DrugsUsedforCongestiveHeartFailure(CHF)Case137yrsoldfemalePalpitation(心悸)10years,withpinkfrothysputumrecently.Therewererheumaticfever20yearsago.PE:tem.37.5℃,breathrate30/min,HR:148/min,orthopnoea(端坐呼吸)，mitralface（二尖瓣面容）,bubbleandwheezingsoundatbothlungs.Noedemaonbothlegs.Diagnosis:leftheartfailure.STAGEDISABILITYCLASS1MILDNosymptomsCanperformordinaryactivitieswithoutanylimitationsCLASS2MILDMildsymptoms-occasionalswellingSomewhatlimitedinabilitytoexerciseordootherstrenuousactivitiesCLASS3MODERATENoticeablelimitationsinabilitytoexerciseorparticipateinmildlystrenuousactivitiesComfortableonlyatrestCLASS4SEVEREUnabletodoanyphysicalactivitywithoutdiscomfortSomeHFsymptomsatrest3Etiology(病因?qū)W) Heartunabletoprovideadequateperfusion（灌注）ofperipheralorganstomeettheirmetabolicrequirementsSymptom：peripheralandpulmonaryedema.CHFisacommonendpointformanydiseasesofcardiovascularsystem.Itcanbecausedby:

-Inappropriateworkload(負(fù)荷過(guò)重volumeorpressureoverload)-Restrictedfilling（充盈受限）

-Myocyteloss（心肌減少）Compensation（代償）inCHFHeartfailureisusuallyaccompaniedbyanincreasein:Sympatheticnervoussystem(SNS)Chronicup-regulationoftherenin-angiotensin-aldosteronesystem(RAAS)andeffectsofaldosteroneonheart,vessels,andkidneys.Inafailingheart,thelossofcontractilefunctionleadstoadeclineinCOandadecreaseinarterialBP.Baroreceptors(壓力感受器）sensethehemodynamicchangesandinitiatecountermeasures（對(duì)策）trytomaintainnormalBP.ActivationoftheSNSservesasacompensatorymechanisminresponsetotheearlierThishelpsmaintainadequatecardiacoutputby:Increasingmyocardialcontractilityandheartrate(β1-adrenergicreceptors)Increasingvasomotortone(α1-adrenergicreceptors)tomaintainsystemicbloodpressureFigurep.203kat§1.PathophysiologyofCHFI.functionalandstructuralchangesinCHFFunctional:decreasedcontractivity&CO,FromhemodynamicstandpointHFcanbesecondarytosystolicdysfunctionordiastolicdysfunctionStructural:cellularchanges，remodelingCellularchanges

ChangesinCa2+handling.

Changesinadrenergicreceptors:

?

Slight

inα1receptors?β1receptorsdesensitization

followedbydownregulation

Changesincontractileproteins

Programcelldeath(Apoptosis)

IncreaseamountoffibroustissueII.NeurohormonalchangesN/HchangesFavorableeffectUnfavor.effect

SympatheticactivityHR,contractility,vasoconst.Vreturn,fillingArteriolarconstrictionAfterloadworkloadO2consumptionRenin-Angiotensin–AldosteroneSalt&waterretention

VRVasoconstrictionafterloadVasopressinSameeffectSameeffectinterleukins&TNFMayhaverolesinmyocytehypertrophyApoptosis

EndothelinVasoconstrictionVRAfterloadIII.Changesincardiacadrenoceptorsignaltransduction1.β1receptorsdownregulation2.β1receptorsdesensitization3.increasedGRKsactivityManagementofCHFismultifaceted,withthelong-termaimsof:relievingsymptomsimprovinghemodynamics(血流動(dòng)力學(xué))improvingqualityoflifeanddecreasemortality.IV.ClassificationofdrugsforCHF1.Renin-angiotensinsysteminhibitorACEIAT1antagonistsAldosteroneantagonist2.Diuretics3.βBlockers4.digitalis5.vasodilators6.non-digitalisinotropicdrugs§2.RASinhibitorsI.ACEIforCHF1.Decreasecardiacafterloadbyvasodilation2.decreasealdosterone&cardiacpreload3.inhibitmyocardial&vascularremodeling4.improvehemodynamics5.decreasesympatheticactivityGoodforCHFpts（病人）ineverystageDrycoughII.AT1blockersLosartan,valsartan,irbesartanNodrycoughIII.AldosteroneantagonistsSpironolactone（螺內(nèi)酯）IncreaseNa+&H2OexcretionandK+sparingInhibitmyocardial&VSMremodeling（重構(gòu)）§3DiureticsIncreaseNa+&H2Oexcretion,decreasebloodvolume&cardiacpreloadDecreaseveinpressure&edemaThemosteffectivesymptomaticreliefMildsymptomsHCTZ(氫氯噻嗪)Chlorthalidone(氯噻酮)BlockNareabsorbtioninloopofhenleanddistalconvolutedtubulesThiazidesareineffectivewithGFR<30--/minMoresevereheartfailure→loopdiureticsLasix(20–320mgQD),FurosemideBumex(Bumetanide1-8mg)Torsemide(20-200mg)Mechanismofaction:InhibitchloridereabsortioninascendinglimbofloopofHenleresultsinnatriuresis,kaliuresisandmetabolicalkalosisAdversereaction:

pre-renalazotemia(氮血癥) Hypokalemia Skinrash ototoxicityK+Sparing(節(jié)約的)AgentsTriamterene&amiloride–actsondistaltubulesto↓KsecretionSpironolactone(Aldosteroneinhibitor)

recentevidencesuggeststhatitmayimprovesurvivalinCHFpatientsduetotheeffectonrenin-angiotensin-aldosteronesystemwithsubsequenteffectonmyocardialremodelingandfibrosis§4βBlockersHasbeentraditionallycontraindicatedinptswithCHFNowtheyarethemainstayintreatmentonCHF&maybetheonlymedicationthatshowssubstantialimprovementinLVfunctionInadditiontoimprovedLVfunctionmultiplestudiesshowimprovedsurvivalTheonlycontraindicationisseveredecompensated（失代償）CHFMechanismforCHFtreatmentPartoftheirbeneficialeffectsmayderivefromslowingofheartrateanddecreasemyocardialO2consumptionbyblockβ1.β-Blockersmaybebeneficialthroughresensitizationofthedown-regulatedreceptor,improvingmyocardialcontractility.ReducereninreleasebyblockingβRinkidneySuggestedmechanismsalsoincludereducedremodeling§5DigitalisglycosidesRecentstudieshaveshownthatdigitalisdoesnotaffectmortalityinCHFpatientsbutcausessignificant ReductioninhospitalizationReductioninsymptomsofCHF

TheroleofdigitalishasdeclinedsomewhatbecauseofsafetyconcernHistoryofdigitalisSourcedfromfoxgloveplant1785,Dr.WilliamWithering’smonographondigitalisHasaprofoundeffectonthecardiaccontractilityStructureofdigitalisOOHHHHOHCH3HCH3OOH136121417內(nèi)酯環(huán)甾核苷元圖26-2強(qiáng)心苷的化學(xué)結(jié)構(gòu)OCH3OHOH3PharmacokineticsThemorelipidsoluble,themoreandquicktheabsorptionbyp.o,andthelongerthet1/2willbeDigoxin(地高辛)---moderate,digitoxin(洋地黃毒苷)---longlastingWellabsorbedorally10%ofpopulationhavebacteriainthegut,whichinactivatedigoxin,needinganincreaseddoseinsuchBewareofusingantibioticsinsuchpatientsDigoxinhasaverynarrowther.MarginPharmacologicaleffectsI.onheart1.positiveinotropicactionForceofcontractionresemblestothatofthenormalheartImprovedcirculationleadstoreducedsympatheticactivityVagaltoneisenhanced&VagotoniceffectthisleadstoreductioninHRFinallymyocardialO2demandisreducedMechanismofactionPositiveinotropiceffect:by↑intracellularCa&enhancingactin-myosincrossbrideformation(bindstotheNa-KATPase→inhibitsNapump→↑intracellularNa→↑Na-Caexchange2.negativechrono-tropicactionImprovedcirculationreflectivelyleadstoincreasedVagaltoneVagotoniceffectofdigitalis3.effectsonconductivetissuesandcardiacelectrophysiologyII.OnnerveandendocrinesystemStimulateCNS,SNSattoxicdoseDecreaseplasmareninlevel&inhibitRASIII.Diuresisincreasedrenalbloodflow&glomerulusfiltrationfollowedimprovedcardiacfunctionInhibitNa/K/ATPaseinrenaltubule,decreaseNareabsorptionInhibitSNS,decreasealdosteroneClinicalusesCHF:notfirstchoicedrugnowSevereLVsystolicdysfunctionOnlyafterinitiationofdiuretics,ACEI,beta-blockerstherapyCannotstoptheprogressionofpathologicalchangescausingheartfailure,anddoesnotprolonglifeinpatientswithCHFAntiarrhythemiaManagementofpatientswithchronicatrialfibrillationAtrialflutterSupraventriculartachycardiaDigitalisToxicityDigitalistoxicityisoneamongmostcommonestencountered(why?)NarrowsafetymarginTherapeuticconcentration-0.5-1.5ng/mlOftenthefirststepisdiscontinuationofRxDigoxinlevelsmustbemonitoredcloselyPharmacologicalandtoxiceffectsaregreaterinhypokalemicpatients.K+-depletingdiureticsareamajorcontributingfactortodigoxintoxicity.1.CardiacreactionPalpitations,arrhythmias,bradycardia,AVnodeblock,tachycardiaToxicitycanbetreatedwithhigherthannormaldosesofpotassium.PhenytoincantakedigitalisawayfromNa/K/ATPaseDigoxinantibody(digibind)isusedspecificallytotreatlife-threateningdigoxinoverdose.2.Noncardiacmanifestations

Anorexia,Nausea,vomiting,Headache,Xanthopsiasotoma(黃視),Disorientation§6VasodilatorsDecreasethepre-or/andafter-loadofheartNitroglycerin(硝酸甘油)Hydralazine(肼屈嗪)Nitroprussidesodium(硝普鈉)