臨床藥理-治療充血性心力衰竭藥物 課件

治療充血性心力衰竭藥物

DrugsforCongestiveHeartFailure

心力衰竭（heartfailure）是各種原因引起的心肌舒縮障礙，導(dǎo)致心輸出量不能滿足機(jī)體需求的一組臨床綜合征。充血性心衰是其中最主要的一種。 慢性或充血性心力衰竭（congestiveheartfailure,CHF）是各種病因所引起的多種心臟疾病（冠心、高心、肺心、風(fēng)心、心肌病等）的終末階段，當(dāng)靜脈回流足夠的情況下，心臟排出量絕對(duì)或相對(duì)減少，不能滿足機(jī)體組織需求的一種臨床或病理綜合征。心衰病人運(yùn)動(dòng)耐量下降，壽命縮短。Concept: CHFisacomplexclinicalsyndromecharacterizedbyimpairedventricularperformance,exerciseintolerance,ahighincidenceofventriculararrhythmias,andshortenedlifeexpectancyThesignsandsymptoms

Thesignsandsymptomsofheartfailureincludetachycardia,decreasedexercisetoleranceandshortnessofbreath,peripheralandpulmonaryedema,andcardiomegaly.

動(dòng)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癥狀為主。 心力衰竭不是一種獨(dú)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(lái)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(duì)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。Pathophysiology心力衰竭時(shí)機(jī)體的代償機(jī)制:AugmentedsympatheticactivitySodiumandwaterretentionMyocardialhypertrophyVentriculardilatation1．心臟本身的代償 心率加快、心肌收縮加強(qiáng)--快速發(fā)生 心臟擴(kuò)大和肥大—緩慢發(fā)生 是心臟本身儲(chǔ)備功能的動(dòng)員。2．心臟外的代償 血容量增加 血液重分配及紅細(xì)胞增多 等幾方面的心臟外代償作用。 機(jī)體的代償機(jī)制雖然有助于維持機(jī)體所需的心輸出量要求，但長(zhǎng)時(shí)間代償機(jī)制的激活可加重心臟的負(fù)擔(dān)。 在CHF的長(zhǎng)期發(fā)病過(guò)程中，各種代償機(jī)制對(duì)心臟和動(dòng)脈血管等的影響可產(chǎn)生惡性循環(huán)，加重心臟負(fù)擔(dān)，最終加重心力衰竭。實(shí)際上慢性心衰的發(fā)展過(guò)程就是在心肌氧供不足和維持機(jī)體循環(huán)血供需求之間不斷平衡的矛盾發(fā)展過(guò)程。心衰的一些代償機(jī)制Inadditiontotheeffectsshown,angiotensinIIincreasessympatheticeffectsbyfacilitatingnorepinephrinerelease.

慢性心衰的藥物治療：

應(yīng)減輕負(fù)荷，降低能耗，保護(hù)心臟。達(dá)到改善血流動(dòng)力學(xué)；改善運(yùn)動(dòng)耐量；延長(zhǎng)生命。

而不是病馬加鞭，只增強(qiáng)心肌收縮力心衰的血流動(dòng)力學(xué)指標(biāo)：壓力指標(biāo)：LVEDP，±dP/dtmax；容積指標(biāo)：SV，CO，CI，EF（正常0.67,心衰<0.45,嚴(yán)重心衰<0.3）時(shí)間指標(biāo)：PEP，LVET，T-dP/dtmax抗心衰藥物的發(fā)展和演變洋地黃時(shí)代（從民間的治療水腫藥物而來(lái)）利尿藥（噻嗪類、汞撒利）非苷類強(qiáng)心藥（兒茶酚胺類，磷酸二酯酶抑制劑-氨力農(nóng)、米力農(nóng)）擴(kuò)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pharmacologicintervention

inCHF 抗心衰藥物是主要用于治療CHF的藥物，主要有強(qiáng)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-blockerscandecreasemortalityConsensusrecommendationsforthemanagementofCHFPatientswithheartfailureshouldfirstbeevaluatedtoassessLVejectionfraction.Patientswithsystolicdysfunction(EF<40%)shouldthenundergothefollowingtreatment:水鈉潴留：利尿藥ACEIs，ARBs和/或beta-blocker室率快的房顫：強(qiáng)心苷（地高辛）重癥患者延長(zhǎng)壽命：醛固酮受體拮抗劑fluidretention-adiuretic.ACEinhibitorandbeta-blockershouldbeinitiatedandmaintainedunlessspecificallycontraindicated.（Patientswithsevereheartfailureshouldprobablynotreceiveabeta-blocker）Digoxin-inpatientswithrapidatrialfibrillation.Spironolactone,analdosteroneantagonist,mayreducemortalityinpatientswithsevereheartfailure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

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分泌醛固酮NOPGI(-)ACE和ACEIs作用示意圖舒張血管Captopril第1個(gè)在臨床上廣泛應(yīng)用的ACEI。含巰基，可致味覺(jué)異常。Enalapril前體藥，不含巰基。藥效和作用時(shí)間比cartopril強(qiáng)。ARBs-angiotensinreceptorblockersangiotensinreceptorantagonists(AT1ReceptorAntagonists)areaseffectiveasACEinhibitorsintreatingheartfailure,butitappearsthattherapeuticefficacymaybecomparablelosartan,candesartan,valsartanPositiveInotropicEffect

（抑制Na+,K+-ATPase）ElectrophysiologicalActions

（加上增強(qiáng)迷走）RegulationofSympatheticNervousSystemActivity

Thereisevidencethatdigitalismayactdirectlytosensitizationofbaroreceptorresponseandtherebyexertsomeofitsbeneficialeffectsthroughreductionofsympathetictone

TherecentDigitalisInvestigationGroup(DIG)clinicaltrialindicateddigoxindidnotreduceoverallmortalityinpatientswithheartfailure(whowerereceivingdiureticsandACEinhibitors),butdidreducetherateofhospitalizationOtherinotropicagents 只適用于急性心衰，長(zhǎng)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

Thoughbeta-blockerswerewidelyconsideredtobecontraindicatedforpatientswithheartfailureonlyadecadeago,theyarenowconsideredfirst-linetherapyforpatientswithmildtomoderateheartfailure現(xiàn)認(rèn)為脂溶性的效果更好。metoprololcarvedilolbisoprololTheadverseeffects:worseningofsymptoms,hypotension,andbradycardiaThesesymptomscanbeminimizedbyinitiatingtherapywithlowdosesandgraduallyincreasingdosageuntiltolerabletherapeuticdosesarereachedBeta-blockersarecontraindicatedinpatientswithasthmaorseverebradycardiaEffectofspironolactoneonsurvivalinpatientswithmoderateorseverecongestiveheartfailureinarandomizeddouble-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OtherAgentswithTherapaeuticPotential

Endothelin-1Antagonists

Thevasoconstrictorpeptide,endothelin-1,isknowntobeelevatedinheartfailureandisapredictorofmortalityinpatientswithheartfailure.Animalmodelsofheartfailureindicateendothelinreceptorantagonistssuchasbosentanmayhavelong-termbenefitsinreversingmyocardialremodelingandimprovingsurvival.Short-term,small-scaletrialsinhumansindicatepossiblebeneficialeffectsonsystemicandpulmonaryhemodynamicsxanthineoxidaseinhibitorBackground:Highserumuricacid(SUA)levelsareastrong,independentmarkerofimpairedprognosisinpatientswithmoderatetosevereCHF.Resultsandconclusion:Oxypurinoldidnotproduceclinicalimprovementsinunselectedpatientswithmoderate-to-severeheartfailure. However,post-hocanalysissuggeststhatbenefitsoccurinpatientswithelevatedSUAinamannercorrelatingwiththedegreeofSUAreduction.Impactofoxypurinolinpatientswithsymptomaticheartfailure.ResultsoftheOPT-CHFstudy.JAmCollCardiol2008;51(24):2301-9.Stepsinthetreatmentofchronicheartfailure.________________________________________ 1.Reduceworkloadoftheheart

a.Limitactivitylevel

b.Reduceweight

c.Controlhypertension

2.Restrictsodium

3.Restrictwater(rarelyrequired)

4.Givediuretics

5.GiveACEinhibitoranddigitalis1

6.Giveb-blockerstopatientswithstableclassII-IIIheartfailure

7.Givevasodilators__________________________________________1Manycliniciansuseangiotensin-convertingenzymeinhibitorsbe