Diuretics

Roll no.
Farva Arshad 2366
Alishba Arif 2332
Maham Ishfaq 2342
Shahnila Asif 2322
  Diuretics:
“The simplest definition of a diuretic is that it is a agent that increases the rate of
urine formation.”

Natriuretic: (Sodium excreting)

The agents which increases the excretion of sodium .

Saluretic:
The agents which increases the excretion of salts.

Kidney:
Plays a major role in regulating the volume and chemical composition in body’s internal environment .

Nephron:
is the basic structural unit. Each kidney contains approx “1-Million” such units.

Kidneys in normal healthy young adult handle, blood flow in 1-200 lit/min.
The Major portion of filterate is reabsorbed from proximal distal tubule.
The unwanted material are left behind and excreted along with H 2O …………..
o There are four main sites for the action of
diuretics in Nephron.

1) Proximal Convoluted Tubule

2) Thick Ascending Limb. (Loop of Henle)
3) Distal Convoluted Tubule
4) Collecting Tubule
 Uses of Diuretics:

• Main uses of Diuretics are:

•Cardiac Oedema (related to Congestive Heart Failure)
•Nephrotic Syndrome.
•Diabetes Insipidus.
•Natural Oedema.
•Cirrhosis of the Liver.
•Oedema of Pregnancy.
•Used to lower Intraocular and cerebrospinal Fluid Pressure.
Site-1 Diuretics:

Carbonic Anhydrase Inhibitors:

Introduction of sulfonamide as “Anti-Bacterial.” it was
observed to produce “Mild Uresis."
Are weak Diuretics.
 Successful research for more potent duration is
ensured.

These agents inhibit the carbonic Anhydrase enzyme.

How Carbonic Anhydrase enzymes act?

 Luminal Membrane Proximal Tubule Cell Pre Tubular
Capillary
H2O H2O
+ +
CO2 CO2

carbonic
anhydrase

H2CO3 H2CO3

H H
+ +
HCO3 HCO3 HCO3

Na Na Na
Enzyme increases the rate at which Equilibrium is obtained.
C-A is present in Luminal membrane causes Dehydration.

H2CO3 CO2 + H2O

CO2 entered in the proximal Tubule cell combine and

H2O and from carbonic acid
C-A increases the hydration.
CO2 + H2O H2CO3
• H+ produced secreted through Luminal membrane
into Tubular Lumen in Exchange of Na+.
Na+ which inter the tubular cell, and HCO3 produced
in tubular cell then enter peritubular blood supply.

At proximal tubule 75% glomerular filtration is

reabsorbed. Reabsorption of Na+ simultaneously
with iso-osmotic amount of H2O.
 Inhibition of Carbonic Anhydrase:

Carbonic acid is thought to be normal substrate thus fits into the

cavity and complexes with enzyme. Complex is strongly
stabilized by with force of H-bonding. R

Enzymes: C O H
O
S H

O H
O H O H
N R
H
H O
R N H
N H O C

Carbonic Acid Enzyme Sulfonamide(C-A-T)

Sulfonamides:
Have equally good geometry to fit in the cavity
of enzyme and have the same four areas of H-
bonding.
Sulfonamides competitively prevent the binding of
Carbonic acid on enzyme, so inhibit the action of
enzyme So acid base imbalance occurs and ultimately
dieresis.
• Development of Carbonic Anhydrase Inhibitors:
Sulfonamides:
Introduced as anti-Bacterial agents in 1930s.
It was observed that it also produces the Diuresis. Later it
was seen, this effect is due to the
Inhibition of Carbonic Anhydrase.
However it was also seen that inhibition is Weak. Dose
needed for adequate diuresis causes severe side effects.
Attempts were made to improve the CarbonicAnhydrase
inhibitory propertyofsulfonamides.
Several sulfonamide derivatives were synthesized and
screened for then
Diuretic property in vivo Carbonic Anhydrase inhibitory
activity in Vitro.
This group emerged Heterocyclic sulfonamides, M-
Disulfamoyal Benzene derivatives.
 N N O N N
O
NH-CH-CH3
H2NO2S S H2NO2S S N C CH
3
Acetazolamide Methazolamide

HeteroCyclic Sulfonamide

NH2

Sulfanilamide

H2NO2S

M-Disulfamoyal (Benzene)

Cl Br CF3 NH2

NH2

H2NO2S SO2NH2
 Cl CH3

SO2NH2
H2NO2 Cl
S

Cl
SO2NH2
SO2NH2
DiChloro Phenamide Disulfamide
 N N
Acetazolamide:
NH2 + NH2-H2O + NH4SCN
Synthesis H2N S
Hydrazine Ammonium
hydrate Thiocyanate S H2N

1,2 (Thiocarbamoyl)
Hydrazine
 Phosgene

N N
N N
Acylation
O
Aq.Cl2
H3C N
SO2Cl Oxidation
H S H2N SH
S

NH3

N N
O
Acetzolamide
H3C C NH SO2NH2
Uses:
Used in drug induced oedma.
Also used in cardiac oedema.
Used to lower intra-occular pressure prior to surgery
in acetate conditions of angle
closure Glaucoma.
Used in epilepsy.
 Methazolamide:
Synthesis

N N
N N Cl H2C
O Cl
N S
H3C HN SH P-Chloro benzyl
S
S chloride O C CH3
2-Acetamido- CH3
5-mercapto-
1,3,4-Thiadiazole
Cl
CH3ONa
CH3Br

H3C N N

O S CH2
S
H3C C NH
 Oxidation
AqCl2

H3C N N

O SO2Cl
S NH3
H3C C N Amidation

H3C N N

O SO2NH2
S
H3C C N

Methazolamide
Uses:

•Actions are similar to that of Acetazolamide, but has

less onset of action and longer duration of action.
Diclofenamide (Dichlophenamide):
Synthesis: OH OH

Cl ClSO2 Cl
+ ClSO2OH

o-Chlorophenol Chlorosulfonic acid

SO2Cl

NH3

Cl OH

H2NSO2 Cl H2NSO2 Cl

PCl5

SO2NH2 SHO2NH2
Diclofenamide

Uses:
•To lower the intraocular pressure by reducing the secretion
of aqueous humor
•Recommended for the treatment of both primary and
secondary glaucoma
Disulfamide:
Synthesis: OH OH

Cl ClSO2 Cl
+ ClSO2OH

o-Chlorophenol Chlorosulfonic acid

SO2Cl

NH3

Cl OH

Cl H2NSO2 Cl
H2NSO2

PCl5

SO2NH2 SHO2NH2

Diclofenamide

•Actions are similar to that of chlorothiazide

•Used in the treatment of oedema.
Structure activity of carbonic anhydrase inhibitors:
Heterocyclic sulfonamide:
Prototype drug.
4 N N3

O
5
2
H2NO2S NH C CH4
S
1
Acetzolamide

•Sulfamoyl group is absolutely essential for the inhibition of

carbonic anhydrase and hence for dieresis.
•The sulfomyl nitrogen atom must remain unsubstituted for
activity.
•This is feature to all sulfonamides are inactive except
sulfanilamide.
Substitution of methyl group on one of the ring
nitrogen group retain the activity e.g. Methazolamide
Disulfamoyl benzene derivatives:
•Only 1,3 disulfamoyl benzene lack diuretic activity

Inactive

SO2NH2
NH2SO2

•Key substitution led to compounds with diuretic activity

e.g.
Cl

Cl

H2NO2S SO2NH2

Dichlorphenamide
Site II Diuretics :
Loop Diuretics or high ceiling diuretics:
There are three groups
•Organomercurials
•Anthanilic acid derivaties (2 Amino benzoic acid) & 3
Amino benzoic acid derivatives.
•Phenoxy acetic acid derivatives
Organomercurials:
They cause dieresis by an inhibition of sodium
reabsorption at site II
Organomercurials have several serious limitations due
to which they are not used now. Now they are replaced
with other diuretics
•Not reliable diuretic when given orally due to poor
and erratic absorption.
•When given parentrally, onset of action is two-hours.
•Diuretic response is acid base dependent.
•Ineffective when urine is alkaline.
•They are cardio & nephro toxic.
They are absolutely withdraw on the introduction of
Thiazides and thiazide like agent i.e. Frusemide.
Anthracitic acid derivatives (2 amino benzoic acid) &3 amino
benzoic acid derivative:
Mechanism of action:
They inhibit the | Na+| |K+| 2Cl- co transport system located on
luminal membrane of cells of their ascending limb of Henle’s loop
•They inhibit the reabsorption of sodium, chloride ions from the
ascending f Henle (Site II)
•Approximately 20% to 25% of filtered load of sodium that is
normally reabsorbed at this segment is inhibited.
•Destroyed the hypertonicity of medullary interstitium which is due
to 20 to 25% sodium reabsorption
•20-25% filtered sodium along with chloride and water is excreted
causes diuretic.
•Their actions are independent of acid base balance.
•Molecular basis of action is not known. However the furosemide
causes the renel vasodilation and increases the glomerular
filteration.
Frusemide (lasix):
Synthesis:
COOH COOH

Cl
Cl
(1) ClSO2OH

NH2SO2

Cl Cl
Chlorosulphonic acid
2,4-dichlorobenzoic acid O
NH2 CH3
(2) NH3 (Amidation)
COOH Furfuryl amine

NaHCO3

O
NH2O2S NH CH2

Cl
Frusemide
Uses:
•High efficacy
•Rapid onset of action
•Short duration of action
•Used for the treatment of oedema associated with
renal disease nephritic syndrome, cirrhosis of liver and
congestive heart failure.
•It has a edge over other diuretics when greater
diuretic effect is required.
•May employed in the treatment of hypertension
Bametanide:
COOH

H2NO2S NH(CH2)3CH3

3-Butylamino,4-phenoxy,5-sulfamoylbenzoic acid

Uses:
•Used in the treatment of renal insufficiency.
•Used in oedema.
•Used in drug poisoning e.g. Barbiturate poisoning in
attempted suicide.
Structure activity relationship:
Common structural requirements for

CHOOH CHOOH

1 1
NH2
6 2 6 2

5 3 5 3
4 4
H2NO2S NH2 H2NO2S

X X
3-Aminobenzoic acid derivative 2-Aminobenzoic acid derivative

•At 1- position substitution should be acidic e.g. COOH group provide optimal
activity but Tetrazole may shows the respectable diuretic property
•Sulfamoyl at -5 position is essential for optimal high ceiling diuretic activity.
•Activating group X at position-4 Cl & CF3 at position are substituted for diuretic
activity like thiazide.
These may be replaced with Phenoxy, Aloxy, Aniline, benzyl, benzoyl.
Major differences:
2 Amino group
Extremely limited
No derivations are allowed
e.g. only Furfuryl, benzyl, thinylmethyl yield derivation
with maximal diuretic activity.
Substitution on 3 Amino group:
Widely substituents are allowable on 3 Amino group
without (jeopardizing) the optimal diuretic activity
E.g. Bumetanide.

(CH3)2 CH3
Butyl group
Phenoxy acetic acids

 Ethacrynic acids:
 Mechanism of action:
 It inhibits the reabsorption of 20% to 25% of filtered load
of sodium at site-2 i.e. 1Na+|1K+|2Cl- cotransport system.
Located on the luminal membrane of cells in thick
ascending limb of Henle’s loop.
 Decrease the glomerulus filteration through feedback
mechanism.
 Ethacrynic acid induces acute increase in renal excretion
rate of sodium, chloride, potassium and calcium.
Synthesis:

OCH2CH2COOH
O

+ CH3CH2CH2 C Cl
Cl

Cl

2,3-dichlorophenoxy acetic acid Butryl chloride

Friedel craft reaction

 OCH2COOH
O

CH3 CH2 CH2 C

H C H Formaldehyde
+

(CH3)2NH Dimethylamine
 O

OCH2 C OH
O

CH3 CH2 CH2 C Cl

Cl

Ethacrynic acid
Uses:

It has same indications cital for frusemide and

bumetonides.
When high ceilig diuretic is indicated to the
individual who have known hypersensitivity to
sulfamoyl containing drugs.
Ethacrynic acid is better substitute.
Structure activity relationship:

Cl Cl
O
3
2

4 1
CH3 CH2 C C OCH2 COOH

5 6

CH2
For optimal activity in phenoxy acetic acid
derivatives, phenoxy acetic acid moity is placed on
position 1 in benzene ring.
Acrylolyl moity located para position to phenoxy
acetic acid.
Activity group i.e. Cl or CH3 should be on 3 or 2
and 3 position.
Alkyl group of 2 to 4 carbons atoms should be on
the α- position of carbonyl on acryloyl moity.
 Site III diuretics:
Thiazides and thiazides like diuretics:
Development of thiazides
Chloraminophenamide
It is an intermediate in the development of diuretics which
undesirable proportions of carbonic anhydraseinhibitors
which are as follows.
Metabolize acidosis.
Hypokalemia.
Decrease glomerular filteration.
Sulphonamide sensitivity.
e.g. utricaria, drug fever, interstitial nephritis.
So safer diuretics are obtained from chloraminophenramide.
 Cl NH2

H2NSO2 SO2NH2

Chloraminophenamide

O Aldehyde ketone

H
H

Cl N R Cl N R

H
NH N
S H
H2NSO2 S
H2NSO2
O
Thiazide O

Hydrothiazide
Orally active.
Not influenced by acid base balance of the individual.

Mechanism of action:
It inhibit the reabsorption of sodium (and then by
chloride) in “distal convulated tubules” or in connecting
tubules.
Short system that connect distal tubule to cortical
collecting tubules.
They excrete about 5 to 8% of filtered load of Na+.
Inhibition of sodium reabsorption at site-3. Delivered
more filtered load of sodium at faster rate at site-4.
There is exchange of luminal fluid sodium for intracellular
potassium.
Increases the excretion of potassium.
Most of thiazides possess carbonic anhydrase activity that
is associated with slight increase in the renal excretion of
bicarbonate.
Resistance like carbonic anhydrase inhibitor is not
developed in thiazides.
Thiazides:
Chlorthiazides synthesis:
Cl Cl
NH2 NH2
-H2O2
+2ClSO2OH

H H ClO2S SO2Cl

3-Chloramiline Chlorosulphonic 3-Chloramiline

acid 2,6-Disulphonyl Chloride

2NH3
 Cl NH2

H2NSO2 SO2NH2

H C OH
Formic acid

Cl
N

NH
H2NO2S S

O O

Chlorothiazide
Uses:

Use in the treatment of oedema assosiative with

congestive heart failure, renal and hepatic disorders.
Also used in the treatment of hypertension or in
combination with other antihypertensive drugs.
Also used in oedema associated with corticosteroid
therapy.
Hydrochlorthiazide:

H
O
Cl Cl N
NH2
H C H H
NH
H2NO2S SO2NH2 Formaldehyde NO2S S

3-Chloramiline O O
4,6-Disulphonamide H
Hydrochlorothiazide
 Uses:

actions are similar to chlorthiazide but it is 10 times

more potent than the chlorthiazide.
Prolong uses causes hypokalemiawhich may be
presented by supplymentation of potassium salts.
 Cyclopenthiazide
Cl O
NH2

+H C CH2

H2NO2S SO2NH2 Cyclopentyl

acetaldehyde

Condensation
-H2O

Cl N
CH2

NH
H2NO2S S

Cyclopenthaizide
Uses:
Possess actions and uses similar to those of
chlorthiazide
Bendroflunethiazide:
Synthesis:
O

HF3CO2 H C CH2
NH2

Phenylacetaldehyde

H2NSO2 SO2NH2

3-Amino,triflyromethyl
2,4-Disulphonamide

F3 C N
CH 2

N
H2NO2S S

O O

Bendroflumethiazide
Uses:

Use to control and management of oedema,

nephrosis, nehritis, cirrhosis, ascites, congestive
heart failure.
Also use to control hypertension.
 Other thiazide:
Bezthiazide:

Cl N
CH2 S CH2

NH
NH2O2S S

O O

Benzthiazide

•Similar actions as that chlorthiazide.

 Methycyclothiazide:

Cl N
CH2Cl

N CH3
H2NSO2 S

O O

Methycyclothiazide

•100 times more potent than chlorthiazide.

Polythiazide:

Cl N
CH2 SCH2 CF3

N CH3
H2NSO2 S

O O

Polythiazide

•Long acting diuretic and antihypertensive

agent
 Structure activity
relationship:

•At position-2 small alkyl group e.g. Ch3 can be substituted. E.G. Methylchlothiazide.
•Position-3 is important for molecular modification.
•Substituent at position-3 play dominant role in determining potency and duration of
action.
Methylchlothiazide:
100 times more potent than that Chlorthiazides
•Loss of double bond between 3 and 4 position increases the potency from 3-10 times.
•Substitution at 4, 5 or 8 position decreases the activity.
•At 6 positions the substitution of activating group is essential for diuretic activity. e.g.
Cl, Br, cf3 and no2 groups.
•The sulfomoyl group at position 7 is prerequisite for diuretic activity.
•Sulfomoyl group Para to activating group in meta Disulfamoyal benzenes can be
replaced with other electronegative group with the retention of diuretic activity.
These are called Thiazide like diuretics because they have same site of action, efficacy,
electrolyte excretion pattern and adverse effects.
e.g.
 5 4N
R R1
3
6

1 N 2
7
H2N2OS 8 S
O O

CH3
Cl OH
NH

H2N2OS C
CH3
O

Salicylanilide
(xipamide)
Site IV Diuretics
Potassium sparing diuretics:
Negative feature if previously discussed diuretics.
They increase the renal excretion rate of potassium and cause the
“hypokalemia”.
Chemically distinct diuretics have emerged that increases the
sodium and chloride excretion with that increase in urinary
excretion rate of potassium. These agents are known as
potassium sparing diuretics or Antikaliuretic agent. These act on
site 4.
Cortical collecting tubule:
These are of three groups
•Aldosterone Antagonist (Spironolactone).
•2,4,7 tri amino-6 aryl peteridines (Triamterene)
•Pyrazinoyl quanidine ( Amilozide)
 Spironolactone:
Site and mechanism of action:
•Spironolactone inhibits the re-absorption of 2% to 3% of filtered load of sodium
at site 4 by inhibiting the actions of Aldosterone; which is anti-diuretic hormone which
causes the re-absorption of sodium and chloride.
Synthesis: Mg Br
O
O
Br C CH

Mg C CH

OH
OH

Dihydroepiandrosterone

HOH

OH
C CH

OH
 O
OH C
OH
C C
carboxylation
CO2
O

cyclization Hydrogenation

OH

Openaur oxidation
 O

Dehydrogenation chloronil
O

HS

thioacetal C CH3
O
 O

O S C O
CH3

Spironolactone
 Uses:
•Spironolactone may be used alone as mild diuretic to remove edema
associated with congestive heart failure, cirrhosis nephritic syndrome or
as Antihypertensive.
•Its primary use is in combination with diuretic that act as site 2 and 3 to
reduce the loss of potassium which is associated with later.
Structure activity relationship or development of Spironolactone:
In 1950’s it was observed that progesterone inhibit the anti-diuretic
effect of Aldosterone. O

C CH3

O
Progestrone
•Intensive effect was launched to develop Steroidal derivatives
that possessed only the Anti mineral-o-corticoid activity of
progesterone.
Spironolactone was selected from these derivatives .
O

O S C O
CH3

Spironolactone
2, 4 , 7 tri amino, 6 aryl pteridines:
Triamterene:
•It inhibit the 2-3% filtered load of sodium from
•distal convulated tubules
•collecting tubules (site 4)
•Intra cellular concentration of sodium decreases at site-4.
•Excretion of potassium and hydrogen ion is linked with sodium re absorption at site-4.
•Concomitant reduction in the excretion rate of potassium and hydrogen.

Synthesis: O N NH2
N NH2
NH2 NH2
C H
Benzaldehyde condensation N
N
NH2 N
C NH2
NH2

2,4,6-tetraaminopyrimidine
 HCN

N NH2
NH2

N
NH2
CN CH3 NH2

OH Cyclization

N N NH2
NH2

N
N

H NH2
 Air oxidation

NH2 N N
NH2

N
N
NH2
Triametrene
 Uses:
•in treatment of edema associated with congestive heart failure
or cirrhosis.
•should not be given to patients of impaired renal function
•not used in hypertension alone used drug along with
hydrochlorothiazide to prevent the hyperkalemia.
Pyrazinoyl quanidines:
Hmiloride HCl (midamor):
Mechanism of action:
•Inhibit 2-3% filtered load of sodium at site-4 and
•potassium secretion is reduced or eliminated not recognized
the presence of aldosterone for diuretic property
Synthesis:

N SOCl2 Cl N
O
O
sulfonyl chlorate CH3
CH3

NH2 Cl NH2
N
N

Methyl-3-amino pyrizine-2-carboxylate controlled NH3

 Cl N
O
CH3

NH2 N

NH
NH2 C NH2 Quinidine

NH
Cl N
NH NH2

NH2
N
NH2

HCl amiloride
Uses:
•used alone in the treatment of edema associated to congestive
heart failure, cirrhosis, nephritic system.
•also used in treatment of hypertension.
•also used with diuretics of site 2 and site 3 to inhibit the loss of
which is associated with these diuretics.
NH
Cl N
NH NH2

NH2
NH2 N
Structure activity relationship:
•25000 agents were screened for anti kaluretic activity which did
not overlapping the hormonal activity.
•greater activity was observed when pyrizinoyl quanidines are
appropriately substituted.
•optimal activity is observed when 6-position is substituted with
chlorine.
•for optimal activity 3 and 5 amino group should not be
substituted.
•for activity the quanido nitrogen should not be multiply
substituted with alkyl group.
• Amiloride is the most active compound of this series.
Miscellaneous diuretics:
Mnitol:
Osmotic pressure:
Thoephylline:
Direct action on cardiac function:
Not frequently used as diuretic. Diuresis is observed side effect
when used as “bronchodilator”.