第22章利尿藥和脫水藥

DiureticsandDehydrateagents華中科技大學(xué)同濟醫(yī)學(xué)院藥理學(xué)系

授課教師金滿文2013年10月本次課要求掌握的主要內(nèi)容1.利尿藥的分類及代表藥2.各類利尿藥的作用部位和作用機制3.呋塞米的臨床應(yīng)用和不良反應(yīng)4.噻嗪類利尿藥的臨床應(yīng)用和不良反應(yīng)5.螺內(nèi)酯的臨床應(yīng)用和不良反應(yīng)6.甘露醇的臨床應(yīng)用利尿藥是直接作用于腎臟，增加Na+、Cl-等電解質(zhì)和水的排出，使尿量增多的藥物。31、定義(本版教科書)：第一節(jié)利尿藥準確！本版英文摘要：Diureticsincreasetherateofurineflowandsodiumexcretion，usedtoadjustthevolumeand/orcompositionofbodyfluidsinvarietyofclinicalsituations.

描述利尿藥的作用和用途利尿藥增加尿量和排鈉，用于高血壓、心衰、腎衰、腎病綜合征和肝硬化等病變時調(diào)節(jié)體液的量和/或成份。利尿藥是直接作用于小管上皮細胞、增加尿液形成率的物質(zhì)。

Diureticsareagentsthatactdirectlyonthetubularepithelialandincreasedrateofurineformation.4GoodmanandGilman’sThePharmacologicalBasisofTherapeutics,(GG8th,1990)更精細！利尿藥是促進機體鈉和水的凈丟失、增加尿量的藥物。

Diureticsaredrugsthatpromoteanetlossofsodium(Na+)andwaterfromthebody,thenetresultbeinganincreaseinurineflow.

GG10th,20015其實，并非增加尿量的藥物都是利尿藥。如強心苷增加心衰病人的心排量，也使尿量增加，但其不作為利尿藥。Somedrugscanincreaseurineflowbynonrenalmechanisms(e.g.byincreasingcardiacoutputinapatientwithcongestiveheartfailure),butthesedrugsarenotgenerallyregardedasdiuretics.7利尿藥增加尿量和排鈉，用于高血壓、心衰、腎衰、腎病綜合征和肝硬化等病變時調(diào)節(jié)體液的量和/或成份。Diuretics

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

GG11th,2006

6(1)各種水腫：心性、肝腎、腎性。(2)高血壓：根據(jù)病情，選用不同類別藥物。(3)其他：尿崩癥、腎結(jié)石等。82、利尿藥的適應(yīng)癥1.高效利尿藥

highefficacy(ceiling)diuretics

袢利尿藥

Loopdiuretics

鈉鉀氯同向轉(zhuǎn)運抑制劑

(InhibitorofNa+-K+-2Cl-symport)3、利尿藥的分類(Classificationofdiuretics)9代表藥：呋塞米(furosemide)其它：依他尼酸、布美他尼、阿佐塞米等2.中效利尿藥

moderateefficacydiuretics

抑制Na+-Cl-

同向轉(zhuǎn)運(symport)，10因該類藥物以噻嗪類藥物為主，也稱噻嗪類利尿藥

代表藥：氫氯噻嗪非噻嗪類：氯噻酮、吲達帕胺等3.低效利尿藥

Lowefficacydiuretics

①醛固酮拮抗劑(aldosteroneantagonist)：螺內(nèi)酯(spironolactone)、依普利酮(Eplerenon)②腎小管上皮細胞Na+通道抑制藥

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

③碳酸酐酶抑制劑

(inhibitorsofcarbonicanhydrase)：乙酰唑胺（醋唑磺胺）注：①&②:留鉀利尿藥（K+sparingdiuretics）114.滲透性利尿藥

(osmoticdiuretics)，也稱脫水藥：甘露醇等。12第一節(jié)利尿藥作用的生理學(xué)基礎(chǔ)利尿藥的作用主要是影響尿液形成過程的腎小管從吸收和分泌功能。對利尿藥作用機制的認識、新的利尿藥的研發(fā)，均基于對腎臟泌尿生理的了解。Thevolumeofplasmafilteredbythekidneyistermedtheglomerularfilterate(GFR)andisequaltoapproximately180

L/dayforapersonweighing70kg.

Approximately125mlofglomerularultrafiltrateisformedeachminute,yetonly1ml/minofurineisproduced.Therefore,greaterthan99%oftheglomerularultrafiltrateisreabsorbed.13/64GG11th，2006

腎小管和集合管的重吸收15/64Na+channelNaHCO3reabsorptioninproximaltubule.

（近曲小管）

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

+CO2→HCO3-;however,H2O→OH-

+H+,andHCO3-

+H+

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

17/64髓袢升支粗段NaClreabsorptionindistalconvolutedtubuleS,symporter;CH,ionchannel.Numbersinparenthesesindicatestoichiometry.BLandLMindicatebasolateralandluminalmembranes,respectively.遠曲小管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.

EffectsofaldosteroneonlatedistaltubuleandcollectingductSitesofactionofdiuretics21/64Na+channel23藥物尿電解質(zhì)的排泄Na+K+Ca2+Mg2+高效利尿藥＋＋＋＋＋＋＋＋＋＋＋＋中效利尿藥＋＋＋＋＋—＋螺內(nèi)酯氨苯蝶啶阿米洛利＋———乙酰唑胺＋＋＋＋藥物尿電解質(zhì)的排泄Cl－HCO3－H2PO4－H+高效利尿藥＋＋＋＋＋＋＋＋＋中效利尿藥＋＋＋＋＋＋＋＋螺內(nèi)酯氨苯蝶啶阿米洛利＋＋＋—乙酰唑胺＋＋＋＋＋＋＋—常用利尿藥的主要作用部位及機制

藥物主要作用部位機制呋塞米依他尼酸布美他尼髓袢升支粗段髓質(zhì)和皮質(zhì)部抑制Na+-K+-2C1-同向轉(zhuǎn)運體噻嗪類氯噻酮髓袢升支粗段髓質(zhì)部（遠曲小管近端）抑制Na+-C1-同向轉(zhuǎn)運體螺內(nèi)酯遠曲小管遠端集合管競爭醛固酮受體eplerenon阿米洛利氨苯蝶啶阻滯Na+通道，抑制NaCl重吸收乙酰唑胺近曲小管抑制碳酸酐酶活性25/64一.高效利尿藥

呋塞米(furosemide,速尿，呋喃苯胺酸）

第二節(jié)常用利尿藥26/64

了解藥名依他尼酸(etacrynicacid)布美他尼(bumetanide)

托拉塞米(torsemide

)

阿佐塞米(azosemide)

吡咯他尼(piretanide)藥理作用（Pharmacologiceffects）1.利尿↑theurinaryexcretionofNa+,K+,Ca2+,Mg2+,Cl-,HCO3-,

H2PO4-.

增加諸離子經(jīng)尿排泄。27/64作用特點：快、強、短

迅速、強大、短暫

2.擴張血管（EffectsonHemodynamics)腎血流量↑，腎中層皮質(zhì)血流↑，靜脈容量增加↑，左室充盈壓↓

↑totalRBF,RBFtothemidcortex，

↑systemicvenouscapacitance,

↓leftventricularfillingpressure.3.其他作用抑制內(nèi)耳Na+,K+-ATP酶，改變內(nèi)耳淋巴的電解質(zhì)成份耳毒性

28/64NaClreabsorptioninthickascendinglimbandmechanismofdiureticactionofNa+-K+-2Cl-symportinhibitors.

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

MechanismandSiteofAction

29/64高效能利尿藥體內(nèi)過程P153

藥物給藥途徑利尿作用口服吸收（%）t1/2(h)消除途徑開始(min)峰值(min)維持(h)強度呋塞米口服15～6060～1204～61～60～1.5腎臟60%代謝40%靜脈注射5302布美他尼口服3060～1204.5～640～80～0.8腎臟65%代謝35%靜脈注射10451依他尼酸口服201206～80.7幾乎1000.5～1.0腎臟65%代謝35%靜脈注射15453托拉塞米torsimide靜脈注射立即1563～80～3.5腎臟20%代謝70%吡咯他尼口服60～1204～63～800.6～1.5腎臟50%代謝50%30/641.急性肺水腫（Acutepulmonaryedema

）TherapeuticUses

（治療應(yīng)用）31/64leftventricularfillingpressures(左室充盈壓↓）relievespulmonaryedema(緩解肺水腫）venouscapacitance(靜脈容量↑）袢利尿藥的主要用途Amajoruseofloopdiuretics2.其他嚴重水腫

（Otherseriousedema）Theedemaofnephroticsyndrome(幾近唯一)

Theedemaandascitesofliver

cirrhosis3.慢性充血性心衰（Chroniccongestiveheartfailure）

mortality,

theriskofworseningHFimprovementinexercisecapacity

!

encephalopathyorhepatorenalsyndrome!

32/644.高鈣血癥(Hypercalcemia)

抑制Ca2+重吸收，聯(lián)合應(yīng)用輸注生理鹽水，增加Ca2+的排泄。近有報道，對需要使用袢利尿藥的慢性心衰，托拉塞米更有優(yōu)勢（作用時間長，生物利用度個體差異?。?。7.急性腎功能衰竭（Acuterenalfailure）5.加速毒物排泄Toinduceaforceddiuresisto

facilitatemorerapidrenaleliminationoftheoffendingdrug33/64？ThereisnoevidencethatloopdiureticspreventATNorimproveeinpatientswithARF(Kellum).6.高血壓（Hypertension）

用于噻嗪類藥物療效不佳、尤其是伴有腎功能不全容量負荷性高血壓或高血壓危象。AdverseEffects

1.水和電解質(zhì)紊亂(Abnormalitiesoffluidandelectrolytebalance)低血容量、鉀、鈉、氯、鎂、鈣。(6低）2.耳毒性(Ototoxicity)

與內(nèi)耳淋巴液的電解質(zhì)紊亂和耳蝸管基底膜毛細胞損傷有關(guān)。

3.代謝紊亂高尿酸血癥(Hyperuricemia)，高血糖(hyperglycemia),TG↑,LDL-C↑,HDL-C↓。34/64

藥物相互作用Druginteractions

DrugInteractionAminoglycosides氨基苷類

↑ototoxicityanticoagulants華法林↑anticoagulantactivitydigitalisglycosides強心苷↑digitalis-inducedarrhythmiasLithium鋰

↑plasmalevelsoflithiumpropranolol普奈洛爾↑plasmalevelsofpropranolol

sulfonylureas磺酰脲類↑bloodglucoseCisplatin順鉑↑riskofototoxicityNSAIDs非甾體抗炎藥↓diureticresponseProbenecid丙磺舒↓diureticresponseamphotericinB兩性霉素

↑toxicity35/64㈡.中效利尿藥

噻嗪類（thiazides）

氯噻嗪

chlorothiazide氫氯噻嗪

hydrochlorothiazide芐噻嗪

benzthiazide氫氟噻嗪

hydroflumethiazide泊利噻嗪

polythiazide芐氟噻嗪

bendroflumethiazide甲氯噻嗪

methyclothiazide環(huán)戊噻嗪

cyclopenthiazide三氯噻嗪

trichlormethiazide36/64藥理作用

Pharmacologicaleffects1.利尿

中等強度、溫和、持久。尿中Na+、C1-、K+、Mg2+、HCO3-

排出均增加。

2.抗利尿減少尿崩癥患者的尿量，改善口渴等癥狀。機制不清。3.降壓

目前仍作為一線抗高血壓藥物類別之一，視病情，可單用或與其他抗高血壓藥物合用。

37/64NaClreabsorptionindistalconvolutedtubuleandmechanismofdiureticactionofNa+-Cl-symportinhibitors.

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

38/64治療應(yīng)用

TherapeuticUses

1.水腫(Edema)

associated

withheart,liver,andrenaldisease.congestiveheartfailure

hepaticcirrhosis

nephroticsyndrome,chronicrenalfailure,acuteglomerulonephritisMostthiazidediureticsareineffectivewhentheGFRislessthan30to40ml/min.

腎小球率過濾低于30~40ml/min效差！39/642.高血壓（Hypertension）

eitheraloneorincombinationwithotherantihypertensivedrugs①Inexpensive

②Efficacious③Welltolerated

④Oncedaily,donotrequiredosetitration

⑤Fewcontraindications⑥Additiveorsynergisticeffectswithotherclassesofantihypertensiveagents

優(yōu)點多多！safe,↓cardiovascularmorbidityandmortality40/643.尿崩癥包括腎性和垂體性尿崩癥

Themechanismofthisparadoxicaleffectremainsunknown.

①鈣性腎結(jié)石和骨質(zhì)疏松(Calciumnephrolithiasis)&osteoporosis

reduceurinaryexcretionofCa2+

②溴中毒

(Br-

intoxication)SinceotherhalidesareexcretedbyrenalprocessessimilartothoseforCl-

4.其他41/64AdverseEffects

1.電解質(zhì)紊亂(Abnormalitiesoffluidandelectrolytebalance)

低鉀、低鎂、低氯

hypokalemia,hypo-magnesemia,hypochloremia.422.代謝變化

①糖耐量受損Glucosetolerance↓Hyperglycemia②血脂異常(Dyslipidemia)↑LDL-C,TCandTG③高尿酸血癥3.過敏反應(yīng)Druginteractions

自學(xué)

1.Thiazidediuretics

diminishthe

effectsofanti-coagulants,andinsulin.3.

TheeffectivenessofthiazidediureticsmaybereducedbyNSAIDs.

4.Lethaldruginteraction:thiazidediureticsandquinidinetorsadesdepointes2.Thiazidediureticsincreasethe

Effectsofanes-thetics,diazoxide,digitalisglycosides,lithium,loopdiuretics,andvitaminD.

43中效利尿藥的藥理作用、利尿效價與用法藥物作用特點用法（mg/d）起效時間(h)峰值時間(h)持續(xù)時間(h)利尿效價利尿降壓氯噻嗪0.1250～1000氫氯噻嗪1～23～46～12125～5025～50芐噻嗪24～612～18350～20050～200三氯噻嗪2618～24251～4泊利噻嗪2624～28251～42～4甲氯噻嗪26>24102.5～102.5～5氯噻酮

2648～72150～10050～100吲達帕胺

1～3636202.52.544㈢.低效利尿藥

螺內(nèi)酯(spironolactone,安體舒通，antisterone)2.醛固酮拮抗藥(aldosteroneantagonist)依普利酮

(eplerenone)1.腎上皮細胞鈉通道抑制藥(inhibitorsofrenalepithelialNa+channels)氨苯蝶啶（

triamterene，三氨蝶啶）阿米洛利（amiloride，氨氯吡咪）

3.碳酸酐酶抑制藥(inhibitorofcarbonicanhy-drase)乙酰唑胺

(acetazolamide)自學(xué)451.腎上皮細胞鈉通道抑制藥(inhibitorsofrenalepithelialNa+channels)氨苯蝶啶（

triamterene，三氨蝶啶）阿米洛利（amiloride，氨氯吡咪）

MechanismandSiteofAction

Figure46Figure28-8.Na+reabsorptioninlatedistaltubuleandcollectingductandmechanismofdiureticactionofepithelialNa+-channelinhibitors.

Cl-reabsorption(notshown)occursbothparacellularlyandtranscellularly,andtheprecisemechanismofCl-transportappearstobespecies-specific.A,antiporter;CH,ionchannel;CA,carbonicanhydrase.Numbersinparenthesesindicatestoichiometry.Designatedvoltagesarethepotentialdifferencesacrosstheindicatedmembraneorcell.BLandLMindicatebasolateralandluminalmembranes,respectively.↓excretionratesofK+Pharmacologicaleffects

排鈉留鉀利尿↑excretionratesofNa+andCl-

48TherapeuticUses

1.與其他利尿藥合用（利相加、弊相克）①↑thediureticandantihypertensiveresponsetothiazideandloopdiuretics

②↓K+excretioninducedbythiazideandloopdiuretics

2.OtherUses（次要）

Cysticfibrosistoimprovemucociliary

clearanceLithium-inducednephrogenicdiabetesinsipidus

Liddle'ssyndrome*

*李德爾(氏)綜合征:可能為常染色體顯性遺傳,由于腎小管異常,鈉重吸收過強和鉀排泄增多,導(dǎo)致腎素及醛固酮分泌受抑制。49AdverseEffects

1.高血鉀ThemostdangerousadverseeffectofNa+-channelinhibitorsisWhichcanbelife-threatening!

Hyperkalemia

Contraindicatedin

patientswithhyperkalemia

receivingotherK+-sparingdiureticstakingACEinhibitors

takingK+supplements50triamterene氨苯喋啶amiloride阿米洛利nausea,vomitingnausea,vomiting,diarrhea,dizzinessheadachelegcramps(腿痛性痙攣)glucosetolerance↓photosensitizationinterstitialnephritisrenalstones2.其他不良反應(yīng)46螺內(nèi)酯(spironolactone,安體舒通，antisterone)2.醛固酮拮抗藥(aldosteroneantagonist)MechanismandSiteofAction

Figure依普利酮

(eplerenone)2002年上市52Effectsofaldosteroneonlatedistaltubuleandcollectingductanddiureticmechanismofaldosteroneantagonists

MechanismandSiteofAction

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.×Pharmacologicaleffects

1.利尿作用（同小管上皮鈉通道抑制劑）similartoepithelialNa+-channelinhibitors,特點：EfficacyofMRantagonistsisafunctionofendogenouslevelsofaldosterone.

492.其他作用關(guān)注對心血管的作用??！

SpironolactoneEplerenone男性乳房發(fā)育astia月經(jīng)失調(diào)

menstrualirregularities↓室性心律失常

ventriculararrhythmias√↓血壓

Bloodpressure√↓心臟重構(gòu)

myocardialremodeling√↓血管重構(gòu)

vascular

remodeling√↓膠原沉積

collagendeposition√↓心肌僵硬度

myocardialstiffness√↓動粥樣損傷

atheroscleroticlesions√50TherapeuticusesSpironolactoneEplerenone合用

coadministeringwiththiazideorloopdiuretics

頑固性水腫

refractoryedema

(cardiacfailure,hepaticcirrhosis,nephroticsyndrome,andsevereascites

)原發(fā)性醛固酮增多癥primaryhyperaldosteronism急性心梗后的心功能不全AMIcomplicatedby

LVsystolicdysfunction