DIURETIC DRUGS

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
 Glomerulus o le
ri
te
Ar
en t
Afferent Arteriole fer
Ef Juxta-glomerular apparatus (JGA)

Proximal Convoluted Tubule Distal

Convoluted
Tubule

Loop of Henle Collecting Duct

r tex
Co
u lla
d
Me
SITE 1 DIURETICS

CARBONIC
ANHYDRASE
INHIBITORS
SULFANILAMIDE

NH2 After its introduction for the treatment

of bacterial infections , it was observed
to produce a mild diuresis.

It was shown that it induced this effect

Through inhibition of renal Carbonic
Anhydrase .
- but weakly , severe side effect.
SO2NH2
To improve the CA inhibitory property of
sulfanilamide many sulfamoyl - containing
compounds ( - SO2NH2 ) were synthesized and
screened for their diuretic activity and their
ability to inhibit CA.

Two groups of CA inhibitors emerged:

1-Simple heterocyclic sulfonamides.

2- Metadisulfamoylbenzene derivatives.
 HETEROCYCLIC SULFONAMIDES

NH2

Sulfanilamide
H2NO2S

CH3
N N N N

H2NO2S S NH C CH3 NH C CH3

H2NO2S S
O O
Acetazolamide Methazolamid
( Diamox ) e
(Neptazane)
 STRUCTURE- ACTIVITY
RELATIONSHIPS
- The prototype is Acetazolamide .

N N The derivatives with the

highest lipid / water
CH3 partition coefficient and
H2NO2S S NH C
lowest pKa have the
O 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 acetazolamidos 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.

11
 Diuretics

Methazolamide, USP
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.

12
METADISULFAMOYLBENZENE DERIVATIVES SAR

Maximal diuretic activity is observed Substitution with an amino

When this position is substituted with: group increases saluretic ,
Cl , Br , CF3 or NO2 but decrease CA inhibitory
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 SO 2NH2
H2NO2S SO2NH2
Chloraminophenamide
Dichlorphenamide
( Daranide )
Carbonic anhydrase inhibitors
Clinical indications:
1. Given primarily to decrease intraocular
pressure by decreasing the rate of aqueous humor
formation to treat glaucoma
- Acetazolamide : ( Diamox)
- Methazolamide : ( Neptazane )
- Dichlorphenamide : ( Daranide )
 2. Urinary alkalinization
Will increase excretion of uric acid .

Acetazolamide will increase renal excretion of weak acids (i.e.

aspirin)
3. Acute mountain sickness

Symptoms: weakness, dizziness, insomnia, and nausea

Above 3,000 meters there is increase risk of pulmonary or

cerebral edema
Edema can be decreased if acetazolamide is taken 24 hours
before ascent
Toxicity
1. Diuretic effectiveness decreases significantly with use over 2-3
days because of bicarbonate wasting
Metabolic acidosis

2. Enhances renal stone formation

Calcium salts are relatively insoluble at alkaline pH

3. Renal potassium (K+) wasting occurs in the collecting ducts

 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
A) ORGANOMERCURIALS:
.THEY WERE THE MAIN DIURETIC THERAPY FROM 1926 TO THE EARLY 1950S

Limitations of the organomercurials

They cannot be given orally because of poor
and erratic absorption.
After their parenteral administration there is
a one- to two-hour lag in the onset of the
diuresis.
Their activity depend on the acid-base status
of the individual (i.e., they are ineffective
when the urine is alkaline),
They are cardio- and nephro-toxic
THE 5-SULFAMOYL-2- AND -3-AMINOBENZOIC ACID
.DERIVATIVES

3 H
X N R
Uses:
4

2

Edema, H2NO2S
5
1 COOH
6
Hypertension,
Hypercalciuria (i.e., R

an elevated urinary
N
concentration of 4 3
X
calcium) are prone to 2

the formation of 5 1

calcium-containing H2NO2S 6
COOH

stones within the

urinary tract.
:SAR OF 5-SULFAMOYL-2- AND -3-AMINOBENZOIC ACID DERIVATIVES

R
3 H
X 4 N R N
2 X 4 3
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
 :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-2-AMINOBENZOIC ACID-5
X 4 2 NH R

H2NO2S 5 1 COOH

- The substituents that can be tolerated on the 2- amino group are limited and no deviation are
allowed on the few moieties that are acceptable .
- Only furfuryl , benzyl and thienylmethyl (in decreasing order) yield derivatives of diuretic
Activity

>
R=
>
CH2 CH2 CH2
O S
furfuryl benzyl thienylmethyl

CL NH CH2 CL NH CH2
O O

H2NO2S N
COOH H2NO2S
N
Furosemide N
N
( Lasix ) Azosemide
 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
( Bumex )
 Adverse Effects:
1.Hypokalemic alkalosis.
2.Fluid and electrolyte losses
3.Reduction in plasma volume may result
from long-term use of these diuretics.
That leads to an increase in the
reabsorption of solutes normally handled
by the proximal tubule.
4. Hypersensitivity reactions such as
urticaria, fever, and interstitial nephritis.
Mechanism of Action:
They inhibit the 1Na+/1K+/2Cl- cotransport
system located on the luminal membrane
of cells of the thick ascending limb of
Henles loop
 PRODUCTS
Cl NH CH2
Furosemide, (Lasix). O
4-Chloro-N-furfuryl-5-
sulfamoylanthranilic acid H2NO2S COOH
Bumetanide. (Bumex)
3-(Butylamino)-4-phenoxy-
5-sulfamoylbenzoic acid.

NH (CH2)3CH3

Assay: H2NO2S COOH

1) Spectrophotometric in the UV region

2) Acid-base titration
 SYNTHESIS OF FUROSEMIDE

Cl Cl Cl Cl
1) ClSO3H

2) NH3
COOH H2NO2S COOH

Furfurylamine

, 130 C

Cl NH CH2
O

H2NO2S COOH
 Cl

PHENOXYACETIC ACIDS,
.ETHACRYNIC ACID, (EDECRIN)
Cl O CH2COOH
CH2
C
H3CH2C C

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
 PHARMACOKINETICS
Ethacrynic acid alkylate the Cl Cl

thiol endogenous O

compounds as glutatione H3CH2C O CH2 COOH

(RSH = glutathione) to give

the sulfhydryl-containing H H

conjugates, this conjugate is RSH

converted to the ethacrynic
acid-cysteine and ethacrynic Cl Cl
acid-N-acetyl cysteine O
conjugates. H3CH2C H O COOH

Ethacrynic acid-cysteine
conjugate is unstable in H S H

vitro and in vivo that release R

ethacrynic acid, cysteine.

Ethacrynic acid, ethacrynic acid glutatione, ethacrynic
acid-cysteine are equiefficacious diuretics.
 Cl

:SARS Cl O CH2COOH
CH2
C
H3CH2C C

Optimal diuretic activity is achieved when:

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 CH 3-) 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 to the
carbonyl on the acryloyl moiety.
5.Hydrogen atoms occupy the terminal position
of the carbon-carbon double bond of the
acryloyl moiety.
 PHENOXYACETIC ACIDS

- Non mercury containing compound . Activating gp(-Cl,-CH3)

occupy 3 position or 2&3
- Optimal diuretic activity is achieved when :

Cl Cl
O 3 2

CH3CH2 C O CH2 COOH

4 1

Alkyl subst. of H H Ethacrynic acid

2 to 4 carbon An oxyacetic acid moiety
( Edecrin ) Is placed in the 1-position
atoms in length
occupy the On the benzene ring
position to the
carbonyl on the A sulfhydryl reactive acryloyl moiety
acryloyl moiety.
is located para to the oxyacetic group
Hydrogen atoms occupy
the terminal position of the
C=C of the acryloyl moiety .
SYNTHESIS OF ETHACRYNIC ACID
Cl Cl Cl

Cl ONa Cl O CH2COOH AlCl3 Cl O CH2COOH

CH3CH2CH2COCL
+ ClCH2COOH
H3CH2CH2COC
2,3-dichloro sodium phenolate
HCHO
(CH3)2NH

Cl
Cl
Cl O CH2COOH
Cl O CH2COOH
OH
O
CH3CH2C C
CH3CH2CH C
CH2
H2C
N heat
H3C CH3 N
-NH-(CH3)2 H3C CH3

Cl

Cl O CH2COOH
CH2
C
H3CH2C C

O
 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
 5 4
Cl 6 N 3 R
:STRUCTURE-ACTIVITY RELATIONSHIPS
7 2 NH
1) The 2-position can tolerate small alkyl groupsH2as
NO2CH
S
3
. 8
S O
O 1

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.
 :ADVERSE EFFECTS

1) Hypersensitivity reactions, Cross-

hypersensitivity may also occur between
thiazides and sulfamoyl-containing diuretics.
2)Hypokalemia
3)A slight reduction in the cardiac output,
plasma volume and blood pressure.
4)Increase in the proximal tubule
reabsorption of luminal fluid and solutes due
to the reduction in plasma volume.
5)hypercalcemia or hyperuricemia.
6)Reduction in the glomerular filtration rate.
7)hyperglycemia
Uses:
Treatment of edema, hypertension.
 EXAMPLES OF THIAZIDE DIURETICS

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

sulfonamide 1,1 -dioxide O O

Hydrochlorothiazide
 :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
 Cl N CH2SCH2

Benzthiazide NH

(Hydrex)
H2NO2S S

O O
6-Chloro-3- Benzthiazides

[(phenylmethyl) F3C
H
N CH2
thio]methyl]-2H-1,2,4-
benzothiadiazine-7- H2NO2S S
NH

sulfonamide 1,1- O O

dioxide. Bendroflumethiazide

Bendroflumethiazide,
3-Benzyl-3,4-dihydro-
6 (trifluoromethyl)-
2H-1,2,4-
benzothiadiazine-7-
sulfonamide 1, 1-
 THIAZIDE-LIKE DIURETICS

The sulfamoyl group para to the

activating group of thiazides could be
replaced by several other electronegative
groups (X-) with retention of diuretic
activity (as R = amide, carbonyl, carboxyl
groups, etc) in the meta-
disulfamoylbenzene,
These diuretics known as thiazide-like
diuretics.
X R'
Their site
X of action,
R' efficacy, electrolyte
excretion pattern, and adverse effects
resemble the thiazides. H NO S R
H2NO2S SO2NH2 2 2
 3
Cl 2 4

CHLORTHALIDONE (1 1 OH
(HYGROTON) 5
H2NO2S 1
6
2 3
HN

O
2-Chloro-5-(1-hydroxy-3-oxo-1-
isoindolinyl)benzenesulfonamide.
Assay:
By chromatographic method (HPLC) for analysis
Synthesis: Cl 1) HNO
Cl
2

2)SO2 , CuCl2
H2N ClO2S

O COOH O COOH

SOCl2

Cl
Cl
OH NH3
Cl
H2NO2S
ClO2S
HN
O
O
O
 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.
 ALDOSTERONE ANTAGONISTS O

SPIRONOLACTONE, (ALDACTONE). 21
12 18O 17 20
11 13
19 16
1 14
7-(Acetylthio)-17-hydroxy-3- 2 9
15
10 8
oxopregn-4-ene-21-carboxylic H
7
acid -lactone
O 3 5 S CH3
4 6

Uses Adverse Effects

Treatment of edema
Antihypertensive agent.
Primary use is in
combination with diuretics
that act at site 2 or 3 to
reduce the kypokalemic
effect of the latter groups
of diuretics.
Hyperkalemia
Metabolic acidosis.
Gynecomastia in men and
Breast tenderness and
menstrual disturbances in
women because of its
residual hormonal activity.
Minor GIT symptoms.
 Aldosterone induction of Na+/K+ ATPase in distal DCT cell

Mineralocorticoid Receptor
Aldosterone

Na+/K+ ATPase
mRNA

Aldosterone is the principal mineralocorticoid. It is an adrenal steroi

The receptor is a member of the Nuclear Hormone Receptor family
:METABOLISM

Spironolactone is metabolized to Canrenone which is an

active aldosterone antagonist.
O O

O O

H H H H

O S CH3 O
Canrenone
O
 :SYNTHESIS

O O
O

O O
O
-2H CH3COSH
Thiolacetic acid
H H H H O
H H
O O S
O
TRIAMINO-6-ARYLPTERIDINES-2,4,7 8 1
,TRIAMTERENE
H2N 7 N N 2 NH2

N3
6 N 4
5
NH2
2,4,7-Triamino-6-phenyl-pteridine
SARs:
Para-substitution of phenyl ring with (-OH group) increase
activity
The phenyl group can be replaced by small heterocyclic
rings
The amino groups must be un-substituted.
It has a structural similarity to folic acid and certain
dihydrofolate reductase inhibitors, but it has little, if any,
of their activities.
Adverse Effects:
Hyperkalemia, renal stones formation, GIT sympotoms.
Uses:
Treatment of edema, hypertension .
Used in combination with other diuretics that act at site 2
 3. Pyrazinoylguanidines
O + - Over 25,000 agents were examined in an
NH2 Cl-
Attempt to discover an antikaliuretic with
Cl 6 N 2 C NH C NH
1 2 no hormonal activity .
5
- Optimal diuretic activity is observed
4 3
when
H2N N NH2 1- The 6 position is substituted with
chlorine.
Amiloride Hydrochloride 2- The amino group at 3 , 5 position are
( Midamor , Moduretic ) unsubstituted .
3- the guanidino nitrogen are not substituted
with alkyl group .
- Moderately plasma protein bound, oral bioavailability 15-20%, used in combination with
hydrochlorthiazide (Moduretic).

- Mechanism of Action: Plugs the sodium channels preventing electrogenic

reabsorption of 2-3% of the filtered Na+ . Directly blocks Na+ entry through
sodium-selective ion channels, which directly alters the Na+/K+ exchange
mechanism in the distal nephron

- Side effects: hyperkalemia,, nausea, vomiting, headache, diarrhea

PYRAZINOLYLGUANIDINES:
.AMILORIDE HYDROCHLORIDE
Uses and Adverse effects as triametrine
Synthesis:
O O

N CH3 Cl N CH3
O O
SO2Cl2

Benzene
N NH2 Cl N NH2

NH3
DMSO

O NH2Cl
O
Cl N
N NH2 Cl N CH3
H O
guanidine
H2N N NH2
H2N N NH2
 :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

 OH
OH
OH
MANNITOL HO
OH
OH

The prototypic osmotic diuretic,

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
 O
THEOPHYLLINE H
H3C N
N

O N N

CH3

The prototypic xanthine, is known

to promote a weak diuresis by
stimulation of cardiac function and
by a direct action on the nephron.
Although theophylline is
infrequently used as a diuretic, a
diuresis may be an observed side
effect when it is used as a
bronchodilator.