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Part4

DrugsforTreatmentofCongestiveHeartFailureContents

OverviewACEinhibitorsDiureticsreceptorblockersCardiacglycosideOthersHeart(cardiac)failureissaidtohaveoccurredwhentheheartisnolongerabletomaintainthecirculationtothetissuesfornormalmetabolism.1.

Pathophysiologicalchangesofcongestiveheartfailure(CHF)(1)Functionandstructurechanges(2)Increasedsympatheticactivityanddown-regulationofreceptor(3)Activatedrenin-angiotensin-aldosteronesystem(RAAS)A.

OverviewPathophysiologicalchangesofCHFPathophysiologicalchangesofCHFCardiacfailureCardiacoutputVenouspressureVenoushyperemiaPulmonarycirculation:cough,emptysis,dyspneaSystemiccirculation

hyperemia

:jugularveindistension,edemaBloodsupplyRenalbloodflowRenin-angiotensionⅡAldosteroneSodiumandwaterretentionChangesinhemodynamicsofCHFA.

Overview2.GradesofCHF

Ⅰ(A):nosymptomsⅡ(B):physicalactivitieswerelimitedandsymptomscouldbeinducedbygeneralactivityⅢ(C):physicalactivitiesweremarkedlylimitedⅣ(D):symptomsappearevenatrest3.TherapeuticstrategiesinCHF(1)Increasingcontractilityofthecardiacmuscles(2)InhibitingRAAS(3)Reducingsympatheticactivity(4)Dilatingvessels(5)Diuresis

A.

Overview

Cardiacremodeling

Decreaseoverload

DrugtherapyforCHFACEI:

captopril卡托普利

enalapril依那普利AT1receptorantagonists:

losartan氯沙坦

irbesartan伊白沙坦B.

Angiotensinconvertingenzymeinhibitors(ACEI)andangiotensinreceptorantagonistsCardiovascularremodelingvasodilatationSystemicandlocalACEI1.PharmacologicaleffectsInhibitingtheproductionofAngIIvasoconstriction

;sodiumretention

;cardiacremodeling(myocardialhypertrophy)

InhibitingthedegradationofbradykininvasodilatationIncreasingANPandscavengingfreeradicals

B.

Angiotensinconvertingenzymeinhibitors(ACEI)andangiotensinreceptorantagonistsBox

ActionsofangiotensinII

throughactivatingAT1receptorsConstrictingvessels,increaseperipheralresistanceandreturnedbloodvolume.Increasingsympathetictension,promotereleaseofsympathetictransmitter.Stimulatingreleaseofaldosterone.Rapidlyinducingexpressionofc-fos,c-jun,Egr-1,c-myc,etc.CardiovasculareffectsDecreaseresistanceofperipheralvesselsDilatecoronaryartery,increasebloodsupplyofheartandkidney,improvecardiacandrenalfunctionReversemyocardialhypertrophyandventricularremodelingB.

Angiotensinconvertingenzymeinhibitors(ACEI)andangiotensinreceptorantagonistsB.

Angiotensinconvertingenzymeinhibitors(ACEI)andangiotensinreceptorantagonists2.Clinicaluses(1)CHFincreasemotortolerancedecreasemortality(2)Hypertension

3.Adverseeffects

HypotensionCoughandangioedemaHyperpotassemia

RashesandalteredtastesContraindications:pregnancyandstenosisofrenalarteryB.

Angiotensinconvertingenzymeinhibitors(ACEI)andangiotensinreceptorantagonistsAT1receptorantagonistsComparedwithACEI:BlockingactionsofangiotensinIIdirectlyNotaffectingbradykininmetabolismProtectingrenalfunctionUsedforCHFandhypertension

B.

Angiotensinconvertingenzymeinhibitors(ACEI)andangiotensinreceptorantagonists1.Pharmacologicaleffects

ReducebloodvolumebyincreasingNa+andwaterexcretionReduceNa+-Ca2+exchangeinvascularsmoothmusclecells2.ClinicalusesCHF:grandI–IV(mainlyusedinII–III),

aloneorcombinedwithotherdrugsEdema,hypertension,etc.3.Adverseeffectsimbalanceofelectrolytes/acid-base;plasmalevelofrenin;hypokalemia;hyperuricemia;hyperglycemia/hyperlipidemiaC.

DiureticsTherapeuticeffectsofdiureticsinCHFMaindiureticsThiazidesLoopdiureticsK+sparingdiuretics类别(主要作用部位)其他分类名作用机制利尿应用非利尿应用碳酸酐酶抑制药（近曲小管）/抑制碳酸酐酶利尿药耐受的病人,与袢利尿药合用青光眼，高山病，代谢性碱中毒渗透性利尿药（髓袢及其他部位）脱水药增高尿液渗透压急性肾功能衰竭脑水肿，青光眼袢利尿药（髓袢升支粗段）1.高效能利尿药2.Na+-K+-2C1—同向转运体抑制药抑制Na+-K+-2C1—同向转运各种严重水肿，急性肾功能衰竭高钙血症，加速毒物排出噻嗪类利尿药（远曲小管）1.中效能利尿药2.Na+-C1—同向转运体抑制药抑制Na+-C1—同向转运各种水肿高血压，高尿钙症，尿崩症保钾利尿药（集合管、末段远曲小管）低效能利尿药1.拮抗醛固酮作用（螺内酯）2.抑制上皮细胞Na+通道（氨苯蝶啶，阿米洛利）水肿（尤其对伴有醛固酮增高者，如肝硬化病人）失钾和/或失镁Commonlyused:carvedilol卡维地洛,bisoprolol比索洛尔,sustained-releasemetoprolol缓释型美托洛尔

1.Pharmacologicaleffects(1)Blockingeffectsofcatecholaminesonmyocardium:decreasingheartrateandcardiacoxygendemand(2)Up-regulatingreceptor(3)InhibitingRAASandVP(vosopressin,加压素):anti-myocardialhypertrophyandremodeling(4)Reducingcardiacoxygenremand,vasodilatation(receptorblock)(5)Anti-arrhythmicandanti-hypertensiveeffects

D.

receptorblockers2.Clinicaluses(1)CHF:grandII-IIIdecreasingmortality(2)Otheruses:

hypertension,arrhythmias,angina,etc.D.

receptorblockersTherapeuticeffectsof

receptorantagonistsoncardiacfunctioninCHFpatientsD.

receptorblockers3.AdverseeffectsInhibitionofcardiacfunctionContraindications:

severeheartfailuresevereA-VblockhypotensionworseningbronchialasthmaD.

receptorblockersE.

Cardiacglycoside

(digitalis)Cardiacglycoside

:Itisakindofglycosidecompoundswhichcanselectivelyactoncardiacmuscle,andincreasetheforceofmyocardialcontraction.

Digoxin地高辛E.

Cardiacglycoside

(digitalis)1.Pharmacologicaleffects(1)Positiveinotropiceffects

inhibitingNa+-K+-ATPase

freeCa2+

excitation-contractioncoupling

cardiacoutput

organbloodsupply

Vmax

diastolicduration

venousreturn

coronarybloodsupply

cardiacoxygenconsumptionE.

Cardiacglycoside

(digitalis)InhibitionofNa+-K+-ATPasebydigitalisandpotentiationofcardiacmusclecontraction(2)Negativechronotropiceffects

Reflexinhibitionofsympatheticactivity

cardiacoutput

Sympatheticactivity

HRIncreasingvagalactivity

directly

ReducingAVconduction:ventricularrate

E.

Cardiacglycoside

(digitalis)(3)Electrophysiologicaleffects

decreasingautomaticityofsinoatrialnode

slowconduction,especiallyAVconduction

increasingautomaticityofPurkinjefibresshorteningERPoffastresponsecellsMechanisms:intracellularNa+

,K+

,Ca2+

MDP,afterdepolarization

E.

Cardiacglycoside

(digitalis)Overdose:Na+

,K+

,Ca2+

MDP

afterdepolarizationElectrophysiologicalbasisfordigitalisoverdoseECG:

P-R;S-T/Twave;variousarrhythmiasP-RS-T/Twave

prematuralventricularbeat(4)OthereffectsVessels:vasoconstriction

Centralnervoussystem:

CTZdopamineD2receptormentalandvisiondisordersKidneyincreasebloodsupplyofkidneydiureticeffect:decreaseNa+reabsorption

E.

Cardiacglycoside

(digitalis)2.Clinicaluses(1)Congestiveheartfailure(CHF)

especiallyassociatedwithatrialfibrillationandsinustachycardia(2)Arrhythmias

atrialfibrillation/atrialflutter:

paroxysmalsurpraventriculartachycardia

E.

Cardiacglycoside

(digitalis)3.Adverseeffects(1)Gastrointestinaleffectsnausea,vomiting,etc.(2)CNSeffectsalterationofcolorperception〔色视,suchasyellowvision黄视〕;headache,fatigue,confusion,etc.E.

Cardiacglycoside

(digitalis)(3)Cardiactoxicity

arrhythmias：prematuralbeats,

tachycardia，atrioventricularblock,sinusbradycardia,etc.Prevention：DoseindividualizationAvoidingprovocationfactors:plasmaK+

,anddruginteractions,etc.Treatment：

KCl,phenytoinorlidocaine,i.v.

Atropine:A-Vblock,sinusbradycardia

Fabsegmentofdigoxinantibody,i.v.E.

Cardiacglycoside

(digitalis)Druginteractionsthatprobablyinducedigitaliscardiotoxicity4.Administration(1)Loading+maintainingdosesfulldose(digitalization)+maintainingdosesforseverepatients(2)Maintainingdose