Diuretics and DehydrantsDiuretics and Dehydrants

Zheng Zhang

Department of Pharmacology

School of Pharmaceutical Sciences

Central South University

Drugs inducing a state of increased urine flow are Drugs inducing a state of increased urine flow are

called diureticscalled diuretics

Actions:1. Increase the volume of urine

2. Change the ionic composition and pH of

the urine and blood

DiureticsDiureticsPart I

Excretion of Water and Electrolytes

I. OverviewI. Overview

a) Tubule fluid ( 原尿 )

Source: filtration of plasma entering the kidney to the Bowman’s capsule

Components: glucose, sodium bicarbonate, amino acid,

other organic solutes, electrolyte (Na+, K+ and Cl-),

and low molecular weight plasma components

原尿量 终尿量

(1~2升 )180 升

Tubule fluid 180 L/day Urine Volume 1.5 L/day

b) Factors determine urine formation Glomerular filtration ( 肾小球滤过 )

Reabsorption ( 重吸收 ) and excretion ( 分泌 ) of

renal tubules ( 肾小管 )

GFR excretion Reabsorption

GFRexcretion

Reabsorption

Urine flow increase

Tubular reabsorptionSmall molecules

Water Glucose, amino acids, sodium, chloride, calcium, bicarbonate

Tubular secretion Larger molecules

Potassium, phosphate, Hydrogen, Ammonium

c) Functional zones of nephronec) Functional zones of nephroneI.I. Proximal convoluted tubule (Proximal convoluted tubule ( 近曲小管）近曲小管）II.II. Descending limb of Henle’s loop (Descending limb of Henle’s loop ( 髓袢降支髓袢降支 ))

III.III. Ascending limb of Henle’s loop (Ascending limb of Henle’s loop ( 髓袢升支髓袢升支 ))

IV.IV. Distal convoluted tubule (Distal convoluted tubule ( 远曲小管远曲小管 ))

V.V. Collecting duct tubule (Collecting duct tubule ( 集合管集合管 ))

1. Proximal convoluted tubule1. Proximal convoluted tubule

Location:Location: kidney cortex kidney cortex

Function: Function: reabsorption of almost all of glucose, reabsorption of almost all of glucose,

and other organic solutes, amino acids, 85% and other organic solutes, amino acids, 85%

sodium bicarbonatesodium bicarbonate, 40% , 40% sodium chloridesodium chloride, ,

and 40% waterand 40% water

Acid secretory system:Acid secretory system: uric acid, diuretics, uric acid, diuretics,

antibiotics, etcantibiotics, etc

Carbonic anhydrase (CA)

BicarbonateBicarbonateReabsorptionReabsorption

Cl--base- Exchanger

ATP

CA

HCO3- + H+ H+ + HCO3

-

H2CO3

+

H2O + CO2 CO2 + H2O

H2CO3

CA

Proximalconvoluted tube

Cl-

Base-

Lumen-urine

Interstitium-blood

Na+

K+

Na+

Na+/H+ Exchanger

HCO3-

CO2

CA inhibitor

--

2. Thin descending limb of Henle’s loop2. Thin descending limb of Henle’s loop

Location:Location: medullar ( medullar ( 髓质髓质 ), with hypertonic ), with hypertonic

medullary interstitium (medullary interstitium ( 间质间质 ))

Function:Function: water highly permeable and reabsorbed water highly permeable and reabsorbed

by passive absorptionby passive absorption

Water channel or aquaporin (AQP)Water channel or aquaporin (AQP)

Specific channel for water permeabilitySpecific channel for water permeability Widely distributed: kidney, lung, bronchia, Widely distributed: kidney, lung, bronchia,

sweating gland, and reproductive systemsweating gland, and reproductive system Play an important in the reabsorption of water in Play an important in the reabsorption of water in

the thin descending limb of Henle’s loopthe thin descending limb of Henle’s loop Deficiency results in diseases, e.g. nephrogenic Deficiency results in diseases, e.g. nephrogenic

diabetes , insipidus (diabetes , insipidus ( 肾性尿崩症肾性尿崩症 ))

3. Thick ascending limb of Henle’s loop3. Thick ascending limb of Henle’s loop

Location:Location: Both medullar and cortex Both medullar and cortex

Characteristic:Characteristic: Impermeable to water Impermeable to water

Function: Function: NaCl reabsorption (35% filtered sodium), NaCl reabsorption (35% filtered sodium),

dilutingdiluting ( (稀释稀释 ) of tubular fluid (diluting segment), ) of tubular fluid (diluting segment),

medullary hyper-tonicity (medullary hyper-tonicity ( 髓质高渗髓质高渗 ) and ) and

concentrationconcentration ( (浓缩浓缩 ) of urine) of urine

ATPK+

Thickascending

limb

Mg2+, Ca2+

Lumen-urine

Interstitium-blood

Na+

K+

Na+

Cl-

K+

2 Cl-

K+(+)Potential

Loop diuretics

-

4. Distal convoluted tubule4. Distal convoluted tubule

10% filtered NaCl is reabsorbed10% filtered NaCl is reabsorbed

CaCa2+2+ is reabsorbed actively by way of Ca is reabsorbed actively by way of Ca2+2+

channels in the lumenal membrane and the channels in the lumenal membrane and the

basolateral Nabasolateral Na++-Ca-Ca2+2+ exchanger exchanger

Relative impermeable to waterRelative impermeable to water

Further dilution of tubular fluidFurther dilution of tubular fluid

ATP

Distalconvoluted

tubule

Ca2+

Lumen-urine

Interstitium-blood

Na+

K+

Na+

Na+

Cl-

Ca2+

R PTHDiuretics(Thiazide)

_

5. Collecting tubule5. Collecting tubule

2-5% filtered NaCl is reabsorbed2-5% filtered NaCl is reabsorbed

NaNa++ reabsorption in principle cells ( reabsorption in principle cells ( 主细胞主细胞 ) )

results in Kresults in K++ excretion and negative excretion and negative

potential in lumen (potential in lumen ( 腔内负电位腔内负电位 ), Cl), Cl-- is is

reabsorptreabsorpteded in by intercalated cells ( in by intercalated cells ( 旁细旁细胞胞 ))

Water highly permeable: ADH increases Water highly permeable: ADH increases

water permeability through water channelwater permeability through water channel

ATP

Collectingtubule

H2O

Lumen-urine

Interstitium-blood

Na+

K+

Na+

R ADH

K+

ATP

AldosteroneR

H+

HCO3-

Cl-

Principal cell

Intercalatedcell

AQP Potassium-sparingdiuretics

__

II. Classification of DiureticsII. Classification of Diuretics

Act on thick ascending limb of Henle (Act on thick ascending limb of Henle ( 髓髓袢升枝袢升枝 ) in the cortex and medullar) in the cortex and medullar,, e.g. e.g.

furosemide (furosemide ( 呋塞米呋塞米 ), ethacrynic acid (), ethacrynic acid ( 依他依他尼酸尼酸 ), and bumetanide (), and bumetanide ( 布美他尼布美他尼 ))

1. High efficacy diuretics ( 高效利尿药 ):

2. Moderate efficacy diuretics 2. Moderate efficacy diuretics

(( 中效利尿药中效利尿药 ):):

Act on thick ascending limb of Henle in the Act on thick ascending limb of Henle in the

cortex and early distal convoluted tubule cortex and early distal convoluted tubule

(( 远曲小管远曲小管 ),), e.g. thiazides ( e.g. thiazides ( 噻嗪类噻嗪类 ) and ) and

chlortalidone (chlortalidone ( 氯噻酮氯噻酮 ))

Act on distal convoluted tubule (Act on distal convoluted tubule ( 远曲小远曲小管管 ) and collecting tubule () and collecting tubule ( 集合管集合管 ),), e.g. e.g.

spironolactone (spironolactone ( 螺内酯螺内酯 ), triamtrerene (), triamtrerene ( 氨苯氨苯喋啶喋啶 ), and amiloride (), and amiloride ( 阿米洛利阿米洛利 ) )

proximal convoluted tubule (proximal convoluted tubule ( 近曲小管近曲小管 )) , ,

e.g. acetazolamide (e.g. acetazolamide ( 乙酰唑胺乙酰唑胺 ))

3. Low efficacy diuretics ( 低效利尿药 ):

CA InhibitorsProximal tubule

Loop DiureticsLoop of Henle

ThiazidesDistal tubule

K+-sparing diureticsCollecting tubule

III. Commonly used diureticsIII. Commonly used diuretics

A. High efficacy diureticsA. High efficacy diuretics

Agents: furosemide (Agents: furosemide ( 呋塞米或速尿呋塞米或速尿 ), ), Site of action: Site of action: ascending limb of Henle’s ascending limb of Henle’s

looploop Not limited by acidosis (Not limited by acidosis ( 酸中毒酸中毒 ))

1. Loop diuretics

NaNa++-K-K++-2Cl-2Cl-- cotransporter cotransporter

NaCl reabsorption

Diluting function

Concentration function

K+ recycle

Lumen positive potential

Ca2+ and Mg2+ reabsorption

Induce renal prostaglandin G (PG) Induce renal prostaglandin G (PG)

synthesis:synthesis:

Renal Vasodilation and redistribution of blood flowDecrease in renin releaseIncrease in venous capacitance

PharmacokineticsPharmacokinetics

Quickly absorbedQuickly absorbed

Eliminated by renal secretion and glomerular Eliminated by renal secretion and glomerular

filtration, tfiltration, t1/21/2 = 1 h, depends on renal function = 1 h, depends on renal function

Diuretic effects correlate with urinary excretionDiuretic effects correlate with urinary excretion

Clearance reduced by indomethacin (Clearance reduced by indomethacin ( 吲哚美辛吲哚美辛 ) )

and probenecid (and probenecid ( 丙磺舒丙磺舒 ))

Therapeutic usesTherapeutic uses

1. Acute pulmonary and intracranial edema 1. Acute pulmonary and intracranial edema

(( 急性肺水肿和急性脑水肿急性肺水肿和急性脑水肿 ):):①① An efficient and prompt therapy for acute An efficient and prompt therapy for acute

pulmonarypulmonary

②② Relieve intracranial edema, especially Relieve intracranial edema, especially

appropriate in patients with CHFappropriate in patients with CHF

2. Other edematous status ( 其它严重水肿 ):Caused by heart, renal or hepatic disease

3. Acute and chronic renal failure (3. Acute and chronic renal failure ( 急、慢性肾功急、慢性肾功能衰竭能衰竭 ):):

4. 4. Hypercalcemia (Hypercalcemia ( 高钙血症高钙血症 ):):

Increase urine volume and K+ excretion; Flush out intratubular casts and ameliorate

obstruction Do not delay the progression of renal failure

The loop of Henle is an important site of calcium reabsorption

Administration of saline with loop diuretics increase Ca2+ excretion

5. Ameliorate excretion of toxic chemicals 5. Ameliorate excretion of toxic chemicals

(( 加速某些毒物的排泄加速某些毒物的排泄 ):):

Detoxification of drugs excreted by the kidney, Detoxification of drugs excreted by the kidney,

e.g. long-acting barbitals, salicylates, bromide e.g. long-acting barbitals, salicylates, bromide

(( 溴溴 ), fluoride (), fluoride ( 氟氟 ) and iodide () and iodide ( 碘碘 )) Saline should be administered simultaneouslySaline should be administered simultaneously

Adverse effectsAdverse effects

1. 1. Water and electrolyte disorder (Water and electrolyte disorder ( 水与电解质紊乱水与电解质紊乱 ):): Hypovolemia (Hypovolemia ( 低血容量低血容量 ), hypokalemia (), hypokalemia ( 低血钾低血钾 ), ),

hyponatremia (hyponatremia ( 低血钠低血钠 ), hypokalemia alkalosis (), hypokalemia alkalosis ( 低低钾性碱中毒钾性碱中毒 ), and hypomagenesemia (), and hypomagenesemia ( 低血镁低血镁 , ,

chronic use)chronic use)

2. 2. Ototoxicity (Ototoxicity ( 耳毒性耳毒性 ):):①① Dose-related hearing loss, reversibleDose-related hearing loss, reversible

②② Permanent deaf: ethracrynic acid (Permanent deaf: ethracrynic acid ( 利尿酸利尿酸 ))

③③ Increased with renal insufficiency or other ototoxic drugs Increased with renal insufficiency or other ototoxic drugs

combinationcombination

3.3. Hyperuricemia (Hyperuricemia ( 高尿酸血症高尿酸血症 ):): Uric reabsorption Uric reabsorption

Attack of gout (Attack of gout ( 痛风痛风 ))

4.4. Others:Others: Nausea, vomiting, gastro-intestinal bleeding, allergic Nausea, vomiting, gastro-intestinal bleeding, allergic

reaction , cross-reactivity with sulfonamides (reaction , cross-reactivity with sulfonamides ( 磺胺类磺胺类药物药物 ))

Actions of loop diureticsActions of loop diuretics

B. Moderate efficacy diureticsB. Moderate efficacy diuretics

Agents: hydrochlorothiazide (Agents: hydrochlorothiazide ( 氢氯噻嗪氢氯噻嗪 )) Location of action: Location of action: distal convoluted distal convoluted

tubuletubule Contain Contain sulfonamide groupsulfonamide group

Thiazides

Actions and mechanismsActions and mechanisms

1. diuresis: mild and permanent1. diuresis: mild and permanent Na+-Cl- cotransporter

Na+ and Cl-

excretion

Na+-K+

exchange

K+ excretion

Na+-Ca2+

exchange

Ca2+ Reabsorption

Parathyroid Hormone PTH

2. Anti-diuresis2. Anti-diuresis

Na+ and Cl- excretion

Plasma osmolarity

Reduce polydipsia (烦渴 )

Urine volume

3. Hypotensive effect3. Hypotensive effect

Early stage: diuresis and decrease in blood volumeEarly stage: diuresis and decrease in blood volume

Late stage: vasodilation of peripheral vasculatureLate stage: vasodilation of peripheral vasculature

PharmacokineticsPharmacokinetics

Completely absorbed, onset of action in Completely absorbed, onset of action in

1~2 h, t1~2 h, t1/21/2 = 4~6 h = 4~6 h

Chlorthiazide (Chlorthiazide ( 氯噻嗪氯噻嗪 ) is less lipid-) is less lipid-

soluble, absorbed slowly and long-actingsoluble, absorbed slowly and long-acting Competition for organic acid secretory Competition for organic acid secretory

system, decrease uric acid excretionsystem, decrease uric acid excretion

Therapeutic usesTherapeutic uses

1. Edema:1. Edema: Useful in edema with various causesUseful in edema with various causes Higher degree of response in mild and moderate Higher degree of response in mild and moderate

edemaedema Efficacy correlates with degree of renal damage in Efficacy correlates with degree of renal damage in

nephrogenic edema (nephrogenic edema ( 肾性水肿肾性水肿 ))

2. Hypertension2. Hypertension

First line hypotensive agents First line hypotensive agents

In combination with other hypotensive agentsIn combination with other hypotensive agents

3. Other diseases3. Other diseases

Nephrotic insipidus （尿崩症） and

pituitary insipidus which is not responsive

to ADH

Nephrolithiasis ( 肾结石 ) due to

hypercalciuria ( 高尿钙 )

Adverse effectsAdverse effects

1. Electrolyte disorder (1. Electrolyte disorder ( 电解质紊乱电解质紊乱 ):): Hypokalemia, hyponatremia, Hypokalemia, hyponatremia,

hypomagenesemia, and hypochloremia hypomagenesemia, and hypochloremia

alkalosisalkalosis

2. Hyperuricemia ( 高尿酸血症 ):

Extracellular fluid volume Uric acid

reabsorption

①① Hyperglycermia in patients with diabetic or Hyperglycermia in patients with diabetic or

abnormal glucose tolerance testabnormal glucose tolerance test

②② Increase cholesterol and low density lipoproteinsIncrease cholesterol and low density lipoproteins

3. Metabolic change: hyperglycemia and

hyperlipidemia:

4. Allergic reaction:

Cross-reactive with sulfonamides

C. Low efficacy diureticsC. Low efficacy diuretics

A.A. Potassium-sparing diuretics:Potassium-sparing diuretics:

a)a) Direct antagonism of mineralocorticoid receptorsDirect antagonism of mineralocorticoid receptors, ,

e.g. spironolactone (e.g. spironolactone ( 螺类酯螺类酯 ))

b)b) Inhibition of NaInhibition of Na++ flux through ion channels flux through ion channels, e.g , e.g

triamterene (triamterene ( 氨苯蝶啶氨苯蝶啶 ) and amiloride () and amiloride ( 阿米洛阿米洛利利 ))

B.B. Carbonic anhydrase (CA) inhibitor:Carbonic anhydrase (CA) inhibitor: e.g. e.g.

acetazolamide (acetazolamide ( 乙酰唑胺乙酰唑胺 ))

Spironolactone or Antisterone (Spironolactone or Antisterone ( 安体舒通安体舒通 ))

Sites of action: Sites of action: Cortical collecting tubule and late distal convoluted Cortical collecting tubule and late distal convoluted tubuletubule

Actions and mechanisms Competitive antagonist of aldosterone Reduce intracellular formation of active

metabolites of aldosterone Na+ reabsorption, K+ and H+ secretion

Triamtrerene and AmilorideTriamtrerene and Amiloride

Action:Action: Increase NaIncrease Na++ excretion and K excretion and K++ retention retention （保留）（保留）

Sites of action:Sites of action: Late distal convoluted tubule and the Late distal convoluted tubule and the collecting tubulecollecting tubule

A.A. NaNa++ channel activity channel activity Na Na++- K- K++ exchange exchange and Naand Na++ reabsorption reabsorption lumen negative lumen negative position position K K++ excretion excretion diuresis diuresis

B.B. Inhibit NaInhibit Na++-H-H++ and Na and Na++-Ca-Ca2+2+ antiporters ( antiporters ( 反向转反向转运子运子 ) ) H H++ and Ca and Ca2+2+ excretion excretion (amiloride at (amiloride at high concentrations)high concentrations)

Mechanisms of action

Therapeutic usesTherapeutic uses

1.1. Refractory edemaRefractory edema （难治水肿） （难治水肿） secondary to secondary to

hyperaldosteronism:hyperaldosteronism:

Edema caused by hepatic cirrhosis and nephron Edema caused by hepatic cirrhosis and nephron

syndromesyndrome

2.2. Chronic congestive heart failure:Chronic congestive heart failure:

A.A. Diuresis and increase in NaDiuresis and increase in Na++ excretion excretion

B.B. Amelioration of other conditionsAmelioration of other conditions

Carbonic anhydrase (CA)

HCO3- and Na+

reabsorption

HCO3- secretion

Choroid plex（脉络膜）

HCO3-

secretion

Proximal tubule Ciliary

body

Cerebrospinalfluid

Aqueous humor

Acetazolamide ( 乙酰唑胺 )

Therapeutic usesTherapeutic uses

1.1. Glaucoma (Glaucoma ( 青光眼青光眼 ):): Decrease the rate of aqueous formationDecrease the rate of aqueous formation

Management of several forms of glaucomaManagement of several forms of glaucoma

2. Acute mountain sickness (2. Acute mountain sickness ( 高山病高山病 ):):

Symptoms of acute mountain sickness: Symptoms of acute mountain sickness:

weakness, dizziness, headache, life-weakness, dizziness, headache, life-

threatening pulmonary and cerebral edemathreatening pulmonary and cerebral edema

decrease cerebrospinal fluid

3. Urinary alkalization (3. Urinary alkalization ( 碱化尿液碱化尿液 ):):

Enhance the excretion of uric acid, and Enhance the excretion of uric acid, and

weak acid substances (e.g. Aspirin)weak acid substances (e.g. Aspirin)

4. Metabolic alkalosis ( 代谢性碱中毒 ):

a) Alkalosis due to excess use of diuretics

in chronic heart failure

b) Metabolic alkalosis secondary to

respiratory acidosis

Dehydrants (Dehydrants ( 脱水药脱水药 ))

Osmotic diuretics (Osmotic diuretics ( 渗透性利尿药渗透性利尿药 ))

Part II

1. Tissue dehydration (脱水 ): increase

osmolarity of plasma

2. Osmotic diuresis: increase water

and ions excretion

Agents:Agents:

Mannitol (Mannitol ( 甘露醇甘露醇 ))

Sorbitol (Sorbitol ( 山梨醇山梨醇 ))

Hypertonic glucose (Hypertonic glucose ( 高渗葡萄高渗葡萄糖糖 ))

Urea (Urea ( 尿素尿素 ))

1.1. Not penetrated into tissues through capillaryNot penetrated into tissues through capillary

2.2. Do not undergo metabolism in the bodyDo not undergo metabolism in the body

3.3. Could be filtrated by glomerulusCould be filtrated by glomerulus

4.4. Without any important tubular reabsorptionWithout any important tubular reabsorption

Characteristics:Characteristics:

Mannitol (Mannitol ( 甘露醇甘露醇 ))

Action and therapeutic uses:nAction and therapeutic uses:n1.1. Dehydration:Dehydration: reduce intracranial and intraocular reduce intracranial and intraocular

（眼内）（眼内） pressure; osmotic diarrheapressure; osmotic diarrhea （腹泻） （腹泻） and and

elimination ofelimination of

toxins from GI tracttoxins from GI tract

2. Diuretics:2. Diuretics: Prevention of acute renal failure Prevention of acute renal failure

20% solution for venous injection or dropping20% solution for venous injection or dropping

Adverse reactions and contraindicationsAdverse reactions and contraindications

1.1. Headache, lethargy (Headache, lethargy ( 困倦困倦 ), and mental confusion ), and mental confusion

((精神错乱精神错乱 ) occur) occur rarely;rarely;

2.2. Sex hormonal effectsSex hormonal effects

3.3. Chronic use causes hyperkalemiaChronic use causes hyperkalemia （（ renal failurrenal failur

ee））

PharmacokineticsPharmacokinetics

Triamtrerene:Triamtrerene: Metabolized in the liverMetabolized in the liver Active metabolites and final metabolites cleared by Active metabolites and final metabolites cleared by

the kidneythe kidney tt1/2 1/2 = 4.2 h= 4.2 h

Amiloride:Amiloride:

Cleared by the kidney, tCleared by the kidney, t1/21/2 = 21 h = 21 h

Therapeutics uses:Therapeutics uses: refractory edema, in refractory edema, in

combination with other diureticscombination with other diuretics

Adverse effects:Adverse effects: rarerare Nausea, vomitting, diarrhea, drowsinessNausea, vomitting, diarrhea, drowsiness

Chronic uses causes hyperkalemiaChronic uses causes hyperkalemia

In combination with indomethacin: acute renal In combination with indomethacin: acute renal

failurefailure