Diuretics （利尿药）

Shi-Hong Zhang（张世红）shzhang713@zju.edu.cnDept. Pharmacology, School of Medicine, Zhejiang University

DefinitionDiuretics are drugs that can promote the

production of urine and sodium excretion (natriureesis).

Sodium excretion is usually accompanied with the excretion of other cations, as well as anions.

2

25 ％ Na+

尿液的浓缩与稀释

2~5 ％ Na+

10 ％ Na+

3

H2O

Ca2+, K+, Mg2+

65-70 ％ Na+

urine concentration

Dilute urine

urine concentration

Proximal convoluted tubule 近曲小管

HCO3- resorption: carbonic

anhydrase (CA，碳酸酐酶 )

Organic acid secretory systems

有机酸分泌系统 are located in the

middle third of the proximal

tubule: uric acid, NSAIDs,

diuretics, antibiotics.

Organic base secretory systems

有机碱分泌系统 : creatinine 肌酐 ,

choline 胆碱 , etc

CA inhibitorAcetazolamide乙酰唑胺

㈠

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Thick ascending limb of loop of Henle 髓袢

25% of the filtered sodium

Water 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

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Distal convoluted tubule 远曲小管

10% of the filtered NaCl

Water impermeable

Thiazide diuretics

（噻嗪类利尿药）

parathyroid hormone（ PTH, 甲状旁腺激素）

⊕

㈠

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Collecting tubule 集合管

2-5% of NaCl reabsorbed Principal cells 主细胞 are the

major sites of Na+, K+, and H2O

transportation （ Na+ 、 Cl-重吸收， K+分泌）

Intercalated cells 闰细胞 are

the primary sites of proton

secretion （ H+分泌，少量 K+

重吸收）

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Potassium-retaining diuretics

（保钾利尿药）

㈠

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肾小管转运系统及利尿药、脱水药作用部位 8

及钠通道阻断剂

Classification of diureticsLoop diuretics: high-ceiling diuretics (high efficacy), act at thick

ascending limb of Henle loop, inhibit Na+-K+-2Cl-

symporter: furosemide (呋塞米 )

Thiazide diuretics: moderate efficacy, act at distal convoluted tubule, inhibit Na+-Cl- symporter: hydrochlorothiazide (氢氯噻嗪 )

K+-retaining (sparing) diuretics: low efficacy, act at late distal tubule and collecting duct, inhibit renal epithelial Na+ channels or aldosteron: spironolactone (螺内酯 )

Carbonic anhydrase inhibitors: acetazolamide (乙酰唑胺 )碳酸酐酶抑制剂

Osmotic diuretics渗透性利尿药 : mannitol (甘露醇 )

袢利尿药

噻嗪类利尿药

保钾利尿药

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常用利尿药对电解质排泄及排钠力的比较

药物尿电解质排泄

主要作用部位 机制Na+ K+ Cl- HCO3

-

高效利尿药

+++ + ++++ ±髓袢升支粗段髓质和皮质部

抑制 Na+ -K+-2Cl-

共同转运系统

中效利尿药

++ + ++ + 远曲小管近段 抑制 Na+ -Cl- 共同转运系统

低效利尿药

+ - + 0远曲小管远段

和集合管对抗醛固酮，阻

滞 Na+ 通道

乙酰唑胺

+ ++ 0 +++ 近曲小管 抑制胞内 H+ 形成，抑制 H+ -Na+ 交换

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㈠

Carbonic anhydrase inhibitors碳酸酐酶抑制剂

Acetazolamide乙酰唑胺

Basic Pharmacology of Diuretics

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• Pharmacological effects: Inhibits bicarbonate (HCO3-)

reabsorption (excretion rises to 35% of filtered load);

HCO3- depletion leads to enhanced (compensatory) NaCl

reabsorption by the remainder of the nephron 肾单位 .

Acetazolamide 乙酰唑胺

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Acetazolamide 乙酰唑胺

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• Clinical use: open angle glaucoma, metabolic

alkalosis 代谢性碱中毒 , prevention of acute mountain

sickness (pulmonary, cerebral edema), urinary

alkalinization 碱化尿液 , short-term add-on therapy of

edema.

Adverse effects:

•Sulfonamide toxicity: allergic reaction, marrow

depression, skin toxicity, renal toxicity

•Significant bicarbonate loss and hyperchloremic

metabolic acidosis 高氯性代谢性酸中毒

•Renal stones (Ca salts deposits)

•Renal potassium wasting (K+ excretion ↑ in collecting

tubule)

•Drowsiness 困倦 and paresthesias 感觉异常•Rapid development of tolerance

Acetazolamide 乙酰唑胺

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sulfonamide derivatives磺胺类衍生物

phenoxyacetic acid derivatives苯氧乙酸衍生物

The diuretic activity correlates with their secretion by the proximal tubule

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

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sulfonylurea derivatives  磺酰尿类衍生物

Torsemide 托拉塞米托拉塞米

Loop diuretics

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Furosemide 呋塞米

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Pharmacodynamics

(1) Diuretic effectsa) Inhibits the Na+-K+-2Cl- symporter of the luminal

membrane in the thick portion of the ascending limb of the loop of Henle, and reduces the reabsorption of Na+, K+ and Cl-.

b) Increases excretion of Ca2+, Mg2+ by abolition of transepithelial potential difference 跨膜电位差 .

Furosemide

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(1) Diuretic effects

c)Blocks kidney’s ability to concentrate urine, impairs

kidney’s ability to excrete a dilute urine by decreasing

the hypertonic medullary interstitium 髓质部高渗 .

d)Most efficacious among the diuretics, 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.

Furosemide

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(2) Vasodilatation (induced-synthesis of renal prostaglandin)

Renal vasodilatation: renal blood flow Dilates veins: cardiac preload , pulmonary

edema

Furosemide

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Clinical Indications:

(1) Severe edema: not the first choice for chronic edema

following cardiac, hepatic or renal diseases, used for those that

are intractable by thiazides (噻嗪类利尿药 ).

(2) Acute pulmonary edema: left heart failure

(3) Prevention of acute renal failure: in the early stage,

increases the rate of urine flow and enhance K+ excretion, but

do not ameliorates renal failure.

(4) Hypercalcemia高钙血症(5) Detoxication解毒 of toxins or drug overdose: mild

hyperkalemia高钾血症 ; anion overdose: bromide (Br-), fluoride

(F-), and iodide (I-).

Furosemide

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Adverse effects and toxicity

(1) Water-electrolyte imbalance: dehydration 脱水、

hypokalemia 低钾血症、 hypomagnesemia 低镁血症、

hyponatremia 低钠血症、 hyperchloremic metabolic

alkalosis 低氯性代谢性碱中毒， can be reversed by K+

replacement (combined with Mg2+) and correction of

hypovolemia血容量过低 .

Furosemide

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Adverse effects and toxicity

(2) Ototoxicity 耳毒性 : tinnitus, vertigo, hearing damage,

contraindicated to combine with aminoglycoside

antibiotics 氨基糖苷类抗生素 or the patients who have

diminished renal function.

(3) Hyperuricemia 高尿酸血症 : caused by competitive

excretion竞争性分泌 with uric acid and enhancement of uric

acid reabsorption in the proximal tubule.

Furosemide

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Adverse effects and toxicity

(5) Allergic reactions: Skin rash, eosinophilia 嗜酸粒细胞增多症 and, less often, interstitial nephritis 间质性肾炎

(6) Other effects: RAAS activity , postdiuretic Na+

retention, arrhythmias (hypokalemia), hyperglycemia,

increase in LDL cholesterol, etc.

Note: Consumption of NSAIDs is a major cause of

apparent diuretic resistance.

Furosemide

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Other loop diuretic drugs

Bumetanide 布美他尼： 40-50 times more potent than furosemide, more reliable absorption (80% vs 10-90%), less ototoxicity.

Torasemide 托拉塞米： stronger and longer action, more reliable absorption (80%), less K+/Ca2+ waste.

Etacrynic acid 依他尼酸： weaker action with more severe adverse effects, less allergic reaction.

Loop diuretics 袢利尿药

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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

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Indapamide 吲达帕胺

Chlortalidone 氯噻酮

Metolazone 美托拉宗

Thiazides

• Come from the effort to synthesize more potent carbonic

anhydrase inhibitors碳酸酐酶抑制剂 . Some retain

significant carbonic anhydrase inhibitory activity.

• The prototypical thiazide is hydrochlorothiazide 氢氯噻嗪 .

• All can be administered orally, chlorothiazide is the only

thiazide available for parenteral胃肠外 administration.

• All are secreted by the organic acid secretory system in the

proximal tubule, and compete with the secretion of uric acid.

• Are classified into short-, medium-, and long-acting thiazides

according to action duration (<12h, 12-24h, >24h). 26

1. Pharmacodynamics

(1) Diuretic effects

Act on distal convoluted tubule, inhibit Na+-Cl- symporter, decrease kidney’s ability to dilute urine

Increase the excretion of Na+, Cl-, K+, Mg2+, HCO3-, but

increase the reabsorption of Ca2+ in distal convoluted tubule

The diuretic action of thiazides depends in part on renal prostaglandin production like loop diuretics.

Thiazides

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Thiazide diuretics

（噻嗪类利尿药）

parathyroid hormone（甲状旁腺激素）

⊕

㈠

Thiazides

⊕

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3. Clinical indications:

(1) Antihypertensive effects

Blood volume , spasm responsiveness of arterial smooth

muscles

(2) Edema:

Used in treatment of mild and moderate edema in cardiac

and renal diseases, and hepatic diseases with cautions

(risk of hypokalemia); Restriction of Na+ intake should be

attempted at the same time.

(3) Nephrolithiasis 肾结石 due to idiopathic hypercalciuria

( 特发性高尿钙症 ): Increase Ca2+ reabsorption.

Thiazides

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(4) Nephrogenic diabetes insipidus ( 尿崩症）Mechanisms remain unknown, may relate to the

ability to produce a hyperosmolar urine.

Can substitute for the antidiuretic hormone (ADH) 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 thiazides.

Thiazides

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4. Adverse effects(1) Imbalance of electrolytes hypokalemia hypomagnesemia

hyponatremia hypochloremia

cautions: dose individualization, K+ supplementation

(2) Dysfunction of metabolism hyperglycemia hyperlipidemia

hyperuricemia

contraindicated in patients with diabetes and gout (痛风 )

Thiazides

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4. Adverse effects

(3) Hypersensitivity Bone marrow suppression, necrotizing vasculitis坏死性血管

炎 , interstitial nephritis间质性肾炎 , etc.

Photosensitivity or generalized dermatitis皮炎

(4) Others Weakness, fatigability易疲劳 , and paresthesias感觉异常

Thiazides

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(1) Antagonize aldosterone 拮抗醛固酮 at the late distal tubule and cortical collecting tubule

Spironolactone 螺内酯，安体舒通 Eplerenone 依普利酮(2) Inhibit Na+ influx in the luminal membrane

Triamterene 氨苯喋啶 Amiloride 阿米洛利

Potassium-sparing diuretics

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^

Potassiu-retaining diuretics

（保钾利尿药）

㈠

Potassium-sparing diuretics

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Spironolactone (antisterone)A synthetic steroidBlocks aldosterone receptorsDecreases Na+ reabsorption and K+ excretion

Weak, slow-acting, and lasting duration

Eplerenone, a new spironolactone analog with greater selectivity for aldosterone receptors.

Potassium-sparing diuretics

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Action of spironolactone:

Blocks the effects of aldosterone

AIP: aldosterone induced protein

1. Activation of Na+ membrane-bound channels

2. Redistribute (3)3. De novo synthesis of (3)4. Activation of membrane-

bound Na+/K+ ATPase5. Redistribution of (4)6. De novo synthesis of (4)7. Changes in permeability of

tight junctions8. Increased mitochondrial

production of ATP36

Triamterene 氨苯喋啶Amiloride 阿米洛利Amiloride is excreted unchanged in the urine.

Triamterene is metabolized in the liver and excreted from kidney, has a shorter half-life and must be given more frequently than amiloride.

Both induce blue fluorescent urine.

Block renal epithelial Na+ channels: decreases Na+-K+ exchange

Potassium-sparing diuretics

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Clinical Indications: Mineralocorticoid 盐皮质激素 excess:

Primary hypersecretion (Conn's syndrome, ectopic

ACTH production)

Secondary aldosteronism (醛固酮增多症 , from heart

failure, hepatic cirrhosis硬化 , nephrotic syndrome肾病综合征 , and other conditions associated with diminished

effective intravascular volume)

Combined with other diuretic drugs

Potassium-sparing diuretics

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Adverse effects(1) Hyperkalemia

(2) Hyperchloremic metabolic acidosis: by inhibiting H+ secretion in parallel with K+ secretion

(3) Sex hormone-like effects: gynecomastia(男性乳腺发育 )

(4) Acute renal failure: only found in the combination of triamterene with indomethacin (氨苯蝶啶 +吲哚美辛 )

(5) Kidney stones: triamterene (poorly soluble)

(6) Megaloblastosis巨幼红细胞性贫血 : Triamterene (folic acid antagonist)

(7) GI reactions: nausea, vomiting

(8) CNS reactions: headache, fatigue, diziness

Potassium-sparing diuretics

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常用利尿药对电解质排泄及排钠力的比较

药物尿电解质排泄

主要作用部位 机制Na+ K+ Cl- HCO3

-

高效利尿药

+++ + ++++ ±髓袢升支粗段髓质和皮质部

抑制 Na+ -K+-2Cl-

共同转运系统

中效利尿药

++ + ++ + 远曲小管近段 抑制 Na+ -Cl- 共同转运系统

低效利尿药

+ - + 0远曲小管远段

和集合管对抗醛固酮，阻

滞 Na+ 通道

乙酰唑胺

+ ++ 0 +++ 近曲小管抑制碳酸酐酶及

胞内 H+ 形成，抑制 H+ -Na+ 交换

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(1) An osmotic agent is inert pharmacologically,

freely filtered at glomerulus and undergo

limited reabsorption.

(2) Dehydrant effect

(3) Diuretic effect (osmotic diuretic effect)

Dehydrant Agents (Osmotic Diuretics)

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Clinical Indications

(1) Given by iv infusion, results in increase in urine volume

(2) Reduction of intracranial and intraocular pressure: used in brain edema following brain injury and glaucoma

(3) Acute renal failure: prevention and early treatment

(4) Dialysis disequillibrium syndrome

Mannitol甘露醇

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OH OH OH OH

OH OH

Adverse effects

(1) Extracellular volume expansion: pulmonary

edema, etc.

(2) Hyponatremia and dehydration: headache,

nausea, vomiting, etc.

Contraindicated in anuric 无尿症 due to severe

renal diseases, active cranial bleeding, heart

failure

Mannitol

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Other dehydrant drugs

Urea 尿素Isosorbide 异山梨醇Sorbitol 山梨醇Glycerin 甘油Hypertonic glucose (50%) 高渗葡萄糖Hypertonic saline (7.5-10%) 高渗盐水

Dehydrant Agents (Osmotic Diuretics)

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45

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Clinical pharmacology of diuretic

• Natriuresis induced by diuretics is finite (diuretic braking). • Mechanisms include activation of the sympathetic nervous

system, activation of renion-angiotensin-aldosterone axis,

decreased aterial blood pressure, hypertrophy of renal

epithelial cells, increased expression of renal epithelial cells,

increased expression of renal epithelial transporters, and

perhaps alterations in nariuretic hormones such as atrial

natriuretic peptide (ANP).• Diuretic resistance may be induced by NSAIDs and

decrease in RBF, which diminish the concentration of

diuretics at the active site in the tubular lumen.

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Clinical pharmacology of diuretic

• Options to deal with diuretic resistance:

1) Bed rest

2) Increase the dose

3) Smaller dose more frequently or iv infusion

4) Combination therapy

5) Reduce salt intake

6) Administration shortly before food intake

Diuretic combinations

1. Loop Agents & Thiazides• Salt and water reabsorption in either the thick ascending

limb or the distal convoluted tubule can increase when the other is blocked.

• Thiazide diuretics may produce a mild natriuresis in the proximal tubule that is usually masked by increased reabsorption in the thick ascending limb.

• Mobilize large amounts of fluid and K+-wasting is extremely common. High risk to induce hyponatremia, hypotension, and worsening renal function.  Reserve for the occasional patient with high resistance to loop diuretics

• Metolazone and hydrochlorothiazide are the two thiazides most commonly used in combination with a loop diuretic.48

2. Potassium-Sparing Diuretics & Loop Agents or Thiazides

• When hypokalemia cannot be managed with dietary NaCl restriction or KCl supplements in patients using loop diuretics or thiazides, the addition of a potassium-sparing diuretic can significantly lower potassium excretion.

• it should be avoided in patients with renal insufficiency.

Diuretic combinations

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