This presentation highlights on the introduction, classification, structures, SAR and mechanism of action of different Diuretics. Pharmacy students will be benefited by this content.

1. DIURETICS
Dr. Vishal S. More,
Assistant Professor,
Dept. of Pharmaceutical Chemistry,
Amrutvahini College of Pharmacy, Sangamner.

2. INTRODUCTION
The kidneys do the major work of urinary system.
The structural and functional units of kidneys are
Nephron.
The clinical importance of urinary system includes
hypertension, heart failure, renal failure, nephritic
syndrome, and cirrhosis.
The haemodynamics of renal system has a capability
to alter the aforesaid pathological conditions.

3. FUNCTIONS OF RENAL SYSTEM
Regulation of blood ionic compounds: The kidneys help to regulate
the blood ions, i.e., sodium (Na+), potassium (K+), calcium (Ca2+),
chloride (Cl-) and phosphate ions (HPO4
2-)
Regulation of blood pH: The kidneys excrete a variable amount of
hydrogen ions (H+) into the urine and conserve bicarbonate (HCO3
-)
ions, which regulate pH of blood.
Regulation of fluid volume: The kidneys adjust blood volume by
eliminating water in urine.
Regulation of blood pressure (BP): BP is regulated by kidneys
through an enzyme-renin secreted by juxta glomerular cells, which
activates the renin-angiotensin-aldosterone (RAA) pathway.
Increased renin causes increase in BP.

4. Maintenance of blood osmolarity: The kidneys produce two
hormones, calcitrol and erythropoietin. Calcitrol, the active form of
vitamin D helps to regulate calcitrol homeostasis and erythropoietin
stimulates the production of red blood cells (RBCs).
Regulation of blood glucose level: The kidneys can use the amino
acid of glutamine in gluconeogenesis and release blood to maintain
sugar level.
Excretion of metabolite waste products and foreign substances:
Metabolic products like ammonia, urea, bilurubin, creatinine, uric
acid, and other substances, i.e., toxins of exogenous compounds and
drug metabolites, etc., are excreted through urine.
FUNCTIONS OF RENAL SYSTEM

5. DRUGS ACTING ON URINARY SYSTEM
Renal haemodynamics is altered by diuretics in
clinical medicine.
The therapeutic applications of diuretics are mainly
concerned with hypertension and heart failure.
The normal renal physiological process includes
glomerular filtration and tubular reabsorption.

6. The nephron. BC, Bowman’s capsule; CD, collecting duct; DCT, distal
convoluted tubule; DLH, descending limb of the Loop of Henle; G,
glomerulus; PCT, proximal convoluted tubule; PST, proximal straight
tubule; TALH, thick ascending limb of the loop of Henle.

7. Na+
Cl–
S
Y
M
P
O
R
T
I
N
H
I
B
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T
O
R
S
THIAZIDES

8. H
Y
D
R
O
T
H
I
A
Z
I
D
E
S

9. C
A
R
B
O
N
I
C
A
N
H
Y
D
R
A
S
E
I
N
H
I
B
I
T
O
R
S
SULPHONAMIDE DERIVATIVES

10. SULPHOMOYL BENZOIC ACID DERIVATIVES
L
O
O
P
D
I
U
R
E
T
I
C
S HIGH CEILING DIURETICS

11. PHENOXY ACETIC ACID DERIVATIVE
L
O
O
P
D
I
U
R
E
T
I
C
S

12. K+
S
P
A
R
I
N
G
D
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U
R
E
T
I
C
S
PTERIDINE DERIVATIVE AND RELATED COMPOUND
ALDOSTERONE
INHIBITOR
STEROID

13. O
S
M
O
T
I
C
D
I
U
R
E
T
I
C
S
DIAMIDE
DIOL (OXYGEN
CONTAINING
HETEROCYCLE)
SUGAR
ALCOHOL

14. MODE OF ACTION OF THIAZIDES AND
HYDROTHIAZIDES
The sites of action for these drugs are cortical diluting
segment or DT. Here they inhibit Na+-Cl– symport at the
luminal membrane.

15. SAR OF THIAZIDE DIURETICS
•The 2nd position can tolerate the presence of small alkyl
groups such as CH3
•Substituents with hydrophobic character in the 3rd position
increases saluretic activity 1000 times.
•Substituents include –CH2Cl, –CHCl2, –CH2C6H5, –CH2S
•The increase in saluretic activity correlates with the lipid
solubility.

16. •Saturation of double bond between the 3rd and 4th position
of nucleus increases the diuretic activity approximately
3-fold to 10-fold. Example- Hydrochlorthiazide
•Hydrogen atom at the 2nd position is more acidic due to
the presence of neighbouring electron withdrawing the
sulphone group.
SAR OF THIAZIDE DIURETICS

17. A free sulphamoyl or potentially free sulphamoyl group at 7th
postion is essential for activity.
N7- Caproyl chlorthiazide is excreted as chorothiazide, the
loss of sulphamoyl group eliminates the diuretic effect, but
not the antihypertensive action, example, diazoxide.
• Direct substitution of the 4th , 5th , or 8th position with an
ethyl group usually results in diminished diuretic activity.
SAR OF THIAZIDE DIURETICS

18. •Substitution of the 6th position with an activating group is
essential for diuretic activity. The substiutents include Cl, Br,
and CF3 groups.
• The acidic protons make positive the formation of water-
soluble sodium salt that can be used for intravenous
administration of the diuretics.
SAR OF THIAZIDE DIURETICS

19. MOA OF CARBONIC ANHYDRASE INHIBITORS
CAse is an enzyme that is present in the PT that
catalyses the reversible reaction,
Carbonic acid spontaneously ionizes as:-
H2CO3 H+ + HCO3
-
CAse inhibitors reversibly inhibits CAse resulting in the
slowing of hydration of CO2 and decrease the availability of
H+ to exchange with luminal Na+ through Na+-H+
antiporter.

20. SAR OF CARBONIC ANHYDRASE INHIBITORS
Two groups of CAse inhibitors are:-
1. Heterocylic sulphonamides
2. Meta-disulphamoyl benzene derivatives

21. 1. HETEROCYLIC SULPHONAMIDES
 The C-2 Sulphamoyl Group is important for activity.
 The free sulphamolyl moiety is necessary to bind with Zn++
in the enzyme; hence, substitution of sulphamoyl group
gives inactive compound.
 The moiety to which the sulphamoyl group is attached must
be aromatic in character.
Aromatic

22.  The heterocyclic sulphonamides with higher partition
coefficient and lowest Pka value have greatest CAse
inhibitory and diuretic activites. Example- acetazolamide,
methazolamide.
 N-alkylation with methyl group on ring N- of acetazolamide
yields active compound (methazolamide).
N-alkylation

23. m-Disulphamoyl benzene do not have diuretic activity.
Substituted m-sulphamoyl benzene exhibits diuretic
activity.
The unsubstituted sulphamoyl moiety is essential for the
activity; any substitution leads to affect the potency of the
compound.
2. Meta-disulphamoyl benzene derivatives

24. The sulphamoyl moiety can be replaced with similar
electrophilic groups (e.g. carboxyl, carbamoyl) that may
increase the potency of the compound.
Maximum diuretic activity is obtained when 4th position is
substituted by Cl, Br, CF3, or NO2 group.
Substitution of amino group at 6th position increases
aleuronic activity, but decreases CAse inhibitor activity.

25. MODE OF ACTION OF HIGH CEILING OR LOOP
DIURETICS
A glycoprotein with 12 membrane-spanning
domains has found its function as
Na+-K+-2Cl--co-transporters. Many epithelia in
the loop of henle performing secretory absorbing
functions, loop diuretics attach to the chloride-
binding site of these proteins to inhibit transport
functions.

26. SAR OF LOOP DIURETICS
They are either 5-sulphamoyl-2-amino benzoic acid or 5-
sulphamoyl-3-amino benzoic acid derivatives.
The carbonyl group at C-1 provides optimal diuretic activity.
 The substitution of activating group (X) in the position 4 by
Cl, alkoxy, aniline, benzyl, or benzoyl group at 4th position
increases the diuretic activity.
 The presence of sulphamoyl group in the 5th position is
essential for activity.
 The two series of 5-sulphamoyl benzoic acid differ in the
nature of the functional group that substituted in 2nd and 3rd
position.

27. SAR OF LOOP DIURETICS
The presence of furfuryl, phenyl, and thienyl methyl group
at 2nd amino group of 5-sulphomoyl-2-amino benzoic acid
gives maximum diuretic activity.
The wide range of alkyl group can be substituted at 3rd
amino group of 5-sulfamoyl-3-amino benzoic acid without
modifying the optimal diuretic activity.
A molecule with a weakly acidic group to direct the drug to
the kidney and an alkylating moiety to react with sulphydryl
groups and lipophilic groups seemed to provide the best
combination of a diuretic in the class.

28. I. 5-SULPHAMOYL-2-AMINO BENZOIC ACID DERIVATIVES
The presence of
furfuryl, phenyl, and
thienyl methyl group
at 2nd amino group
of 5-sulphomoyl-2-
amino benzoic acid
gives maximum
diuretic activity.
Optimal
diuretic
activity

29. II. 5-SULPHAMOYL-3-AMINO BENZOIC ACID DERIVATIVES
The wide range of alkyl
group can be substituted
at 3rd amino group of
5-sulfamoyl-3-amino
benzoic acid without
modifying the optimal
diuretic activity.

30. MODE OF ACTION OF POTASSIUM SPARING
DIURETICS
Pteridine derivatives and related compounds,
Spironolactone- These drugs act on Na+ channel from the
luminal side and block the actions. Thus, it reduces the
lumen negative transepithelial potential difference, which
governs K+ and H+ secretion.

31. MODE OF ACTION OF OSMOTIC DIURETICS
Osmotic diuretics are nonelectrolytes, which are freely
filtered at the glomerulus and are not significantly reabsorbed
from the tubules, and presence of these agents in the urine
causes an increase in the electrolytes and volume flow.
Mannitol, urea, glycerol, and isosorbide are the four osmotic
diuretics, which are freely filtered through the glomerulus and
are insignificantly reabsorbed from the tubules; they mainly
induce diuresis by inhibiting sodium and water reabsorption in
the PTs and the henle’s loop.

33. Thank you