Diuretics

Huifang Tang ( 汤慧芳 )tanghuifang@zju.edu.cn

Dept. Pharmacology, Schoolof Medicine , Zhejiang University

The Kidney:The Kidney:Excretion of water, ions,Excretion of water, ions, and toxic metabolites; and toxic metabolites;

Balance in electrolytes, Balance in electrolytes, water, and acid-base in twater, and acid-base in the body.he body.

EE xcretion in the kidneyxcretion in the kidney 1. Solutes (1. Solutes ( 溶质溶质 )) 1)1) IonsIons (electrolytes)(electrolytes) 2) Organic anions (weak acids) an2) Organic anions (weak acids) andd o organic cations (weak bases)rganic cations (weak bases) 3) Other solutes3) Other solutes 2. Water2. Water

Glomerular filtrationGlomerular filtrationTubule secretion and reabTubule secretion and reabsorptionsorption

OverviewOverview

65-7065-70 ％ ％ NaNa++

1010 ％ ％ NaNa++

2525 ％ ％ NaNa++

urine concentratio

n

2~52~5 ％％ NaNa++

11 ：对流扩散：对流扩散，溶于水中的离子借助于水流排出细胞外；，溶于水中的离子借助于水流排出细胞外； 22 ：简单扩散：简单扩散，为脂溶性物，为脂溶性物质进入细胞的方式；质进入细胞的方式； 33 ：通道介导的扩散：通道介导的扩散，离子通过蛋白构成的孔道（通道）顺电，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；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； 44 ：载体介导：载体介导的扩散的扩散，离子在载体蛋白的帮助下，顺膜内外电化学梯度进行转运；，离子在载体蛋白的帮助下，顺膜内外电化学梯度进行转运； 55 ：： ATPATP 介导介导的转运的转运，以，以 ATPATP 水解提供能量，离子逆膜内外电化学梯度进行转运；水解提供能量，离子逆膜内外电化学梯度进行转运； 66 ：同向转运：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；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； 77 ：反向转运：反向转运，在主，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动转运一种离子的同时，带动另一种离子作反方向转运

1. Excretion of inorganic ion

近曲小管有机酸和有机碱分泌近曲小管有机酸和有机碱分泌11 ：原发性主动转运；：原发性主动转运； 22 ：继发性主动转运；：继发性主动转运； 33 ：三次主动转运；：三次主动转运； AA-- ：有：有机酸；机酸； CC++ ：有机碱；：有机碱； KGKG2-2- ：： -- 酮戊二酸或其他二羧酸。酮戊二酸或其他二羧酸。

2. Excretion of organic ion

Proximal convoluted tubule ( 近曲小管 )

ATP-ATP- 结合盒转运体（ 结合盒转运体（ ATP-binding cassette transporter , ABCATP-binding cassette transporter , ABC 转运体）转运体）

1212 次跨膜结构次跨膜结构

图 图 、 、 1717 次跨膜结构次跨膜结构

1212 次跨膜结构次跨膜结构

6 6 次跨膜结构次跨膜结构

溶质载体类转运体（溶质载体类转运体（ solute carrier, SLCsolute carrier, SLC ））• 有机阴离子转运体家族（有机阴离子转运体家族（ organic anion transporter, OATorganic anion transporter, OAT ））• 有机阳离子转运体家族（有机阳离子转运体家族（ organic cation transporter, OCTorganic cation transporter, OCT ））•寡肽转运体寡肽转运体 (oligopeptide transporter, PEPT)(oligopeptide transporter, PEPT)

•核苷转运体（核苷转运体（ nucleoside transporter, NT nucleoside transporter, NT ））

AQPsAQPs 有通透水分子的特殊构有通透水分子的特殊构型。例如，型。例如， AQP1AQP1 的的 N-N- 和和 C-C-末端均在细胞内，由末端均在细胞内，由 66 个跨膜个跨膜区和区和 55 个袢（个袢（ AA ～～ EE ）组成， ）组成， BB 和和 EE 袢有天冬酰胺袢有天冬酰胺 -- 脯氨酸脯氨酸 --丙氨酸（丙氨酸（ NPANPA ）结构，该两个）结构，该两个袢在细胞膜形成水孔道，形状袢在细胞膜形成水孔道，形状类似于“砂漏（类似于“砂漏（ hourglasshourglass ）”；）”；四个四个 AQP1AQP1 分子组成四聚体结分子组成四聚体结构，其中一个构，其中一个 AQP1AQP1 分子的细分子的细胞外部分有一个长的多糖链。胞外部分有一个长的多糖链。

Water excretionWater excretionWater channels or aquaporins (AQPs) Water channels or aquaporins (AQPs)

AQP0AQP0 ～～ AQP12AQP12

3. Excretion of H2O

Function and modulation of AQP2 and AQP3 Function and modulation of AQP2 and AQP3 Collecting tubule cells cells

ADHADH

Luminal spaceLuminal spaceor AQP4

or AQP4

ADHADH ：：antidiuretiantidiuretic hormonec hormone ，， 抗利尿激素抗利尿激素

65-7065-70 ％ ％ NaNa++

1010 ％ ％ NaNa++

2525 ％ ％ NaNa++

urine concentratio

n

2~52~5 ％％ NaNa++

Proximal convoluted tubule( 近曲小管 )

65-70% Na+ reabsorptionreabsorption60 % H2O reabsorptionreabsorption

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,

AmilorideAmiloride(( 阿米洛利阿米洛利 ), ephedrine(), ephedrine( 麻黄麻黄碱碱 ), ), morphine, quinine )

CA inhibitorAcetazolamide乙酰唑胺

㈠

Thick ascending limb of henle’s loop（髓袢升支粗段）

25% Na+ reabsorptionreabsorption25% C25% Ca+ reabsorptionreabsorption50-60% Mg2+ reabsorptionreabsorptionWater is impermeable due

to lack of AQP 水通道蛋白

Loop diuretics（袢利尿药）

㈠

Cation resorption 阳离子重吸收

13

Distal convoluted tubule( 远曲小管 )10% Na+ reabsorptionreabsorptionWater impermeable

Thiazide diuretics

（噻嗪类利尿药）

parathyroid hormone（ PTH, 甲状旁腺激素）

⊕

㈠

14

Collecting tubule and duct （集合管）

2-5% Na+ reabsorptionreabsorption 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

A diuretic is any substance influeA diuretic is any substance influencing the rates of transport of Nncing the rates of transport of Naa++, K, K++, Cl, Cl--, HCO, HCO33

- - and urate, increaand urate, increases urine and solute excretion. ses urine and solute excretion.

ThiazidesThiazides

Loop diureticsLoop diuretics

KK++ sparing sparing diureticsdiuretics

65-7065-70 ％ ％ NaNa++

1010 ％ ％ NaNa++

2525 ％ ％ NaNa++

Classification of diuretics1 、 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 )

11 、、 Loop diuretics (Loop diuretics (NaNa++-K-K++-2Cl-2Cl-- cotransporter inhibitors cotransporter inhibitors): ): Furosemide (Furosemide ( 呋塞米呋塞米 ) : ) : most potent diuretic effects; most potent diuretic effects; KK++

only used for severe patientsonly used for severe patients

Sulfonamide derivatives磺酰胺类衍生物

phenoxyacetic acid derivatives苯氧乙酸衍生物

The diuretic activity correlates with their secretion by the proximal tubule

1 、 Loop diuretics （袢利尿药）

呋塞米呋塞米

布美他尼布美他尼

依他尼酸依他尼酸sulfonylurea derivatives 磺酰脲类衍生物

Torsemide 托拉塞米托拉塞米

FurosemideFurosemide （呋塞米）（呋塞米）1. Pharmacological effects1. Pharmacological effects

(1) Diuretic effects(1) Diuretic effectsInhibiting the Na+-K+-2Cl- cotransporter (symport) of the lu

minal 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.

Blocking kidney’s ability Blocking kidney’s ability to concentrateto concentrate uriurine ne by decreasing the hypertonic medullary interstitby decreasing the hypertonic medullary interstitium.ium.

Impairing kidney’s ability Impairing kidney’s ability to dilute urineto dilute urine..

Also,Also, increasing excretion of Caincreasing excretion of Ca2+2+, Mg, Mg2+2+, HCO, HCO33--

by abolition of transepithelial potential diffeby abolition of transepithelial potential difference.rence.

(2) Vasodilatation(2) Vasodilatation

Renal vasodilatation: renal blood flow Renal vasodilatation: renal blood flow Dilating veins: cardiac preload Dilating veins: cardiac preload

Loop diureticsLoop diuretics

65-7065-70 ％ ％ NaNa++

1010 ％ ％ NaNa++

2525 ％ ％ NaNa++

2. 2. Clinical usesClinical uses(1) Severe edema:(1) Severe edema: ineffective with thiazidesineffective with thiazides

(2) Acute pulmonary edema:(2) Acute pulmonary edema: heart failureheart failure

(3) Acute renal failure:(3) Acute renal failure: combined with dopamine combined with dopamine (( 多巴胺多巴胺 ))

(4) Hypercalcemia(4) Hypercalcemia

(5) Detoxication of toxins or drug overdose(5) Detoxication of toxins or drug overdose

3. Adverse effects3. Adverse effects

(1) Imbalance of water and electrolytes:(1) Imbalance of water and electrolytes: acute hypovolumia; hypokalemia; acute hypovolumia; hypokalemia; etc.etc.

(2) Ototoxicity:(2) Ototoxicity: hearing damagehearing damage （听力损害）（听力损害） ,, contraindicated to combine with aminoglycontraindicated to combine with aminoglycoside antibiotics (coside antibiotics ( 氨基苷类抗生素氨基苷类抗生素 ))

(3) Other effects:(3) Other effects: GI reactions, hyperuricemia GI reactions, hyperuricemia (( 尿酸增高尿酸增高 ), arrhythmias, RAAS activity ), arrhythmias, RAAS activity , , etc.etc.

Other loop diuretic drugsOther loop diuretic drugs BumetanideBumetanide （（布美他尼）布美他尼）：： 40-60 times

more potent than furosemide, more reliable absorption (80% -95%), less ototoxicity.

TorasemideTorasemide （（托拉塞米）托拉塞米）：： stronger and longstronger and longer actionser actions ，， more reliable absorption (80%), less K+/Ca2+ waste.

Etacrynic acidEtacrynic acid （（依他尼酸）依他尼酸）：： weaker actions weaker actions and more severe adverse effectsand more severe adverse effects

22 、、 Thiazide diuretics (Thiazide diuretics (NaNa++-Cl-Cl-- cotransporter inhibitor cotransporter inhibitorss): ): Hydroxychlorothiazide (Hydroxychlorothiazide ( 氢氯噻嗪氢氯噻嗪 ) : ) :

moderate potent diuretic effects; moderate potent diuretic effects; KK++

most widely used for CHF and hypertensive patientsmost widely used for CHF and hypertensive patients

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

Thiazides 噻嗪类 非噻嗪类

28

Indapamide 吲达帕胺

Chlortalidone 氯噻酮

Metolazone 美托拉宗

Thiazide and thiazide-like diuretics

Loop diureticsLoop diuretics

KK++ sparing sparing diureticsdiuretics

65-7065-70 ％ ％ NaNa++

1010 ％ ％ NaNa++

2525 ％ ％ NaNa++

thiazides thiazides

Thiazide diuretic drugs

1.1. Pharmacological effects and clinical uses Pharmacological effects and clinical uses

(1) Diuretic effects(1) Diuretic effects

Acting onActing on distal convoluted tubule, distal convoluted tubule, inhibiting Nainhibiting Na++--ClCl- - cotransporter (symport)cotransporter (symport)

Decreasing kidney’s ability Decreasing kidney’s ability to dilute urineto dilute urine Increasing the excretion of NaIncreasing the excretion of Na++, Cl, Cl--, K, K++, Mg, Mg2+2+, HCO, HCO33

--, , but increasing the reabsorption of Cabut increasing the reabsorption of Ca2+2+ in distal co in distal convoluted tubulenvoluted tubule

Used in treatment of Used in treatment of mild and moderate edemild and moderate edemama in cardiac and renal diseases, and in cardiac and renal diseases, and hepatic hepatic diseases with cautionsdiseases with cautions;;

Used in treatment of Used in treatment of hypercalciuria (hypercalciuria ( 高尿钙高尿钙症症 )) and calcium oxalate stones in urinary trac and calcium oxalate stones in urinary tract.t.

(2) Antihypertensive effects(2) Antihypertensive effects blood volume blood volume spasm responsiveness of arterial smooth spasm responsiveness of arterial smooth

muscles muscles

(3) Diabetes insipidus ((3) Diabetes insipidus ( 尿崩症尿崩症）） Thiazides have the unique ability to produce Thiazides have the unique ability to produce

a hyperosmolar urine, and can substitute for a hyperosmolar urine, and can substitute for the the antidiuretic hormoneantidiuretic hormone in the treatment of in the treatment of nephrogenic diabetes insipidus.nephrogenic diabetes insipidus.

The urine volume of such individuals may droThe urine volume of such individuals may drop from 11 L/day to 3 L/day when treated with p from 11 L/day to 3 L/day when treated with the drug.the drug.

2. 2. Adverse effectsAdverse effects(1) Imbalance of eletrolytes(1) Imbalance of eletrolytes hypokalemia hypomagnesemiahypokalemia hypomagnesemia hyponatremia hypochloremiahyponatremia hypochloremia cautions:cautions: dose individualization, K dose individualization, K++ supplement supplement(2) Dysfunctio of metabolism(2) Dysfunctio of metabolism hyperglycemiahyperglycemia hyperlipidemia hyperlipidemia hyperuricemiahyperuricemia contraindicatedcontraindicated in diabetes and gout ( in diabetes and gout ( 痛风痛风 ) patients) patients(3) Hypersensitivity(3) Hypersensitivity bone marrow suppression, dermatitis, necrotizing vascbone marrow suppression, dermatitis, necrotizing vasc

ulitis, interstitial nephritis, ulitis, interstitial nephritis, etc.etc.

33 、、 Potassium-sparing diuretPotassium-sparing diureticsics

Antagonists of mineralocorticoid Receptors (aldosterone Antagonists ） SpironolactoneSpironolactone 螺内酯螺内酯

Inhibitors of renal epithelial Na+ channels TriamtereneTriamterene 氨苯蝶啶氨苯蝶啶 AmilorideAmiloride 阿米洛利阿米洛利

SpironolactonSpironolactonee

TriamterenTriamtereneAmilorideeAmiloride

KK++ sparing diuretics: sparing diuretics: weaker diuretic effects; weaker diuretic effects; KK++

used for the patients with increased aldosteroneused for the patients with increased aldosterone

Spironolactone Spironolactone 螺内酯螺内酯

Spironolactone Spironolactone 螺内酯螺内酯 Aldosterone Aldosterone 醛固酮醛固酮

Spironolactone Spironolactone 螺内酯螺内酯1. 1. Pharmacological effectsPharmacological effectsBlocking aldosterone receptorBlocking aldosterone receptorDecreasing NaDecreasing Na++ reabsorption and K reabsorption and K++ excretion excretion Weaker, slow actingWeaker, slow acting （（ 1d1d ）） , and lasting , and lasting

durationduration(2-4d)(2-4d)

2.2. Clinical uses Clinical usesEdema with increased aldosterone levelsEdema with increased aldosterone levelsCombined with other diuretic drugsCombined with other diuretic drugs3. Adverse effects3. Adverse effects(1) (1) HyperkalemiaHyperkalemia(2) Sex hormone-like effects(2) Sex hormone-like effects(3) GI reactions(3) GI reactions(4) CNS reactions(4) CNS reactions

Triamterene Triamterene 氨苯蝶啶氨苯蝶啶

AmilorideAmiloride 阿米洛利阿米洛利

triamterenetriamterene 氨苯蝶氨苯蝶啶啶

amilorideamiloride 阿米洛利阿米洛利

TriamtereneTriamterene 氨苯蝶啶氨苯蝶啶 AmilorideAmiloride 阿米洛利阿米洛利1. 1. Pharmacological effectsPharmacological effectsBlocking renal epithelial NaBlocking renal epithelial Na++ channels: channels: decredecre

asing Naasing Na++-K-K++ exchange exchangeFast Fast actingacting （（ 2h2h ）） , and lasting duration , and lasting duration 16h-24h16h-24h

2. Clinical uses2. Clinical usesSimilar to spironolactoneSimilar to spironolactone3. Adverse effects3. Adverse effectsHyperkalemia, GI reactions, Hyperkalemia, GI reactions, etc.etc.

Relative changes in the compositionof urine induced by potassiumsparingdiuretics.

Relative changes in the compositionof urine induced by loop diuretics.

Relative changes in the composition ofurine induced by thiazide diuretics.

4 、 Carbonic anhydrase inhibitor( 碳酸酐酶抑制剂， sulfanilamides )

Acetazolamide 乙酰唑胺 dorzolamide brinzolamide

Relative changes in the compositionof urine induced by acetazolamide.

Pharmacokinetics: Acetazolamide is given orally once to four times daily. It is secreted by the proximal tubule.Mechanism of action: Acetazolamide inhibits carbonic anhydraselocated intracellularly (cytoplasm) and on the apical membrane of the proximal tubular epithelium. Therapeutic uses:a.Treatment of glaucoma: It is useful in the chronic treatment of glaucoma but should not be used for an acute attack. b.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+.

55 、、 Osmotic diureticsOsmotic diuretics DehDehydrant agentsydrant agents

甘油甘油

异山梨醇异山梨醇

尿素尿素

甘露醇甘露醇

MannitolMannitol 甘露醇甘露醇

OH OH OH OHOH OH OH OH

OH OHOH OH

Dehydrant agentsDehydrant agents

1. 1. Pharmacological effectsPharmacological effects(1) Dehydrant effects(1) Dehydrant effects(2) Diuretic effects(2) Diuretic effects (osmotic diuretic effects) (osmotic diuretic effects)

2. 2. Clinical usesClinical uses(1) Brain edema(1) Brain edema(2) Glaucoma(2) Glaucoma(3) Acute renal failure:(3) Acute renal failure: prevention and early treatprevention and early treat

mentment

Dehydrant agents 3.3. Adverse effects Adverse effects(1) Elevated extracellular osmolality:(1) Elevated extracellular osmolality: pulmonapulmona

ry edema, ry edema, etc.etc.(2) Hyponatremia and dehydration:(2) Hyponatremia and dehydration: headache, headache,

nausea, vomiting, nausea, vomiting, etc.etc.

Contraindicated Contraindicated inin anuric (anuric ( 无尿无尿 ) duo to sever) duo to severe renal diseases, active cranial bleeding (e renal diseases, active cranial bleeding ( 颅颅内出血内出血 ), heart failure), heart failure

Dehydrant agents Dehydrant agents Other dehydrant drugsOther dehydrant drugs

SorbitolSorbitol 山梨醇山梨醇

Hypertonic glucose (Hypertonic glucose (50%50%)) 高渗葡萄糖高渗葡萄糖

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

Thank you for attention!Thank you for attention!