利尿劑英文課件

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 thickascendinglimbofHenle sLoopNa 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 thetubularfluidbecomesdilute dilutionfunctionAtthesametime thereabsorptionofionsatthislimbproducesahypertonicrenalmedulla Whentheurinepassthroughthecollectingduct thehypertonicinterstitialfluidsuckswateroutofthetubules therebythetubularfluidbecomesconcentration concentrationfunction 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 ethacrynicacidhavetheirmajoractionontheascendinglimboftheloopofHenle loopdiuretics 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 ClassificationofDiuretics Highefficacydiuretics loopdiuretics ModerateefficacydiureticsLowefficacydiuretics 27 Moderateefficacydiuretics classificationthiazidesHydrochlorothiazideChlorothiazideCyclopenthiazidethiazide likediureticsChlorthalidonethemostwidelyuseddiureticdrugsaffectthedistaltubule 28 Pharmacokinetics AllthiazidesareabsorbedwhengivenorallyTheyareexcretedunchangedintheurineandarenoteffectivewhenrenalfunctionisseverelyimpairedHydrochlorothiazideItsrenalexcretioncompeteswithuricacid 29 Mechanismofaction actmainlyinthedistaltubuletodecreasethereabsorptionofNa byinhibitionofNa Cl cotransporterontheluminalmembraneincreasetheconcentrationofNa andCl inthetubulefluidacid basebalanceisnotusuallyaffected 30 Cl apicalmembrane Basolateralmembrane interstitialfluid Parathormonecalcitriol Na Cl symporter 31 Pharmacologicaleffects Diureticactivity10 offilteredsodiumisexcretedPromotepotassiumexcretionincreasetheNa inthefiltratearrivingatthedistaltubulemorepotassiumisexchangedforsodiumEnhanceCa2 reabsorptiondecreaseCa2 excretionfromurineinthedistalconvolutedtubule 32 Pharmacologicaleffects Relativechangesinthecompositionofurineinducedbythiazidediuretics 33 Pharmacologicaleffects HypotensiveeffectinitialhypotensiveeffectsdecreaseinbloodvolumeandthereforeadecreaseincardiacoutputcontinuedhypotensiveeffectsNa excretion intercellularNa concentration Na Ca2 exchange intercellularCa2 concentration sensitivityofbloodvesselresponsetoNA reducedperipheralvascularresistancecausedbyrelaxationofarteriolarsmoothmuscle 34 ClinicalUses Edemamildandmoderatecardiacedema CHF HypertensioneitherusesaloneorincombinationwithotherantihypertensivedrugsNephrolithiasisduetoidiopathichypercalciuria osteoporosisdecreaseCa2 intubularfluidincreaseCa2 inplasma 35 ClinicalUses DiabetesinsipidusUsedforthepalliationofnephrogenicandpituitarydiabetesinsipidus Typicalsymptoms polydipsiaandpolyuriamechanism 36 Sideeffects Electrolytedisturbanceshypokalemia magnesiumdeficiencyHyperuricemiaandinducedgoutincreasesabsorptionofuricacidandcompetesforthetransportmechanismwithuricacidHyperglycemiaandhyperlipidemiadecreaseglucosetolerance reduceinsulinsecretionandglucoseutilization aggravatespreexistingdiabetesincreasesplasmaconcentrationsofLDL cholesterol triglyerideandtotalcholesterol 37 Sideeffects Hypovolemiaovertreatment acutelossofexcessivefluidleadstoposturalhypotensionanddizzinessOthersphotosensitive thrombocytopenia agranulocytosisThiazidesbindingwithquinidinecanleadtopolymorphicventriculartachycardia 38 ClassificationofDiuretics Highefficacydiuretics loopdiuretics ModerateefficacydiureticsLowefficacydiuretics K sparingdiuretics 39 Lowefficacydiuretics actinthelatedistaltubulesandcollectingtubuletoinhibitNa reabsorptionandK secretionThesedrugsreducepotassiumsecretion sotermasK retentiondiureticsorK sparingdiureticsHighefficacyandmoderateefficacydiureticsincreaseK excretion sotermasK lossingdiureticsMajoruseisincombinationwithotherdiureticstoreducesodiumreabsorptionandpreventpotassiumlossinthetubule 40 Spironolactone MechanismofactionaldosteroneregulateNa reabsorptionandK secretionatlatedistaltubulesandcollectingductSpironolactoneisacompetitiveantagonisttoaldosteronebindwithcytoplasmicaldosteronereceptorspromotesNa excretionblunttheK secretion 41 42 lumen apicalmembrane interstitialfluid Collectingtubule Basolateralmembrane AIP aldosterone inducedprotein SP spironolactone ALD aldosterone Triamtereneamiloride spironolactone aldosterone 42 Spironolactone Pharmacologicaleffectslessthan2 3 ofthefilteredsodiumisexcretedeffectiveonlyintheincreasingstatusofaldosteroneandineffectivefortotaladrenoprivalanimalthehigherthelevelofendogenousaldosterone thegreatertheeffectsofspironolactoneonurinaryexcretion 43 Relativechangesinthecompositionofurineinducedbypotassium sparingdiuretics 44 Spironolactone ClinicalUsesEdemaofprimaryhyperaldosteronismandrefractoryedemaassociatedwithsecondaryaldosteronism cardiacfailure hepaticcirrhosis nephroticsyndrome andsevereascites incombinationwithotherdiureticstoreducesodiumreabsorptionandpreventpotassiumlossinthetubuleinhibitsrenalexcretionofdigoxin thedosagesofdigoxinneedtobereducedifbothdrugscombineduse 45 Triamtereneandamiloride Pharmacologicaleffectsdirectlyblocksodiumionchannelsinthelatedistaltubulesandclollecingduct inhibitNa reabsorptionandpromoteitsexcretiondonotblockthealdosteronereceptorstilleffectivefortotaladrenoprivalanimalThemajoruseisincombinationwithotherdiuretics 46 47 lumen apicalmembrane interstitialfluid Col