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1、第22章 利尿药和脱水药 Diuretics and Dehydrate agents,华中科技大学同济医学院药理学系,授课教师 金满文,2014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.呋塞米的临床应用和不良反应4.噻嗪类利尿药的临床应用和不良反应5.留钾类利尿药的临床应用和不良反应6.甘露醇的临床应用,利尿药是直接作用于肾脏，增加Na+、Cl-等电解质和水的排出，使尿量增多的药物。,3,1、定义(本版教科书)：,概述,本版英文摘要：Diuretics increase the rate of urine flow and sodium
2、 excretion，used to adjust the volume and/or composition of body fluids in variety of clinical situations.,描述利尿药的作用和用途,利尿药增加尿量和排钠，用于各种临床状态下调节体液的量和/或成份。,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。,Diuretics are agents that act directly on the tubular epithelial and increased rate of urine formation.,4,Goodman and Gil
3、mans The Pharmacological Basis of Therapeutics,(GG 8th,1990),更准确！,利尿药是促进机体钠和水的净丢失、增加尿量的药物。,Diuretics are drugs that promote a net loss of sodium(Na+)and water from the body,the net result being an increase in urine flow.,GG 10th,2001,5,其实，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。,Some drugs can
4、 increase urine flow by nonrenal mechanisms(e.g.by increasing cardiac output in a patient with congestive heart failure),but these drugs are not generally regarded as diuretics.,6/70,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 increase the rate of urine flow and sodium excretion and a
5、re used to adjust the volume and/or composition of body fluids in a variety of clinical situations,including hypertension,heart failure,renal failure,nephrotic syndrome,and cirrhosis.GG 11th,2006,7,本版英文摘要：Diuretics increase the rate of urine flow and sodium excretion，used to adjust the volume and/or
6、 composition of body fluids in variety of clinical situations.,(1)各种水肿：心性、肝性、肾性。(2)高血压：根据病情，选用不同类别利尿药。(3)其他：尿崩症、肾结石等。,8,2、利尿药的适应症,1.高效利尿药 high efficacy(ceiling)diuretics 袢利尿药 Loop diuretics 钠钾氯同向转运抑制剂 Inhibitor of Na+-K+-2Cl-symport,3、利尿药的分类(Classification of diuretics),代表药：呋塞米(furosemide),9/70,其它：依
7、他尼酸、布美他尼、阿佐塞米、托拉塞米等,2.中效利尿药 moderate efficacy diuretics 抑制Na+-Cl-同向转运(symport)，,因该类药物以噻嗪类药物为主，也称噻嗪类利尿药。,噻嗪类：氯噻嗪、氢氯噻嗪、环戊噻嗪等非噻嗪类：氯噻酮、吲达帕胺等,代表药：氢氯噻嗪,10/70,3.低效利尿药 Low efficacy diuretics 醛固酮拮抗剂(aldosterone antagonist)：螺内酯(spironolactone)、依普利酮(Eplerenon),肾小管上皮细胞Na+通道抑制药(inhibitors of epithelial Na+channe
8、l)：氨苯蝶啶(triamterene)、阿米洛利(amiloride),注：&:留钾利尿药（K+sparing diuretics）,11/70,碳酸酐酶抑制剂(inhibitors of carbonic anhydrase)：乙酰唑胺（醋唑磺胺）,4.渗透性利尿药(osmotic diuretics)，也称脱水药：甘露醇等。,非肽类加压素2受体拮抗剂(non-peptide vasopression V2-receptor antagonist)托伐普坦(Tolvaptan),12/70,13/70,第一节 利尿药作用的生理学基础,利尿药的作用主要是影响尿液形成过程的肾小管重吸收和分泌功
9、能。,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。,The volume of plasma filtered by the kidney is termed the glomerular filte rate(GFR)and is equal to approximately 180 L/day for a person weighing 70 kg.,Approximately 125 ml of glomerular ultrafiltrate is formed each minute,yet only 1 ml/min of urine is produce
10、d.Therefore,greater than 99%of the glomerular ultrafiltrate is reabsorbed.,14/70,健康成年人肾小球滤过量约180 L/d。,肾小管和集合管的重吸收,16/70,Na+,channel,NaHCO3 reabsorption in proximal tubule.（近曲小管）A,antiporter;S,symporter;CH,ion channel.(The actual reaction catalyzed by carbonic anhydrase is OH-+CO2HCO3-;however,H2O OH
11、-+H+,and HCO3-+H+H2CO3,so the net reaction is H2O+CO2 H2CO3)Numbers in parentheses indicate stoichiometry.BL and LM indicate basolateral and luminal membranes,respectively.,（近曲小管）,S,symporter;CH,ion channel.Numbers in parentheses indicate stoichiometry.Designated voltages are the potential differenc
12、es across the indicated membrane or cell.The mechanisms illustrated here apply to the medullary,cortical,and post macular segments of the thick ascending limb.BL and LM indicate basolateral and luminal membranes,respectively.,18/70,髓袢升支粗段,NaCl reabsorption in distal convoluted tubule,S,symporter;CH,
13、ion channel.Numbers in parentheses indicate stoichiometry.BL and LM indicate basolateral and luminal membranes,respectively.,远曲小管,Na+reabsorption in late distal tubule and collecting duct.Cl-reabsorption(not shown)occurs both paracellularly and transcellularly,and the precise mechanism of Cl-transpo
14、rt appears to be species-specific.A,antiporter;CH,ion channel;CA,carbonic anhydrase.Numbers in parentheses indicate stoichiometry.Designated voltages are the potential differences across the indicated membrane or cell.BL and LM indicate basolateral and luminal membranes,respectively.,AIP,aldosterone
15、-induced proteins;ALDO,aldosterone;MR,mineralocorticoid receptor;CH,ion channel;activation of membrane-bound Na+channels;redistribution of Na+channels from cytosol to membrane;de novo synthesis of Na+channels;activation of membrane-bound Na+,K+-ATPase;redistri-bution of Na+,K+-ATPase from cytosol to
16、 membrane;de novo synthesis of Na+,K+-ATPase;changes in permeability of tight junctions;increased mito-chondrial production of ATP.BL and LM indicate basolateral and luminal membranes,respectively.,Effects of aldosterone on late distal tubule and collecting duct,Sites of action of diuretics,22/70,Na
17、+,channel,23,常用利尿药的主要作用部位及机制,26/70,一.高效利尿药 呋塞米(furosemide,速尿，呋喃苯胺酸）,第二节 临床使用的利尿药,托拉塞米(torsemide)阿佐塞米(azosemide)布美他尼(bumetanide)吡咯他尼(piretanide)依他尼酸(etacrynic acid),27/70,药理作用（Pharmacologic effects）,1.利尿 the urinary excretion of Na+,K+,Ca2+,Mg2+,Cl-,HCO3-,H2PO4-.增加诸离子经尿排泄。,28/70,作用特点：,快、强、短,迅速、强大、短暂,
18、2.扩张血管（Effects on Hemodynamics)肾血流量，肾中层皮质血流，静脉容量增加，左室充盈压（total RBF,RBF to the midcortex，systemic venous capacitance,left ventricular filling pressure.）,3.其他作用 抑制内耳 Na+,K+-ATP酶，改变内耳淋巴的电解质成份 耳毒性,29/70,NaCl reabsorption in thick ascending limb and mechanism of diuretic action of Na+-K+-2Cl-symport inhi
19、bitors.,S,symporter;CH,ion channel.Numbers in parentheses indicate stoichiometry.Designated voltages are the potential differences across the indicated membrane or cell.The mechanisms illustrated here apply to the medullary,cortical,and post macular segments of the thick ascending limb.BL and LM ind
20、icate basolateral and luminal membranes,respectively.,Mechanism and Site of Action,30/70,高效能利尿药体内过程 P153,31/70,1.急性肺水肿（Acute pulmonary edema）,Therapeutic Uses（治疗应用）,32/70,袢利尿药的主要用途 A major use of loop diuretics,2.其他严重水肿（Other serious edema）,The edema of nephrotic syndrome(几近唯一),The edema and ascites
21、 of liver cirrhosis,3.慢性充血性心衰（Chronic congestive heart failure）,mortality,the risk of worsening HF improvement in exercise capacity,!encephalopathy or hepatorenal syndrome!,33/70,4.高钙血症(Hypercalcemia)抑制Ca2+重吸收，联合应用输注生理盐水，增加Ca2+的排泄。,近有报道，对需要使用袢利尿药的慢性心衰，托拉塞米更有优势（作用时间长，生物利用度个体差异小）。,7.急性肾功能衰竭（Acute rena
22、l failure）袢利尿药不作为ARF的常规用药。对于等待肾替代治疗或肾功能已恢复、但有明显体液超负荷或水肿时可考虑用袢利尿药（NICE，2013指南）。,5.加速毒物排泄 To induce a forced diuresis to facilitate more rapid renal elimination of the offending drug,34/70,6.高血压（Hypertension）在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、充分权衡利弊后，可用。,？没有证据显示袢利尿药改善ARF患者的结局 There is no evidence tha
23、t loop diuretics improve outcome in patients with ARF.,Adverse Effects,1.水和电解质紊乱(Abnormalities of fluid and electrolyte balance)低血容量、钾、钠、氯、镁、钙；低氯碱血症。(7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.高尿酸血症(Hyperuricemia)痛风患者慎用。,35/70,4.其他 胃肠道反应，少数患者可发生白细胞、血小板减少，也可发生过敏。,药物相互作用 Drug interactions,36/
24、70,二.中效利尿药 噻嗪类（thiazides）,37/70,药理作用 Pharmacological effects,1.利尿 中等强度、温和、持久。尿中Na+、C1-、K+、Mg2+、HCO3-排出均增加。,3.抗利尿 减少尿崩症患者的尿量，改善口渴等症状。机制不清。,2.降压 降压作用稳定可靠。其降压机制包括血容量降低和血管舒张作用。,38/70,NaCl reabsorption in distal convoluted tubule and mechanism of diuretic action of Na+-Cl-symport inhibitors.,S,symporter;
25、CH,ion channel.Numbers in parentheses indicate stoichiometry.BL and LM indicate basolateral and luminal membranes,respectively.,Mechanism and Site of Action,39/70,Inexpensive,Efficacious,Well tolerated,Once daily,do not require dose titration,Few contraindications,Additive or synergistic effects wit
26、h other classes of antihypertensive agents,优点多多！,cardiovascular morbidity and mortality,40/70,25毫克100片，3.00元！,1.高血压（Hypertension）目前仍作为一线抗高血压药物类别之一，视病情，可单用或与其他抗高血压药物合用。,治疗应用 Therapeutic Uses,41/70,美国 JNC 8,JAMA.2014;311(5):507-520,42/70,The current Guidelines reconrm that diuretics(including thiazide
27、s,chlorthalidone and indapamide),beta-blockers,calcium antagonists,angiotensin-converting enzyme(ACE)inhibitors and angiotensin receptor blockers are all suitable for the initiation and maintenance of antihypertensive treatment,either asmonotherapy or in some combinations.,Eur Heart J.2013;34(28):21
28、592219,欧洲最新指南再次肯定的一线抗高血压药物包括：利尿药（中效利尿药）、受体阻滞剂、钙拮抗剂、ACE-I和ARB。,2.水肿(Edema)associated with heart,liver,and renal disease.,congestive heart failure,hepatic cirrhosis,nephrotic syndrome,chronic renal failure,acute glomerulonephritis,Most thiazide diuretics are ineffective when the GFR is less than 30 to
29、 40 ml/min.肾小球率过滤低于3040 ml/min 效差！,43/70,3.尿崩症 包括肾性和垂体性尿崩症 The mechanism of this paradoxical effect remains unknown.,钙性肾结石和骨质疏松(Calcium nephrolithiasis)&osteoporosis reduce urinary excretion of Ca2+,溴中毒(Br-intoxication)Since other halides are excreted by renal processes similar to those for Cl-,4.其他
30、,44/70,Adverse Effects,1.电解质紊乱(Abnormalities of fluid and electrolyte balance)低钾、低镁、低氯 hypokalemia,hypo-magnesemia,hypochloremia.,45,2.代谢变化,糖耐量受损 Glucose tolerance Hyperglycemia,血脂异常(Dyslipidemia)LDL-C,TC and TG,高尿酸血症,3.过敏反应,Drug interactions 自学,1.Thiazide diuretics diminish the effects of anti-coag
31、ulants and insulin.,3.The effectiveness of thiazide diuretics may be reduced by NSAIDs.,4.Lethal drug interaction:thiazide diuretics and quinidine torsades de pointes,2.Thiazide diuretics increase the Effects of anes-thetics,diazoxide,digitalis glycosides,lithium,loop diuretics,and vitamin D.,46,中效利
32、尿药的药理作用、利尿效价与用法,47,三.低效利尿药,螺内酯(spironolactone,安体舒通，antisterone),2.醛固酮拮抗药(aldosterone antagonist),依普利酮(eplerenone),1.肾上皮细胞钠通道抑制药(inhibitors of renal epithelial Na+channels),氨苯蝶啶（triamterene，三氨蝶啶）,阿米洛利（amiloride，氨氯吡咪）,48,托伐普坦(Tolvaptan),3.肾非肽类加压素2受体拮抗剂(non-peptide vasopression V2-receptor antagonist),
33、4.碳酸酐酶抑制药(自学),1.肾上皮细胞钠通道抑制药(inhibitors of renal epithelial Na+channels),氨苯蝶啶（triamterene，三氨蝶啶）,阿米洛利（amiloride，氨氯吡咪）,Mechanism and Site of Action,Figure,49,Figure 28-8.Na+reabsorption in late distal tubule and collecting duct and mechanism of diuretic action of epithelial Na+-channel inhibitors.Cl-re
34、absorption(not shown)occurs both paracellularly and transcellularly,and the precise mechanism of Cl-transport appears to be species-specific.A,antiporter;CH,ion channel;CA,carbonic anhydrase.Numbers in parentheses indicate stoichiometry.Designated voltages are the potential differences across the in
35、dicated membrane or cell.BL and LM indicate basolateral and luminal membranes,respectively.,excretion rates of K+,Pharmacological effects,排钠留钾利尿,excretion rates of Na+and Cl-,51,Therapeutic Uses,1.与其他利尿药合用（利相加、弊相克）,the diuretic and antihypertensive response to thiazide and loop diuretics,K+excretion
36、 induced by thiazide and loop diuretics,2.其他应用（次要）,Cystic fibrosis to improve mucociliary clearance,Lithium-induced nephrogenic diabetes insipidus,Liddles syndrome*,*李德尔(氏)综合征:可能为常染色体显性遗传,由于肾小管异常,钠重吸收过强和钾排泄增多,导致肾素及醛固酮分泌受抑制。,52,Adverse Effects,1.高血钾 The most dangerous adverse effect of Na+-channel in
37、hibitors is,Which can be life-threatening!,Hyperkalemia,Contraindicated in patients with hyperkalemia receiving other K+-sparing diuretics taking ACE inhibitors taking K+supplements,53,2.其他不良反应,54,螺内酯(spironolactone,安体舒通，antisterone),2.醛固酮拮抗药(aldosterone antagonist),Mechanism and Site of Action,Figu
38、re,依普利酮(eplerenone)2002年上市,55,Effects of aldosterone on late distal tubule and collecting duct and diuretic mechanism of aldosterone antagonists,Mechanism and Site of Action,AIP,aldosterone-induced proteins;ALDO,aldosterone;MR,mineralocorticoid receptor;CH,ion channel;activation of membrane-bound Na
39、+channels;redistribution of Na+channels from cytosol to membrane;de novo synthesis of Na+channels;activation of membrane-bound Na+,K+-ATPase;redistri-bution of Na+,K+-ATPase from cytosol to membrane;de novo synthesis of Na+,K+-ATPase;changes in permeability of tight junctions;increased mito-chondria
40、l production of ATP.BL and LM indicate basolateral and luminal membranes,respectively.,Pharmacological effects,利尿作用（同小管上皮钠通道抑制剂）,similar to epithelial Na+-channel inhibitors,特点：醛固酮拮抗剂的效应是内源性醛固酮水平的函数 Efficacy of MR antagonists is a function of endogenous levels of aldosterone.,57,其他作用 关注对心血管的作用！,58,T
41、herapeutic uses,59/70,Adverse Effects 不良反应,60/70,61/70,The Structure of tolvaptan,商品名(Trade Name)：SamskaTM,3.非肽类加压素2受体拮抗剂 non-peptide vasopression V2-receptor antagonist,托伐普坦(Tolvaptan),H2O,H2O,H2O,H2O,62/70,治疗应用,63/70,The use of SAMSCA for the treatment of clinically significant hypervolemic and eu
42、volemic hyponatremia(serum sodium 125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction),including patients with Syndrome of Inappropriate Antidiuretic Hormone(SIADH),heart failure and cirrhosis.Approval letter,钾低钠血症 包括高容和等容低钠血症（血清钠低于125 mEq/L，或
43、无明显低钠血症但有症状且限制液体摄入不能矫正者，包括抗利尿激素失衡综合征、心衰、肝硬化。,64/70,不良反应,1.渗透性脱髓鞘综合征,(osmotic demyelination syndrome,ODS)，可致昏迷和死亡。具认为 与血钠水平升高过快有关。,2.肝脏损伤 包括致死性肝衰竭,托伐普坦疗程应不超过30天，随时警惕与肝脏受损相关的症状。Samsca should not be taken for more than 30 days.Tell your doctor right away if you develop or have worsening of any of these
44、 signs and symptoms of liver problems.,四.脱水药,(Dehydrate agents),渗透性利尿药(Osmotic diuretics),甘露醇(mannitol,i.v.),山梨醇(sorbide),甘油(glycerin),尿素(urea,i.v.),65/70,The Osmotic diuretics,undergo limited reabsorption by the renal tubule,are relatively inert pharmacologically,are freely filtered at the glomerul
45、us“自由”滤过,the osmolality of plasma,Dehydrate,Osmotic diureses,stayed in blood vessels“呆”在血管内,and tubular fluid,在肾小管重吸收有限,相对无药理活性,脱水,利尿,66/70,药理作用,1.脱水 对脑、眼前房等部位作用尤显。,甘露醇(mannitol,i.v.),67/70,Therapeutic Uses,预防急性肾功衰 acute renal failure,透析失平恒综合征 dialysis disequilibrium syndrome,青光眼急性发作 acute attacks o
46、f glaucoma,脑水肿 cerebral edema,眼科术前术后 pre-and postoperatively in ocular surgery,68/70,Adverse Effects,hyponatremia,frank pulmonary edema,headache,nausea,and vomiting,(with heart failure or pulmonary congestion),略,69/70,Summary of the site and mechanism of action of diuretics,V2 antagonist,复习题,1.利尿药的分类及代表药？2.比较各类利尿药的作用部位和作用机制？3.呋塞米的临床应用和不良反应？4.噻嗪类利尿药的临床应用和不良反应？5.留钾类利尿药的临床应用和不良反应？6.甘露醇的临床应用？,告 示,为尽可能避开餐厅高峰，取消课间休息，连续授课90 min，11:40下课。请提前做好相应准备。,
