利尿藥公開課Chapter26目的了解各類利尿藥的作用部位，掌握呋塞米（速尿），氫氯噻嗪類，螺內(nèi)酯，氨苯喋啶（三氨喋啶），甘露醇等的作用，應(yīng)用，不良反應(yīng)。Chapter26內(nèi)容利尿藥的定義。復(fù)習(xí)泌尿生理過程，說明各段腎小管的再吸收及分泌功能。聯(lián)系說明各類利尿藥排電解質(zhì)的情況。利尿藥在治療水腫，高血壓，心力衰竭時的意義。利尿藥按作用部位的分類。主要作用于近曲小管的利尿藥：碳酸酐酶抑制劑醋唑磺胺，弱效，排出HCO3-的堿性尿。Chapter26內(nèi)容主要作用于髓袢升支的利尿藥：呋塞米，布美他尼的利尿作用，特點(diǎn)，強(qiáng)效，速效。抑制髓袢升支粗段的髓質(zhì)段和皮質(zhì)段的Na+-K+-2Cl-共同轉(zhuǎn)運(yùn)系統(tǒng)，抑制其對Cl-的主動再吸收及Na+的被動再吸收。抑制腎臟的濃縮和稀釋功能。臨床應(yīng)用于嚴(yán)重水腫，急性肺水腫和腦水腫，腎功能衰竭等。不良反應(yīng)。簡述丁苯氧酸的作用和應(yīng)用。主要作用于髓袢升支皮質(zhì)段的利尿藥：噻嗪類藥物：以氫氯噻嗪為例說明這類藥物利尿作用的特點(diǎn)，中效。作用在髓袢升支粗段對Na+-Cl-共同轉(zhuǎn)運(yùn)系統(tǒng)。降壓作用。治療尿崩癥的作用。不良反應(yīng)。比較同類藥物的利尿強(qiáng)度。附氯噻酮。Chapter26內(nèi)容主要作用于遠(yuǎn)曲小管和集合管的利尿藥：這類藥物的作用特點(diǎn)，留鉀，弱效。抑制遠(yuǎn)曲小管和集合管的Na+-K+交換，排Na+留K+。螺內(nèi)酯（安體舒通）對抗醛固酮而利尿。氨苯喋啶直接抑制Na+的再吸收。臨床應(yīng)用。不良反應(yīng)。附氨氯吡咪。中草藥：簡述澤瀉，茯苓，豬苓，車前的利尿效果。脫水劑：定義。甘露醇與山梨醇的脫水作用及滲透性利尿作用。應(yīng)用與不良反應(yīng)。高滲葡萄糖的脫水作用。DiureticsDefinitionRenaltubuletransportmechanismsClassificationofdiureticsHighefficacydiuretics(Loopdiuretics)DiureticAgentsModerateefficacydiureticsLowefficacydiureticsClinicalusesofdiureticsOsmoticagentsDiureticAgentsDefinitionDiureticagentsareactingontherenaltubules,increaseexcretionofelectrolytes&water,increasetheamountofurine.Theyareusedtotreatedemacausedbyvariousdiseases,andalsotreatsomenon-edemadiseases,e.g.hypertension,renalstones,hypercalcaemia.DiureticAgentsRenaltubuletransportmechanismsProximaltubuleLoopofhenleDistalconvolutedtubuleCollectingtubuleDiureticAgentsClassificationofdiureticsHighefficacydiuretics(Loopdiuretics)Moderateefficacydiuretics(thiazides)LowefficacydiureticsDiureticAgentsHighefficacydiuretics(Loopdiuretics)Furosemide(呋塞米)Bumetanide(布美他尼)Torasemide(托拉塞米)Etacrynicacid(依他尼酸)DiureticAgentsFurosemide(呋塞米)Absorbedrapidlybyoral,F=40%,duration4-6hr.AfterIV,theeffectsoffurosemideresponsewithin5mins,duration2-3hr.Proteinbindingis95%.T1/2=1hr,itmaybeprolongto10hrs.inrenaldysfunction.DiureticAgentsPharmacologicaleffectsDiureticeffectsarerapid,strongandshort,dependentondose;individualdifferentia;InhibitionofNa+-K+-2Cl―co-transportsysteminthethickascendinglimboftheloopofhenle,↓diluteandconcentratefunctionsofkidney,excretelargerisotonicurine.DiureticAgentsTheycancause30-40%offilteredsodiumtobeexcreted,accordingtotheirnatriureticcapacity,loopdiureticsarehighlyefficacious.LargeamountsofNa+,Cl―,K+anddivalentcations(Ca2+,Mg2+)areexcretedandCl―lossismorethanNa+inurine.DiureticAgentsDecreaserenalvascularresistance;increaserenalbloodflowandcauseredistributionofbloodflowwithintherenalcortex.Increasereninrelease,prostacyclinmayplayanimportantroleinmediatingthereninreleaseresponsetoloopdiuretics.DiureticAgentsImprovepulmonarycongestionandreduceleftventricularfillingpressuresbyincreasingsystemicvenouscapacitance.Inhibitelectrolytetransportininnerear,alteratetheelectrolytecompositionofendolympha,thismaycontributetodruginducedototoxity.DiureticAgentsUsesSeriousedemaedemaofnephroticsyndrome,nephrosis;ascitesoflivercirrhosisoredemapatientswhodonotrespondtosaltrestrictionsorthiazides;chroniccongestiveheartfailuretominimizevenousandpulmonarycongestion.DiureticAgentsAcutepulmonaryedema&brainedemaPreventandtreatacuteorchronicrenalfailurefurosemidecanincreasetheratesofurineflowandenhanceK+excretioninacuterenalfailureDiureticAgentsPromoteexcretionoftoxicsubstancesOthersTreathypertensioncrisisTreatacutehypercalcaemiaTreathyperkalemiaDiureticAgentsSideeffectsWaterandElectrolytedisturbancehypovalume,hypokalemia,hyponatremia,hypomagnesemia,hypochloremicmetabolicalkalosis.Duringdiuretictherapy,hypokalemiaisthemostcommon.Alsocommonlysecondarytosevereliverdiseaseorcongestivecardiacfailure.DiureticAgentsOtotoxicityHearinglossordeafness,theycanbepotentiatedbyanotherototoxicdrugs(e.g.aminoglycosides).Hyperuricemiaandinducedgoutcausedbyhypovolemia-associatedenhancementofuricacidreabsorptionintheproximaltubule.DiureticAgentsOthersGIcomplaint,largedosecauseulcerandbleedingofGI.Malformation,notbeusedforpregnantwomenAgranulocytosis,DiureticAgentsBumetanide(布美他尼)Torasemide(托拉塞米)Ethacrynicacid(依他尼酸)DiureticAgentsContraindicationsTheyhavecross-reactivityinpatientswhoaresensitivetoothersulfonamides.Hepaticcirrhosis,borderlinerenalfailure,congestiveheartfailure,whenoverzealoususe.DiureticAgentsModerateefficacydiuretics(thiazides)Hydrochlorothiazide(氫氯噻嗪)Chlortalidone(氯噻酮)Bendrofluazide(芐氟噻嗪)Cyclopenthiazide(環(huán)戊噻嗪)DiureticAgentsHydrochlorothiazide(氫氯噻嗪)Allareabsorbedbygivenorally,Hydrochlorothiazideisabsorbedslowly,lessthan10%,t1/2=1.5hr,excretedunchangedintheurineandnoteffectivewhenrenalfunctionisseverelyimpaired.Itisexcretedcompeteswithuricacid,souricacidsecretoryratemaybereduced.DiureticAgentsPharmacologicaleffectsDiureticeffectmoderate,primarysiteofactionisthedistalconvolutetubule,inhibittheNa+-Cl-co-transporterintheluminalbasolateralmembranebyaNa+pumpcompetingfortheCl-bindingsitewhichisdistinctfromtheactionoftransporterintheloopofhenle.ThiazidesinhibitsodiumabsorptionbyexchangingofNa+-K+andH+-Na+.DiureticAgentsTherenalcortexhasahigh-affinityreceptorforthiazidediuretics.Variablydecreasetheglomerularfiltrationrate,butdonotaffectrenalbloodflow.EnhanceCa2+reabsorptioninthedistalconvolutedtubule,decreasesCa2+excretionfromurine.HypotensiveeffectAnti-diureticeffectDiureticAgentsUsesEdema:itisavailableusedformildandmoderatecardiacedema(congestiveheartfailure).Thediureticeffectforrenaledemadependsontherenalfunction.HypertensionDiabetesinsipidus.DiureticAgentsAdverseeffectsElectrolytedisturbanceshypokalemia,hypomagnesemia,hyponatremia,Hypovolaemia，HyperuricemiaandinducedgoutitincreasesabsorptionofuricacidandcompetesforthetransportmechanismwithuricacidDiureticAgentsHyperglycemiaandhyperlipidemiaglycosuria,aggravatespreexistingdiabetes,increasesconcentrationsofcholesterolandtriglycerides,totalcholesterolincreases.Thiazidediureticdecreaseglucosetolerance,reduceinsulinsecretionandglucoseutilization.DiureticAgentsOthersphotosensitive,thrombocytopenia,agranulocytosis,thiazideswithquinidinecanleadtopolymorphicventricular,tachycardia.DiureticAgentsLowefficacydiureticsSpironolactone(螺內(nèi)酯，antisterone安體舒通)Triamterene(氨苯喋啶)&Amiloride(阿米洛利)Acetazolamide(乙酰唑胺，diamox醋唑磺胺)DiureticAgentsThepotassium-sparingdiureticsreduceNa+absorptioninthecollectingtubulesandducts.Na+absorption(andK+secretion)atthissiteisregulatedbyaldosterone.AldosteroneenhancesK+secretionbyincreasingNa+/K+ATPaseactivityandNa+andK+channelactivities.DiureticAgentsNa+absorptioninthecollectingtubulegeneratesalumen-negativeelectricalpotential,whichenhancesK+secretion.Aldosteroneantagonistsinterferewiththisprocess.DiureticAgentsSpironolactone(螺內(nèi)酯，antisterone安體舒通)Directantagonizetheeffectsofaldosteroneatthereceptorsasacompetitiveantagonist,Itismetabolizedintheliver.Slowonesetofaction,requiringseveraldays.DiureticAgentsSpironolactonebindstocytoplasmicaldosteronereceptorsandpreventstranslocationofthereceptorcomplextothenucleus.Itmayalsoreducetheintracellularformationofactivemetabolitesofaldosteronebyinhibitionof5α-reductaseactivity.DiureticAgentsTriamterene(氨苯喋啶)&Amiloride(阿米洛利)Triamtereneismetabolizedintheliver,butrenalexcretionisamajorrouteofeliminationfortheactiveformandthemetabolites.Ithasashorterhalf-lifethanamiloride.Amilorideisexcretedunchangedintheurine.DiureticAgentsTriamtereneandamiloridedonotblockthealdosteronereceptor,directlyinterferewithNa+entrythroughthesodium-selectiveionchannelsintheapicalmembraneofthecollectingtubule.DiureticAgentsSinceK+secretioniscoupledwithNa+entryinthissegment,theseagentsarealsoeffectiveK+-sparingdiuretics.Becausetheactionsofthemaredependentonrenalprostaglandinproduction,theactionsofthemcanbeinhibitedbynonsteroidalanti-inflammtorydrugsundercertainconditions.DiureticAgentsTheyaremostusefulinstatesofmineralocorticoidexcess,dueeithertoprimaryhypersecretionortosecondareyaldosteronism.InthesettingofenhancedmineralocorticoidsecretionandcontinuingdeliveryofNa+todistalnephronsites,renalK+wastingoccurs.DiureticAgentsThisisduetoK+secondarybythecollectingtubule.K+-sparingdiureticsofeithertypemaybeusedinthissettingtoblunttheK+secretoryresponseandpreventdepletionoftheintracellularK+stores.DiureticAgentsToxicityHyperkalemiaHyperchloremicmetabolicacidosisGynecomastiaAcuterenalfailureKidneystonesDiureticAgentsContraindicationsSusceptiblehyperkalemiapatientsPatientswithchronicrenalinsufficiencyPatientswithliverdiseaseDiureticAgentsClinicalusesofdiureticsCardiacedemaRenaledemaCirrhoticedemaAcutehydrocephalusandpulmonaryedemaOsmoticAgentsOsmoticagents20%mannitol(甘露醇)25%sorbitol(山梨醇)50%glucose(葡萄糖)OsmoticAgentsTh