Diuretic Drugs

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Diuretics (“water pills”) are the drugs which
increase the urine out put (or) urine volume .

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Diuretics
A chemical agent that increases the rate of urine formation.
Reabsorption of Na in the kidney results in the reabsorption of
water. It follows that inhibition of Na reabsorption will result in
diuresis. Because of this, the term diuretic has come to mean any
agent that will inhibit the tubular absorption of sodium.

Primary mechanism of most diuretics: direct inhibition of Na
transport at one or more of the four major anatomical sites in the
nephron, bec. Na transport at each of these location is unique,
different rigid str.al feature must be possessed to inhibit Na
reabsorp.
• Diuretics can be classified by their electrolyte excretion
patterns, they possess some combination of:

Natriuretic – enhanced sodium excretion

Chloruretic – enhanced chloride excretion

Saluretic – enhanced sodium chloride excretion

Kaliuretic – enhanced potassium excretion

Bicarbonaturetic – enhanced sodium bicarbonate excretion

Calciuretic – enhanced calcium excretion

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Classification
• Diuretics may be classifi ed under the following two categories:

I. Mercurial diuretics

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II. Nonmercurial diuretics
The nonmercurial diuretics may be classified on the basis of their
chemical structure as follows:

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Nephron sites of action of diuretics

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Carbonic Anhydrase Inhibitors

• Discovered shortly after the introduction of sulphanilamide as an antibacterial.

• It was observed that sulphanilamide also produced systemic acidosis and an
alkaline urine (HCO3− excretion).

• It was shown that this activity was a result of renal carbonic anhydrase (CA)
inhibition.

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HETEROCYCLIC SULFONAMIDES

NH2

Sulfanilamide
H2NO 2S

CH3
N N N N

H2NO2S S NH C CH3 NH C CH3
H2NO2S S
O O
Acetazolamide Methazolamide
( Diamox ) (Neptazane)
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STRUCTURE- ACTIVITY RELATIONSHIPS

-The prototype is Acetazolamide .

N N The derivatives with
the highest lipid / water
partition coefficient
H2NO2S S NH C CH3
and lowest pKa have
O the greatest CA
inhibitory and diuretic
activity.

The sulfamoyl group
is essential for the The sulfamoyl nitrogen atom
production of diuresis must remain unsubstituted to
retain the activity .
Structure – activity relationships

1- The sulfamoyl group is absolutely essential for the in vitro carbonic anhydrase
inhibitory activity.
2- The sulfamoyl nitrogen atom must remain unsubstituted to both in vivo and in vitro
activities This feature explains why all of the antibacterial sulfonamide except
sulfanilamide, are incapable of inhibiting carbonic anhydrase or exerting a
diuresis.
3- Substitution of a methyl group on one of acetazolamido’s ring nitrogens yields
methazolamide, a product that retains carbonic anhydrase inhibitory activity &
even more potent.
4- Sulfamoyl group must be attached to a moiety that possess aromatic character.
Methazolamide
CH3
CH3
N N
H2N
S O
N
S
O O

N-(3-Methyl-5-sulfamoyl-1,3,4-thiadiazol-2(3H)-ylidene)-acetamide

Methazolamide is more potent carbonic anhydrase inhibitor than acetozolamide (the
prototype), but is rarely used as diuretic. It is used in treatment of glaucoma, because it
displays improved penetration into the eye.
Metadisulfamoylbenzene derivatives SAR
Maximal diuretic activity is observed Substitution with an amino
When this position is substituted group increases saluretic ,
with: but decrease CA inhibitory
Cl , Br , CF3 or NO2 activity

SO2NH2 The sulfamoyl moiety can be
replaced with a similarly electrophilic
SO2NH2 An unsubstituted Group ( carbonyl , carbamoyl ) that may
sulfamoyl is of paramount increase diuretic potency While decreasing CA
importance inhibitory activity

Cl Cl NH2
Cl

H2NO2S SO2NH2
H2NO2S SO2NH2
Chloraminophenamide
Dichlorphenamide
( Daranide )
SITE 2 Diuretics, High ceiling or loop diuretics
The diuretics that belong to this class are of extremely diverse
chemical structure, such as

• 1. The organomercurial diuretics,

• 2. The 5-Sulfamoyl-2- and -3-aminobenzoic acid derivatives. For
example, furosemide and bumetanide respectively.

• 3. Phenoxyacetic acid derivatives as ethacrynic acid

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The 5-Sulfamoyl-2- and -3-aminobenzoic acid
derivatives.

3 H
• Uses: X 4
2
N R

• Edema, 5
1
H2NO2S COOH
• Hypertension, 6

• Hypercalciuria (i.e., an elevated R
urinary concentration of calcium) are
N
prone to the formation of calcium- 3
X 4
containing stones within the urinary 2

tract. 5 1
H2NO2S 6
COOH

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5-SULFAMOYL-3-AMINOBENZOIC ACID

R

N
X 3
2

H2NO2S 5 1 COOH

R= A wide variety of alkyl groups

H (CH2)3 CH3
N N
O O

H2NO2S COOH H2NO2S COOH
Bumetanide Piretanide
SAR of 5-Sulfamoyl-2- and -3-aminobenzoic acid
derivatives:
R
3 H
X 4 N R N
2 4 3
X
2
5
H2NO2S 1 COOH 5 1
6 H2NO2S COOH
6

1) The substituent at the 1-position must be acidic, The carboxyl group
provides optimal diuretic activity, but other groups, as tetrazole, may
have respectable diuretic activity.

2) A sulfamoyl group in the 5-position is essential for optimal high-ceiling
diuretic activity.

3) The activating group (x-) in the 4-position can be Cl- or CF3-, a
phenoxy-, alkoxy-, anilino-, benzyl-, or benzoyl- group
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SAR of 5-Sulfamoyl-2- and -3-aminobenzoic acid
derivatives:
1) Major differences between the two series of 5-sulfamoyl-benzoic acids in the
nature of the functional groups that can be substituted into the 2-and 3-positions
with the retention of maximal diuretic activity:
i) Substituent that can be tolerated on the 2-amino group of the 5-
sulfamoyl-2-aminobenzoic acid series are extremely limited, and no deviations are
allowed on the few moieties that are acceptable. For example, only furfural-,
benzyl-, and thienylmethyl (in decreasing order) yield derivatives with maximal
diuretic activity.
ii) Substituent, on the 3-amino group of the 5-sulfamoyl-3- aminobenzoic
acid can very widely without affecting optimal diuretic activity.
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Synthesis of Furosemide
Cl Cl Cl Cl
1) ClSO3H

2) NH3
COOH H2NO2S COOH

Furfurylamine

, 130 C

Cl NH CH2
O

H2NO2S COOH

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Cl

Cl O CH2COOH

Phenoxyacetic acids, CH2
C
Ethacrynic Acid, (Edecrin). H3CH2C C

O

 2,3-Dichloro-4-(2-methylene-1-oxobutyl)phenoxyacetic acid

 Uses:

 1.Same uses as cited for furosemide and bumetanide.

 2. Ethacrynic acid is prescribed for individual who has a known hypersensitivity to
Sulfamoyl containing drugs.

 Adverse Effects:

 1. Same adverse effects noted with. Furosemide and bumetanide except those related to
sulfamoyl group.

 2. Ototoxicity and GIT effects (GIT hemorrhage) more than furosemide and bumetanide,

 Mechanism of Action: As Furosemide
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Cl
SARs:
Cl O CH2COOH
CH2
C
H3CH2C C

Optimal diuretic activity is achieved when: O

1. An oxyacetic acid moiety is placed in the 1-position on the benzene ring,

2. A sulfhydryl-reactive acryloyl moiety is located para to the oxyacetic acid group,

3. Activating groups (Cl- or CH3-) occupy either the 3-position or the 2- and 3-
positions.

4. Alkyl substituent of two- to four-carbon atoms in length occupy the position α to
the carbonyl on the acryloyl moiety.

5. Hydrogen atoms occupy the terminal position of the carbon-carbon double bond
of the acryloyl moiety.
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Site 3 Diuretics, Thiazide and Thiazide-like
Diuretics
Cl NH2

H2NO2S SO2NH2

Acylating agent Aldehydes or Ketones

5 4 H R
Cl 6 N 3 R Cl N H

7 2 NH NH
H2NO2S S O H2NO2S S
8
O 1 O
O
Thiazides Hydrothiazides

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5 4
Cl 6 N 3 R
Structure-Activity Relationships:
7 2 NH
H2NO2S S O
8
O 1
1) The 2-position can tolerate small alkyl groups as CH3.

2) Substitutents in the 3-position determine the potency and duration of action of
the thiazides.

3) Saturation of C-C bond between the 3 and 4 positions of the benzothiadiazine-1,1-
dioxide nucleus increases the potency of this class of diuretics approximately 3-10
fold.

4) Direct substitution of the 4-, 5-, or 8-position with an alkyl group usually results in
diminished diuretic activity,

5) Substitution of the 6-position with an activating group is essential for diuretic
activity. The best substituent include Cl-, Br-, CF3-, and NO2- groups.

6) The sulfamoyl group in the 7-position is essential for diuretic activity.
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Examples of thiazide diuretics

Cl N
• Chlorothiazide
• 6-Chloro-2H-1, 2,4-benzothiadiazine-7-sulfonamide
NH
1,1-dioxide. H2NO2S S
• Hydrochlorothiazide, (Esidrix) O O
• 6-Chloro-3, 4-dihydro-2H-1, 2,4-benzothiadiazine-7- Chlorothiazide
sulfonamide 1,1 -dioxide H
Cl N

NH
H2NO2S S

O O
Hydrochlorothiazide

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Synthesis:
Cl NH2 Cl NH2

+ ClSO2OH

ClO2S SO2Cl

NH3

H
Cl N Cl NH2
HCHO

NH
H2NO2S S H2NO2S SO2NH2
O HCOOH
Hydrochlorothiazide O H2 HCOCl

Cl N

NH
Chlorothiazide H2NO2S S
O
O
OH2
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Site 4 Diuretics, Potassium-sparing diuretics

Diuretics that increase sodium and chloride excretion, without a concomitant
increase in the urinary excretion rate of potassium. These agents are known as
potassium-sparing diuretics or anti-kaliuretic agents.
Classification:
1) Aldosterone antagonists (e.g. Spironolactone)
2) Direct-acting diuretics (e.g. triamterene and amiloride)
Properties and uses:
These agents are not potent diuretics when used alone but, when combined with a
thiazide – eg, Aldactizide
They reduce potassium loss, increase sodium excretion
Minimize alkalosis.
The onset of diuresis with combination therapy is much more rapid than with
spironolactone alone.

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Aldosterone antagonists
Spironolactone

7-(Acetylthio)-17-hydroxy-3-oxopregn-4-ene-21-carboxylic acid -lactone

O

21

Uses 12 18O 17 20
Treatment of edema 19 11 13 16
1
Antihypertensive agent. 14
9
Primary use is in combination with 2
10 8 15
H
diuretics that act at site 2 or 3 to
reduce the kypokalemic effect of the O 3 5 7 S CH3
4 6
latter groups of diuretics.
O

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Osmotic diuretics:

• They have the following key features:

• 1. They are passively filtered by glomerular filtration.

• 2. They undergo limited reabsorption in the renal tubules

• 3. They are metabolically and pharmacologically inert,

• 4. They have a high degree of water solubility

• Examples, Mannitol, Theophylline

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OH
OH
Mannitol OH
HO
The prototypic osmotic diuretic, OH
OH
D-Mannitol is a water-soluble, lipid-insoluble hexahydroxy alcohol. It does not diffuse
GIT or renal tubule epithelium.

Mannitol should be given by the intravenous route.

Mannitol enters renal luminal fluid only by glomerular filtration. Its high luminal fluid
concentration creates an osmotic effect that may prevent the reabsorption of up to 28%
of the filtered load of water.

• Mannitol may be employed prophylactically to avoid acute renal failure or the reduction
of CSF volume and pressure.

• Because solutions of mannitol may expand the extracellular fluid volume, they should
not be used in patients with severe renal disease or cardiac decompensation.
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Thank You
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