利尿药公开课

利尿药公开课Chapter26目的了解各类利尿药的作用部位，掌握呋塞米（速尿），氢氯噻嗪类，螺内酯，氨苯喋啶（三氨喋啶），甘露醇等的作用，应用，不良反应。Chapter26内容利尿药的定义。复习泌尿生理过程，说明各段肾小管的再吸收及分泌功能。联系说明各类利尿药排电解质的情况。利尿药在治疗水肿，高血压，心力衰竭时的意义。利尿药按作用部位的分类。主要作用于近曲小管的利尿药：碳酸酐酶抑制剂醋唑磺胺，弱效，排出HCO3-的碱性尿。Chapter26内容主要作用于髓袢升支的利尿药：呋塞米，布美他尼的利尿作用，特点，强效，速效。抑制髓袢升支粗段的髓质段和皮质段的Na+-K+-2Cl-共同转运系统，抑制其对Cl-的主动再吸收及Na+的被动再吸收。抑制肾脏的浓缩和稀释功能。临床应用于严重水肿，急性肺水肿和脑水肿，肾功能衰竭等。不良反应。简述丁苯氧酸的作用和应用。主要作用于髓袢升支皮质段的利尿药：噻嗪类药物：以氢氯噻嗪为例说明这类药物利尿作用的特点，中效。作用在髓袢升支粗段对Na+-Cl-共同转运系统。降压作用。治疗尿崩症的作用。不良反应。比较同类药物的利尿强度。附氯噻酮。Chapter26内容主要作用于远曲小管和集合管的利尿药：这类药物的作用特点，留钾，弱效。抑制远曲小管和集合管的Na+-K+交换，排Na+留K+。螺内酯（安体舒通）对抗醛固酮而利尿。氨苯喋啶直接抑制Na+的再吸收。临床应用。不良反应。附氨氯吡咪。中草药：简述泽泻，茯苓，猪苓，车前的利尿效果。脱水剂：定义。甘露醇与山梨醇的脱水作用及渗透性利尿作用。应用与不良反应。高渗葡萄糖的脱水作用。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(氢氯噻嗪)Chlortalidone(氯噻酮)Bendrofluazide(苄氟噻嗪)Cyclopenthiazide(环戊噻嗪)DiureticAgentsHydrochlorothiazide(氢氯噻嗪)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(螺内酯，antisterone安体舒通)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(螺内酯，antisterone安体舒通)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