Diuretics

Pharmacology of Renal System
 Components of renal system

 Kidneys
 Ureters
 Urinary bladder
 Urethra
 Components of nepheron
 Renal corpuscle
a) Bowman’s capsule
b) Glomerulus
 Renal tubule
 PCT
 Loop of henle
 Thin descending loop of Henle
 Thick ascending loop of Henle
 DCT
 Collecting duct
• What are the renal transport mechanisms
in:
– Proximal convoluted tubule 60-70%
– Thick portion of ascending limb of the loop of

Henle. 25%
– Distal convoluted tubule 5-10%
– Cortical collecting tubule 5% (Aldosterone and

ADH)
Functions of Renal System
 Excretion of waste products
 Maintenance of acid-base balance
 Regulation of systemic blood
pressure
 Process of urine formation

 Glomerular filtration
 Tubular secretion
 Tubular re-absorption
Diuretic Drugs
These are drugs which increase the rate of

urine flow and sodium excretion and are used
to adjust the volume and/or composition of
body fluids in a variety of clinical situations,
including:
Hypertension, heart failure, renal failure, and
liver cirrhosis
• How could urine output be increased ?
↑ Glomerular filtration Vs ↓ Tubular reabsorption
(the most important clinically)
• Purpose of Using Diuretics

 To induce diuresis
 To facilitate the flow of fluid in edema (udder
edema, cerebral edema, glaucoma)
 Hypertension
 Hyperaldosteronism
 Congestive heart failure (CHF)
1. Carbonic anhydrase inhibitors
 Acetazolamide
 Site of action: PCT

 Mode of action: Inhibition of CA enzyme
 Effects:
 Prevents the reabsorption of water, carbon
dioxide and bicarbonte
 Partial inhibition of sodium reabsorption
 Enhanced flow of alkaline urine
Mode of action of Acetozolamide
In the lumen H+ react with HCO3- to form H2CO3
Acetozolamide
H2CO3 rapidly decomposes to Co2 & H2O by CA -
-
CO2 is lipophilic & rapidly diffuses across the luminal membrane
into epethelial cells where it reacts with H2O to form H2CO3 by CA
resulting in complete abolition
H2CO3 spontaneously ionizes to H & HCO3 (in the cell)
+ -
of NaHCO3 reabsorption
 blood volume  BP
HCO3- transported across basolateral membrane in exchange
for Na+ through Na+-HCO3-symporter
Net effect is transport of NaHCO3 from the tubular

lumen to interstitial space followed by movement of H2O
i.e.  blood volume  BP
Acetozolamide
Na+-H+ antiporter Na+-HCO3- symporter
Na+ Na+ Na+

Na +
H+ H+ HCO3- HCO3-
HCO3-
CA inhibitor
H2CO3 H2CO3
CA - - CA
CO2 + H2O CO2+ H2O
Lumen Blood
Clinical uses:
 Hydrocephalus (cerebral edema)
 Glaucoma
 To enhance urination
 Adverse effect:
 Systemic acidosis (due to reduced level of
bicarbonate in the plasma)
2. Osmotic diuretics
 Glycerol
 Mannitol
Site of action: Thin descending loop of Henle
Mode of action:
Increase the osmolarity of tubular fluid
Help to draw more water from
intracellular and interstitial environments
causing enhanced flow of urine
 Glycerol can be given orally however
sometimes it can cause vomiting
 Mannitol is unable to get absorbed after oral

administration
 Activation of rennin angiotensin

aldosterone system terminates their diuretic
action
3. Loop diuretics
Frusemide/Furosemide (Lasix)
Ethacrynic acid
Site of action: Thick ascending loop of Henle

Mode of action: Block the action of Na+/K+/2Cl
symport system
• Considered as most potent diuretics

Mode of action of Loop diuretics
Loop diuretics
Absorbed from GIT and go to site of action
Acts on the ascending loop of Henle
Inhibit Na+-K+-2Cl- symport
Reduced NaCl reabsorption
Diuresis   blood volume  BP

Loop diuretics
(Furosemide, Bumetanide, Ethacranic acid)
Na+-K+-2Cl- symport Na+ pump (Na+-K+ ATPase)
Loop diuretics
-
Na+ Na+ K+ K+
Cl- Cl- ATPase
K+ K+ Na+
Cl-
K+ Channel Cl- Channel
Lumen Blood
Effects:
• Diuresis
• Natriuresis
• Kaliuresis
Adverse effects:
• Ototoxicity
• Nephrotoxicity
• Hypokalemia
4. Thiazide diuretics
• Chlorothiazide
• Hydrochlorothiazide
 Site of action: DCT
 Mode of action: Block Na+/Cl- symport system
 Effects:
 Diuresis
 Natriuresis
 Commonly used to treat udder edema

Mode of action of Thiazide diuretics
Thiazide
Go to site of action by
Glomerular filtration & Tubular secretion
Acts on luminal membrane of distal collecting tubule

at distal tubule
 Na+-Cl- symport mechanism
 Na+ reabsorption
 Na+ excretion and diuresis   blood volume  BP

Thiazide diuretics
Na+ pump
Na -Cl symporter
+ -
K+ Channel (Na+-K+ ATPase)
Thiazide
-
Na+ Na+ K+ K+
ATPase
Cl- Cl- Na+
K+ K+ Cl-
K+ Channel Cl- Channel
Lumen Blood
Thiazide diuretics
Adverse effects
• Hyperuricemia ( serum uric acid)
• Hypercalcemia
• Hyperglycemia
Contraindications:
• Gout
• Diabetes mellitus
5. Potassium sparing diuretics
• Triamterone
• Amiloride
 Site of action: Collecting duct
 Mode of action: Block Na+/K+ antiport
system
 Effects:
 Diuresis
Natriuresis
Potassium retention
• Primarily used to treat cerebral edema
• These drugs can cause hyperkalemia so

they are contraindication in patients taking
potassium supplements
• Triamterone can cause megaloblastic

anemia
6. Aldosterone receptor antagonists
• Spironolactone
 Site of action: Collecting duct
 Mode of action: Interference with renin-
angiotensin-aldosterone system
Effects:
 Reduce the reabsorption of water and sodium
 Cause diuresis and natriuresis
 Reduce the osmolarity and osmolality of blood
Mode of action of Aldosterone receptor antagonists
Aldosterone (AL)
Aldosterone penetrates the cell from interstitial side and

binds with mineralocorticoid receptor (MR)
Spironolactone binds to MR
& prevent AL action
MR -receptor complex translocates to the nucleus & binds to

specific sequences of DNA and promote mRNA synthesis
 Na+ excretion and diuresis
 blood volume  BP
mRNA then directs synthesis of aldosterone induced proteins (AIPs)
The AIPs activate Na+ Channel, translocate Na+ channel to luminal

membrane, increase Na+ channel and Na+-K+ ATPase and ATP formation
from mitochondria
Na+ reabsorption and excretion of K+ and H+   blood volume   BP

Spironolactone
(Aldosterone receptor antagonist)
- Spironolactone
MR MR-AL AL
mRNA
Nucleus
Amiloride Na+-K+ ATPase
- AIP
Na+ Channel
Na+ Na+ Na+

ATPase
K
+ K+
K+
Lumen Blood
• Spironolactone is also used for the
treatment of hyperaldosteronism
Adverse effects:
• Impairment of the receptor occupancy of
testosterone and progesterone
• Can cause sexual dysfunction in case of
overdosage or prolonged use

Diuretics

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Pharmacology of Renal System

 Components of renal system

– Thick portion of ascending limb of the loop of

– Distal convoluted tubule 5-10%

– Cortical collecting tubule 5% (Aldosterone and

 Process of urine formation

These are drugs which increase the rate of

• Purpose of Using Diuretics

 Site of action: PCT

In the lumen H+ react with HCO3- to form H2CO3

Net effect is transport of NaHCO3 from the tubular

Na+-H+ antiporter Na+-HCO3- symporter

Na+ Na+ Na+

 Mannitol is unable to get absorbed after oral

 Activation of rennin angiotensin

Site of action: Thick ascending loop of Henle

• Considered as most potent diuretics

Absorbed from GIT and go to site of action

Acts on the ascending loop of Henle

Inhibit Na+-K+-2Cl- symport

Reduced NaCl reabsorption

Diuresis   blood volume  BP

Na+-K+-2Cl- symport Na+ pump (Na+-K+ ATPase)

K+ Channel Cl- Channel

 Commonly used to treat udder edema

Acts on luminal membrane of distal collecting tubule

 Na+-Cl- symport mechanism

 Na+ excretion and diuresis   blood volume  BP

Cl- Cl- Na+

K+ Channel Cl- Channel

• These drugs can cause hyperkalemia so

• Triamterone can cause megaloblastic

Aldosterone penetrates the cell from interstitial side and

MR -receptor complex translocates to the nucleus & binds to

The AIPs activate Na+ Channel, translocate Na+ channel to luminal

Na+ reabsorption and excretion of K+ and H+   blood volume   BP

Na+ Na+ Na+

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