利尿剂英文课件.ppt

Diuretics,YannaWuPh.D.,M.D.AssociateProfessorDepartmentofPharmacologySchoolofBasicMedicineTianjinMedicalUniversityEmail:wuyanna,1,introduction,Diureticsactonrenaltubules,promotetheproductionofurineareusedtotreatedemaandunedemadiseases(hypertension,heartfailure,renalfailure,andcirrhosis),2,PhysiologyofKidneys,Processofurineformation,180Lfiltrate,1-2Lfinalurine,99%,nephron,renalcorpuscle,3,Reabsorptionoftubulesandcollectingtubes,ProximalconvolutedtubulesNaHCO3(Na+,HCO3-)arereabsorbedepitheliumispermeabletoionsandwater,andpermitpassiveflowineitherdirection-Na+reabsorptionisaccompaniedbypassiveabsorptionofwaterCarbonicanhydraseinhibitors(acetazolamide)reduceNa+-H+exchange,inturn,sodiumreabsorptionisdecreased,4,Na+-K+-ATPase,Na+-H+-exchanger,Carbonicanhydrase,diffuses,Na+-HCO3-symporter,basolateralmembrane,apicalmembrane,bicarbonate,Carbonicacid,Carbondioxide,5,Reabsorptionoftubulesandcollectingtubes,thickascendinglimbofHenlesLoopNa+/K+/2Cl-cotransportsystemwaterisimpermeableatthissegment,tubularfluidishypotonicwithrespecttoplasmaasitentersthedistalconvolutedtubule(diluted)inhibitorsofNa+/K+/2Cl-symporterblockitsfunction,increaseexcretionofNa+,K+,Cl-,Mg2+,Ca2+,6,apicalmembrane,Basolateralmembrane,Na+/K+/2Cl-cotransportsystem,lumen-positiveelectricalpotential,Na+-K+-ATPase,interstitialfluid,7,dilutionfunctionandconcentrationfunction,Inthethickascendinglimb,largeamountofionsarereabsorbed,butwaterisimpermeableatthissegment,asaresult,thetubularfluidbecomesdilutedilutionfunctionAtthesametime,thereabsorptionofionsatthislimbproducesahypertonicrenalmedulla.Whentheurinepassthroughthecollectingduct,thehypertonicinterstitialfluidsuckswateroutofthetubules,therebythetubularfluidbecomesconcentrationconcentrationfunction,8,Reabsorptionoftubulesandcollectingtubes,DistalconvolutedtubuleNa+/Cl-symporterbothparathormoneandcalcitriolincreaseCa2+reabsorptionfurtherdilutedthissegmentisinthecorticalpart,thehypertonicstateofrenalmedullaisnotaffected,9,Cl-,apicalmembrane,Basolateralmembrane,interstitialfluid,Parathormonecalcitriol,Na+/Cl-symporter,10,Reabsorptionoftubulesandcollectingtubes,latedistaltubulesandcollectingtubulesNa+/K+exchangereabsorptionofNa+anditscoupledsecretionofK+isregulatedbyaldosteroneabsorptionofwaterisregulatedbyantidiuretichormone(ADH)Promotescollectingtubulespermeabletowatermodulatestheconcentrationoffinalurine,11,lumen-negativeelectricalpotential,alltheseagentsareK+-sparingdiuretics,12,ClassificationofDiuretics,HighefficacydiureticsModerateefficacydiureticsLowefficacydiuretics,13,ClassificationofDiuretics,HighefficacydiureticsModerateefficacydiureticsLowefficacydiuretics,14,Highefficacydiuretics,Furosemide,bumetanide,ethacrynicacidhavetheirmajoractionontheascendinglimboftheloopofHenleloopdiuretics,15,Pharmacokinetics,absorbedrapidlybyoraladministration.Bioavailabilityis50-70%.Ifgiveniv,theeffectsoffurosemideresponsewithin5mins,durationtime2-3hrs.50-60Lofurineexcretionwithin24hoursafterusinglargedosesoffurosemide.Proteinbindingrateis95%.t1/21hr,whichmaybeprolongedto10hrinrenaldysfunction.,16,Mechanismofaction,inhibittheNa+/K+/2Cl-cotransporterinthethickascendinglimboftheloopofHenlereabsorptionofNa+,Cl-,Ca2+andMg2+aredecreasedsecretionofK+isincreasedthemostefficaciousofthediureticdrugstheascendinglimbaccountsforthereabsorptionof25%-30%offilteredNaCldownstreamsitesarenotabletocompensateforthisincreasedNa+load,17,apicalmembrane,Basolateralmembrane,Na+/K+/2Cl-cotransportsystem,lumen-positiveelectricalpotential,Na+-K+-ATPase,interstitialfluid,18,Pharmacologicaleffects,DiureticactivityDiureticactivityisrapid,strongandshortLargeamountsofNa+,Cl-,K+,Ca2+andMg2+areexcretedandCl-lossismorethanNa+inurine,Relativechangesinthecompositionofurineinducedbyloopdiuretics,19,Pharmacologicaleffects,Decreaserenalvascularresistance,increaserenalbloodflowredistributionofbloodflowwithintherenalcortexIncreasereninreleaselargevolumedepletionreflexlyactivatethesympatheticnervoussystemandstimulatetheintrarenalbaroreceptormechanisminducesrenalprostaglandinssynthesisinthekidney,20,Pharmacologicaleffects,RelievepulmonarycongestionandreduceleftventricularfillingpressuresincreasesystemicvenouscapacitanceincongestiveheartfailurepatientInhibitelectrolytetransportininnerearalternatetheelectrolytecompositionofendolymph,contributetodruginducedototoxity,21,ClinicalUses,emergencysituationsacutepulmonaryedemaandbrainedemabumetanideorfurosemideisfirstchoiceSeriousedemaedemaofnephroticsyndrome,nephrosis;ascitesoflivercirrhosisedemapatientswhodonotrespondtosaltrestrictionsorthiazidesChroniccongestiveheartfailuretominimizevenousandpulmonarycongestion,22,ClinicalUses,HyperkalemiaAcuteorchronicrenalfailureincreasetheratesofurineflowandenhanceK+excretioninacuterenalfailureconvertoliguricrenalfailuretononoliguricfailureAcutehypercalcemiaHypertensioncrisisDetoxication,23,Sideeffects,Electrolytedisturbancehypokalemia,hyponatremia,hypomagnesemia,hypochloremicmetabolicalkalosisinducecardiacarrhythmiaspotassium-sparingdiureticsordietarysupplementationwithpotassiumOtotoxicityhearinglossordeafnesswhichcanbepotentiatedbyrenaldysfunctionorcombinedwithanotherototoxicdrugs(eg,aminoglycosideantibiotics),24,Sideeffects,Hyperuricemiahypovolemia-associatedenhancementofuricacidreabsorptionintheproximaltubuleOthersHyperglycemiaincreaseLDL-CanddecreaseHDL-Cinplasma,25,Interaction,firstorsecondgenerationofcephalosporinspotentiatesototoxicityofloopdiueticsNSAIDsreduceNa+excretionbyinhibitingPGssynthesisinthekidneywarfariniscapableofcompetitivebindingplasmaproteinwithloopdiuretics,26,27,可编辑,ClassificationofDiuretics,Highefficacydiuretics(loopdiuretics)ModerateefficacydiureticsLowefficacydiuretics,28,Moderateefficacydiuretics,classificationthiazidesHydrochlorothiazideChlorothiazideCyclopenthiazidethiazide-likediureticsChlorthalidonethemostwidelyuseddiureticdrugsaffectthedistaltubule,29,Pharmacokinetics,AllthiazidesareabsorbedwhengivenorallyTheyareexcretedunchangedintheurineandarenoteffectivewhenrenalfunctionisseverelyimpairedHydrochlorothiazideItsrenalexcretioncompeteswithuricacid,30,Mechanismofaction,actmainlyinthedistaltubuletodecreasethereabsorptionofNa+byinhibitionofNa+/Cl-cotransporterontheluminalmembraneincreasetheconcentrationofNa+andCl-inthetubulefluidacid-basebalanceisnotusuallyaffected,31,Cl-,apicalmembrane,Basolateralmembrane,interstitialfluid,Parathormonecalcitriol,Na+/Cl-symporter,32,Pharmacologicaleffects,Diureticactivity10%offilteredsodiumisexcretedPromotepotassiumexcretionincreasetheNa+inthefiltratearrivingatthedistaltubulemorepotassiumisexchangedforsodiumEnhanceCa2+reabsorptiondecreaseCa2+excretionfromurineinthedistalconvolutedtubule,33,Pharmacologicaleffects,Relativechangesinthecompositionofurineinducedbythiazidediuretics,34,Pharmacologicaleffects,HypotensiveeffectinitialhypotensiveeffectsdecreaseinbloodvolumeandthereforeadecreaseincardiacoutputcontinuedhypotensiveeffectsNa+excretion-intercellularNa+concentration-Na+/Ca2+exchange-intercellularCa2+concentration-sensitivityofbloodvesselresponsetoNA-reducedperipheralvascularresistancecausedbyrelaxationofarteriolarsmoothmuscle,35,ClinicalUses,Edemamildandmoderatecardiacedema(CHF)HypertensioneitherusesaloneorincombinationwithotherantihypertensivedrugsNephrolithiasisduetoidiopathichypercalciuria;osteoporosisdecreaseCa2+intubularfluidincreaseCa2+inplasma,36,ClinicalUses,DiabetesinsipidusUsedforthepalliationofnephrogenicandpituitarydiabetesinsipidus.Typicalsymptoms:polydipsiaandpolyuriamechanism,37,Sideeffects,Electrolytedisturbanceshypokalemia,magnesiumdeficiencyHyperuricemiaandinducedgoutincreasesabsorptionofuricacidandcompetesforthetransportmechanismwithuricacidHyperglycemiaandhyperlipidemiadecreaseglucosetolerance,reduceinsulinsecretionandglucoseutilization,aggravatespreexistingdiabetesincreasesplasmaconcentrationsofLDL-cholesterol,triglyerideandtotalcholesterol,38,Sideeffects,Hypovolemiaovertreatment,acutelossofexcessivefluidleadstoposturalhypotensionanddizzinessOthersphotosensitive,thrombocytopenia,agranulocytosisThiazidesbindingwithquinidinecanleadtopolymorphicventriculartachycardia,39,ClassificationofDiuretics,Highefficacydiuretics(loopdiuretics)ModerateefficacydiureticsLowefficacydiuretics(K+-sparingdiuretics),40,Lowefficacydiuretics,actinthelatedistaltubulesandcollectingtubuletoinhibitNa+reabsorptionandK+secretionThesedrugsreducepotassiumsecretion,sotermasK+retentiondiureticsorK+sparingdiureticsHighefficacyandmoderateefficacydiureticsincreaseK+excretion,sotermasK+lossingdiureticsMajoruseisincombinationwithotherdiureticstoreducesodiumreabsorptionandpreventpotassiumlossinthetubule.,41,Spironolactone,MechanismofactionaldosteroneregulateNa+reabsorptionandK+secretionatlatedistaltubulesandcollectingductSpironolactoneisacompetitiveantagonisttoaldosteronebindwithcytoplasmicaldosteronereceptorspromotesNa+excretionblunttheK+secretion,42,43,lumen,apicalmembrane,interstitialfluid,Collectingtubule,Basolateralmembrane,AIP:aldosterone-inducedprotein;SP:spironolactone;ALD:aldosterone,Triamtereneamiloride,spironolactone,aldosterone,43,Spironolactone,Pharmacologicaleffectslessthan2-3%ofthefilteredsodiumisexcretedeffectiveonlyintheincreasingstatusofaldosteroneandineffectivefortotaladrenoprivalanimalthehigherthelevelofendogenousaldosterone,thegreatertheeffectsofspironolactoneonurinaryexcretion,44,Relativechangesinthecompositionofurineinducedbypotassium-sparingdiuretics,45,Spironolactone,ClinicalUsesEdemaofprimaryhyperaldosteronismandrefractoryedemaassociatedwithsecondaryaldosteronism(cardiacfailure,hepaticcirrhosis,nephroticsyndrome,andsevereascites)incombinationwithotherdiureticstoreducesodiumreabsorptionandpreventpotassiumlossinthetubuleinhibitsrenalexcretionofdigoxin,thedosagesofdigoxinneedtobereducedifbothdrugscombineduse,46,Triamtereneandamiloride,Pharmacologicaleffectsdirectlyblocksodiumionchannelsinthelatedistaltubulesandclollecingduct,inhibitNa+reabsorptionandpromoteitsexcretiondonotblockthealdosteronereceptorstilleffectivefortotaladrenoprivalanimalThemajoruseisincombinationwithotherdiuretics,47,48,lumen,apicalmembrane,interstitialfluid,Collecti