1. Diuretics Huifang Tang (汤慧芳) tanghuifang@zju.edu.cn
Dept. Pharmacology, Schoolof Medicine , Zhejiang University

2. The Kidney: Excretion of water, ions, and toxic metabolites;
Balance in electrolytes, water, and acid-base in the body.

3. Overview Excretion in the kidney Glomerular filtration
1. Solutes (溶质)
1) Ions (electrolytes)
2) Organic anions (weak acids) and organic cations (weak bases)
3) Other solutes
2. Water
Glomerular filtration
Tubule secretion and reabsorption

4. 65-70％ Na+
10％ Na+
25％ Na+
2~5％Na+
urine concentration

5. 1. Excretion of inorganic ion
1：对流扩散，溶于水中的离子借助于水流排出细胞外；2：简单扩散，为脂溶性物质进入细胞的方式；3：通道介导的扩散，离子通过蛋白构成的孔道（通道）顺电化学梯度进入细胞，通道开闭受电压、化学物质和机械力等的门控；4：载体介导的扩散，离子在载体蛋白的帮助下，顺膜内外电化学梯度进行转运；5：ATP介导的转运，以ATP水解提供能量，离子逆膜内外电化学梯度进行转运；6：同向转运，在主动转运一种离子的同时，带动另一种离子作同方向转运；7：反向转运，在主动转运一种离子的同时，带动另一种离子作反方向转运

6. 2. Excretion of organic ion
近曲小管有机酸和有机碱分泌
1：原发性主动转运；2：继发性主动转运；3：三次主动转运；A-：有机酸；C+：有机碱；KG2-：-酮戊二酸或其他二羧酸。

7. Proximal convoluted tubule (近曲小管)
ATP-结合盒转运体（ ATP-binding cassette transporter , ABC转运体）
12次跨膜结构 图
、 次跨膜结构
6 次跨膜结构
溶质载体类转运体（solute carrier, SLC）
有机阴离子转运体家族（organic anion transporter, OAT）
有机阳离子转运体家族（organic cation transporter, OCT）
寡肽转运体(oligopeptide transporter, PEPT)
核苷转运体（nucleoside transporter, NT ）

8. Water channels or aquaporins (AQPs)
3. Excretion of H2O
AQPs有通透水分子的特殊构型。例如，AQP1的N-和C-末端均在细胞内，由6个跨膜区和5个袢（A～E）组成， B和E袢有天冬酰胺-脯氨酸-丙氨酸（NPA）结构，该两个袢在细胞膜形成水孔道，形状类似于“砂漏（hourglass）”；四个AQP1分子组成四聚体结构，其中一个AQP1分子的细胞外部分有一个长的多糖链。
Water excretion
Water channels or aquaporins (AQPs)
AQP0～AQP12

10. Luminal space
or AQP4
ADH：
antidiuretic hormone， 抗利尿激素
ADH
AQP2减少：遗传性肾源性尿崩症、锂盐、低蛋白饮食、慢性肾衰竭、肾病综合征、肾缺血、顺铂、钙通道阻滞药等；
AQP2增加：血管加压素、充血性心力衰竭、肝硬化等。
or AQP4
Function and modulation of AQP2 and AQP3 Collecting tubule cells

11. 65-70％ Na+
10％ Na+
25％ Na+
2~5％Na+
urine concentration

12. Proximal convoluted tubule(近曲小管)
65-70% Na+ reabsorption
60 % H2O reabsorption
HCO3- resorption: carbonic anhydrase (CA，碳酸酐酶)
Organic acid secretory systems 有机酸分泌系统 :
Metabolites (uric acid),
drugs (most of cephalosporins, loop diurects, NSAIDs, most of the b-lactams, thiazide diuretics, most of the sulfonamides, Acetazolamide(乙酰唑胺)
Organic base secretory systems
有机碱分泌系统:
Metabolites (choline),
drugs (H2 receptor blocker, Amiloride(阿米洛利), ephedrine(麻黄碱), morphine, quinine )
CA inhibitor
Acetazolamide
乙酰唑胺 ㈠

13. Thick ascending limb of henle’s loop （髓袢升支粗段）
25% Na+ reabsorption
25% Ca+ reabsorption
50-60% Mg2+ reabsorption
Water is impermeable due to lack of AQP水通道蛋白
Loop diuretics
（袢利尿药） ㈠
袢利尿药影响各离子的重吸收。
Cation resorption阳离子重吸收

14. Distal convoluted tubule(远曲小管)
10% Na+ reabsorption
Water impermeable ㈠
parathyroid hormone
（PTH,甲状旁腺激素）
Thiazide diuretics
（噻嗪类利尿药）
进入细胞的钾离子和氯离子可通过各自的离子通道进入细胞间隙和血液 ⊕

15. Collecting tubule and duct（集合管）
2-5% Na+ reabsorption
Principal cells(主细胞) : the major sites of Na+, K+, and H2O transportation（Na+、Cl-重吸收，K+分泌）
Intercalated cells( 闰细胞) : the primary sites of proton secretion（H+分泌，少量K+重吸收）
Potassium-retaining diuretics
（保钾利尿药） ㈠
保钾利尿药：抗醛固酮或抑制钠通道

16. A diuretic is any substance influencing the rates of transport of Na+, K+, Cl-, HCO3- and urate, increases urine and solute excretion.

17. Thiazides K+ sparing diuretics Loop diuretics 65-70％ Na+ 10％ Na+

18. Classification of diuretics
1、Loop diuretics: high efficacy (high-ceiling) diuretics.
Affected sites: thick ascending tubule of Henle’s loop;
Effect: inhibiting Na+-K+-2Cl- co-transporter;
Classical drug: furosemide(呋塞米), etc.
2、Thiazide diuretics: moderate efficacy diuretics.
Affected sites: distal convoluted tubule;
Effect: inhibiting Na+-Cl- co-transporter;
Classical drug: hydrochlorothiazide(氢氯噻嗪), etc.
3、K+-sparing diuretics: low efficacy diuretics.
Affected sites: late distal tubule and collecting duct
Effect: inhibiting renal epithelial Na+ channels;
Classical drug: spironolactone(螺内酯), etc.
4、Carbonic anhydrase inhibitors( 碳酸酐酶抑制剂) :
acetazolamide (乙酰唑胺)
5、Osmotic diuretics(渗透性利尿药): mannitol (甘露醇)

19. 1、Loop diuretics (Na+-K+-2Cl- cotransporter inhibitors):
Furosemide (呋塞米) : most potent diuretic effects; K+ 
only used for severe patients

20. 1、Loop diuretics（袢利尿药）
Sulfonamide derivatives
磺酰胺类衍生物
phenoxyacetic acid derivatives
苯氧乙酸衍生物
依他尼酸
呋塞米
sulfonylurea derivatives 磺酰脲类衍生物
布美他尼
Torsemide 托拉塞米
The diuretic activity correlates with their secretion by the proximal tubule

21. Furosemide（呋塞米） 1. Pharmacological effects (1) Diuretic effects
Inhibiting the Na+-K+-2Cl- cotransporter (symport) of the luminal membrane in the thick portion of the ascending limb of the loop of Henle, and reducing the reabsorption of Na+, K+ and Cl-.
Most efficacious among the diuretic drugs, because the ascending limb accounts for the reabsorption of 25-30% of filtered NaCl and downstream sites are not able to compensate for this increased Na+ load.

22. Blocking kidney’s ability to concentrate urine by decreasing the hypertonic medullary interstitium.
Impairing kidney’s ability to dilute urine.
Also, increasing excretion of Ca2+, Mg2+, HCO3- by abolition of transepithelial potential difference.
(2) Vasodilatation
Renal vasodilatation: renal blood flow 
Dilating veins: cardiac preload 

23. 65-70％ Na+
10％ Na+
25％ Na+
Loop diuretics

24. 2. Clinical uses (1) Severe edema: ineffective with thiazides
(2) Acute pulmonary edema: heart failure
(3) Acute renal failure: combined with dopamine (多巴胺)
(4) Hypercalcemia
(5) Detoxication of toxins or drug overdose

25. 3. Adverse effects (1) Imbalance of water and electrolytes:
acute hypovolumia; hypokalemia; etc.
(2) Ototoxicity: hearing damage（听力损害）, contraindicated to combine with aminoglycoside antibiotics (氨基苷类抗生素)
(3) Other effects: GI reactions, hyperuricemia (尿酸增高), arrhythmias, RAAS activity , etc.

26. Other loop diuretic drugs
Bumetanide（布美他尼）： times more potent than furosemide, more reliable absorption (80% -95%), less ototoxicity.
Torasemide（托拉塞米）：stronger and longer actions， more reliable absorption (80%), less K+/Ca2+ waste.
Etacrynic acid（依他尼酸）：weaker actions and more severe adverse effects

27. 2、Thiazide diuretics (Na+-Cl- cotransporter inhibitors):
Hydroxychlorothiazide (氢氯噻嗪) :
moderate potent diuretic effects; K+ 
most widely used for CHF and hypertensive patients

28. Thiazides噻嗪类 非噻嗪类 Thiazide and thiazide-like diuretics 苄氟噻嗪 氯噻嗪 氢氯噻嗪
Indapamide 吲达帕胺
苄氟噻嗪
氯噻嗪
氢氯噻嗪
氢氟噻嗪
甲氯噻嗪
泊利噻嗪
三氯噻嗪
Chlortalidone氯噻酮
Metolazone美托拉宗

29. thiazides K+ sparing diuretics Loop diuretics 65-70％ Na+ 10％ Na+

30. Thiazide diuretic drugs
1. Pharmacological effects and clinical uses
(1) Diuretic effects
Acting on distal convoluted tubule, inhibiting Na+-Cl- cotransporter (symport)
Decreasing kidney’s ability to dilute urine
Increasing the excretion of Na+, Cl-, K+, Mg2+, HCO3-, but increasing the reabsorption of Ca2+ in distal convoluted tubule

31. Used in treatment of mild and moderate edema in cardiac and renal diseases, and hepatic diseases with cautions;
Used in treatment of hypercalciuria (高尿钙症) and calcium oxalate stones in urinary tract.
(2) Antihypertensive effects
blood volume 
spasm responsiveness of arterial smooth muscles 

32. (3) Diabetes insipidus (尿崩症）
Thiazides have the unique ability to produce a hyperosmolar urine, and can substitute for the antidiuretic hormone in the treatment of nephrogenic diabetes insipidus.
The urine volume of such individuals may drop from 11 L/day to 3 L/day when treated with the drug.

33. (1) Imbalance of eletrolytes
2. Adverse effects
(1) Imbalance of eletrolytes
hypokalemia hypomagnesemia
hyponatremia hypochloremia
cautions: dose individualization, K+ supplement
(2) Dysfunctio of metabolism
hyperglycemia hyperlipidemia
hyperuricemia
contraindicated in diabetes and gout (痛风) patients
(3) Hypersensitivity
bone marrow suppression, dermatitis, necrotizing vasculitis, interstitial nephritis, etc.

34. 3、Potassium-sparing diuretics
Antagonists of mineralocorticoid Receptors (aldosterone Antagonists）
Spironolactone 螺内酯
Inhibitors of renal epithelial Na+ channels
Triamterene 氨苯蝶啶
Amiloride 阿米洛利

35. K+ sparing diuretics: weaker diuretic effects; K+  Spironolactone
TriamtereneAmiloride
K+ sparing diuretics:
weaker diuretic effects; K+ 
used for the patients with increased aldosterone

36. Spironolactone 螺内酯
Spironolactone 螺内酯
Aldosterone 醛固酮

37. Spironolactone 螺内酯 1. Pharmacological effects 2. Clinical uses
Blocking aldosterone receptor
Decreasing Na+ reabsorption and K+ excretion
Weaker, slow acting（1d）, and lasting duration(2-4d)
2. Clinical uses
Edema with increased aldosterone levels
Combined with other diuretic drugs
3. Adverse effects
(1) Hyperkalemia
(2) Sex hormone-like effects
(3) GI reactions
(4) CNS reactions

38. Triamterene 氨苯蝶啶 Amiloride 阿米洛利

39. 1. Pharmacological effects
Triamterene 氨苯蝶啶
Amiloride 阿米洛利
1. Pharmacological effects
Blocking renal epithelial Na+ channels: decreasing Na+-K+ exchange
Fast acting（2h）, and lasting duration 16h-24h
2. Clinical uses
Similar to spironolactone
3. Adverse effects
Hyperkalemia, GI reactions, etc.

40. Relative changes in the composition of
urine induced by thiazide diuretics.
Relative changes in the composition
of urine induced by loop diuretics.
Relative changes in the composition
of urine induced by potassiumsparing
diuretics.

41. 4、Carbonic anhydrase inhibitor (碳酸酐酶抑制剂，sulfanilamides )
Acetazolamide 乙酰唑胺 dorzolamide brinzolamide
Pharmacokinetics: Acetazolamide is given orally once to four times daily. It is secreted by the proximal tubule.
Mechanism of action:
Acetazolamide inhibits carbonic anhydrase
located intracellularly (cytoplasm) and on the apical membrane of the proximal tubular epithelium.
Therapeutic uses:
Treatment of glaucoma: It is useful in the chronic treatment of glaucoma but should not be used for an acute attack.
Mountain sickness:
Adverse effects: Metabolic acidosis (mild), potassium depletion, renal stone formation, drowsiness, and paresthesia may occur. The drug should be avoided in patients with hepatic cirrhosis, because it could lead to a decreased excretion of NH4+.
Relative changes in the composition
of urine induced by acetazolamide.

43. 5、Osmotic diuretics Dehydrant agents甘油
异山梨醇
甘露醇 尿素

44. Mannitol 甘露醇
OH OH OH OH
OH OH

45. Dehydrant agents 1. Pharmacological effects 2. Clinical uses
(1) Dehydrant effects
(2) Diuretic effects (osmotic diuretic effects)
2. Clinical uses
(1) Brain edema
(2) Glaucoma
(3) Acute renal failure: prevention and early treatment

46. Dehydrant agents 3. Adverse effects
(1) Elevated extracellular osmolality: pulmonary edema, etc.
(2) Hyponatremia and dehydration: headache, nausea, vomiting, etc.
Contraindicated in anuric (无尿) duo to severe renal diseases, active cranial bleeding (颅内出血), heart failure

47. Dehydrant agents Other dehydrant drugs Sorbitol 山梨醇
Hypertonic glucose (50%) 高渗葡萄糖

49. 类 别
(主要作用部位)
其他分类名
作用机制
利尿应用
非利尿应用
碳酸酐酶抑制药（近曲小管） /
抑制碳酸酐酶
利尿药耐受的病人,与袢利尿药合用
青光眼，高山病，代谢性碱中毒
渗透性利尿药（髓袢及其他部位）
脱水药
增高尿液渗透压
急性肾功能衰竭
脑水肿，青光眼
袢利尿药（髓袢升支粗段）
1. 高效能利尿药
2. Na+-K+-2C1-同向转运体抑制药
抑制Na+-K+-2C1-同向转运
各种严重水肿，急性肾功能衰竭
高钙血症，加速毒物排出
噻嗪类利尿药（远曲小管）
1. 中效能利尿药
2. Na+-C1-同向转运体抑制药
抑制Na+-C1-同向转运
各种水肿
高血压，高尿钙症，尿崩症
保钾利尿药（集合管、末段远曲小管）
低效能利尿药
1. 拮抗醛固酮作用（螺内酯）
2. 抑制上皮细胞Na+通道（氨苯蝶啶，阿米洛利）
水肿（尤其对伴有醛固酮增高者，如肝硬化病人）
失钾和/或失镁

50. Thank you for attention!