1、 华中科技大学同济医学院药理学系华中科技大学同济医学院药理学系 授课教师授课教师 金满文金满文20142014年年1010月月是直接作用于是直接作用于肾脏肾脏，增加，增加Na+、Cl-等电等电解质和水的排出，使尿量增多的药物。解质和水的排出，使尿量增多的药物。31、定义、定义(本版教科书本版教科书)：概述概述本版英文摘要：本版英文摘要：Diuretics increase the rate of urine flow and sodium excretion，used to adjust the volume and/or composition of body fluids in varie
2、ty of clinical situations. 描述利尿药的作用和用途描述利尿药的作用和用途利尿药利尿药增加尿量和排钠增加尿量和排钠，用于各种临床状态下调节，用于各种临床状态下调节体液的量和体液的量和/或成份。或成份。利尿药利尿药是是直接作用于小管上皮细胞直接作用于小管上皮细胞、增加尿、增加尿液形成率的物质。液形成率的物质。 Diuretics are agents that act directly on the tubular epithelial and increased rate of urine formation. 4Goodman and Gilmans The Phar
3、macological Basis of Therapeutics, (GG 8th, 1990)更准确！更准确！利尿药利尿药是促进机体钠和水的净丢失、增加尿是促进机体钠和水的净丢失、增加尿量的药物。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, 20015其实，其实，并非增加尿量的药物都是利尿药。如并非增加尿量的药物都是利尿药。如强心苷强心苷增加心
4、衰病人的心排量，也使尿量增加心衰病人的心排量，也使尿量增加，但其不作为利尿药。增加，但其不作为利尿药。Some drugs can 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利尿药利尿药增加尿量和排钠增加尿量和排钠，用于高血压、心衰、，用于高血压、心衰、肾衰、肾病综合征和肝硬
5、化等病变时调节肾衰、肾病综合征和肝硬化等病变时调节体液的量和体液的量和/或成份。或成份。Diuretics increase the rate of urine flow and sodium excretion and are 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.
6、 GG 11th, 2006 7本版英文摘要：本版英文摘要：Diuretics increase the rate of urine flow and sodium excretion，used to adjust the volume and/or composition of body fluids in variety of clinical situations. (1)各种水肿：各种水肿：心性、肝性、肾性心性、肝性、肾性。(2)高血压：高血压：根据病情，选用不同类别利尿药。根据病情，选用不同类别利尿药。(3)其他：其他：尿崩症、肾结石等。尿崩症、肾结石等。 82、利尿药的适应症、利尿
7、药的适应症 high efficacy (ceiling) diuretics Loop diuretics Inhibitor of Na+-K+-2Cl- symport(Classification of diuretics)9/70 moderate efficacy diuretics 抑制抑制Na+-Cl- 同向转运同向转运(symport)，因该类药物以噻嗪类药物为主，也称因该类药物以噻嗪类药物为主，也称 氯噻酮、吲达帕胺等氯噻酮、吲达帕胺等10/70 Low efficacy diuretics (aldosterone antagonist)： 螺内酯螺内酯(spironol
8、actone)、 依普利酮依普利酮 (Eplerenon) (inhibitors of epithelial Na+ channel)： 氨苯蝶啶氨苯蝶啶(triamterene)、 阿米洛利阿米洛利(amiloride) （K+ sparing diuretics）11/70 (inhibitors of carbonic anhydrase)： 乙酰唑胺（醋唑磺胺）乙酰唑胺（醋唑磺胺） (osmotic diuretics)，也称，也称脱水药脱水药： 甘露醇等甘露醇等。(non-peptide vasopression V2-receptor antagonist) 托伐普坦托伐普坦(T
9、olvaptan)12/7013/70第一节第一节 利尿药作用的生理学基础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能。肾小管重吸收和分泌功能。对利尿药作用机制的认识、新的利尿药的对利尿药作用机制的认识、新的利尿药的研发，研发，均基于对肾脏泌尿生理的了解。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 for a
10、 person weighing 70 kg. Approximately of glomerular ultrafiltrate is formed each minute, yet only of urine is produced. Therefore, greater than of the glomerular ultrafiltrate is reabsorbed.14/7016/70NaHCO3 reabsorption in proximal tubule. A, antiporter; S, symporter; CH, ion channel. (The actual re
11、action catalyzed by carbonic anhydrase is OH- + CO2HCO3-; however, H2O OH- + 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. S, symporter; CH, ion channel. Numbers in
12、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 indicate basolateral and luminal membranes,
13、respectively. 18/70NaCl reabsorption in distal convoluted tubuleS, symporter; CH, ion channel. Numbers in parentheses indicate stoichiometry. BL and LM indicate basolateral and luminal membranes, respectively. 远曲小管远曲小管Na+ reabsorption in late distal tubule and collecting duct. Cl- reabsorption (not
14、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 indica
15、ted membrane or cell. BL and LM indicate basolateral and luminal membranes, respectively. AIP, aldosterone-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
16、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-chondrial production of ATP. BL and LM indicate basolateral and luminal me
17、mbranes, respectively. Effects of aldosterone on late distal tubule and collecting duct22/7023药药 物物尿电解质的排泄尿电解质的排泄Na+K+Ca2+Mg2+高效利尿药高效利尿药 中效利尿药中效利尿药螺内酯螺内酯氨苯蝶啶氨苯蝶啶阿米洛利阿米洛利托伐普坦托伐普坦乙酰唑胺乙酰唑胺药药 物物尿电解质的排泄尿电解质的排泄ClHCO3H2PO4H+高效利尿药高效利尿药中效利尿药中效利尿药 螺内酯螺内酯氨苯蝶啶氨苯蝶啶阿米洛利阿米洛利托伐普坦托伐普坦乙酰唑胺乙酰唑胺常用利尿药的主要作用部位及机制常用利尿药的主要作
18、用部位及机制 药物药物主要作用部位主要作用部位机制机制依他尼酸依他尼酸布美他尼布美他尼髓袢升支粗段髓质髓袢升支粗段髓质和皮质部和皮质部抑制抑制NaNa+ +-K-K+ +-2C1-2C1- -同向转运体同向转运体氯噻酮氯噻酮髓袢升支粗段髓质髓袢升支粗段髓质部（远曲小管近端）部（远曲小管近端）抑制抑制NaNa+ +-C1-C1- -同向转运体同向转运体远曲小管远端远曲小管远端集合管集合管竞争阻断醛固酮受体竞争阻断醛固酮受体eplerenon阿米洛利阿米洛利氨苯蝶啶氨苯蝶啶阻滞阻滞NaNa+ +通道，抑制通道，抑制NaClNaCl重吸重吸收收托伐普坦托伐普坦集合管集合管阻断加压素阻断加压素V V2
19、 2受体受体乙酰唑胺乙酰唑胺近曲小管近曲小管抑制碳酸酐酶活性抑制碳酸酐酶活性26/70一一. .高效利尿药高效利尿药 呋塞米呋塞米(furosemide, 速尿，呋喃苯胺酸）速尿，呋喃苯胺酸） 托拉塞米托拉塞米(torsemide ) 阿佐塞米阿佐塞米(azosemide) 布布美他尼美他尼(bumetanide) 吡咯吡咯他尼他尼(piretanide) 依依他尼酸他尼酸(etacrynic acid)27/70药理作用药理作用（Pharmacologic effects）. . the urinary excretion of Na+, K+, Ca2+, Mg2+, Cl-, HCO3-
20、, H2PO4-. 增加诸离子经尿排泄。增加诸离子经尿排泄。28/70作用特点：作用特点： 快、强、短快、强、短 迅速、强大、短暂迅速、强大、短暂 （Effects on Hemodynamics) 肾血流量肾血流量，肾中肾中层皮质血流层皮质血流，静脉容量增加静脉容量增加，左室充盈压左室充盈压 （total RBF, RBF to the midcortex， systemic venous capacitance, left ventricular filling pressure.） 3.3.抑制内耳抑制内耳 Na+,K+-ATP酶，改变内耳淋酶，改变内耳淋巴的电解质成份巴的电解质成份 耳
21、毒性耳毒性 29/70NaCl reabsorption in thick ascending limb and mechanism of diuretic action of Na+-K+-2Cl- symport inhibitors. S, symporter; CH, ion channel. Numbers in parentheses indicate stoichiometry. Designated voltages are the potential differences across the indicated membrane or cell. The mechanis
22、ms 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. Mechanism and Site of Action 30/70高效能利尿药体内过程高效能利尿药体内过程 P153 药药 物物给药途径给药途径利尿作用利尿作用口服吸收口服吸收（% %）t t1/21/2(h)(h)消除途径消除途径开始开始(m
23、in)(min)峰值峰值(min)(min)维持维持(h)(h)强度强度口服口服1515606060601201204 46 61 160601.51.5肾脏肾脏60%60%代谢代谢40%40%静脉注射静脉注射5 530302 2布美他尼布美他尼口服口服303060601201204.54.56 6404080800.80.8肾脏肾脏65%65%代谢代谢35%35%静脉注射静脉注射101045451 1依他尼酸依他尼酸口服口服20201201206 68 80.70.7几乎几乎1001000.50.51.01.0肾脏肾脏65%65%代谢代谢35%35%静脉注射静脉注射151545453 3托拉
24、塞米托拉塞米torsimidetorsimide静脉注射静脉注射立即立即15156 63 380803.53.5肾脏肾脏20%20%代谢代谢70%70%吡咯他尼吡咯他尼口服口服60601201204 46 63 380800.60.61.51.5肾脏肾脏50%50%代谢代谢50%50%31/70 （治疗应用）（治疗应用）32/70left ventricular filling pressuresrelieves pulmonary edemavenous capacitance A major use of loop diuretics The edema of syndrome The e
25、dema and ascites of cirrhosismortality, the risk of worsening HF in exercise capacity ! encephalopathy or hepatorenal syndrome ! 33/7034/70噻嗪类药物疗效不佳、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尤其是伴有肾功能不全容量负荷性高血压或高血压危象、压危象、充分权衡利充分权衡利 弊后弊后，可用。，可用。 . ( (低血容量、低血容量、钾钾、钠、氯、镁、钠、氯、镁、钙；低氯碱血症。钙；低氯碱血症。(7(7低）低） 与内耳淋巴液的电解质紊与
26、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。乱和耳蜗管基底膜毛细胞损伤有关。 35/70Drug interactions DrugInteractionanticoagulants 华法林华法林 anticoagulant activity Lithium 锂锂 plasma levels of lithium propranolol 普奈洛尔普奈洛尔 plasma levels of propranolol sulfonylureas 磺酰脲类磺酰脲类 blood glucoseCisplatin 顺铂顺铂 risk of ototoxicity Probenecid 丙磺舒丙磺舒
27、 diuretic response amphotericin B 两性霉素两性霉素 toxicity 36/70 氯噻嗪氯噻嗪 chlorothiazide苄噻嗪苄噻嗪 benzthiazide氢氟噻嗪氢氟噻嗪 hydroflumethiazide泊利噻嗪泊利噻嗪 polythiazide苄氟噻嗪苄氟噻嗪 bendroflumethiazide甲氯噻嗪甲氯噻嗪 methyclothiazide环戊噻嗪环戊噻嗪 cyclopenthiazide三氯噻嗪三氯噻嗪 trichlormethiazide37/70Pharmacological effects中等强度、温和、持久。中等强度、温和、持久
28、。尿中尿中Na+、C1-、K+、Mg2+、HCO3- 排出均增加。排出均增加。 减少尿崩症患者的尿量，改善口渴等症减少尿崩症患者的尿量，改善口渴等症状。机制不清。状。机制不清。降压作用稳定可靠。其降压机制包括血容量降压作用稳定可靠。其降压机制包括血容量降低和血管舒张作用。降低和血管舒张作用。 38/70NaCl reabsorption in distal convoluted tubule and mechanism of diuretic action of Na+-Cl- symport inhibitors. S, symporter; CH, ion channel. Numbers
29、 in parentheses indicate stoichiometry. BL and LM indicate basolateral and luminal membranes, respectively. 39/70Inexpensive Efficacious Well tolerated Once daily, do not require dose titration Few contraindicationsAdditive or synergistic effects with other classes of antihypertensive agents 优点多多！优点
30、多多！ cardiovascular morbidity and mortality40/7025毫克毫克100片片，3.00元元！1. 高血压高血压（Hypertension）目前仍作为一线抗高血压药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物类别之一，视病情，可单用或与其他抗高血压药物合用。合用。 Therapeutic Uses 41/70美国美国 JNC 8JAMA. 2014; 311(5):507-52042/70The current Guidelines reconfirm that diuretics (including ), beta-bloc
31、kers, 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):21592219欧洲最新指南再次肯定的一线抗高血压药物包欧洲最新指南再次肯定
32、的一线抗高血压药物包括：括：、受体阻受体阻滞剂、滞剂、钙拮抗剂、钙拮抗剂、ACE-I和和ARB。 2.2.水肿水肿( (Edema) ) associated with heart, liver, and renal disease.congestive heart failure hepatic cirrhosis nephrotic syndrome, chronic renal failure, acute glomerulonephritis 43/703包括肾性和垂体性尿崩症包括肾性和垂体性尿崩症 The mechanism of this paradoxical effect re
33、mains unknown. (Calcium nephrolithiasis) & osteoporosis reduce urinary excretion of Ca2+ ( (Br- intoxication) Since other halides are excreted by renal processes similar to those for Cl- 44/70 ( (hypokalemia, hypo-magnesemia, hypochloremia. 45 . thiazide diuretics and quinidine 46中效利尿药的药理作用、利尿效价与用法中
34、效利尿药的药理作用、利尿效价与用法药物药物作用特点作用特点用法（用法（mg/dmg/d）起效时间起效时间(h)峰值时间峰值时间(h)持续时间持续时间(h)利尿利尿效价效价利尿利尿降压降压氯噻嗪氯噻嗪0.12501000氢氯噻嗪氢氯噻嗪1234612125502550苄噻嗪苄噻嗪246121835020050200三氯噻嗪三氯噻嗪2618242514泊利噻嗪泊利噻嗪262428251424甲氯噻嗪甲氯噻嗪2624102.5102.55 47 (aldosterone antagonist) (eplerenone) 48托伐普坦托伐普坦(Tolvaptan)(non-peptide vasopr
35、ession V2-receptor antagonist)(自学自学 49Figure 28-8. Na+ reabsorption in late distal tubule and collecting duct and mechanism of diuretic action of epithelial Na+-channel inhibitors. Cl- reabsorption (not shown) occurs both paracellularly and transcellularly, and the precise mechanism of Cl- transport
36、 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. 51 1. 与
37、其他利尿药合用与其他利尿药合用 （利相加、弊相克）（利相加、弊相克）the diuretic and antihypertensive response to thiazide and loop diuretics thiazide and loop diuretics *李德尔李德尔(氏氏)综合征综合征:可能为常染色体显性遗传可能为常染色体显性遗传,由于肾小管异常由于肾小管异常,钠重吸收过强和钾排钠重吸收过强和钾排泄增多泄增多,导致肾素及醛固酮分泌受抑制。导致肾素及醛固酮分泌受抑制。52 Contraindicated in 53氨苯喋啶氨苯喋啶阿米洛利阿米洛利54(aldosterone
38、antagonist) (eplerenone) 55Effects of aldosterone on late distal tubule and collecting duct and diuretic mechanism of aldosterone antagonists AIP, aldosterone-induced proteins; ALDO, aldosterone; MR, mineralocorticoid receptor; CH, ion channel; activation of membrane-bound Na+channels; redistributio
39、n 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-chondrial production o
40、f ATP. BL and LM indicate basolateral and luminal membranes, respectively. Efficacy of MR antagonists is a function of endogenous levels of aldosterone. 57 58 59/70Adverse Effects 不良反应不良反应 60/7061/70The Structure of tolvaptan商品名商品名(Trade Name)：SamskaTMnon-peptide vasopression V2-receptor antagonist
41、(Tolvaptan)H2OH2OH2OH2O62/7063/70The use of SAMSCA for the treatment of clinically significant hypervolemic and euvolemic 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 Inap
42、propriate Antidiuretic Hormone (SIADH), heart failure and cirrhosis. mEq/L，或无明显低钠血症但有症状且限制，或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、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。心衰、肝硬化。64/70(osmotic demyelination syndrome, ODS)，可致昏迷和，可致昏迷和死亡。具认为死亡。具认为 与血钠水平升高过快有关。与血钠水平升高过快有关。包括致死性肝衰竭包括致死性肝衰竭托伐普坦疗程应不超过托伐普坦疗程应不超过3030天，随
43、时警惕与肝脏受损相天，随时警惕与肝脏受损相关的症状。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 signs and symptoms of liver problems. 四四.脱水药脱水药 65/70 “呆呆”在血管内在血管内 66/70 67/70 68/70 (with heart failure or pulmonary congestion ) 69/70Summary of the site and mechanism of action of diuretics V2 antagonist告告 示示为尽可能避开餐厅高峰，取消课间休息，为尽可能避开餐厅高峰，取消课间休息，连续授课连续授课90 min，11:40下课。请提前下课。请提前做好相应准备。做好相应准备。
