DIURETICS

By Gauri Chaturvedi
M.Sc. Student
All India Institute of Medical Science
New Delhi - 110029
 INTRODUCTION
 Kidney serves as a natural filter of blood and removal of waste product, which are
diverted to urinary bladder.

 Kidney plays several essential regulatory and excretory roles in vertebrate animals

 Functional unit of kidney is nephron.

 The function of kidney are:

o Excretion of wastes- urea and ammonium

o Reabsorption of vital nutrients
o Acid-base homeostasis
o Osmolarity regulation
o Hormone secretion- erythropoietin and rennin
 MECHANISM OF URINE FORMATION
• It consists of the following steps
1. Glomerular filtration
2. Tubular reabsorption
3. Active tubular secretion
• Urine formation begins with glomerular filtration, Urine output
is about 1-1.5L/day

• The volume filtered is about 180L/day, of which more than

99% gets reabsorbed in the renal tubules.

• Four main parts of nephron are

Site-1 - Proximal Convoluted tubules.
Site-2 - Descending limb of loop of henle.
Site-3 - Ascending limb of loop of henle.
Site-4 - Early & Late Distal Convoluted Tubule (DCT)

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 Classification
1. High Efficacy (Loop) Diuretics (Inhibitors of Na+ K+ 2Cl- Cotransporter) – [Site-3]
a. Sulphamoyl derivatives – Furosemide, Bumentanide
b. Phenoxyacetic acid derivatives – Ethacrynic acid
c. Organomercumials - Mersalyl

2. Medium Efficacy Diuretics (Inhibitors of Na+ Cl- Symport) – [Site-4]

a. Benzothiadiazines ( thiazides) – Hydrochlorothiazide, Benzthiazides ,Hydroflumethiazides.
b. Thiazides like( related heterocyclics ) – Chlorthalidone, Metolazone, Chlorthiazide.

3. Weak or Adjuvent Diuretics

a. Carbonic anhydrase inhibitors- Acetazolamide – [Site-1]

b. Potassium Sparing Diuretics – [Site-4]
1. Aldosterone antagonist – Spironolactone, Eplerenone.
2. Directly action ( Inhibitors of renal epithelial Na + channel)- Triamterene, Amiloride.
c. Osmotic diuretics – Mannitol, Isosorbide, Glycerol
d. Xanthines - Theophylline
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 HIGH CEILING DIURETICS (LOOP DIURETICS)

o Site of action of loop diuretics is thick ascending limb of loop of

henle.
o Binds to luminal side of Na+ K+ 2Cl- cotransporter and blocks its
function.
o Loop diuretics cause a significant increase in Na + K+ , Cl- , Ca2+ and
Mg2+ excretion.
o Furosemide has weak carbonic anhydrase inhibiting activity hence

increases the excretion of HCO3- and PO43- .

o Loop diuretics are called high-ceiling diuretics because they are highly
efficacious- have maximal Na+ excretion capacity when compared to
thiazides and potassium sparing diuretics.

o They are rapidly absorbed through the gastrointestinal tract.

o Furosemide and bumetanide are administered by oral, i.v. and i.m. routes.
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Therapeutics uses Adverse effects

 In renal, hepatic and cardiac oedema,  Hypokalaemia, hypocalcaemia and hypomagnesaemia

loop diuretics are preferred.  Hyperglycaemia, hyperuricaemia and
 In hypercalcaemia as it promotes the hyperlipidaemia
excretion of Ca2+ in urine.  Ototoxicity
 Cerebral oedema.  Hypersensitivity
 Hypertension.
 in mild hyperkalaemia.

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 MEDIUM EFFICACY DIURETICS ( THIAZIDES)

• Thiazides inhibits Na+ Cl- symport in DCT and increasing Na+ and Cl-
excretion.
• Ca2+ exceretion is decreased and uric acid.
• The excretion of Mg2+ is enhanced.
• Diazoxide is a benzothiazide derivative and vasodilation by activating
ATP sensitive K+ channels.
• There is increased delivery of Na+ to the late distal tubules, Hence there
is increased exchange of Na+ K+ which results in K+ loss
• CHLORTHALIDONE is longest acting thiazide.
• BENDROFLUMETHIAZIDE has almost 100% bioavailability.

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Therapeutics uses Adverse effects

 Hypercalciurea  Hypokalaemia, hypercalcaemia and

 Hypertension hypomagnesaemia.
 Edema  Hyperglycaemia.
 Diabetes insipidus  Impotence , so not preferred to young
 Heart failure males

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WEAK OR ADJUNCTIVE DIURETICS

(a). Carbonic anhydrase inhibitors

o These agents are sulphonamide in structure.

o CA inhibitor only inhibit luminal carbonic anhydrase enzyme.
o Intracellularly CA converts H2O and CO2 to carbonic acid (H3CO3). H3CO3

dissociates into H+ and HCO3- .

o The H+ ion exchange with luminal Na+ . In the lumen, the H+ ion combine with
HCO3- and form H2CO3. The H2CO3 dissociates into CO2 and H2O with the help
of carbonic anhydrase which is present near the brush border.
o Drugs in this class by inhibiting CA enzyme, prevent the formation of H + ions.
Thus Na+H+ exchange is prevented
o Metabolic acidosis results as a result of HCO3- loss in urine.

o There is an increase in Na+ and K+ excretion.

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Therapeutics uses Adverse effects

 Glaucoma  Hepatic cirrhosis.

 Acute mountain sickness  Chronic Obstructive pulmonary disease (COPD)
 To alkaline urine in acidic drug poisoning
 Epilepsy

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 Potassium sparing diuretics
• These drugs act in the late DCT and CD.

Aldosterone antagonist
• Drugs are – Spironolactone & eplerenone

Directly action ( Inhibitors of renal epithelial Na+ Channels)

• Drugs are Triamterene, Amiloride

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Aldosterone antagonist
• Drugs are – Spironolactone & eplerenone

 Aldosterone enters the cells and bind to specific receptors (MR) in the cytoplasm of LDT & CD.
 The MR-AL complex enters the cell nucleus where it induce the aldosterone induce proteins (AIP).
 Spironolactone are competitive inhibitors of aldosterone antagonist at the receptor of distal tubules.
 The net effect of AIP is to retain Na + excretion and K+ retention.
 Canrenone is an active metabolite of spironolactone

Adverse effects-

• Hyperkalemia
• Hirsuitism
• Impotence
• Menstrual irregularities
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Directly action ( Inhibitors of renal epithelial Na + Channels)
• Drugs are Triamterene, Amiloride

 Direct inhibitor of renal epithelial Na + Channel.

 Both directly block the Na+ channel in the luminal membrane of the cell of
the late DCT and CD
 The net effect of these drug is to increase Na + excretion and retain K+ .
 Amiloride decreases Mg2+ and Ca2+ excretion and increase urine excretion.

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Osmotic diuretics – Mannitol, Isosorbide, Glycerol

o Site of action is in the loop of henle and proximal tubules.

o Osmotic diuretics draw water from tissue by osmotic action. This results in increased excretion of water and
electrolyte.

Mannitol
• Administered intravenously.
• Pharmacologically inert and is freely filtered at the glomerulus.

• Contraindicated in congestive cardiac failure (CCF) and pulmonary oedema.

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THANK YOU