Diuretics

INTRODUCTION
Diuretics are chemicals
that increase the rate of
urine formation by
increasing the urine flow
rate.

MECHANISM OF
ACTION
The primary target organ
for diuretics is the kidney,
where these drugs
interfere with the
reabsorption of sodium
and other ions from the
lumina of the nephrons,
which are the functional
units of the kidney.
LOOP DIURETICS (Furosemide)

• Furosemide is a loop diuretic also called as that prevents body from absorbing too much salt, allowing the salt
to instead be passed in urine.
• Mechanism of Action:
• Furosemide is a loop diuretic that inhibits the Na+/K+/2Cl- cotransporter in the ascending
thick loop of Henle.
• It is often called a high-ceiling diuretic because it is more effective than other diuretics.
• Furosemide decreases the sodium, chloride, and potassium reabsorption from the tubule.
• Subsequently, these ions are retained in the renal tubule and presented to the distal nephron.
• Dilute urine is produced because water is retained in the tubule when it reaches the distal
tubule.
• In addition, there is an associated urine loss of Mg++ and Ca++.
• THERAPEUTIC APPLICATIONS
It is effective for the treatment of edemas connected with cardiac, hepatic, and renal sites.
Because it lowers the blood pressure similar to the thiazide derivatives, one of its uses is in the treatment of
hypertension.
Synthesis of Furosemide
STRUCTURE ACTIVITY RELATIONSHIP
(SAR)
• At position number 2 there are 2 groups attached. The methyl amine and
furan group. Both are essential and un-substituted.
• If we substitute these 2 groups with any other groups or change the position of
these 2 groups, the activity of furosemide will be terminated.
• At position 4 there is a chloride group. It is also essential and unsubstituted.
• If we substitute this group with any other group or change the position of this
group, the activity of furosemide will be terminated.
Furosemide
• Position 3 and 6 are vacant.
CARBONIC ANHYDRASE INHIBITORS (ACETAZOLAMIDE)

• In 1937, it was proposed that acidification of the urine was caused by the secretion of hydrogen
ions by tubular cells of kidney.
• Hydrogen ions were provided by the action of enzyme (carbonic anhydrase) which catalyzes the
reaction.
CO2 + H2O CA→ H2CO3 → H+ + HCO3

• So, inhibition of carbonic anhydrase resulted in lesser exchange or low exchange of hydrogen
ions with the sodium ions.
• So, Na+ ions were excreted out with water and diuretic effect was noted.
Mechanism of action
• Acetazolamide is a reversible inhibitor of the carbonic anhydrase enzyme that results in
reduction of hydrogen ion secretion at the renal tubule and an increased renal excretion of
sodium, potassium, bicarbonate and water.
• It can be used as a diuretic or to treat glaucoma as it prevents excessive build-up of aqueous
humor.
• It also inhibits carbonic anhydrase in the central nervous system to minimize abnormal and
excessive discharge from CNS neurons.
• Acetazolamide can be administered to patients with metabolic alkalosis to promote reabsorption
of hydrogen ions at the level of the renal tubule.

Metabolic alkalosis is defined as a disease state where the body's pH is elevated

to greater than 7.45 secondary to some metabolic process.
Synthesis of Acetazolamide
acetylation of amino
group

1-thio-3,4-diazo-2-acetamide-5-
sulphhydral
1- thio-3,4-diazole-2-amino-5-sulphhydral

Hypochlorous acid

amination of sulfural chloride

1-thio-3,4-diazo-2-acetamide-5-thionyl chloride
Detail
• The starting compound is 1-thio-3,4-diazo-2-amino-5-sulph hydral or 1- thio-3,4-diazole-2-amino-5-
sulphhydral.
• In the first step acetylation of amino group of 1-thio-3,4-diazo-2-amino- 5-sulph hydral takes place and the
resulting structure is 1-thio-3,4-diazo-2-acetamide-5-sulphhydral (product I).
• In the next step there is a reaction between Product I and hypochlorous acid with the formation of 1-thio-
3,4-diazo-2-acetamide-5-sulfural chloride or 1-thio-3,4-diazo-2-acetamide-5-thionyl chloride (product II).
• In the third step amination of sulfural chloride of product II takes place with the formation of 1-thio-3,4-
diazo-2-acetamide-5-sulphamoyl (Acetazolamide)
• All those drugs that contains sulfonyl group (SO2) are called as ‘Sulphones.’ Sulphamoyl (SO2NH2) group is
called as sulphonamides.
STRUCTURE ACTIVITY RELATIONSHIP (SAR)

• The structure of acetazolamide is a 5 membered ring (heterocyclic) having 1 sulfur and 2 nitrogen. This
heterocyclic ring with hetero elements is essential and unsubstituted.
• At position no.2 if we substitute this acetamide with other amide ion, any other group or if we change
position 2 to any other position, therapeutic activity will be terminated.
• If we substitute Sulphamoyl group at position no.5 with any other group or change position to any other
position, therapeutic activity will be terminated
• Another derivative Methazolamide is prepared. It is same as acetazolamide but is not used due to less
activity than acetazolamide.

Methazolamide
THIAZIDE DIURETICS

• BENZOTHIADIAZIDE
• It is 3rd group of diuretics called as thiazide diuretics. It is also called as benzothiadiazide.
• INTRODUCTION
• It is special class of diuretic which is used for treatment of hypertension and edema. This class was
developed by “Merck” in 1950.
• The first member/derivative of this class is chlorothiazide, was marketed by “Merck” under trade name
“Diuril”
• In 1958, another derivative of this class “hydrochlorothiazide” was developed by “Ciba-Geigy”. Ciba-geigy is
a swiss pharmaceutical company, the latest name of this company is ‘Novartis”. Ciba-Geigy marketed this
drug under trade name “Esidrix”

chlorothiazide
MECHANISM OF ACTION
• It inhibits active chloride reabsorption at early Distal
convoluted tubule via Na-Cl co-transporter,
resulting in an increase excretion of sodium,
chloride and water.
• Thiazide like benzothiazide also inhibits sodium ion
transport across renal tubules through binding to
the thiazide sensitive sodium chloride co-
transporter.
• It also increases calcium reabsorption at DT, hence,
decrease the excretion of calcium. As water
excretion increases, results in increased urination.
Synthesis of Chlorothiazide
Synthesis of hydrochlorothiazide

5-chloro-2,4-disulfamyl-aniline
STRUCTURE ACTIVITY RELATIONSHIP (SAR)

• The structure of chlorothiazide contains heterocyclic ring with hetero atoms which are essential and
substituted.
• At position 6, there is halogen by halogenation which is chloride, and it is essential and unsubstituted. If we
substitute it with any other group or we change the position of this group, therapeutic activity will be
terminated.
• At position 7 Sulphamoyl group is essential and unsubstituted.
• Benzene ring (aromatic ring) is also essential and unsubstituted.
• Hydrochlorothiazide is 10 times more potent than chlorothiazide with minimum toxicity.
POTASSIUM SPARING DIURETICS (SPIRONOLACTONE)

• Spironolactone is the combination of two words: Spirono and lactone.

• The word spirono is from the word “spiro” which means respiration, breathing,
connector or bridge.
• They are called as connector or bridge because there is connection between
two rings, one is steroidal ring and other is lactone ring.
• Lactones are cyclic esters. Esters are formed when carboxylic acid reacts with
alcohol.
• Lactams are cyclic amides. Amides are carboxylic acid derivatives.
• This drug was developed by Pfizer in 1959. Pfizer marketed this drug under the
trade name Aldactone. Spironolactone is also called as Antiandrogen and
mineralocorticoid antagonist.
• MECHANISM OF ACTION
• Spironolactone is a specific pharmacological antagonist of aldosterone, acting primarily through competitive
binding of receptor at the aldosterone dependent sodium-potassium exchange site in the distal convoluted
renal tubule.
STRUCTURE ACTIVITY RELATIONSHIP (SAR)

• As a whole steroidal ring contains 17 positions. At position number 3 there

is a ketone group which is essential and unsubstituted. If we substitute this
group with any other group or if we change the position of this group the
therapeutic activity will be lost.
• At position number 10 and 13 there are methyl groups which are essential
and unsubstituted. If we substitute these groups with any other groups or if
we change the position of these groups the therapeutic activity will be lost.
• At position number 7 there is a thioacetyl group which is essential and
unsubstituted. If we substitute this group with any other group or if we
change the position of this group the therapeutic activity will be lost.
• At position number 17 there is a lactone ring which is essential and
unsubstituted. If we substitute this ring with any other ring or group or if
we change the position of this ring the therapeutic activity will be lost.