第23章+利尿药和脱水药-双语版定稿-蓝底黄

第23章利尿药和脱水药

DiureticsandDehydrateagents华中科技大学同济医学院药理学系授课教师金满文2010年10月本次课要求掌握的主要内容1.利尿药的分类及代表药2.各类利尿药的作用部位和作用机制3.噻嗪类利尿药的临床应用和不良反应4.呋塞米的临床应用和不良反应5.螺内酯的临床应用和不良反应6.甘露醇的临床应用中文：利尿药是直接作用于肾脏，增加电解质和水的排出，使尿量增多的药物。2定义(本版教科书)：第一节利尿药英文：Diureticsaredrugsthatincreasetherateofurineflowandsodiumexcretion.

很准确！欠准确！？？但是，并非增加尿量的药物都是利尿药。如强心苷增加心衰病人的心排量，也使尿量增加，但其不作为利尿药。Somedrugscanincreaseurineflowbynonrenalmechanisms(e.g.byincreasingcardiacoutputinapatientwithcongestiveheartfailure),butthesedrugsarenotgenerallyregardedasdiuretics.3利尿药是直接作用于小管上皮细胞、增加尿液形成率的物质。

Diureticsareagentsthatactdirectlyonthetubularepithelialandincreasedrateofurineformation.5GoodmanandGilman’sThePharmacologicalBasisofTherapeutics,(GG8th，1990)非常准确！利尿药是促进机体钠和水的净丢失、增加尿量的药物。

Diureticsaredrugsthatpromoteanetlossofsodium(Na+)andwaterfromthebody,thenetresultbeinganincreaseinurineflow.

GG10th,20016利尿药增加尿量和排钠，用于高血压、心衰、肾衰、肾病综合征和肝硬化等病变时调节体液的量和/或成份。Diuretics

increasetherateofurineflowandsodiumexcretionandareusedtoadjustthevolumeand/orcompositionofbodyfluidsinavarietyofclinicalsituations,includinghypertension,heartfailure,renalfailure,nephroticsyndrome,andcirrhosis.

GG11th,2006

4临床用于：治疗各种水肿、高血压、尿崩症、肾结石等。8本版教科书：利尿药的适应症对利尿药作用机制的认识、新的利尿药的研发，均基于对肾脏泌尿生理的了解。RenalAnatomyandPhysiology9Na+channelFigure28-5..NaHCO3reabsorptioninproximaltubule.

A,antiporter;S,symporter;CH,ionchannel.(TheactualreactioncatalyzedbycarbonicanhydraseisOH-

+CO2→HCO3-;however,H2O→OH-

+H+,andHCO3-

+H+

→H2CO3,sothenetreactionisH2O+CO2→H2CO3.)Numbersinparenthesesindicatestoichiometry.BLandLMindicatebasolateralandluminalmembranes,respectively.S,symporter;CH,ionchannel.Numbersinparenthesesindicatestoichiometry.Designatedvoltagesarethepotentialdifferencesacrosstheindicatedmembraneorcell.Themechanismsillustratedhereapplytothemedullary,cortical,andpostmacularsegmentsofthethickascendinglimb.BLandLMindicatebasolateralandluminalmembranes,respectively.

GG11th，200611Figure28-7.NaClreabsorptionindistalconvolutedtubuleS,symporter;CH,ionchannel.Numbersinparenthesesindicatestoichiometry.BLandLMindicatebasolateralandluminalmembranes,respectively.Figure28-8.Na+reabsorptioninlatedistaltubuleandcollectingduct.

Cl-reabsorption(notshown)occursbothparacellularlyandtranscellularly,andtheprecisemechanismofCl-transportappearstobespecies-specific.A,antiporter;CH,ionchannel;CA,carbonicanhydrase.Numbersinparenthesesindicatestoichiometry.Designatedvoltagesarethepotentialdifferencesacrosstheindicatedmembraneorcell.BLandLMindicatebasolateralandluminalmembranes,respectively.AIP,aldosterone-inducedproteins;ALDO,aldosterone;MR,mineralocorticoidreceptor;CH,ionchannel;①activationofmembrane-boundNa+channels;②redistributionofNa+channelsfromcytosoltomembrane;③denovosynthesisofNa+channels;④activationofmembrane-boundNa+,K+-ATPase;⑤redistri-butionofNa+,K+-ATPasefromcytosoltomembrane;⑥denovosynthesisofNa+,K+-ATPase;⑦changesinpermeabilityoftightjunctions;⑧increasedmito-chondrialproductionofATP.BLandLMindicatebasolateralandluminalmembranes,respectively.Figure28-9.EffectsofaldosteroneonlatedistaltubuleandcollectingductRenalAnatomyandPhysiology15Na+channelThevolumeofplasmafilteredbythekidneyistermedtheglomerularrate(GFR)andisequaltoapproximately180

L/dayforapersonweighing70kg.

Approximately125mlofglomerularultrafiltrateisformedeachminute,yetonly1ml/minofurineisproduced.Therefore,greaterthan99%oftheglomerularultrafiltrateisreabsorbed.161.高效利尿药

highefficacy(ceiling)diuretics

袢利尿药Loopdiuretics钠钾氯同向转运抑制剂(InhibitorofNa+-K+-2Cl-symport)二、利尿药的分类(Classificationofdiuretics)18代表药：呋塞米(furosemide)其它：依他尼酸、布美他尼、阿佐塞米等2.中效利尿药

moderateefficacydiuretics

抑制Na+-Cl-

同向转运(symport)，也称噻嗪类利尿药

代表药：氢氯噻嗪非噻嗪类：氯噻酮、吲达帕胺等193.低效利尿药

Lowefficacydiuretics

①醛固酮拮抗剂(aldosteroneantagonist)：螺内酯(speronolactone)、Eplerenon②肾小管上皮细胞Na+通道抑制药

(inhibitorsofepithelialNa+channel)：氨苯蝶啶(triamterene)、阿米洛利(amiloride)

③碳酸酐酶抑制剂

(inhibitorsofcarbonicanhydrase)：乙酰唑胺（醋唑磺胺）注：①&②:留钾利尿药（K+sparingdiuretics）2021药物尿电解质的排泄Na+K+Ca2+Mg2+高效利尿药＋＋＋＋＋＋＋＋＋＋＋＋中效利尿药＋＋＋＋＋—＋螺内酯氨苯蝶啶阿米洛利＋———乙酰唑胺＋＋＋＋药物尿电解质的排泄Cl－HCO3－H2PO4－H+高效利尿药＋＋＋＋＋＋＋＋＋中效利尿药＋＋＋＋＋＋＋＋螺内酯氨苯蝶啶阿米洛利＋＋＋—乙酰唑胺＋＋＋＋＋＋＋—常用利尿药的主要作用部位及机制

药物主要作用部位机制呋塞米依他尼酸布美他尼髓袢升支粗段髓质和皮质部抑制Na+-K+-2C1-同向转运体噻嗪类氯噻酮髓袢升支粗段髓质部（远曲小管近端）抑制Na+-C1-同向转运体螺内酯集合管竞争醛固酮受体eplerenon阿米洛利氨苯蝶啶阻滞Na+通道，抑制NaC1重吸收乙酰唑胺近曲小管抑制碳酸酐酶活性21㈠.高效利尿药

呋塞米(furosemide,速尿，呋喃苯胺酸）依他尼酸(etacrynicacid，利尿酸)已少用布美他尼(bumetanide，丁苯氧酸)托拉塞米(torsemide

)

阿佐塞米(azosemide)

吡咯他尼(piretanide)二、常用利尿药22Pharmacologiceffects（药理效应）1.EffectsonUrinaryExcretion↑theurinaryexcretionofNa+,K+,Ca2+,Mg2+,Cl-,HCO3-,

H2PO4-.

增加诸离子经尿排泄。23作用特点：快、强、短

高效能利尿药体内过程

药物给药途径利尿作用口服吸收（%）t1/2(h)消除途径开始(min)峰值(min)维持(h)强度呋塞米口服15～6060～1204～61～60～1.5肾脏60%代谢40%静脉注射5302布美他尼口服3060～1204.5～640～80～0.8肾脏65%代谢35%静脉注射10451依他尼酸口服201206～80.7几乎1000.5～1.0肾脏65%代谢35%静脉注射15453托拉塞米torsimide静脉注射立即1563～80～35肾脏20%代谢70%吡咯他尼口服60～1204～63～800.6～1.5肾脏50%代谢50%2.EffectsonHemodynamics↑totalRBF,RBFtothemidcortex，

↑systemicvenouscapacitance,

↓leftventricularfillingpressure.

血流动力学效应：肾血流量↑，肾中层皮质血流↑，静脉容量增加↑，左室充盈压↓3.OtherActions

↓Na+,K+-ATPase(intheinnerearchangeintheelectrolytecompositionofendolymph

ototoxicity

)

其它作用：抑制内耳Na+,K+-ATP酶，改变内淋巴的电解质成份耳毒性

23Figure28-6.NaClreabsorptioninthickascendinglimbandmechanismofdiureticactionofNa+-K+-2Cl-symportinhibitors.

S,symporter;CH,ionchannel.Numbersinparenthesesindicatestoichiometry.Designatedvoltagesarethepotentialdifferencesacrosstheindicatedmembraneorcell.Themechanismsillustratedhereapplytothemedullary,cortical,andpostmacularsegmentsofthethickascendinglimb.BLandLMindicatebasolateralandluminalmembranes,respectively.

GG11th，2006MechanismandSiteofAction

241.急性肺水肿（Acutepulmonaryedema

）TherapeuticUses

（治疗应用）↓leftventricularfillingpressuresrelievespulmonaryedema

↑venouscapacitance252.其他严重水肿（Otherseriousedema）Theedemaofnephroticsyndrome

Theedemaandascitesofliver

cirrhosis3.慢性充血性心衰（Chroniccongestiveheartfailure）↓mortality,↓theriskofworseningHFimprovementinexercisecapacity

!

encephalopathyorhepatorenalsyndrome!

4.高血压（Hypertension）

用于噻嗪类药物疗效不佳、尤其是伴有肾功能不全容量负荷性高血压或高血压危象。267.急性肾功能衰竭（Acuterenalfailure）6.药物过量(Drugoverdose)

Toinduceaforceddiuresisto

facilitatemorerapidrenaleliminationoftheoffendingdrug5.高钙血症(Hypercalcemia)

combinedwithisotonicsalineadministration

27？ThereisnoevidencethatloopdiureticspreventATNorimproveoutcomeinpatientswithARF(Kellum,1998).

AdverseEffects

1.水和电解质紊乱(Abnormalitiesoffluidandelectrolytebalance)

低钠、钾、镁、钙、氯、血容量。(6低）2.耳毒性(Ototoxicity)

与内耳淋巴液的电解质紊乱和耳蜗管基底膜毛细胞损伤有关。

3.代谢紊乱高尿酸血症(Hyperuricemia),高血糖(hyperglycemia),TG↑,LDL-C↑,HDL-C↓。（3高1低）28

Druginteractions

DrugInteractionAminoglycosides氨基苷类

↑ototoxicityanticoagulants抗凝药↑anticoagulantactivitydigitalisglycosides强心苷↑digitalis-inducedarrhythmiasLithium锂

↑plasmalevelsoflithiumpropranolol普奈洛尔↑plasmalevelsofpropranolol

sulfonylureas磺酰脲类↑bloodglucoseCisplatin顺铂↑riskofototoxicityNSAIDs非甾体抗炎药↓diureticresponseProbenecid丙磺舒↓diureticresponseamphotericinB两性霉素

↑toxicity29㈡.中效利尿药

噻嗪类（thiazides）

氯噻嗪chlorothiazide氢氯噻嗪hydrochlorothiazide苄噻嗪benzthiazide氢氟噻嗪hydroflumethiazide泊利噻嗪polythiazide苄氟噻嗪bendroflumethiazide甲氯噻嗪

methyclothiazide环戊噻嗪cyclopenthiazide三氯噻嗪

trichlormethiazide31Figure28-7.NaClreabsorptionindistalconvolutedtubuleandmechanismofdiureticactionofNa+-Cl-symportinhibitors.

S,symporter;CH,ionchannel.Numbersinparenthesesindicatestoichiometry.BLandLMindicatebasolateralandluminalmembranes,respectively.MechanismandSiteofAction

37Pharmacologicaleffects1.EffectsonUrinaryExcretion

中等强度、温和、持久。尿中Na+、C1-、K+、Mg2+、HCO3-排出均增加。

2.EffectsonRenalHemodynamicsnoinfluenceonRBFandTGF,↑intratubularpressur,↓GFR。

3.OtherActions

inhibitedcyclicnucleotidephosphodi-esterases,mitochondrialoxygenconsumption,andrenaluptakeoffattyacids;however,theseeffectsarenotofclinicalsignificance.

TGF:tubuloglomerularfeedback38TherapeuticUses

1.水肿(Edema)

associated

withheart,liver,andrenaldisease.congestiveheartfailure

hepaticcirrhosis

nephroticsyndrome,chronicrenalfailure,acuteglomerulonephritisMostthiazidediureticsareineffectivewhentheGFRislessthan30to40ml/min.

342.高血压（Hypertension）

eitheraloneorincombinationwithotherantihypertensivedrugs①Inexpensive

②Efficacious③Welltolerated

④Oncedaily,donotrequiredosetitration

⑤Fewcontraindications⑥Additiveorsynergisticeffectswithotherclassesofantihypertensiveagents

优点多多！safe,↓cardiovascularmorbidityandmortality353.肾性糖尿病性尿崩症(Nephrogenicdiabetesinsipidus)

urinevolume↓50%.Themechanismofthisparadoxicaleffectremainsunknown.

4.钙性肾结石和骨质疏松(Calciumnephrolithiasis)&osteoporosis

reduceurinaryexcretionofCa2+

5.溴中毒

(Br-

intoxication)SinceotherhalidesareexcretedbyrenalprocessessimilartothoseforCl-

AdverseEffects

1.水电解质紊乱(Abnormalitiesoffluidan