含巰基，可致味覺異常。Enalapril前體藥，不含巰基。藥效和作用時間比cartopril強。2021/1/1218ARBs-angiotensinreceptorblockersangiotensinreceptorantagonists(AT1ReceptorAntagonists)areaseffectiveasACEinhibitorsintreatingheartfailure,butitappearsthattherapeuticefficacymaybecomparablelosartan,candesartan,valsartan2021/1/1219InotropicDrugs-digitalisThebeneficialeffectsofcardiacglycosidesinthetreatmentofheartfailurehavebeenattributedtoapositiveinotropiceffectonfailingmyocardiumandefficacyincontrollingtheventricularrateresponsetoatrialfibrillation.Thecardiacglycosidesalsomodulateautonomicnervoussystemactivity,anditislikelythatthismechanismcontributessubstantiallytotheirefficacyinthemanagementofheartfailure.2021/1/1220PositiveInotropicEffect〔抑制Na+,K+-ATPase〕ElectrophysiologicalActions〔加上增強迷走〕RegulationofSympatheticNervousSystemActivityThereisevidencethatdigitalismayactdirectlytosensitizationofbaroreceptorresponseandtherebyexertsomeofitsbeneficialeffectsthroughreductionofsympathetictone2021/1/1221TherecentDigitalisInvestigationGroup(DIG)clinicaltrialindicateddigoxindidnotreduceoverallmortalityinpatientswithheartfailure(whowerereceivingdiureticsandACEinhibitors),butdidreducetherateofhospitalization2021/1/1222Otherinotropicagents 只適用于急性心衰，長期應(yīng)用于慢性心衰后，病人死亡率增加。Beta-AdrenergicAgonistsdopamine,dobutamine,prenalterolLevodopaandibopamineCyclicNucleotidePhosphodiesterase(PDE-III,cGMP-inhibitablePDE)InhibitorsBipyridines-amrinoneandmilrinone

imidazolonederivatives-enoximoneandpiroximone

2021/1/1223Beta-BlockersandCHFAnumberofstudiesbeginninginthe1970shaveshownthatbeta-blockerscanimprovesymptomsandventricularfunctioninpatientswithmoderatetosevereheartfailure,andmayslowtheprogressionofheartfailureinsomepatients(reviewedinBristow,Circulation101:558(2000))

2021/1/1224Thoughbeta-blockerswerewidelyconsideredtobecontraindicatedforpatientswithheartfailureonlyadecadeago,theyarenowconsideredfirst-linetherapyforpatientswithmildtomoderateheartfailure現(xiàn)認為脂溶性的效果更好。metoprololcarvedilolbisoprolol2021/1/1225Theadverseeffects:worseningofsymptoms,hypotension,andbradycardiaThesesymptomscanbeminimizedbyinitiatingtherapywithlowdosesandgraduallyincreasingdosageuntiltolerabletherapeuticdosesarereachedBeta-blockersarecontraindicatedinpatientswithasthmaorseverebradycardia2021/1/1226DiureticsMostpateintswithheartfailurerequiretreatmentwithdiureticstorelievesymptomsoffluidretention(edemaandcongestion),buttheirisnoevidencethatdiureticsslowtheprogressionofthediseaseordecreasemortality.Loopdiuretics(furosemide)arethemosteffectivediuretics多用于嚴重水鈉潴留和腎功能不全時。Thiazidediureticsactonthedistalloopandarelesseffectivethanloopdiuretics用于輕度水鈉潴留。Concurrentuseoftwodiureticswithdifferentsitesofactionmaybeneededinpatientswhodonotrespondwelltoasingleoraldiuretic2021/1/1227Themostcommonadverseeffectofdiuretictherapyispotassiumdepletionwhichcanbepreventedbyuseofsupplementalpotassium,anACEinhibitor,orapotassium-sparingdiuretic(spironolactoneoramiloride)AldosteroneAntagonists Recentclinicaltrialsindicatethataddingspironolactone(螺內(nèi)酯)tostandardtreatmentcansignificantlydecreasemortalityinpatientswithsevereheartfailure2021/1/1228Effectofspironolactoneonsurvivalinpatientswithmoderateorseverecongestiveheartfailureinarandomizeddouble-blindclinicalstudy.(Reproduced,withpermission,fromPittBetal:Theeffectofspironolactoneonmorbidityandmortalityinpatientswithsevereheartfailure.NEnglJMed1999;341:709醛固酮受體拮抗劑螺內(nèi)酯降低充血性心衰病人死亡率2021/1/1229OtherAgentswithTherapaeuticPotential

Endothelin-1Antagonists

Thevasoconstrictorpeptide,endothelin-1,isknowntobeelevatedinheartfailureandisapredictorofmortalityinpatientswithheartfailure.Animalmodelsofheartfailureindicateendothelinreceptorantagonistssuchasbosentanmayhavelong-termbenefitsinreversingmyocardialremodelingandimprovingsurvival.Short-term,small-scaletrialsinhumansindicatepossiblebeneficialeffectsonsystemicandpulmonaryhemodynamics2021/1/1230xanthineoxidaseinhibitorBackground:Highserumuricacid(SUA)levelsareastrong,independentmarkerofimpairedprognosisinpatientswithmoderatetosevereCHF.Resultsandconclusion:Oxypurinoldidnotproduceclinicalimprovementsinunselectedpatientswithmoderate-to-severeheartfailure. However,post-hocanalysissuggeststhatbenefitsoccurinpatientswithelevatedSUAinamannercorrelatingwiththedegreeofSUAreduction.Impactofoxypurinolinpatientswithsymptomaticheartfailure.ResultsoftheOPT-CHFstudy.JAmCollCardiol;51(24):2301-9.2021/1/1231Stepsinthetreatmentofchronicheartfailure.________________________________________ 1.Reduceworkloadoftheheart

a.Limitactivitylevel

b.Reduceweight

c.Controlhypertension

2.Restrictsodium

3.Restrictwater(rarelyrequired)

4.Givediuretics

5.GiveACEinhibitoranddig