diuretic agents 利尿药与脱水药 weiping zhang （张纬萍） weiping601@zju.edu.cn...

Diuretic AgentsDiuretic Agents利尿药与脱水药利尿药与脱水药

Weiping ZhangWeiping Zhang （张纬萍）（张纬萍）weiping601@zju.edu.cnTel: 88208223Tel: 88208223Dept. Pharmacology, Medical School, Zhejiang UniversityDept. Pharmacology, Medical School, Zhejiang University

The Kidney:The Kidney:

Excretion water, Excretion water, ions, and toxic ions, and toxic metabolitesmetabolites

Renal structures for Renal structures for urine generation urine generation (A)(A) and and osmotic gradient osmotic gradient (B)(B)

Thin descending limb

Thin ascending limb

Thick ascending limb

convoluted

Functional proteins in cell membrane

A.A. Excrete functin of kidneyExcrete functin of kidney1. Excretion of inorganic ion

A.A. Excrete functin of kidneyExcrete functin of kidney

1. Excretion of inorganic ion

(1) ATP mediated active transport: Na+-K+ pump, Ca2+-ATP, H+-ATP

(2) Symporter (Cotransporter): Na+-K+-2Cl- symporter, Na+-K+ symporter

(3) Antiporter (countertransporter): Na+-H+ exchanger, Ca2+-Na+ exchanger, HCO3

- -H+ exchanger

(4) Ion channel: Na+, K+, Cl-

2. Excretion of organic ion

(1) Anionic transporter （阴离子转运体） Metabolites (uric acid), drugs (most of cephalosporins, loop di

urects, NSAIDs, most of the -lactams, thiazide diuretics, most of the sulfonamides)

(2) Cationic transporter （阳离子转运体） Metabolites (choline), drugs (amiloride, efedrina, H2 receptor a

ntagonists, morphine, quinine)

ABCABC 转运体转运体

溶质载体类转运体（溶质载体类转运体（ SLCSLC ））

2. Excretion of organic ion

3. Excretion of H2O

A.A. Excrete functin of kidneyExcrete functin of kidney3. Excretion of H2O

Proximal Tubule: AQP1, 7; Collecting Tubule: AQP2, 3, 4; No AQPs in ascending limb of Loop of Henle and distal tubule

The regulation of AQPs: H2O

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。

2525 ％％ NaNa++

65-7065-70 ％％ NaNa++

1010 ％％ NaNa++

Proximal Tubuleluminal membrane

Basolateral membrane

carbonic anhydraseacetazolamide

Organic acid secretion system

s are located in the middle thi

rd of the proximal tubule: uri

c acid, nonsteroidal anti-infla

mmatory drugs NSAIDs, diur

etics, antibiotics.

Organic base secretion

Systems: creatinine, choline, e

85 % HCO3-

60 % H2O60 % Na+

Loop of Henle

25% of the filtered sodium

Water impermeable

Blocked by "loop" diuretics

Ca2+-ATP H+-ATP

Renal structures for Renal structures for urine generation urine generation (A)(A) and and osmotic gradient osmotic gradient (B)(B)

Thin descending limb

Thin ascending limb

Thick ascending limb

convoluted

Distal Convoluted Tubule

10% of the filtered NaCl

Water impermeable

Blocked by diuretics of the thiazide class.

Affected by parathyroid hormone

Collecting Tubule

• 2–5% of NaCl reabsorption• principal cells are the major sites of Na+, K+, and H2O transport

• intercalated cells （暗细胞）are the primary sites of proton secretion.

IntroductionIntroduction What do diuretics do?

They all increase renal sodium excretion thereby reducing blood volume.

What are the different types of diuretics?

Different classes of diuretics interfere with different sodium transport processes that are featured along the nephron.

What determines their potency?

Diuretic dose, bioavailability, serum protein binding, the quantity of sodium delivered at the site of action, the ability more distal nephron segments to reabsorb the excess sodium (compensation).

What are the major side-effects of diuretics?

Low blood volume and the disturbance of electrolytes (K+, Na+, Cl-, Ca2+ and HCO3

Are there special uses of specific diuretics?

All diuretics cause reduction in extracellular sodium and fluid and are useful in treating hypertension, CHF and other edema-forming states. Because specific diuretics may have other actions, they may be useful for treating other conditions.

IntroductionIntroduction

Factors that Factors that CounteractCounteract Diuretic Action After Diuretic Action After Volume DepletionVolume Depletion

RAS: Angiotensin II stimulates proximal sodium reabsorption. Aldosterone increases collecting duct sodium reabsorption;

Sympathetic nervous system: Nnorepinephrine stimulates proximal sodium reabsorption.

These counter-regulatory responses limit the amount of sodium-wasting that can be induced by a fixed diuretic dose.

All of the net sodium losses occur within the first week on a fixed dose of diuretic and dietary salt intake.

Factors that Factors that CounteractCounteract Diuretic Action After Diuretic Action After Volume DepletionVolume Depletion

RAS: Angiotensin II stimulates proximal sodium reabsorption. Aldosterone increases collecting duct sodium reabsorption;

Sympathetic nervous system: Nnorepinephrine stimulates proximal sodium reabsorption.

These counter-regulatory responses limit the amount of sodium-wasting that can be induced by a fixed diuretic dose.

All of the net sodium losses occur within the first week on a fixed dose of diuretic and dietary salt intake.

Classification of diuretic drugsClassification of diuretic drugs Loop diuretics:Loop diuretics: high efficacyhigh efficacy thick ascending limb of Henle loopthick ascending limb of Henle loop inhibiting Nainhibiting Na++-K-K++-2Cl-2Cl- - symportsymport furosemide furosemide 呋塞米呋塞米 Thiazide diuretics:Thiazide diuretics: moderate efficacymoderate efficacy distal convoluted tubuledistal convoluted tubule inhibiting Nainhibiting Na++-Cl-Cl- - symportsymport hydrochlorothiazidehydrochlorothiazide 氢氯噻嗪氢氯噻嗪 KK++-sparing diuretics:-sparing diuretics: low efficacylow efficacy late distal tubule and collecting ductlate distal tubule and collecting duct inhibiting renal epithelial Nainhibiting renal epithelial Na++ channels channels spironolactonespironolactone 螺内酯螺内酯 Carbonic Anhydrase Inhibitors: acetazolamide

Basic Pharmacology of Diuretic AgentsBasic Pharmacology of Diuretic Agents

Patient 1A 65 y.o. man with a long history of chronic obstructive

pulmonary disease (COPD) is in the ICU with congestive heart failure. He was previously treated with diuretics that initially resulted in improvement in his heart failure but he developed further carbon dioxide retention that was felt to be due to the development of metabolic alkalosis (Metabolic alkalosis is primary increase in HCO3

− with or without compensatory increase in Pco2;

pH may be high or nearly normal ) from the diuretic he was receiving.

You still want to induce a diuresis without worsening of his metabolic alkalosis. What do you do?

Carbonic Anhydrase Inhibitors

The prototypical carbonic anhydrase inhibitor is acetazolamide ( 乙酰唑胺） , dorzolamide （多佐胺） , brinzolamide （布林唑胺） Clinical use:Clinical use: carbonic anhydrase–dependent bicarbonate transport at sites other than the kidney. Such as eye, formation of cerebrospinal fluid by the choroid plexus

Clinical use:Clinical use: carbonic anhydrase–dependent bicarbonate transport at sites other than the kidney.

• Eye: glaucoma（青光眼） ;

• Brain: decrease CSF;

• Alkalise urine and increase the acidic drug excretion;

• Correct the metabolic alkalosis

• Allergy

• Hyperchloremic Metabolic Acidosis

• Renal Stones

• Renal Potassium Wasting

• Drowsiness and paresthesias (感觉异常 )

ToxicityToxicity

Back to Patient 1A 65 y.o. man with a long history of chronic

obstructive pulmonary disease is in the ICU with congestive heart failure. He was previously treated with diuretics that initially resulted in improvement in his heart failure but he developed further carbon dioxide retention that was felt to be due to the development of metabolic alkalosis (high bicarbonate) from the diuretics he was on.

You still want to induce a diuresis without worsening of his metabolic alkalosis. What do you do?

Patient 1

The patient had congestive heart failure but also had metabolic alkalosis (elevated bicarbonate level with high pH) that was due to the use of diuretics.

Acetazolamide blocks bicarbonate absorption in the proximal tubule which can lead to bicarbonate wasting in the urine, resulting in a reduction in serum bicarbonate level.

Patient 2The blood pressure of a man with chronic kidney

disease (GFR 20 ml/min) has been increasing in recent weeks as his creatinine has slowly increased (Kidney failure). He has ankle and leg edema.

To control his BP, he has been using an angiotensin converting enzyme inhibitor, beta-blocker and a calcium channel blocker and a thiazide diuretic.

What other measures would you take to improve his blood pressure?

sulfonamide derivative

phenoxyacetic acid derivative

the diuretic activity correlates with their secretion by the proximal tubule

Loop diureticsLoop diuretics

呋塞米呋塞米

布美他尼布美他尼

依他尼酸依他尼酸

ForesemideForesemide

PharmacodynamicsPharmacodynamics(1)(1) Diuretic effectsDiuretic effects

Inhibiting the NaInhibiting the Na++-K-K++-2Cl-2Cl-- cotransporter cotransporter （（ sympsymport)ort)

Most efficacious among the diuretic drugs,Most efficacious among the diuretic drugs,

Blocking kidney’s ability Blocking kidney’s ability to concentrateto concentrate urine urine during hydropenia,during hydropenia, by decreasing the hypertonic mby decreasing the hypertonic medullary interstitium.edullary interstitium.

Impairing kidney’s ability Impairing kidney’s ability to excrete a dilute uto excrete a dilute urinerine..

Also,Also, increasing excretion of Caincreasing excretion of Ca2+2+, Mg, Mg2+2+ by abolby abolition of transepithelial potential difference.ition of transepithelial potential difference.

loop diuretics loop diuretics urine concentrationurine concentration

urine diluteurine dilute

(2) Vasodilatation(2) Vasodilatation ，， maybe related to increase maybe related to increase of PGsof PGs

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

(3) Induce renal prostaglandin synthesis(3) Induce renal prostaglandin synthesis

Clinical Indications & DosageClinical Indications & Dosage(1) Severe edema:(1) Severe edema: ineffective by thiazidesineffective by thiazides

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

(3) Acute renal failure(3) Acute renal failure

(4) Hypercalcemia(4) Hypercalcemia

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

(6) Hyponatremia(6) Hyponatremia

Loop Diuretics to Treat Hyponatremia

In patients with good intravascular volume to start with, loop diuretics will induce the excretion of relatively hypotonic urine (about half isotonic)

Replacement of the volume of urine losses with isotonic sodium chloride (NS) will result in a rise in serum sodium

Toxicity

(1)(1) Imbalance of electrolytesImbalance of electrolytes Hypokalemic Metabolic Alkalosis: Hypokalemic Metabolic Alkalosis: can be reversed by K+

replacement and correction of hypovolemia. Hypomagnesemia: Hypomagnesemia: can be reversed by administration of or

al magnesium preparations. HyponatremiaHyponatremia Hypochloremic Metabolic alkalemiaHypochloremic Metabolic alkalemia

(2) Hyperuricemia:(2) Hyperuricemia: caused by hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule.

Toxicity(3) Ototoxicity:(3) Ototoxicity: hearing damage, hearing damage, contraindicated to cocontraindicated to combine with aminoglycoside antibiotics or the mbine with aminoglycoside antibiotics or the patients who have diminished renal function.

(4) Allergic Reactions:(4) Allergic Reactions: Skin rash, eosinophilia and, less often, interstitial nephritis. less common with ethacrynic acid.

(5) Other effects:(5) Other effects: dehydrationdehydration, arrhythmias, arrhythmias, RAAS actiRAAS activity vity , , etc.etc.

Other loop diuretic drugsOther loop diuretic drugs

Bumetanide Bumetanide 布美他尼布美他尼：： similar to furosemide, bsimilar to furosemide, but less adverse effects and stronger effectsut less adverse effects and stronger effects

TorasemideTorasemide 托拉塞米：托拉塞米： stronger and longer actistronger and longer actionsons

Etacrynic acidEtacrynic acid 依他尼酸：依他尼酸： weaker actions and weaker actions and more severe adverse effectsmore severe adverse effects

Back to Patient 2The blood pressure of a man with chronic kidney

disease (GFR 20 ml/min) has been increasing in recent weeks as his creatinine has slowly increased. He has ankle and leg edema.

To control his b.p., he has been using an angiotensin converting enzyme inhibitor, beta-blocker and a calcium channel blocker and a thiazide diuretic.

What other measures would you take to improve his blood pressure?

Patient 2Most of our patients with late-stage chronic

kidney disease have hypertension. The vast majority of the time, the hypertension of progressive CKD has some volume dependence.

Therefore, use of a diuretic that works in patients with marked renal impairment such as a loop diuretic is appropriate. Loop diuretics need to be used with some care to avoid marked volume depletion that can worsen renal function esp. in the presence of an ACEI or ARB.

Patient 3

You have decided to start a woman on a diuretic for the treatment of hypertension. What factors would make you re-consider the use of certain diuretics?

What if the patient has hypercalcemia?

What if the patient has a history of gout?

What if the patient has a condition that causes hyponatremia?

ThiazidesThiazides

• This kind of drugs are came from the effort to synthesize more potent carbonic anhydrase inhibitors.

• The prototypical thiazide is hydrochlorothiazide.

• All of the thiazides can be administered orally,

ThiazidesThiazides

苄氟噻嗪苄氟噻嗪

氯噻嗪氯噻嗪

氢氯噻嗪氢氯噻嗪

氢氟噻嗪氢氟噻嗪

甲氯噻嗪甲氯噻嗪

泊利噻嗪泊利噻嗪

三氯噻嗪三氯噻嗪

ThiazidesThiazidesBasic Pharmacology of Diuretic AgentsBasic Pharmacology of Diuretic Agents

Short acting thiazides (< 12hrs): hydrochlorothiazide, chlorothiazide

Media acting thiazides （ 12-24 hrs): benzthiazide, hydroflumethiazide, cyclothiazide, trichlormethiazide

Long acting thiazides (>24 hrs): bendrofluazide, methyclothiazide, cyclopenthiazide, polythiazide

Non-ThiazidesNon-Thiazides

Chlortalidone( 氯噻酮 ), indapamide （吲哒帕胺） , metolazone （美托拉宗） , quinethazone （奎乙宗） , xipamide （希帕胺）

1. 1. Pharmacodynamics and clinical indications

(1) Diuretic effects(1) Diuretic effects

Acting on distal convoluted tubule, inhibiting Nainhibiting Na++-Cl-Cl- -

cotransporter (symport)cotransporter (symport)

Decreasing kidney’s ability to dilute urine

Increasing the excretion of Na+, Cl-, K+, Mg2+, HCO3-,

but increasing the re-absorption of Ca2+ in distal convoluted tubule

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

ThiazidesThiazides

thiazides thiazides

urine diluteurine dilute

(2) Antihypertensive effects(2) Antihypertensive effectsblood volume spasm responsiveness of arterial smooth muscles (3) edema: (3) edema: Used in treatment of mild and moderate edema in ca

rdiac and renal diseases, and hepatic diseases with cautions;

(4) nephrolithiasis due to idiopathic hypercalciuria(4) nephrolithiasis due to idiopathic hypercalciuria Increase Ca2+ reabsorption.

ThiazidesThiazides

(5) Diabetes insipidus (5) Diabetes insipidus (( 尿崩症）尿崩症）Thiazides have the unique ability to produce a hyperos

molar 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.

ThiazidesThiazides

2. Adverse effects2. Adverse effects(1) Imbalance of eletrolytes(1) Imbalance of eletrolytes hypokalemia hypomagnesemia hyponatremia hypochloremia cautions: dose individualization, K+ supplement

(2) Dysfunction of metabolism(2) Dysfunction of metabolism hyperglycemia hyperlipidemia hyperuricemia contraindicated in diabetes and gout patients

ThiazidesThiazides

2. Adverse effects2. Adverse effects(3) Hypersensitivity(3) Hypersensitivity Bone marrow suppression, dermatitis, necrotizing vasculitis, in

terstitial nephritis, etc.

(4) Allergic Reactions(4) Allergic ReactionsPhotosensitivity or generalized dermatitis

(5) Others(5) OthersWeakness, fatigability, and paresthesias

ThiazidesThiazides

Back to Patient 3

You have decided to start a woman on a diuretic for the treatment of hypertension. What are some of the factors that would make you reconsider the use of certain diuretics?

What if the patient has hypercalcemia?

What if the patient has a history of gout?

What if the patient has a condition that causes hyponatremia?

Back to Patient 3

Thiazide diuretics are frequently considered as first-line drugs in the treatment of hypertension. Use caution in patients with:

Gout (they reduce renal uric acid excretion)

Hypercalcemia (they reduce calcium excretion)

Hyponatremia (they reduce water excretion)

Hypokalemia

Patient 4

A 30 year-old woman presented with high blood pressure and hypokalemia.

Subsequent evaluation showed that she had high aldosterone levels and low renin levels consistent with primary aldosteronism. She had no adrenal masses on imaging studies.

What should your treatment be?

Potassium-sparing diureticsPotassium-sparing diuretics(1) Antagonize the effects of aldosterone at the late dista

l tubule and cortical collecting tubule

SpironolactoneSpironolactone 螺内酯螺内酯 eplerenone eplerenone 依普利酮依普利酮(2) Inhibition of Na+ influx through ion channels in the l

uminal membrane

TriamtereneTriamterene 氨苯喋啶氨苯喋啶 AmilorideAmiloride 阿米洛利阿米洛利

Spironolactone Spironolactone 螺螺内酯内酯

Aldosterone

Potassium-sparing diureticsPotassium-sparing diuretics

SpironolactoneSpironolactoneA synthetic steroidBlocking aldosterone receptorDecreasing Na+ re-absorption and K+ excretion

Weaker, slow acting, and lasting duration

Eplerenone Eplerenone (依普利酮 ), a new spironolactone analog with greater selectivity for the aldosterone receptor.

TriamtereneTriamterene 氨苯喋啶氨苯喋啶AmilorideAmiloride 阿米洛利阿米洛利Amiloride is excreted unchanged in the urine. Triam

terene is metabolized in the liver and renal excretion. Triamterene is extensively metabolized, it has a shorter half-life and must be given more frequently than amiloride.

Blocking renal epithelial NaBlocking renal epithelial Na++ channels: channels: decreasindecreasing Nag Na++-K-K++ exchange exchange

spironolactone spironolactone

Clinical Indications & DosageClinical Indications & Dosage in states of mineralocorticoid excess:in states of mineralocorticoid excess:Primary hypersecretion (Conn's syndrome, ectopic

ACTH production) secondary aldosteronism (from heart failure, hepatic

cirrhosis, nephrotic syndrome, and other conditions associated with diminished effective intravascular volume)

Combined with other diuretic drugsCombined with other diuretic drugs

ToxicityToxicity

(1) Hyperkalemia (2) Hyperchloremic Metabolic Acidosis: By inhibiting H+ se

cretion in parallel with K+ secretion, (3) Sex hormone-like effects: Gynecomastia (4) Acute Renal Failure: Only found in the combination of tr

iamterene with indomethacin (5) Kidney Stones: triamterene (6) GI reactions

(7) CNS reactions

Patient 4A 30 year-old woman presented with high

blood pressure and hypokalemia.

Subsequent evaluation showed that she had high aldosterone levels and low renin levels consistent with primary aldosteronism. She had no adrenal masses on imaging studies.

What should your treatment be?

Back to Patient 4

Patients with primary aldosteronism and no adrenal adenoma may be treated medically with an aldosterone receptor blocker (e.g., spironolactone).

Although K-sparing Na-channel blockers are sometimes used because they block the renal effects of aldosterone, they do not block the potential non-renal untoward effects of high aldosterone levels.

MannitolMannitol 甘露醇甘露醇

OH OH OH OHOH OH OH OH

OH OHOH OH

Agents That Alter Water Excretion

Osmotic Diuretics

• An osmotic agent that is excreted usually by glomerular filtrAn osmotic agent that is excreted usually by glomerular filtration and not reabsorbed.ation and not reabsorbed.

• The prototypic osmotic diuretic is mannitol.The prototypic osmotic diuretic is mannitol.

• To reduce increased intracranial pressure and to promote pTo reduce increased intracranial pressure and to promote prompt removal of renal toxins.rompt removal of renal toxins.

• natriuresisnatriuresis

Pharmacodynamics(1) Dehydrant effects(1) Dehydrant effects(2) Diuretic effects(2) Diuretic effects (osmotic diuretic effects) (osmotic diuretic effects)

Clinical Indications & DosageClinical Indications & Dosage

(1) to increase urine volume

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

(3) Acute renal failure: prevention and early treatment

Osmotic Diuretics

ToxicityToxicity

(1) Elevated extracellular osmolality:(1) Elevated extracellular osmolality: pulmonary edepulmonary edema, ma, etc.etc.

(2) Hyponatremia and dehydration:(2) Hyponatremia and dehydration: headache, nausea, headache, nausea, vomiting, vomiting, etc.etc.

Contraindicated Contraindicated inin anuric due to severe renal diseaanuric due to severe renal diseases, active cranial bleeding, heart failureses, active cranial bleeding, heart failure

Osmotic Diuretics

Other dehydrant drugsOther dehydrant drugs

SorbitolSorbitol 山梨醇山梨醇Hypertonic glucose (50%)Hypertonic glucose (50%) 高渗葡萄糖高渗葡萄糖Urea Urea 尿素尿素Glycerin Glycerin 甘油甘油IsosorbideIsosorbide 异山梨醇异山梨醇

Diuretic Combinations

1.1. Loop Agents & ThiazidesLoop 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.

Diuretic Combinations

2. Potassium-Sparing Diuretics & Loop Agents or Thiazides2. Potassium-Sparing Diuretics & Loop Agents or Thiazides

• it should be avoided in patients with renal insufficiency

Clinical Pharmacology of Diuretic Agents

1.1. Edematous StatesEdematous States

• To reduce peripheral or pulmonary edema that has accumulated as a result of cardiac, renal, or vascular diseases, or abnormalities in the blood oncotic pressure.

• To mobilize interstitial edema fluid without significant reductions in plasma volume.

• But this therapy will also reduce perfusion of vital organs.• E.g. low blood pressure after cardiac ischemia

2. Heart Failure2. Heart Failure

• Cardiac output in these patients is being maintained in part by high filling pressures and that excessive use of diuretics may diminish venous return and thereby impair cardiac output.

• Metabolic alkalosis

• Hypokalemia

• Diuretics can never correct the underlying cardiac disease.

3. Kidney Disease3. Kidney Disease

• Patients with milder degrees of renal insufficiency can be treated with diuretics when they retain sodium.

• Patients with severe renal function deficiency, diuretic agents are of little benefit,

4. Hepatic Cirrhosis4. Hepatic Cirrhosis• Liver disease is often associated with edema and ascites in co

njunction with elevated portal hydrostatic pressures.

5. Idiopathic Edema5. Idiopathic Edema （特发性水肿）（特发性水肿）

1. Hypertension1. Hypertension

2. Nephrolithiasis2. Nephrolithiasis （肾结石）（肾结石）

3. Hypercalcemia3. Hypercalcemia

4. Diabetes Insipidus4. Diabetes Insipidus （尿崩症）（尿崩症）

Nonedematous StatesNonedematous States

diuretic agents 利尿药与脱水药 weiping zhang （张纬萍） weiping601@zju.edu.cn...

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