心力衰竭知識(shí)課件

Chapter26

Anti-congestiveheartfailuredrugsLNMUPharmacologyChronicorCongestiveHeartFailure，CHFCHFoccurswhenthecardiacoutputisinadequatetoprovidetheoxygenneededbythebody.ThekeydefectinCHFisadecreaseincardiaccontractility,resultingininadequatecardiacoutputTheCausesofHeartFailure

Population-attributablerisk,%010203040506070MaleFemale60393410115864475

Hyper- Myo-

Angina

Diabetes

LVheart

Valvular tension cardial

hyper-

heart infarction

trophy

diseaseThecharacterizationsofCHFDecreaseincardiaccontractility,inadequatecardiacoutput.Intravascularvolumeexpansionandventricularfillingpressures↑,systemicandpulmonaryhypertentension,dyspnea呼吸困難.ActivationofsympatheticnervousandRASMyocardialdysfunction.Ventricularremodeling.VentricularremodelingafteracuteinfarctionVentricularremodelingindiastolic舒張

andsystolic收縮

heartfailureInitialinfarctExpansionofinfarct(hourstodays)Globalremodeling(daystomonths)NormalheartHypertrophiedheart(diastolicheartfailure)Dilatedheart(systolicheartfailure)MyocardialremodelinginCalcineurintransgenichearts(Cell,Vol93,215-228,1998)ClassificationofdrugsusedinCHF1.Renin-angiotensin-aldosteronesysteminhibitors(1)ACEIcaptopril(2)angⅡreceptorblocker(AT1antagonist)losartan(3)aldosteroneantagonistspironolacton2.

Diuretics

thiazides,furosemide3.-receptorblocker

Metoprolol,carvedilol4.

positiveinotropicagents(1)Cardiacglycosides

digoxin,digitoxin(2)non-glycosidepositiveinotropicagentsmilrinone5.vasodilators

nitroprussidesodium6.calciumsensitizerandcalciumchannelblockers

amlodipineSectionII

Inhibitorsofrenin-angiotensin-aldosteronesystem(RAAS)Renin-Angiotensin

System

(RAS)angiotensinogenreninAngiotensinⅠ糜酶旁路ACEAngiotensin

ⅡAT1receptor1.

vasoconstriction,aldosterone↑：BP↑2.

hypertrophy

and

proliferationcardiovascular

remodelingKallikrein-Kinin

System

(KKS)

kininogenaseBradykinin

降解產(chǎn)物AT2receptorNO↑,partfightAT1receptorVasodilation,BP↓ACEI(—)

Thecompositionandphysiological

roleof

RASAT1Blockerspironolactone1.ACEI卡托普利（captopril）（開搏通）依那普利（enalapril）（悅寧定）賴諾普利（lisinopril）（帝益洛）苯那普利（benazepril（洛丁新/諾華）福辛普利（fosinopril）（蒙諾/施貴寶）喹那普利（quinapril）（益恒）雷米普利（ramipril）（瑞泰）培哚普利（perindopril）（雅施達(dá)）西拉普利（cilazapril）（一平蘇）藥物起始劑量目標(biāo)劑量卡托普利6.25mg，tid50mg，tid依那普利2.5mg，bid10～20mg，bid福辛普利5～10mg/d40mg/d賴諾普利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治療慢性心衰的ACEI及其劑量Themechanismforanti-congestiveheartfailureeffect1.

↓peripheralvascularresistance,↓cardiacafterload2.↓aldosterone

3.↓myocardialandventricularremodeling4.changesofhemodynamics

5.

↓theactivityofsympatheticnervoussystemACEI5.antisympatheticeffect↓AT1receptorinpresynapticmembraneofsympatheticnerve→

↓NA

↓AT1receptorinadrenalmedella→

↓NA

↓AT1receptorinCNS→↓centralsympatheticimpulsetransmission→

↓heartloadanddamageACEI1)Thesaltandwaterretention↓

2)Thepreloadandafterload↓3)Thelong-termremodelingoftheheartandvessels↓

﹡Mortality

andmorbidity↓↓TherapeuticapplicationsCHF

HypertensionClinicalusing:ACEIAT1blocker,ARB

氯沙坦(losartan)纈沙坦(valsartan)厄貝沙坦(irbesartan)坎地沙坦(candesartan)依普沙坦(eprosartan)替米沙坦(telmisartan)SectionIIIDiuretics

High-efficacydiuretics(loopdiuretics)FurosemideModerate-efficacydiureticsThiazides;Low-efficacydiureticsSpironolactone；Theycanpromotethelossofsodiumandwaterfromthebodyandprovideareductioninpreloadandafterload.CardiogenicedemarelievethesymptomsmildCHF←Thiazides

moderateCHF←Thiazides+SpironolactoneIfitfailsorfortheseriousCHF←loopdiuretics；ButCautions:Alargedosediuretics↓cardiacoutput;↑sympatheticnerveactivity↑aldosteroneandhypokalemia.←CoadministrationwithspironolactoneDiuretics

SectionIV-receptorblocker1.Drugsactingon-receptor

(1)Carvedilol—α,-receptorblocker.

(2)Metoprolol－1-receptorblockerTherapeuticapplications

MildandmoderateCHFDilatedcardiomyopathy心肌病CHF,ischemicCHF

Improvesymptomsanddecreasemortality

CombinationwithdiureticsandACEIThemedicationshouldbeinitiatedwithlowdoses.-RblockerBronchospasm,bradycardiaandhypotensionOthers:depression,nightmares,fatigue,andsexualdysfunction;asthma;maskinghypoglycemicsymptomsAdverseEffects-RblockerDigitoxin

洋地黃毒苷Digoxin

地高辛

Deslanoside毛花苷丙Strophantin

K

毒毛花苷KSectionV

Cardiacglycosides甾核Steroid

不飽和內(nèi)酯環(huán)Lactonering三分子洋地黃毒糖

tri-digitoxose(↑苷元的作用強(qiáng)度和時(shí)間）ChemicalstructureofDigoxin

苷元aglycone(正性肌力)（C3

、C14)–OH；C17具β構(gòu)型。否則苷元失去強(qiáng)心作用。OOOOHOHCH3HCH3HC18H31O531417BACDEffectsofcardiacglycosidesonheart

(ahighlyselectiveforheart)

1.Positiveinotropicaction(1)

Cardiacglycosides

→

themaximumforce↑→thecontractilityofcardiacmuscle↑

→the

velocity

of

cardiacmusclecontraction↑→

diastolerelativeextension↑

強(qiáng)心苷Anti-congestiveheartfailuredrugsCHFpatients:Cardiac

glycosides→

cardiacoutput↑→cardiacfillingpressures↓

→heartsize↓andvenousandcapillarypressures↓.(2)

Cardiacoutput↑

強(qiáng)心苷Anti-congestiveheartfailuredrugsInnormalindividuals:

contractility↑→myocardialminuteoxygenconsumption(MVO2)↑.b.

InpatientswithCHF:ventricularvolume↓→MVO2↓.(3)Myocardialoxygenconsumption

強(qiáng)心苷Anti-congestiveheartfailuredrugsMyocardialoxygenconsumptionventricularpressure(afterload)ventricularvolume(preload)

contractility

heartrate

ventricularwalltension

O2demand

強(qiáng)心苷Anti-congestiveheartfailuredrugsInhibitthemembrane-boundNa+-K+-ATPase.InhibitionofNa+-K+-ATPaseresultsinintracellularaccumulationofNa+(andlossofintracellularK+).AccumulationofintracellularNa+→slightmovementofextracellularCa2+intothecellsecondarytoactivationofamembraneNa+-Ca2+carrier.ThemechanismforpositiveinotropiceffectDigoxinmayinterferewiththeabilityofthesarcoplasmicreticulumtobindCa2+

→makingmoreCa2+availableforinteractionwithcontractileproteins→Ca2+

↑

→positiveinotropiceffect說教學(xué)過程N(yùn)a+Ca2+K+intracellularextracellularNKANCE×

強(qiáng)心苷Anti-congestiveheartfailuredrugsNKA:Na+-K+-ATPaseNCE:Na+-Ca2+exchangerThemechanismforpositiveinotropiceffect說教學(xué)過程

強(qiáng)心苷Anti-congestiveheartfailuredrugs×CICR:CalciuminducedcalciumreleaseCa2+[Ca]2+i與AP和心肌收縮的關(guān)系ThemechanismforpositiveinotropiceffectThemechanismforpositiveinotropiceffectCardiacglycosidesMLCK:Myosinlightchainkinase肌球蛋白輕鏈激酶SERCA:Sarco-endoplasmicReticulumCalciumAtpase肌漿網(wǎng)鈣泵SOCE:store-operatedcalciumentrychannels鈣池操縱鈣離子通道RYR:Ryanodinereceptor蘭尼堿受體

強(qiáng)心苷Anti-congestiveheartfailuredrugs 強(qiáng)心苷

↓

↓Na+-K+-ATPase

↓

Na+-K+

交換↓

Cell內(nèi)Na+短暫↑

C內(nèi)Na+超負(fù)荷，失K+

↓

↓

↓

影響Na+-Ca2+交換機(jī)制Ca2+超負(fù)荷異位節(jié)律點(diǎn)

↓

↓自律性↑

Na+外流↑，Ca2+內(nèi)流↑ 遲后去極

Na+內(nèi)流↓，Ca2+外流↓

↓

C內(nèi)[Ca2+]i↑ 心律失常 ↓

正性肌力治療量中毒量CICRCICR:Calciuminducedcalciumrelease說教法HR↓Mechanism：A：CO↑→activatingvagusnerve

B：↑sensitivityofvagusSignificance：負(fù)性頻率→心動(dòng)周期↑→舒張期↑→心室充盈好心肌自身供血↑

心肌獲充分休息心功能改善Effectsofcardiacglycosidesonheart2.Negativechronotropicaction

強(qiáng)心苷Anti-congestiveheartfailuredrugs↓竇房結(jié)自律性↓房室傳導(dǎo)↓心房ERP↑浦肯野纖維自律性，↓ERP、傳導(dǎo)與增加迷走神經(jīng)活性有關(guān)3.Electrophysiologicaleffects抑制Na+-K+-ATP酶0-50If,IkandNa+-Ca2+exchangeCa2+channelK+channel增加迷走神經(jīng)活性→Ca2+內(nèi)流↓→房室傳導(dǎo)↓→房撲轉(zhuǎn)為房顫a.therapeuticdose3.Electrophysiologicaleffects

強(qiáng)心苷Anti-congestiveheartfailure→竇房結(jié)細(xì)胞KAch開放頻率↑→K+外流↑→靜息期膜電位↑（多負(fù)）→自律性↓→竇性頻率↓→K+外流↑→心房ERP縮短0-50If,IkandNa+-Ca2+exchangeCa2+channelK+channel促K+外流↑→心房肌靜息電位加大→零相除極速度↑→心房傳導(dǎo)速度↑

(—)Na+-K+-ATP酶→[K+]i↓→最大舒張電位↓（少負(fù)）→接近閾電位→自律性↑；c.toxicdoseb.highdose（提高普氏纖維自律性）→Centralsympatheticactivity↑[Ca2+]i↑；ERP↓（中毒時(shí)室速或室顫的機(jī)制）

強(qiáng)心苷Anti-congestiveheartfailuredrugsK+外流↓→ERP↓最大舒張電位↓→除極發(fā)生在較小的膜電位

強(qiáng)心苷Anti-congestiveheartfailuredrugs電生理特性竇房結(jié)心房房室結(jié)浦肯野纖維自律性↓↑傳導(dǎo)性↑↓↓ERP↓↓與增加迷走神經(jīng)活性有關(guān)抑制Na+-K+-ATP酶是強(qiáng)心苷引起室早、室性心律失常的原因之一治療房顫、房撲使房撲轉(zhuǎn)為房顫3.ElectrophysiologicaleffectsWithmoretoxicconcentration,restingmembranepotentialisreducedasaresultofinhibitionofthesodiumpumpandreducedintracellularpotassium.Glycosidestoxicity:atrioventricularjunctionalrhythm,prematureventriculardepolarization,bigeminalrhythm,andatrioventricularblockade.3.ElectrophysiologicaleffectsRegulationofneuroendocrineactivity--ParasympathomimeticeffectsAtlowerdose:mainlyaffectsatrialandatrioventricularnodalfunction.--SympathomimeticeffectsAtoverdose,enhancetheactivityofsympatheticnervouscentre.Anorexia厭食,nauseaandvomiting,headache,fatigue,….--RAASreninactivity↓;AgⅡ↓;aldosterone↓

強(qiáng)心苷Anti-congestiveheartfailuredrugs1)Effectsonvascular

Innormalindividuals:peripheralvascularresistance

(directaction)InpatientswithCHF:

peripheralvascularresistance

(indirectaction)2)Effectsonkidney

A

diureticeffect.cardiacfunctionimprovementinhibitionofkidneytubular

Na+-K+-ATPaseExtracardiaceffects

強(qiáng)心苷Anti-congestiveheartfailuredrugsPharmacokinetics

SerumPrincipal

AbsorptionProtein

TherapeuticMetabolicDrugs(Peros)Binding

T1/2ConcentrationRouteDigoxin

60～85%25%

36h0.5～2.0ngKidneyDigitoxin90～100%97%

5～7d10～35ng/mlLiver

強(qiáng)心苷Anti-congestiveheartfailuredrugsTherapeuticuses—CHF

強(qiáng)心苷Anti-congestiveheartfailuredrugs2.Arrhythmias:1.心房纖顫：350-600次/分（f波）強(qiáng)心苷→迷走興奮↑→房室傳導(dǎo)↓→

房室結(jié)隱匿性傳導(dǎo)↑→心室率↓

2.心房撲動(dòng)：240-430次/分（F波）強(qiáng)心苷→↓心房ERP→撲動(dòng)變顫動(dòng)→心室率↓；有些病人在停用強(qiáng)心苷后可恢復(fù)為竇性節(jié)律

3.陣發(fā)性室上性心動(dòng)過速：迷走興奮↑（現(xiàn)已少用)房撲房顫fff

強(qiáng)心苷Anti-congestiveheartfailuredrugsDrugactionsanddoses

1.ActionvsEffectorResponse2.Pharmacologicaleffectsanddoseslethaltoxicmax.effectivemin.effectivesubmedicalTherapeuticormedicaldose[Untowardeffects(1)Cardiaceffects(a)Prematureventricularbeatsandventriculartachycardiaandfibrillation(b)A-Vblock(c)Sinusbradycardia

(<60bpm)

強(qiáng)心苷Anti-congestiveheartfailuredrugsSomefactorsevokingtoxicityHypokalemiaHypomagnesemiaHypercalcemiaMyocarditis心肌炎Myocardialanoxia缺氧AcidbaseimbalanceRenalinsufficiencyTreatmentofuntowardeffectsA.

digoxinandpotassium-depletingdiureticsarediscontinued.B.Potassiumchloride;C.Phenytoin.D.Lidocaine.E.Atropine.F.Digoxin-specificantibodyfragment(Fab):(2)Anorexia,nauseaandvomiting(oftentheearliestsign)

(3)Headache,visionchange,includingabnormalcolorperception(oftenyelloworgreen