《药理学》英文课件 Treatment of Congestive Heart Failure

TreatmentofCongestiveHeartFailureOVERVIEWOFCONGESTIVEHEARTFAILURE

Congestiveheartfailure(CHF)isaconditioninwhichtheheartisunabletopumpsufficientbloodtomeettheneedsofthebody.CHFcanbecausedbyanimpairedabilityofthecardiacmuscletocontractorbyanincreasedworkloadimposedontheheart.Threeclassesofdrugs1)vasodilatorsthatreducetheloadonthemyocardium;2)diureticagentsthatdecreaseextracellularfluidvolume;3)inotropicagentsthatincreasethestrengthofcontractionofcardiacPHYSIOLOGYOFMUSCLECONTRACTION

thecardiacmusclecellsareinterconnectedingroupsthatrespondtostimuliasaunit,contractingtogetherwheneverasinglecellisstimulated.Actionpotentialthecellsofcardiacmuscleshowaspontaneous,intrinsicrhythmgeneratedbyspecialized"pace-maker"cellslocatedinthesinoatrial(SA),andatrioventricular(AV)nodes.Thecardiaccellsalsohaveanunusuallylongactionpotential,whichcanbedividedintofivephasesCardiaccontractionTheforceofcontractionofthecardiacmuscleisdirectlyrelatedtotheconcentrationoffree(unbound)cytosoliccalcium.SourcesoffreeintracellularcalciumThefirstisfromoutsidethecell,whereopeningofvoltage-sensitivecalciumchannelscausesanimmediateriseinfreecytosoliccalcium.Thesecondsourceisthereleaseofcalciumfromthesarcoplasmicreticulumandmitochondria,whichfurtherincreasesthecytosoliclevelofcalciumRemovaloffreecytosoliccalciumIffreecytosoliccalciumlevelsweretoremainhigh,thecardiacmusclewouldbeinaconstantstateofcontraction,ratherthanshowingaperiodiccontraction.Mechanismsofremovalincludetwoalternatives.RemovaloffreecytosoliccalciumSodium-calciumexchange:Uptakeofcalciumbythesarcoplasmicreticulumandmitochondria:CompensatoryphysiologicalresponsesinCHFIncreasedsympatheticactivity:Fluidretention:Myocardialhypertrophy:DecompensatedheartfailureIftheadaptivemechanismsfailtomaintaincardiacoutput,theheartfailureistermeddecompensated.TherapeuticstrategiesinCHFreductioninphysicalactivity,lowdietaryintakeofsodiumandtreatmentwithvasodilators,diureticsandinotropicagents.VASODILATORSPreloadisthevolumeofbloodthatfillstheventricleduringdiastole.Afterloadisthepressurethatmustbeovercomeforthehearttopumpbloodintothearterialsystem.Vasodilatorsareusefulinreducingexcessivepreloadandafterload.Angiotensinconvertingenzyme(ACE)inhibitorsdrugsblocktheenzymethatcleavesangiotensinItoformthepotentvasoconstrictor,angiotensinII.Theseagentsalsodiminishtherateofbradykinininactivation.ACEinhibitorsalsodecreasethesecretionofaldosterone,resultingindecreasedsodiumandwaterretention.ActionsonheartACEinhibitorsdecreasevascularresistance,venoustone,andbloodpressure,resultinginanincreasedcar-diacoutputACEinhibitorsmaybeconsideredforsingle-agenttherapyinpatientswhopresentwithmilddyspneaonexertionandwhodonotshowsignsorsymptomsofvolumeoverload.ACEinhibitorsareusefulindecreasingCHFinasymptomaticpatientswithejectionfractionlessthan35%AdverseeffectsTheseincludeposturalhypotension,renalinsufficiency,hyperkalemia,andapersistentdrycough.ThepotentialofsymptomatichypotensionwithACEinhibitortherapyrequirescarefulmonitoring.DIURETICSDiureticsrelievepulmonarycongestionandperipheraledema.Diureticsdecreaseplasmavolumeandsubsequentlydecreasevenousreturntotheheart(preload).Thisdecreasesthecardiacworkloadandoxygendemand.Diureticsalsodecreaseafterloadbyreducingplasmavolume,thusdecreasingbloodpressure.INOTROPICDRUGSDigitalis:mostofthedrugscomefromthedigitalis(foxglove)plant.Theyareagroupofchemicallysimilarcompoundsthatcanincreasethecontractilityoftheheartmuscleandarethereforewidelyusedintreatingheartfailure.

ModeofactionRegulationofcytosoliccalciumconcentration:Cardiacglycosidescombinereversiblywiththesodium-potassiumATPaseofthecardiaccellmembraneresultinginaninhibitionofpumpactivity.ModeofactionIncreasedcontractilityofthecardiac:AdministrationofdigitalisglycosidesincreasestheforceofcardiaccontractilityTherapeuticusesDigoxintherapyisindicatedinpatientswithsevereleftventricularsystolicdysfunctionafterinitiationofdiureticandvasodilationtherapy.Digoxinisnotindicatedinpatientswithdiastolicorright-sidedheartfailure.PharmacokineticsThesedrugsareabsorbedafteroraladministration.alargevolumeofdistribution.

Digoxinhastheadvantageofarelativelyshorthalf-life,Digoxinalsohasamorerapidonsetofaction,Adverseeffectscanoftenbemanagedbydiscontinuingcardiacglycosidetherapy,determiningserumpotassiumlevels,andifindicated,bygivingpotassiumsupplements.Ingeneral,decreasedserumlevelsofpotassiumpredisposeapatienttodigoxintoxicity.Digoxinlevelsmustbemonitoredinthepresenceofrenalinsufficiencyanddosageadjustmentmaybenecessary.SeveretoxicityresultinginventriculartachycardiaAdverseeffectsCardiaceffects:moreseveredysrhythmia,movingfromdecreasedorblockedatrioventricularnodalconduction,paroxysmalsupraventriculartachycardia,totheconversionofatrialfluttertoatrialfibrillation,prematureventriculardepolarization,ventricularfibrillation,andfinally,tocompleteheartblock.GastrointestinaleffectsAnorexia,nausea,andvomitingCNSeffectsTheseincludeheadache,fatigue,confusion,blurredvision,FactorspredisposingtodigitalistoxicityElectrolyticdisturbances:Hypokalemiacan