《药理学》英文课件 Diuretic Drugs

DiureticDrugsOVERVIEWDrugsinducingastateofincreasedurineflowarecalleddiuretics.TheseagentsareiontransportinhibitorsthatdecreasethereabsorptionofNa+atdifferentsitesinthenephron.NORMALREGULATIONOFFLUIDANDELECTROLYTESBYTHEKIDNEYS

Approximately16-20%ofthebloodplasmaenteringthekidneysisfilteredfromtheglomerularcapillariesintoBowman'scapsule.Theseincludeglucose,sodiumbicarbonate,aminoacids,andotherorganicsolutes,pluselectrolytes,suchasNa+,K+,andCI-.fivefunctionalzonesThekidneyregulatestheioniccompositionandvolumeofurinebythereabsorptionorsecretionofionsand/orwateratfivefunctionalzonesalongthenephron,namelytheproximalconvolutedtubule,thedescendingloopofHenle,theascendingloopofHenle,thedistalconvolutedtubule,andthecollectingductProximalconvolutedtubulealmostalloftheglucose,bicarbonate,aminoacids,andothermetabolitesarereabsorbed.ApproximatelytwothirdsoftheNa+isalsoreabsorbedintheproximaltubule;chlorideandwaterfollowpassivelytomaintainelectricalandosmolarequality.AcidsecretorysystemTheproximaltubuleisthesiteoftheorganicacidandbasesecretorysystemsThesecretorysystemsecretesavarietyoforganicacids(suchasuricacid,someantibiotics,diuretics)fromtheblood-streamintotheproximaltubule'slumen.Mostdiureticdrugsaredeliveredtothetubularfluidviathissystem.DescendingloopofHenle

Theremainingfiltrate,whichisisotonic,nextentersthedescendinglimboftheloopofHenleandpassesintothemedullaofthekidney.TheosmolarityincreasesalongthedescendingportionoftheloopofHenlebecauseofthecountercurrentmechanism.Thisresultsinatubularfluidwithathree-foldincreaseinsaltconcentration.AscendingloopofHenle

impermeabletowater.ActivereabsorptionofNa+,K+andCI-ismediatedbyaNa+/K+/2CI-cotransporter.Mg++andCa++entertheinterstitialfluidviatheparacellularpathway.adilutingregionofthenephron.Approximately25-30%ofthetubularsodiumchloridereturnstotheinterstitialfluid,thushelpingtomaintainthefluid'shighosmolarity.Distalconvolutedtubuleimpermeabletowater.About10%ofthefilteredsodiumchlorideisreabsorbedviaaNa+/CI-transporter,whichissensitivetothiazidediuretics.CollectingtubuleandductareresponsibleforNa+K+exchangeandforH+secretionandK+reabsorption,respectively.StimulationofaldosteronereceptorsintheprincipalcellsresultsinNa+reabsorptionandK+secretion.Antidiuretichormone(ADH,vasopressin)receptorspromotethereabsorptionofwaterfromthecollectingtubulesandducts.KIDNEYFUNCTIONINDISEASEInmanydiseasestheamountofsodiumchloridereabsorbedbythekidneytubulesisabnormallyhigh.Thisleadstotheretentionofwater,anincreaseinbloodvolume,andexpansionoftheextravascularfluidcompartment,resultinginedemaofthetissues.CongestiveheartfailureHepaticascites

NephroticsyndromeLOOPORHIGH-CEILINGDIURETICSBumetanide,furosemide,torsemideandethacrynicacidarefourdiureticsthathavetheirmajoractionontheascendinglimboftheloopofHenle

Bumetanide,furosemide,torsemide,ethacrynicacidMechanismofaction:LoopdiureticsinhibittheNa+/K+/CI-cotransportoftheluminalmembraneintheascendinglimboftheloopofHenle.ThereforereabsorptionofNa+,K+,andCI-isdecreasedActionsTheloopdiureticsactpromptly,evenamongpatientswhohavepoorrenalfunctionorwhohavenotrespondedtothiazidesorotherdiuretics.LoopdiureticsincreasetheCa++contentofurine,whilethiazidediureticsdecreasetheCa++concentrationoftheurine.TheloopdiureticscausedecreasedrenalvascularresistanceandincreasedrenalbloodTherapeuticusesTheloopdiureticsarethedrugsofchoiceforreducingtheacutepulmonaryedemaofcongestiveheartfailure.areusefulinemergencysituations,suchasacutepulmonaryedema.arealsousefulintreatinghypercalcemiabecausetheystimulatetubularCa++secretion.PharmacokineticsLoopdiureticsareadministeredorallyorparenterally.Theirdurationofactionisrelativelybrief,1to4hours.AdverseeffectsOtotoxicityHyperuricemia:Furosemideandethacrynicacidcompetewithuricacidfortherenalandbiliary

secretorysystems,thusblockingitssecretionandtherebycausingorexacerbatinggoutyattacks.Acutehypovolemia:Potassiumdepletion:THIAZIDESANDRELATEDAGENTSmostwidelyusedofthediureticdrugs.Theyaresulfonamidederivativesandarerelatedinstructuretothecarbonicanhydraseinhibitors.Thethiazideshavesignificantlygreaterdiureticactivitythanacetazolamide,andtheyactonthekidneybydifferentmechanisms.Allthiazidesaffectthedistaltubule,andallhaveequalmaximumdiureticeffect,differingonlyinpotency,expressedonapermilligrambasis.Chlorothiazide

Chlorothiazide,theprototypethiazidediuretic,wasthefirstmoderndiureticthatwasactiveorallyandwascapableofaffectingthesevereedemaofcirrhosisandcongestiveheartfail-urewithaminimumofsideeffects.MechanismofactionThethiazidederivativesactmainlyinthedistaltubuletodecreasethereabsorptionofNa+byinhibitionofaNa+/CI-cotransporterontheluminalmembrane.Theyhavealessereffectintheproximaltubule.ActionsIncreasedexcretionofNa+andCI-:ChlorothiazidecausesdiuresiswithincreasedNa+andCI-excretion,whichcanresultintheexcretionofaveryhyperosmolarurine.Thislattereffectisuniqueamongtheotherdiureticclasses,whichareunlikelytoproduceahyperosmolarurine.ActionsLossofK+:BecausethiazidesincreasetheNa+inthefiltratearrivingatthedistaltubule,moreK+isalsoexchangedforNa+.ActionsDecreasedurinarycalciumexcretion:ThiazidediureticsdecreasetheCa++contentofurinebypromotingthereabsorptionofCa++.ThiscontrastswiththeloopdiureticswhichincreasetheCa++concentrationoftheurine.Therapeuticuses:Hypertension:Clinically,thethiazideshavelongbeenthemainstayofantihypertensivemedication,sincetheyareinexpensive,convenienttoadminister,andwelltolerated.Therapeuticuses:Congestiveheartfailure:ThiazidescanbethediureticofchoiceinreducingextracellularvolumeinmildtomoderatecongestiveheartfailureTherapeuticuses:Renalimpairment:Patientswithnephroticsyndromeaccompaniedbyedemaareinitiallytreatedwithloopdiuretics;onlyifthistreatmentfailsaretheygivenmetolazoneinconjunctionwithaloopdiuretic.Therapeuticuses:Hypercalciuria:ThethiazidescanbeusefulintreatingidiopathichypercalciuriabecausetheyinhibiturinaryCa++excretion.Thisisparticularlybeneficialforpatientswithcalciumoxalatestonesintheurinarytract.Pharmacokinetics:Thedrugsareeffectiveorally.Mostthiazidestake1to3weekstoproduceastablereductioninbloodpressure,andtheyexhibitaprolongedbiologicalhalf-life(40hours).AllthiazidesaresecretedbytheorganicacidsecretorysystemofthekidneyCARBONICANHYDRASEINHIBITORSAcetazolamideisasulfonamidewithoutantibacterialactivity.Itsmainactionistoinhibittheenzymecarbonicanhydraseintheproximaltubularepithelialcells.However,carbonicanhydraseinhibitorsaremoreoftenusedfortheirotherp