The document covers the mechanism of urine formation and provides a comprehensive overview of diuretics, including their definitions, classifications, mechanisms of action, dosages, and adverse effects. It distinguishes between mercurial and non-mercurial diuretics and details various types such as osmotic, carbonic anhydrase inhibitors, thiazides, potassium-sparing, and loop diuretics, along with their specific uses and side effects. Additionally, it emphasizes the pharmacological applications and structural requirements necessary for diuretic efficacy.

1. -SUSHANT VIMALKUMAR SHETE
(T Y B PHARM ,RCP KASEGAON)
(sushantshete1998@gmail.com)

2. •Learning objective-
 Mechanism of urine formation
 Definition and classification of diuretics
 MOA and SAR of each class
 Their dose and adverse effects
 Pharmacologicaol uses

3. Mechanism of urine formation
Nephron- the functional unit

4. Definition-
Diuretics are the class of drugs which acts on kidney and
are used increase urine volume OR urine output by
increasing the water and sodium secretion in urine
Classification-
1 ) Mercurial Diuretics –
These diuretics contains mercury (Hg) ions in there structure.
They are toxic in nature.
They are less effective & some side effect.
They are less potent.
E.g. – Mersalyl , Meralluride
2) Non-mercurial Diuretics –
These diuretics do not contains mercury (Hg) ions in there
structure.
They are less toxic in nature.
They are more effective & less side effect.
They are more potent.

5. •According to part of nephron on they acting-
As) Omotic Diuretics - e.g. – Mannitol, Glycerol ,Urea,
Isosorbide
B) Carbonic anhydrase inhibitors – e.g. – Acetazolamide
C) Thiazides diuretics – e.g. -
Chlorthiazide,Hydrochlorthiazide,Hydroflumethiazide,
Clopamide
D) Loop Diuretics (High ceiling diuretics)–
i) Sulfamoyl Derivatives – e.g. – Furosemide,
Bumetanide,Torsemide
ii) Phenoxy acetic acid derivatives – e.g. – Ethacrynic acid
E ) Potassium sparing Diuretics –
i) Aldosterone antagonist – e.g.- Spironolactone
ii) Pteridine Derivatives - e.g. – Trimeterene
iii) Sod.channel antagonist - e.g. - Amiloride

6. Sites of action

7. A ) Osmotic Diuretics – E.g. – Mannitol Glycerol
 Structure –
 Site Of Action – Proximal convoluted tubule (PCT) &
loop of henle
 Dose -Usual, 250 mg 2 to 4 times per day.

8. MOA-
1. Retains water isoosmotically in PT-dilutes luminal
fluid which opposes NaCl reabsorption.
2. Inhibits transport processes in the thick AscLH by an
unknown mechanism. Quantitatively this appears to
be the most important cause of diuresis.
 3. Expands extracellular fluid volume (because it does
not enter cells, draws water from the intracellular
compartment)—increases g.f.r. and inhibits renin
release.

9. MOA-

10. Uses-
 drug of choice: non-toxic, freely filtered, non-reabsorbable and non-
metabolized
 administered prophylatically for acute renal failure secondary to trauma,
CVS disease, surgery or nephrotoxic drugs
 short-term treatment of acute glaucoma
 infused to lower intracranial pressure
Side effects-
•increased extracellular fluid volume
•cardiac failure
•pulmonary edema
•Hypernatremia
•hyperkalemia secondary to diabetes or impaired renal function
•headache, nausea, vomiting

11. Carbonic anhydrase inhibitor -
 Structure-
Eg Acetazolamide
•Site of action-
Proximal convoluted tubule
•Dose-
100 to 600 mg per day ; usual, 50 to 100 mg 2 to 3 times per day

13. MOA
 carbonic anhydrase catalyzes formation of HCO3- and H+ from
H2O and CO2
 inhibition of carbonic anhydrase decreases [H+] in tubule lumen
 less H+ for for Na+/H+ exchange increased lumen Na+,
increased H2O retention

14. USES-
 used to treat chronic open-angle glaucoma aqueous humor
has high [HCO3-]
 acute mountain sickness prevention and treatment
 metabolic alkalosis
 mostly used in combination with other diuretics in
resistant patients
SIDE EFFECTS-
 rapid tolerance
 increased HCO3- excretion causes metabolic acidosis
 Drowsiness,fatigue,CNS depression
 paresthesia (pins and needles under skin)
 nephrolithiasis (renal stones)
 K+ wasting

15. Thiazide Diuretics-Chlorothiazide, Hydrochlorothiazide
 Structure-
Chlorthiazide Hydrochlorothiazide
•Site of action-distal convoluted tubule
•Dose-
25 to 200 mg per day ; usual, 50 mg 1 or 2 times daily.

16. Chlorthiazide-
Hydrochlorthiazide-

17. MOA-
 inhibit Na+ and Cl- transporter in distal convoluted
tubules
 increased Na+ and Cl- excretion

18. Uses-
 Hypertension,congestive heart failure
 hypercalciuria: prevent excess Ca2+ excretion to form
stones in ducts
 nephrogenic diabetes insipidus
 treatment of Li+ toxicity
 hypokalemia
 hyponatremia
 hyperglycemia
 hyperuricemia
 hypercalcemia
Side effects-

19. Potassium-sparing diuretics
 Diuretics that increase sodium and chloride
excretion, without increasing excretion rate of
potassium in the urine. These agents are known as
potassium-sparing diuretics.
 Site of action – Collecting duct
 Classification:
 Aldosterone antagonist – Spironolactone
 Pteridine Derivative – Triameterene
 Pyrazine Derivative - Amiloride

20. N
NN
N
H2N NH2
NH2
1
2
3
4
5
6
7
8
Triameterene
Amiloride
N
NNH2
NH2
Cl C NH
O
HC
NH2
NH2
 Spironolactone

21. Mechanism of Action
 Spironolactone
 competitive antagonist of Aldosterone ,for
mineralocorticoid harmone & bind with receptor which is
essential for reabsorption of Na & Cl ions.
 prevents aldosterone & inhibit reabsorption of Na & Cl
ions in renal tubule.
 Triamterene/Amiloride
 inhibit Na+ ion channel therefore prevent entry of Na+
ion into the channel .

22. SAR
 Spironolactone
 Steroidal moiety & Acetyl thio group is essential.
 Triamterene
 Substitution at para position of
phenyl ring with (-OH group) increase activity.
 Substitution at para position of phenyl ring with (-
CH3 group) decreases activity.
 The phenyl group can be replaced by small
heterocyclic rings.
 The amino groups must be present because it is
essential for diuretic activity.
N
NN
N
H2N NH2
NH2
1
2
3
4
5
6
7
8

23. Amiloride
 1- The 6 position (Cl) is must be essential for activity.
 2- The amino group at 3 , 5 position are unsubstituted
because its important for diuretic activity .
 3- the guanidine nitrogen are not substituted with alkyl
group substitution leads to loss of diuretic activity.
N
N
Cl
H2N
C
NH2
NH C
NH2
NH2
O
1
4
2
Cl-
+
35
6

24. Uses-
•primary hyperaldosteronism (adrenal adenoma, bilateral
adrenal hyperplasia)
•congestive heart failure
•cirrhosis
•nephrotic syndrome
•in conjunction with K+ wasting diuretics
Side Effects
•hyperkalemia: monitor plasma [K+]
•spironolactone: gynecomastia
•triamterene: megaloblastic anemia in cirrhosis patients
•amiloride: increase in blood urea nitrogen, glucose intolerance in
diabetes mellitus

25. Loop Diuretics
 It is also known as High ceiling diuretics because it produces a peak
diuresis .
 Site of Action : Loop of Henle
Furosemide
Torsemide Ethacrynic Acid
H2NO2S
NH CH2
COOH
CL
O
N
CH3
NH
SO2NH- C
O
NH HC
CH3
CH3
C O CH2 COOH
Cl
O
Cl
H H
CH3CH2
1
23
4

26. Mechanism of Action
Loop diuretics mainly acts by preventing
or inhibiting reabsorption of sodium and
water into the loop of henle & produces
diuretic effects.

27. SAR of Sulphamoyl Derivatives
H2NO2S
NH
COOH
X R
5
2
1
4•Sulphonamide group is essential for the
Diuretic activity because mono and
disubstitution produces
loss of activity.
•Electron withdrawing group such as Cl, Br,
I, F & phenoxy also important for diuretic
activity.
• At 1st position acidic group is required or
must be present. E.g. COOH group in
Furosemide shows prominent effect.

28. SAR OF Phenoxyacetic acids
Ethacrynic acid
C O CH2 COOH
Cl
O
Cl
H H
CH3CH2
1
23
4
Ethacrynic acid
( Edecrin )
- Optimal diuretic activity is achieved when :
An oxyacetic acid moiety
Is placed in the 1-position
On the benzene ring
A sulfhydryl reactive acryloyl moiety
is located para to the oxyacetic group
Activating gp(-Cl,-CH3)
occupy 3 position or 2&3
Hydrogen atoms occupy
the terminal position of the
C=C of the acryloyl moiety .

29. Uses-
 Edema: cardiac, pulmonary or renal
 Chronic renal failure
 Hypertension & hypercalcemia
 Acute and chronic hyperkalemia
Side effects-
 hypokalemia
 hyperuricemia
 metabolic alkalosis
 hyponatremia
 ototoxicity
 Mg2+ depletion

30. Send your suggestions to sushsantshete1998@gmail.com