The main site of diuretic action is well established for the different groups of diuretics: carbonic anhydrase inhibitors act on the proximal tubulus, loop diuretics on the diluting segment, thiazides on the cortical diluting segment/distal tubulus, and potassium-sparing agents on distal tubulus/collecting ducts.

1. DIURETICS
Md. Saiful Islam
B.Pharm, M.Pharm (PCP)
North South University
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2. INTRODUCTION TO
DIURETICS
•Diuretics are drugs that increase the volume of
urine
•They are known as waterpills
•Used to treat high hypertension, heart
failure,kidney disease.
•Reduce the amounts of sodium and water
reabsorbed into the bloodstream
•Increase the amount of urine, draws excess
fluid from tissues and reduces the water content
of the blood.

3. Classification of Diuretics
Classified according to their action on the sites of
a nephron:
• Site-I Diuretics: Carbonic Anhydrase Inhibitors
• Site-II Diuretics: High-ceiling or loop diuretics
• Site-III Diuretics: Thiazide and thiazide-like
diuretics
• Site-IV Diuretics: Potassium sparing Diuretics

4. SITES OF ACTION OF
DIURETICS

5. CARBONIC ANHYDRASE (CA) INHIBITORS
(SITE 1 DIURETICS)
Carbonic anhydrases (CAs), the enzymes that
catalyze the conversion between carbon dioxide
and bicarbonate.
Properties of CA Inhibitors:
• Inhibit carbonic anhydrase within proximal
tubules
• Presence of a sulfonamide group (-SO2NH2) in
the DRUG structure is required for activity
• It results in impaired sodium, potassium, and
bicarbonate reabsorption

6. Site of Action
Site of Action:
• It acts on the CA present intracellularly and also in the
luminal brush border of proximal tubule.

7. MECHANISM OF ACTION:
• Site-I diuretics inhibits carbonic anhydrase
located intracellularly and on the apical
membrane of the proximal tubular epithelium.
• Carbonic anhydrase catalyse the reaction of
carbon-dioxide and water leading to carbonic
acid(H2CO3) which spontaneously ionizes to H+
and HCO3-.
• The decreased ability to exchange Na+ for H+ in
the presence of site 1 diuretics results in a mild
diuresis.
• Additionally , HCO3- is retained in the lumen with
marked elevation in urinary pH.

9. SITE I DIURETICS: CARBONIC
ANHYDRASE INHIBITORS
 Development of other major classes of
diuretics that are currently in widespread
use
 Aid in our understanding of basic renal
physiology.
Side effects:
• It results in impaired sodium, potassium,
and bicarbonate reabsorption
• It can alter the pH leading to alkalization
of urine.

10. Sulfanilamide :
 Bacterial infections
 A mild diuresis characterized by the presence of
urinary Na+ and a substantial amount of HCO3-.
 Through inhibition of renal CA.However, it was
relatively weak inhibitor of renal CA, and the
dose needed to exert adequate diuresis was
associated with severe adverse effects.

11. •
To improve on the CA-
inhibitory property of
sulfanilamide, many
sulfamoyl-containing
compounds (SO2NH2)
were synthesized and
screened for their
diuretic activity in vivo
and their ability to
inhibit CA in vitro.
Two groups of CA
inhibitors emerged:
1. simple heterocyclic
sulfonamides
2.Meta
disulfamoylbenzene
derivatives

12. STRUCTURAL DEVELOPMENT OF
SITE I DIURETICS:
• Heterocyclic sulfonamides:
SAR studies involves the
simple heterocyclic
sulfonamides, CA inhibitor,
i.e. acetazolamide.
• The sulfamoyl group is
essential for diuresis
production in vivo.
• It should be directly
attached to the hetero
aromatic ring.
• Reduction of this ring
decreases CA inhibitory
activity.

13. • The sulfamoyl nitrogen atom must remain
unsubstituted for diuretic activity. This
feature explains why all antibacterial
sulfonamides except sulfanilamide are
incapable of inhibiting CA or exerting
diuresis.
• Fusion of another ring with the hetero
aromatic ring may be possible which
would give higher diuretic activity (more
efficacy) but lesser potency than the
monocyclic ring.

14. • Substitution of a methyl group on one of
acetazolamide's ring nitrogens yields
methazolamide.
• Methazolamide
• The derivatives with the highest lipid/water
partition coefficients values have the greatest CA-
inhibitory and diuretic activities.

15. SAR: META DISULFAMOYL
BENZENE
Dichlorphenamine1,3-disulfamoyl
Benzene
• The parent compound, 1,3-disulfamoyl benzene has no
diuretic activity.

16. SAR: META DISULFAMOYL
BENZENE
– Sulfamoyl group at position – 1 should remain
unsubstituted
– The sulfamoyl group at position – 3 can be
replaced by similar electrophilic group
– Substitution at position – 4 with –NH2
increases saluretic activity
– Substitution at position – 6 with Cl-, F-, CF3-,
or NO2- gives maximum diuretic activity.

17. DEVELOPEMENT
• A reinvestigation of the sulfonamide diuretics belonging to
the thiadiazine and high-ceiling diuretic type provided
interesting clues regarding possible new applications of
sulfonamide CAIs (Carbonic Anhydrase Inhibitors)
• CA inhibitors were mainly used as anti-glaucoma agent
• In recent years, they are used in anti-obesity therapies
• CA inhibitors were also used as antiepileptic drugs
• Recently CA inhibitors are used in the diagnosis and
treatment of tumors.

18. PHARMACOKINETICS
• Rapidly absorbed from GIT, after oral
administration
• Undergoes little or no
biotransformation
• Attained at high conc. In Proximal
tubular cells, and renal luminal fluid
• Excreted primarily by the kidneys

19. USES
• Treatment of glucoma
• In metabolic alkalosis
• Renal excretion of weak acids
• Acute mountain sickness
• Acts as adjuvant in the treatment of
epilepsy.