Drugs promoting urine output are known as diuretic drugs, which refer only to
those agents that act directly on the kidneys. These drugs primarily increase the
excretion of water and ions like sodium (Na +
), chloride (
), or bicarbonates
) from the body. Glomerular filtration , tubular reabsorption , and
tubular secretion in kidneys determine the excretion of substances.
Tubular reabsorption is a process which involves active transport of electrolytes
and ot her solutes from tubular urine to t ubular cells, and then to extra cellular
fluid. As a result, glomerular filtration is increased. The mechanism of action of
diuretic drugs also involves a decrease in tubular reabsorption.
However, these drugs have no effect on glomerular filtration rate or on the action
of Anti-Diuretic Hormone (ADH) on the distal portion of nephron. Diuretics
effectively treat cardiac oedema (accumulation of fluid in extra vascular tissues),
especially the one which is associated with congestive heart failure.
It is also employed in the treatment of various disorders like nephrotic syndrome,
diabetes insipidus, hypertension, nutritional oedema, oedema of pregnancy, and
liver cirrhosis. They also decrease the intracellular and cerebrospi nal fluid
Diuretics are classified as follows:
1) Carbonic Anhydrase Inhibitors: Acetazolamide, Methazolamide, and
2) Thiazide Derivatives:
i) Chlorothiazide and Analogues:
3) Loop Diuretics: Furosemide, Bumetanide, and Ethacrynic acid.
4) Potassium Sparing Diuretics: Amiloride, Triamterene, and Spironolactone.
5) Osmotic Diuretics: Isosorbide, Mannitol, Glycerol, and Urea.
6) Miscellaneous: Indapamide, Xipamide, Clopamide, Quinethazone,
Metolazone, Chlorthalidone, and Clorexolone.
Diuretics have the following uses:
1) They are used for preventing and easing oedema and ascites that may occur
in the diseased conditions of heart, kidney and liver. Thus, the diuretics are
used for treating oedema related to chronic congestive heart fai lure, acute
pulmonary oedema, oedema caused due to pregnancy, brain oedema , and
cirrhosis related with ascites.
2) They are also used in the treatment of hypertension, diabetes insipidus, renal
calculi, hypocalcaemia, acute and renal failure, and nephritic syndrome.
3) Some diuretics are used in glaucoma, hyperpotassemia, bromide intoxication,
anginal syndrome, epilepsy, migraine, and pre-menstrual depression conditions.
5.1.1. Structure-Activity Relationship
The SAR of diuretics can be studied as follows:
1) Structure-Activity Relationship of High Efficacy Diuretics: Development
of loop diuretics is the result of a research in which thiazide and thiazide -like
diuretics were involved. The 5 -sulfamoyl-2-aminobenzoic acid d erivatives
and the 5 -sulfamoyl-3-aminobenzoic acid derivatives ( figure 5.1) require
some common structural features.
The functional groups substituted in the 2 – and 3 – positions of these two
series of 5-sulfamoylbenzoic acids are different in nature and also retains the
maximum diuretic activity (figure 5 .1). Very limited substituents can be
placed on the 2 -amino group of the 5 -sulfamoyl-2-aminobenzoic acids, and
deviations are not allowed on the few moieties.
For example, the diuretic activity is maximum for derivatives of furfuryl,
benzyl, and thienylmethyl (in decreasing order) moieties. The substituents
that can be placed on the 3 -amino group of the 5 -sulfamoyl-3-
aminobenzoic acids widely differ; however, without affecting the optimal
diuretic activity .
Furosemide and azosemide are the high -ceiling diuretics derived from the 5-
sulfamoyl-2-aminobenzoic acid series; while bumetanide and piretanide are
those derived from the 5-sulfamoyl-3-aminobenzoic acid series.
2) Structure Activity Relationship of Medium Efficacy Diuretics (Thiazide
and Thiazide-like Diuretics)
Generic Name (Trade Name) R1 R2
Chlorothiazide H Cl
Benzthiazide CH2SCH2C6H5 Cl
Flumethiazide H CF3
i) The diuretic activity can be increased by replacing the SO 2 group with
ii) The diuretic activity can be increased by replacing the ri ng nitrogen
atoms at 2-position with methyl. However, if the N -atom at 4-position is
replaced with methyl group , the diuretic activity declines, making the
heterocyclic ring more susceptible to hydrolytic cleavage.
iii) The saluretic activity is increased 1000 folds by adding hydrophobic
substituents in 3 -position, e.g., CH2Cl, CHCl2, CH2C6H5, CH2, and
CH2SCH2C6H5. The resultant increased activity correlates with the
iv) The diuretic activity increases with the saturation of the 3,4-double bond.
v) The diuretic activity increases by adding Cl, Br, or CF 3 substituents in
the 6-position, whereas H or NH2 are weakly active.
vi) The diuretic activity is m aintained by adding a free sulf amoyl or
potentially free sulfamoyl group at 7-position. N7
excreted as chlorothiazide. Removal of sulfamoyl group results in
diminished diuretic activity, but the hypertensive action ( e.g., diazoxide)
is still retained.
Subject:- Medicinal chemistry 2
Semester:- Sem 5
Course:- Bachelor of pharmacy