Diuretics and Dehydrant Agents

Jin WangJin WangInstitute of PharmacologyInstitute of Pharmacology

School of MedicineSchool of MedicineShandong UniversityShandong Universitywangj@sdu.edu.cnwangj@sdu.edu.cn

Section1 Diuretics

Definition

Diuretics are a family of drugs that act on kidney and promote the excretion of urine (including water and electrolyte).

(mainly used in edema)

The physiological basis of diuretics

ⅠExcretion function of kidney

ⅡUrinary physiology of kidney and the sites of diuretics

Excretion of inorganic ion

Excretion of organic ion

Excretion of water

ⅠExcretion function of kidney

ⅠExcretion function of kidney

1. Excretion of inorganic ion Convection Via ion channels Simple diffusion Facilitated diffusion Active transport (primary) Active transport (secondary) Symporter Antiporter

spacelumentubular cell

K+

2Cl-

Na+Na+

Cl-

K+K+

Ca2+

Mg2+

ATP

Na+-K+-2Cl- Symporter

Na+-K+

ATPase

Na+

K+

spacelumen

Cl-

Na+Na+

Cl-K+

ATP

Ca2+Na+

Ca2+

K+

K+

tubular cell

Na+-Cl- Symporter

Na+-K+

ATPase

HCO3-+H+

Na+

K+

Na+

ATP

H2O+CO

2

CO2+ H2O

H++ HCO3-

H2CO

3CA

CA

tubular celllumen space

Na+-H+ Antiporter

Na+-K+

ATPase

Excretion of inorganic ions

ⅠExcretion function of kidney

2. Excretion of organic ionSecondary active transport Anionic transport system Cationic transport system

Pay attention: competition

Excretion of organic ions

ⅠExcretion function of kidney

3. Excretion of waterWater channel – aquaporins (AQPs)

Noble prize in chemistry 2003

Peter Agre(1949-)

1988 protein1991 -cDNA2003 Nobel prize

AQP

Characteristics of AQPs

Water permeation: unique

Water follows passively

Driven by Na+-K+ ATPase

Filtration

Reabsorption

Secretion

Excretion

ⅡUrinary physiology of kidney and the sites of diuretics

原尿量

终尿量

Filtration of glomerular

blood

Tubule fluid

glomerular

tubulus

urine

Reabsorption of renal tubule and collecting tube

Proximal tubulesHenle’s loopDistal convoluted tubulesCollecting tubules

 

1. Proximal tubule

2. thick ascending limb of Henle’s loop

3. Distal tubule and collecting ducts

Proximal Tubule

Na+/ K+ ATPase: maintains gradient Na+ flows down via channel Na+_ H+ exchange: carbonic anhydrase (CA) AQP1/7: Water follows passively

65%~70% of Na+ and water reabsorption Cl- 、 Ca2+ 、 K+ 、 Mg2+ reabsorption

HCO3-+H+

Na+

K+

Na+

ATP

H2O+CO

2

CO2+ H2O

H++ HCO3-

H2CO

3CA

CA

tubular celllumen space

Proximal tubule

acetazolamide

Na+

Na+

TAL: thick ascending limb

1. No AQPs: impermeable to water

2. Transports Na+ by Na+ - K+ - 2Cl- symporter

25-35% of Na+ reabsorbed

Reabsorption of Ca2+ , Mg2+ and Cl-

spacelumen

tubular cell

K+

2Cl-

Na+Na+

Cl-

K+K+

Ca2+

Mg2+

ATP

Symporter

Thick ascending limb of Henle’s loop

Furosemide

K+

Cl-

Na+

NaHCO3NaClNaCl

K+

K+

Mg2+

H2O

2Cl-

Ca2+

Ca2+

(+PTH)

Na+NaCl醛固酮K+

H2O(+ADH)

H+K+

2Cl-

Na+皮质部

髓质部

近曲小管

髓袢

远曲小管 集合管

稀释

浓缩高

渗高

渗

Distal Convoluted Tubule

5~10% of Na+ reabsorbed (1) Na+-Cl- symporter

(2) Ca2+-channel (3) Na+-Ca2+ exchange : parathyroid hormone (PTH) (4) No AQPs: impermeable to water

spacelumen

Cl-

Na+Na+

Cl-K+

Thiazides

ATP

Ca2+Na+

Ca2+

K+

K+

Distal convoluted tubule

tubular cell

PTH

Collecting Duct

Water permeability: main site

Controlled by ADH

Via AQPs(2,3,4)

Driven by medulla osmotic gradient 2-5% of Na+ reabsorbed :

Via Na+ channels

Regulated by ADS

K+ secretion : major site

lumen space

ATP

R

ADHR

Na+

K+

H2O

Cl-

ADSADS-R

K+ -Na+exchange

principal cell

Na+

K+

Na+

K+

spironolactone

Triamterene

Amiloride

NaHCO3NaCl Na+

K+

K+

Mg2+

H2O

2Cl-

Ca2+

Ca2+

(+PTH)

Na+NaCl醛固酮K+

H2O(+ADH)

H+K+

2Cl-

Na+皮质部

髓质部

近曲小管

髓袢

远曲小管 集合管

稀释

浓缩高

渗高

渗

Cl-

Diuretics

Classification

Common used Diuretics

Classification of Diuretics

Ⅰ. Loop (high efficacy diuretics) diuretics

Ⅱ. Thiazide (moderate efficacy ) diuretics

Ⅲ. Potassium-sparing (low efficacy) diuretics

Ⅳ. Carbonic anhydrase inhibitors

Ⅴ. Osmotic diuretics (dehydrants)

Common used Diuretics

Ⅰ.loop diuretics (High efficacy diuretics)

Furosemide (呋塞米 ,

                          呋喃苯氨酸 ,速尿 )

Etacrynic acid (依他尼酸 ,利尿酸 )

Bumetanide (布美他尼 )

Torsemide ( 托拉塞米 )

Pharmacokinetics

1.Absorption 2.Distribution:PPBR>95% 3.Elimination:Anionic transport system

Pharmacological actions

1. Diuresis: fast and strong

Site of action: Thick ascending limb of henle’s loop

Mechanism: ↓ Na+- K+-2Cl- cotransporter

Result：  Na+, K+, 2Cl-, Mg2+, Ca2+ excretion↑

spacelumen

tubular cell

K+

2Cl-

Na+Na+

Cl-

K+K+

Ca2+

Mg2+

ATP

Symporter

Thick ascending limb of Henle’s loop

Furosemide

K+

Cl-

Na+

NaHCO3NaClNaCl

K+

K+

Mg2+

H2O

2Cl-

Ca2+

Ca2+

(+PTH)

Na+NaClADSK+

H2O(ADH)

H+K+

2Cl-

Na+皮质部

髓质部

近曲小管

髓袢

远曲小管 集合管

稀释

浓缩

高

渗高

渗Loop diuretics

肾的稀释功能肾的浓缩功能

高

渗

2. Vasodilation

Renal vessel dilation→renal blood flow↑

Vessel dilation → heart load ↓

Possible mechanism: ↑ PGE2 synthesis

Pharmacological actions

1. Acute pulmonary and cerebral edema2. Severe edema

Cautions3. Renal failure4. Hypercalcemia5. Overdose of some toxicants

Clinical uses

Adverse reactions

1. Electrolyte disorders hyponatremia, hypomagnesemia,

hypochloremia alkalosis, hypokalemia ※

CHF: ↑ digitalis intoxication Hepatic cirrhosis: hepatic coma

2. Ototoxicity: dose-related

Ethacrynic acid > Furosemide > Bumetanide

Pay attention!

Adverse reactions

3. Hyperuricemia

(1) reabsorption of uric acid ↑

(2)  secretion of uric acid ↓

4. GI reactions

5. Allergic reactions

Adverse reactions

Ⅱ. Thiazides(噻嗪类 ): (Moderate efficacy diuretics)

Hydrochlorothiazide

(氢氯噻嗪 ,双氢克尿噻  ,双克 )

Chlorothiazide (氯噻嗪 )

Chlortalidon (氯酞酮 )

Indapamide (吲哒帕胺，寿比山 )

中效利尿药

噻嗪类

短效类＜ 12h

氢氯噻嗪（ hydrochlorothiazide)氯噻嗪（ chlorothiazide)

中效类12~24h

苄噻嗪（ benzthiazide)氢氟噻嗪（ hydroflumethiazide)环噻嗪（ cyclothiazide)三氯噻嗪（ trichlorothiazide)

长效类＞ 24h

苄氟噻嗪（ bendrofluazide)甲氯噻嗪（ methychlorothiazide) 环戊噻嗪（ cyclopenthiazide)泊利噻嗪（ polythiazide)

非噻嗪类 氯噻酮（ Chlortralidone ）吲达帕胺（ Indapamide ）美托拉宗（ Metolazone ）喹乙宗（ Quinethazone ）

Classifications

1. Diuresis: moderate Site of action: early distal tubules

Mechanism: Na+-Cl- symporter inhibition CAI ( in large dose)

Results: Na+, K+, Cl- , Mg2+, HCO-3 excretion ↑

Ca2+ in urine ↓ (↑ Ca2+reabsorption in distal tubules)

Pharmacological actions

spacelumen

Cl-

Na+Na+

Cl-K+

Thiazides

ATP

Ca2+Na+

Ca2+

K+

K+

Distal convoluted tubule

tubular cell

-+

NaHCO3NaClNaCl

K+

K+

Mg2+

H2O

2Cl-

Ca2+

Ca2+

(PTH)

Na+NaClADSK+

H2O(ADH)

H+K+

2Cl-

Na+皮质部

髓质部

近曲小管

髓袢

远曲小管 集合管

稀释

浓缩

高

渗高

渗 高

渗

Thiazides

-+

2. Anti-insipidus effect Possible mechanisms

1) ↓ PDE (磷酸二酯酶）→  intracellular cAMP↑→ water permeability ↑ → water reabsorption ↑

2) excretion of NaCl↑ → plasma Osm ↓ → thirst ↓ → drinking↓ → urine↓

Pharmacological actions

Insipidus (尿崩症 )

尿崩症多是由于抗利尿激素缺乏、肾小管重吸收水的功能障碍，从而引起以多尿、烦渴、多饮与低比重尿为主要表现的一种疾病。本病是由于下丘脑—神经垂体部位的病变所致，但部分病例无明显病因，尿崩症可发生于任何年龄，但以青年为多见。

主要临床表现为多尿、烦渴与多饮，起病常较急。 24h 尿量可多达 5-10L ，但最多不超过 18L 。尿比重常在 1.005

以下，尿渗透压常为 50-200mOsm/kg H O ，尿色淡如清水。

3. Anti-hypertension effect Mechanisms

Early stage: diuretic effect→↓blood volume

Late stage: excretion of Na+↑→Na+-Ca2+

exchange→↓Ca2+ in smooth cell→ artery

tension↓

Pharmacological actions

1. Edema: major indication Mild and moderate cardiac edema:

first choice Renal edema

related to renal function Ascites due to cirrhosis:

combined with spironolactone

Clinical Uses

2. Insipidus

3. Hypertension: first-line drugs Hydrochlorothiazide, Indapamide

4. Idiopathic hypercalciuria

Clinical Uses

1.   Electrolyte disorders Hypokalemia Hypomagnesemia Hyponatremia

2.   Metabolic disorders Hyperglycemia Hyperlipidemia Hyperuricemia

3.   Allergic reaction  

Adverse reactions

Ⅲ. Potassium-sparing diuretics

Spironolactone (螺内酯 , 安体舒通 )

Triamterene (氨苯蝶啶 ) Amiloride (阿米洛利 )

distal tubules and collecting ducts

↑ Na+ excretion , K+ excretion↓

Site of action

lumen space

ATP

R

ADHR

Na+

K+

H2O

Cl-

ADSADS-R

K+ -Na+交换

Tubular cell

Na+

K+

Na+

K+

ADH-R

spironolactone

Triamterene

Amiloride

Antisterone : Spironolactone

Spironolactone aldosterone

O

O

CH3

CH3

SCOCH3O

CH

CH3

O

HO

OC

CH2OH

O

Aldosterone antagonist

Mechanism : competing with ADS

Na+-K+ exchange ↓

Characteristics:

1. Effects dependent on ADS

2. Potassium-sparing diuretics

3. weak, slow and long

Pharmacological effects

1. Edema with high activity of aldosternone:

eg. liver cirrhosis and nephritis syndrome

2. In combination with other diuretics: to

↑diuretic effect ； prevent K loss

3. congestive heart failure

diuretic effect ；（ - ） myocardial

fibrosis

Clinical uses

1. Hyperkalemia

2. Endocrine abnormality (impotence, gynecomastia, hirsutism)

3. GI reactions

4. CNS syndrome

Adverse reactions

Triamterene (氨苯喋啶 ) Amiloride (阿米洛利 )

Non-steroid in structure,

not aldosterone antagonists

Mechanism :

Block Na+ channel → ↓ Na+ reabsorb

→K+ secretion ↓

Clinical uses : intractable edema

Adverse reactions : Hyperkalemia , GI， megaloblastic anemia: Triamterene

Triamterene (氨苯喋啶 ) Amiloride (阿米洛利 )

Ⅳ Carbonic anhydrase inhibitor (CAI)

Acetazolamide ( 乙酰唑胺 )Effects: CAI → H+ and H+-Na+ exchange↓→ Na+, water

and HCO3- excretion↑→diuresis

CAI in ciliary epithelial cells/neurons

→aqueous humor/CSF formation ↓

→intraocular / Intracranial pressure ↓

HCO3-+H+

Na+

K+

Na+

ATP

H2O+CO

2

CO2+ H2O

H++ HCO3-

H2CO

3CA

CA

tubular celllumen space

Proximal tubule

acetazolamide

Clinical uses

1. Glaucoma

2. Acute mountain sickness

3. Alkalization urine

4. Treatment of metabolic alkalosis

Section2 Dehydrants

Common characteristics Poor penetration to capillaries membrane (i.v.) Filtrated by glomerulus easily Not be reabsorped by renal tubules Not be metabolized No toxicity and antigenicity

Mannitol (甘露醇 ) Sorbitol （山梨醇） Isosorbide （异山梨醇） Hypertonic glucose (高渗葡萄糖） Glycerin （甘油）

Common used dehydrants

Pharmacological actions 1. Dehydrant effect i.v.→plasma osmotic pressure↑→

pressure in extra fluid compartments↓ 2. Diuretic effect 1) glomerular infiltration ↑

2) tubular osmotic pressure ↑

Mannitol (甘露醇 , 20%)

1. Brain edema 2. Glaucoma 3. Prevent acute renal failure

Clinical Uses

Adverse reactions

Extracellular volume expansion

Cautions!

表 常用利尿药药代动力学比较 药 物

利尿作用

开始时间（ h） 峰值时间（ h） 维持时间（ h）

袢利尿药

呋塞米 口服 60 分静注 5 ～ 10分

1 ～ 2 15 ～ 20分

6 ～ 8 1 ～ 3

依他尼酸 口服 30 分静注 5 ～ 10分

1 ～ 2 15 ～ 20分

6 ～ 8 1 ～ 3

布美他尼 口服 30 分 静注 5 ～ 10分

1 ～ 2 15 ～ 20分

6 ～ 8 1 ～ 3

噻嗪类利尿药

氯噻嗪 2 4 6 ～ 12

氢氯噻嗪 2 4 6 ～ 12

氢氟噻嗪 1 ～ 2 3 ～ 4 18 ～ 24

苄氟噻嗪 1 ～ 2 6 ～ 12 18 ～ 24

环戊噻嗪 6 7 ～ 12 18 ～ 24

氯酞酮 2 6 48 ～ 72

留钾利尿药

螺内酯 24 48 ～ 72 72 ～ 96

氨苯蝶啶 2 ～ 4 6 7 ～ 9

阿米洛利 2 6 12 ～ 24

常用利尿药对电解质排泄及排钠力比较

尿电解质的排泄

药物 Na+ K+

Cl- HCO3 排钠力(%)

主要作 用部位

机 制

袢利尿剂 +++ + +++ 0 ～ 23 髓袢升支粗段髓质和皮质部

抑制 Na+ 、 K+ 、 2Cl-共同转运系统

噻嗪类 ++ + ++ + ～ 8 髓袢升支粗段皮质部(远曲小管开始部 )

抑制 NaCl再吸收

保钾利尿药 + - - 0 ～ 2 远曲小管、集合管 竞争 ADS-R(螺内酯 )

阻滞 Na+通道(氨苯蝶啶 /阿米洛利 )

乙酰唑胺 + + - +++ ～ 4 近曲小管 抑制碳酸酐酶

水肿时利尿药的选用及注意事项

在应用利尿药前要注意下列几点： ①对基本疾病作病因治疗； ②动员组织间水肿液或体腔中积液进入血液循环，便于利尿消肿。这就要求患者卧床休息并进行支持疗法等；

③用低盐饮食以减少体内Na+量； ④注意治疗失败的可能，如观察肾小球滤过率是否下降，醛固酮分泌是否继发性增多等。

水肿时利尿药的选用及注意事项

（ 1 ）心源性水肿：一般选用噻嗪类利尿药，宜加用钾盐；对中度水肿可用氢氯噻嗪加留钾利尿药；对一般利尿药无效的严重水肿，可合用高效利尿药和留钾利尿药，要定期检查血钾含量。

（ 2 ）肾性水肿：急性肾炎时，一般不用利尿药，必要时用氢氯噻嗪；肾病综合征时，对高度水肿者可用噻嗪类药物加留钾利尿药。效果不明显时可用高效利尿药加留钾利尿药。

（ 3 ）肝性水肿：肝性水肿多伴有继发性醛固酮增多症，一般宜先用留钾利尿药，或留钾利尿药加噻嗪类利尿药，如疗效不显著，可合用留钾及高效利尿药。

（ 4 ）急性肺水肿及脑水肿：静脉注射高效利尿药

Thank you