2. 2
Introduction
Ø
A diuretic is defined as drug that increases the rate of urine
formation.
Ø
The primary action of most diuretics is the direct inhibition of
Na+ reabsorption (increased excretion) at one or more of the
four major sites along the nephron.
Ø
An increased Na+ excretion is accompanied by anion like Cl-
Since NaCl is the major determinant of extracellular fluid
volume.
Ø
Diuretics reduce extracellular fluid volume (decrease in
oedema) by decreasing total body NaCl content.
3. 3
There are four major sites along the nephron that are responsible
for reabsorption:
Site 1: Proximal Convoluted Tubule (PCT)
Site 2: Ascending Loop of Henle
Site 3: Distal Convoluted Tubule (DCT)
Site 4: Late Distal Tubule and Collecting Duct
4. 4
Classification of Diuretics
1) Site 1 Diuretics : Carbonic Anhydrase Inhibitors
Acetazolamide, Methazolamide, Dichlorphenamide,
Chloraminophenamide.
2) Site 2 Diuretics : Loop diuretics (High Ceiling
Diuretics)
Furosemide, Bumetanide and Ethacrynic acid
3) Site 3 Diuretics : Thiazides
Chlorothiazide, Benzthiazide, Hydrochlorothiazide,
Hydroflumethiazide, Bendroflumethiazide.
4) Site 4 Diuretics : Potassium Sparing Diuretics
a. Na+ Channel Inhibitors: Triamterene, Amiloride
b. Aldosterone Antagonists: Spironolactone
5. 5
1) Site 1 Diuretics : Carbonic Anhydrase Inhibitors
Ø
Carbonic anhydrase (CA) inhibitors are derived from the
sulfonamide antibacterials.
Ø
The carbonic anhydrase inhibitors have an unsubstituted
sulfamoyl (—SO2NH2) group.
Ø
Some CA inhibitors have a heterocyclic ring and some
have benzene ring attached to sulfamoyl group.
Ø
Accordingly CA inhibitors have been divided into two
groups:
i) Simple heterocyclic sulfonamides
ii) meta-disulfamoylbenzene derivatives
6. 6
Mechanism of action
This class of diuretics inhibit carbonic anhydrase enzyme in the
membrane and intracellularly in proximal tubules that causes the
decreased reabsorption and increased excretion of Sodium,
Bicarbonates and Potassium.
Adverse Effects
Metabolic acidosis, Hypokalemia (decreased potassium),
decreased glomerular filtration rate, hypersensitivity reactions
Uses
Major use is in the treatment of Glaucoma because it reduces the
rate of formation of aqueous humor, thereby reducing the
intraocular pressure.
7. 7
Structural Activity Relationship
1) SAR involving simple heterocyclic sulfonamides
Acetazolamide is the most important compound of this group.
S
NN
H2NO2S NH C CH3
O
Acetazolamide
a) The sulfamoyl group is essential for activity.
b) The sulfamoyl nitrogen atom must be unsubstituted.
c) Substitution of a methyl group on one of the ring nitrogen
retains CA inhibitory activity, eg. methazolamide.
S
NN
H2NO2S N C CH3
O
CH3
Methazolamide
d) The moiety to which the sulfamoyl group is attached must
possess aromatic character.
8. 8
2) SAR studies involving meta-disulfamoylbenzenes
a) The parent 1,3-disulfamoylbenzene is inactive, but substituted
analogues have diuretic activity
b) Maximum diuretic activity is observed when the position 4 is
substituted with, Cl-, Br-, CF3 or NO2
c) An unsubstituted sulfamoyl moiety at position 3 is essential for
activity
d) Replacement of the sulfamoyl moiety at position 1 with an
electrophilic group (eg., carboxylic group) results in decreased
CA inhibitory activity
H2NO2S SO2NH2
1
2
3
4
5
6
H2NO2S SO2NH2
Cl
Cl
Dichlorphenamide1,3-Disulfamoylbenzene
(inactive)
9. 9
2) Site 2 Diuretics: Loop Diuretics or High Ceiling Diuretics
Diuretics that produce peak diuresis than other diuretics and
act distinctly on renal tubular function (at loop of Henle) are
called loop diuretics or high-ceiling diuretics.
There are three major classes of loop diuretics:
1) Organic Mercurials: Chlormerodrin Hg, Mercaptomerin,
Mersalyl etc
2) Sulfonamide derivatives such as furosemide,
bumetanide etc.
10. 10
1) Organic Mercurials
Ø
The mercurial diuretics essentially contain Hg++ in an
organic molecule.
The organic mercurials have a number of serious limitations:
Ø
When given orally they cannot be relied on to elicit diuresis
because of poor erratic absorption.
Ø
After parenteral administration there is a 1 or 2 hour lag in
the onset of diuresis.
Ø
Their ability to trigger a diuretic response depends on the
acid-base status of the individual (they are ineffective when
the urine is alkaline).
Ø
They are cardiotoxic and nephrotoxic.
11. 11
2) Sulfonamide Derivatives
These agents are 5-Sulfamoylbenzoic acid derivatives,
examples are Furosemide, bumetanide etc.
H2NO2S COOH
Cl NH
CH2
O
Furosemide
Bumetanide
H2NO2S COOH
O
NH
(CH2)3 CH3
1
2
3
4
5
6
1
2
3
4
5
6
There are two series of 5-sulfamoylbenzoic acid derivatives,
that differ in the nature of the functional groups that can be
substituted at 2 and 3 positions.
a) 5-sulfamoyl-2-aminobenzoic acid: Furosemide
b) 5-Sulfamoyl-3-aminobenzoic acid: Bumetanide
12. 12
Structural Activity Relationship
Ø
The substituents at the 1 position must be acidic. The carboxylic
group provides optimal diuretic activity, but other groups such as
tetrazole impart good activity.
Ø
A sulfamoyl group at the position 5 is essential for optimal diuretic
activity.
Ø
The ‘activating’ group at the 4 position can be Cl- or CF3- as in
thiazide diuretics. Better activity was observed when these groups
have been replaced by phenoxy, alkoxy, aniline and benzyl
moieties.
Ø
The substitutions possible on the 2-amino group in 5-sulfamoyl-2-
aminobenzoic acid derivatives is limited in the order furfuryl >
benzyl > thienyl methyl only
Ø
In case of 5-sulfamoyl-3-aminobenzoic acid the 3-amino group
can be widely substituted without much change in the activity.
13. 13
3) Non-sulfonamide Loop Diuretics
Ethacrynic acid is a phenoxyacetic acid derivative which is the
only important member of this class of drugs.
C
Cl Cl
OCH2COOHCCH2CH3
O
CH2
Ethacrynic acid
1
23
4
Structure Activity Relationship
Ø
Activating group (Cl- or CH3-) occupy either the 3 position or the 2
and 3 positions.
Ø
An Acryloyl moiety which reacts with sulfhydryl containing receptor
present in renal tissues should be at the para to the oxyacetic acid
group.
Ø
Reduction or epoxidation of the carbon-carbon double bond in the
acryloyl moiety yielded compounds with little or no diuretic activity.
14. 14
3) Site 3 Diuretics : Thiazides and Thiazide like Diuretics
These agents are 1,2,4-benzothiadiazine-1,1-dioxide derivatives and
are known as thiazides and hydrothiazides (lacking double bond at
position 3-4).
Thiazide Diuretics
H2NO2S
R N
S
NH
R1
O O1
2
3
45
6
7
8
Name R R1
Chlorthiazide -Cl -H
Benzthiazide -Cl CH2S-H2C
15. 15
Hydrothiazide Diuretics
H2NO2S
R N
H
S
NH
R1
O
O1
2
3
45
6
7
8
Name R R1
Hydrochlorothiazide -Cl -H
Hydroflumethiazide -CF3 -H
Mechanism of Action
These block the reabsorption of Na+ (and thereby, the reabsorption
of CI-) in the distal convoluted tubules by inhibiting the luminal
membrane-bound Na+ /CI- cotransport system.
16. 16
Adverse Effects
Hypersensitivity reactions, Hypokalemia, slight reduction in the
cardiac output
Uses
Extremely useful in the treatment of edema associated with mild to
moderate congestive heart failure. Other uses include hypertension,
diabetes insipidus etc.
Structure Activity Relationship
a)Substitutions at position 2 with small alkyl groups such as methyl (-
CH3) does not change the activity
b)Substituents at position 3 determine the potency and duration of
action of the thiazide diuretics.
c)Loss of the carbon-carbon double bond between the 3 and 4
positions of the thiazide nucleus increases the potency approximately
3 to 10 folds.
17. 17
d) Direct substitution at 4, 5 or 8 positions with an alkyl group
usually diminishes diuretic activity.
e) Substitution at the 6 position with an ‘activating’ group is essential
for diuretic activity. The best substituents include Cl-, Br-,
CF3- and NO2- groups. For example replacement of 6-Cl- by 6-
CF3 does not change potency, whereas replacement with CH3
reduces diuretic activity.
f) The sulfonamide group at the position 7 is essential for diuretic
activity. Removal of this group yields compounds with little or
no diuretic activity.
H2NO2S
R N
S
NH
R1
O
O1
2
3
45
6
7
8
18. 18
4) Site 4 Diuretics: Potassium Sparing Diuretics
Ø
A negative feature of all of the above discussed classes of
diuretics is that they increase the renal excretion rate of K+
and can induce hypokalemia.
Ø
Three chemically distinct diuretics have emerged that
increase Na+ and Cl- excretion without a concomitant
increase in the urinary excretion rate of K+. These agents
are known as Potassium-sparing diuretics.
Ø
The potassium sparing diuretics are divided into two groups
on the basis of mechanism of action
a) Na+ channel inhibitors: triamterene and amiloride
b) Aldosterone antagonists: Spironolactone
19. 19
a) Na+ channel inhibitors
Mechanism of action
Ø
Amiloride and triamterene inhibit the sodium channel in the
luminal membrane of collecting tubule and collecting duct.
Ø
Inhibition of the sodium channel thus not only inhibits Na+
reabsorption but also inhibits secretion of K+ and H+,
resulting in conservation of K+ and H+.
Ø
Triamterene is an aminopteridine derivative and has a
structural resemblance to folic acid whereas Amiloride is a
pyrazinoguanidine derivative
N
N
N
N
NH2
NH2NH2
Triamterene
N
N
CCl
NH2NH2
NH C NH2
NHO
1
2
3
4
5
6
Amiloride
must be unsubstitutedmust be unsubstituted
essential for activity
20. 20
b) Aldosterone Antagonists
Ø
Spironolactone is the only available aldosterone
antagonist. A metabolite of spironolactone, “canrenone”, is
also active.
Ø
Spironolactone is steroidal derivative, structurally related to
progesterone
Mechanism of action
Ø
Aldosterone, by binding to its receptor enhances the
passage of Na+ from the luminal fluid into tubular cells
(Na+ reabsorption) and the passage of intracellular K+ into
the luminal fluid at site 4.
Ø
Spironolactone competitively inhibits binding of aldosterone
to its receptor and abolishes its biological effects.
22. 22
REFERENCES
•
Wilson and Gisvold’s Textbook of Organic,
Medicinal and Pharmaceutical Chemistry;
John H. Block, John, M. Beale, Jr.;
Lippincott Williams and Wilkins.
•
Graham L. Patrick, An Introduction to
Medicinal Chemistry, Fourth Edition,
Oxford University Press, New York, 2009,
230-235
