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DIURETICS

INTRODUCTION:

DEFINITION:

Something that promotes the formation of urine by the kidney is called diuretics
Or
Drug inducing a state of increase urine flow are called diuretics.

EXPLANATION:

All diuretics cause a person to 'lose water,' but they do so by diverse means, including inhibiting
the kidney's ability to reabsorb sodium, thus enhancing the loss of sodium and consequently
water in the urine (loop diuretic); enhancing the excretion of both sodium and chloride in the
urine so that water is excreted with them (thiazide diuretic); or blocking the exchange of sodium
for potassium, resulting in excretion of sodium and potassium but relatively little loss of
potassium (potassium-sparing diuretic). Some diuretics work by yet other mechanisms, and some
have other effects and uses, such as in treating hypertension. Substances in food and drinks, such
as coffee, tea, and alcoholic beverages, may act as diuretics.

CLASSIFICATION OF DIURETICS:

Diuretics may be broadly classified into the following two categories.

1. Mercurial Diuretics: Its examples are Chlormerodrin Hg 197, Meralluride,

Mercaptomerin sodium, Merethoxylline Procaine, Mersalyl and Mercumatilin sodium.

2. Non-mercurial Diuretics: The non-mercurial diuretics may be classified on the basis of

their chemical structures together with their physical characteristics as follows :
a) Thiazides diuretics: e.g. benzthiazide, chlorothgiazide, hydrochlorothiazide,
methyclothiazide, polythiazide.
b) Carbonic-Anhydrase Inhibitors: e.g. acetazolamide, methazolamide.
c) Sulphonamide Diuretics: e.g. chlorthalidone, indapamide, metolazone, xipamide,
clopamide.
d) Aldosterone Inhibitors: e.g. spironolactone.
e) ‘Loop’ or ‘High-Ceiling’ Diuretics: e.g. furosemide, bumetanide, ethacrynic acid,
torsemide, piretanide.
f) Xanthine Derivatives: e.g. aminophylline, tea, coffee, soda.
g) ADH antagonists diuretics: e.g. lithium salts, demeclocycline.
h) Osmotic Diuretics: e.g. mannitol, urea, isosorbide.
i) Acidifying salts Diuretics: e.g. ammonium chloride.
j) Miscellaneous Diuretics: e.g. citrates, acetates and bicarbonates of sodium and
potassium, dextran, albumin.

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1. MERCURIAL DIURETICS:

The mercurial diuretics essentially contain Hg++ in an organic molecule. They usually inhibit
sodium reabsorption in the proximal tubuler and ascending loop of Henle. There may be slight
effect in the distal tubule where inhibition of chloride reabsorption also occurs. The mercurials
have been found to enhance K+ excretion though potassium loss is less than that produced by
many other diuretics.
However, the overall action of mercurial diuretics is invariably increased by acidification of
urine. The mercurial diuretics are not very much used in clinical practices due to their
pronounced and marked side-effects such as, mercurialism, hypersensitivity and excessive
diuresis which may lead to electrolyte depletion and vascular complications. Most of the
mercurials are administered by intramuscular route and the availability of orally active diuretics
has limited their use. The mercurial diuretics have the following general formula:

Y —CH2—CH—CH2—Hg—X
|
OR
Where;
X = OH, halide, or heterocyclic moiety,
Y = Substituted side chain or substituted aromatic function
R = Methyl group.

MERALLURIDE

INTRODUCTION:
Meralluride is a mercurial diuretic.

STRUCTURE:

DESCRIPTION:

It is white to slightly yellow powder, slowly decrease on exposure to light. It is saturated solution
is acid to litmus. It is slightly soluble in water, in hot water, glacial acetic acid and alkali
hydroxides. It is almost insoluble in alcohol, chloroform, ether.

PHARMACODYNAMICS:
Mechanism of action:
Mercurial diuretics cause diuresis by reducing the reabsorption sodium in the ascending loop of
Henle, thus causing more water being delivered to the distal convoluted tubule.

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SYNTHESIS OF MERALLURIDE:
Cyclic diacylurea is prepared by the condensation of succinimide and allyl isocyanate which
upon acid hydrolysis affords the cleavage of the ring of the succinimide. Oxymercuration of the
terminal olefin bond in the presence of mercuric acetate in methanol solution gives [3-[3-(3-
caboxy-propionyl ureido]-2-methoxypropyl]-hydroxy mercury. This on condensation with an
equimolar portion of theophylline gives the official compound.

Diagram showing synthesis of Meralluride

CLINICAL USES:

1. Meralluride is employed for the treatment of oedema secondary to congestive heart

failure, the nephrotic state of glomerulo nephritis and hepatic cirrhosis.

DOSE:
 Usual, 1 ml (to 39 mg of Hg and 43.6 mg of anhydrous theophylline) 1 or 2 times a week,
parenteral 1 to 2 ml.

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MERCAPTOMERIN SODIUM

INTRODUCTION:
Mercaptomerin sodium is a mercurial diuretic.

STRUCTURE:

DESCRIPTION:
It is hygroscopic, white powder. Its melting point is 150-155°. It is freely soluble in water. It is
soluble in alcohol while practically insoluble in ether, benzene, chloroform.

PHARMACODYNAMICS:
Mechanism of action:
They usually inhibit sodium reabsorption in the proximal tubuler and ascending loop of Henle.
There may be slight effect in the distal tubule where inhibition of chloride reabsorption also
occurs. The mercurials have been found to enhance K + excretion though potassium loss is less
than that produced by many other diuretics.

SYNTHESIS OF MERCAPTOMERIN:
Camphoric acid on condensation with ammonia and subsequent treatment with allyl isocyanate
affords an intermediate which on reaction with mercuric acetate in methanol gives rise to the
corresponding mercury derivative as acetate. This on treatment with sodium chloride followed by
sodium thioglycollate in aqueous NaOH solution yields the official compound which may be
obtained either by evaporation or by precipitation with an appropriate solvent.

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CLINICAL USES:
It is employed for the treatment of oedema secondary to congestive heart failure, the nephrotic
state of glomerulo nephritis and hepatic cirrhosis.

DOSE:
 Usual, 125 mg once daily; parenteral 15 to 250 mg daily to weekly.

2. NON-MERCURIAL DIURETICS:

The non-mercurial diuretics usually are predominant in terms of their significant clinical
effectiveness and wider applications. They, in general, possess fewer side-effects and are much
less toxic than the corresponding mercurial diuretics. They are used as adjunct specifically in the
treatment of either poisoning or drug over-dosage during which they increase the process of
elimination of poisons or drugs through the kidneys.
These diuretics are also employed to counter water and salt retention caused by various drug
treatments. The most commonly used diuretics are invariably classified by their respective
chemical class, mechanism of action, site of action, or effects on the urine contents.
Nevertheless, these drugs normally exert their action rather widely with regard to their prevailing
efficacy as well as their definite site of action located within the nephron. The real efficacy of a
diuretic is often measured by its ability to enhance the rate of excretion of Na+ ions filtered
usually at the glomerulus ( i.e. the filtered load of sodium) and hence, must not be misunderstood
with the potency, that is the actual amount of the ‘diuretic’ essentially needed to cause a specific
diuretic response. In other words, the efficacy of a diuretic is invariably estimated in portion by
the site of action of the diuretic.

CHLORTHIAZIDE

INTRODUCTION:

Chlorothiazide sodium (Diuril) is a diuretic used within the hospital setting or for personal use to
manage excess fluid associated with congestive heart failure. It is also used as an
antihypertensive. Most often taken in pill form, it is usually taken orally once or twice a day. In
the ICU setting, chlorothiazide is given to diurese a patient in addition to furosemide (Lasix).
Working in a separate mechanism than furosemide, and absorbed enterically as a reconstituted
suspension administered through a nasogastric tube (NG tube), the two drugs potentiate one
another.

STRUCTURE:

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DESCRIPTION:
The white crystalline powde, melting point 342 -343 ° C (while decomposition). It is strongly
dissolved in ethanol slightly soluble in water, chloroform and ether were insoluble.

PHARMACODYNAMICS:
Mechanism of action:
Chlorothiazide acts to inhibit renal tubular reabsorption of electrolytes. Experimental data are
presented which indicate that, under various conditions, anion reabsorption is depressed
unselectively so that the pre-existing ratio (Cl/HCO 3) is not changed during chlorothiazide
diuresis. Thus chlorothiazide acts primarily to block sodium ion reabsorption.
Increased potassium excretion caused by chlorothiazide is viewed as a consequence of the
activity of the drug in blocking sodium reabsorption proximal to the site of potassium secretion.
According to this concept, all chlorothiazide-type compounds will cause potassium depletion in
proportion to their capacity to block proximal sodium reabsorption by diverting more sodium
distally to the site of potassium secretion.

SYNTHESIS OF CHLOROTHIAZIDE:
It may be prepared by the chlorination of 3-chloroaniline with chlorosulphonic acid to yield 3-
chloroaniline - 4, 6-disulphonyl chloride, which is then amidated with ammonia to give the
corresponding 4, 6-disulphonamide analogue. This on heating with formic acid affords
cyclization through double condensation.

SAR OF CHLOROTHIAZIDE DIURETICS:

The SAR of these benzene disulphonamide structural analogues yielded a broad-spectrum of
compounds having a relatively high degree of diuretic activity, which are summarized as stated
under:
1. These diuretics are found to be weakly acidic in nature having a benzothiadiazine 1, 1-
dioxide nucleus.
2. Chlorothiazide being the simplest member of this series of structural analogues having
two pKa (dissociation constant) values of 6.7 and 9.5. The two acidic zones are virtually
due to the presence of;
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a) Presence of a H-atom at the 2-N that essentially attributes the most acidic
character by virtue of the influence of the prevailing electron withdrawing effects
of the neighbouring sulphone moiety.
b) Presence of the sulphonamide (–SO2NH2) functional moiety strategically located
at C-7 position which affords an additional environment (zone) of creating acidity
in the molecule; however, its acidic influence is much less than the 2-N proton.
Importantly, these acidic protons enable the formation of the corresponding water-
soluble sodium salt which may be gainfully used for IV-administration of the
diuretics. As shown below:

3. Presence of an electron-withdrawing moiety at C-6 is an absolute necessity for the

diuretic activity. A few important and vital observations are as enumerated below:
a) Practically negligible diuretic activity is obtained by having a H-atom at C-6.
b) Substitution with a chloro or trifluoromethyl moiety at C-6 are quite active
pharmacologically.
c) Further, the CF3 moiety renders the resulting diuretic compound more lipid-
soluble and also with a much longer duration of action in comparison to its
chloro-substituted derivatives.
d) Presence of electron-releasing moieties, namely: methyl ormethoxylat C-6
position attributes significantly reduced diuretic activity.
4. Removal or possible replacement of the sulphonamide function at C-7 results into such
compounds possessing either little or almost no diuretic activity.
5. Saturation of the prevailing double-bond between 3 and 4 positions to give rise to a
corresponding 3, 4-dihydro structural analogue which is observed to be having nearly 10
times more diuretic activity than the unsaturated analogue.
6. Introduction of a lipophilic functional moiety at C-3 position renders a marked and
pronounced enhancement in the diuretic potency. For instance; aralkyl, haloalkyl, or
thioether substitution, enhances the lipoidal solubility of the molecule to a considerable
extent thereby producing compounds with a much longer duration of action.
7. Alkyl substitution on the N-2 position is observed to lower the polarity and ultimately
enhancing the duration of the ensuing diuretic action.

CLINICAL USES:

1. Chlorothiazide is used in the treatment of oedema associated with congestive heart failure
and renal and hepatic disorders.
2. It is also employed in hypertension, either alone or in conjunction with other
antihypertensive agents.
3. It is also used in oedema associated with corticosteroid therapy thereby increasing the
potassium-depleting action of the latter.

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DOSE:
 Antihypertensive, 250 to 500 mg; usual, antihypertensive, 250 mg 3 times per day;
diuretic 500 mg to 1g; usual, diuretic, 500 mg 1 or 2 times per day.

HYDROCHLOROTHIAZIDE

INTRODUCTION:
Hydrochlorothiazide is a first-line diuretic drug of the thiazide class that acts by inhibiting the
kidneys' ability to retain water. This reduces the volume of the blood, decreasing blood return to
the heart and thus cardiac output and, by other mechanisms, is believed to lower peripheral
vascular resistance. Hydrochlorothiazide is a calcium-sparing diuretic, meaning it can help the
body get rid of excess water while still keeping calcium.

STRUCTURE:

DESCRIPTION:
It is crystalline white powder. Strong reducing agent produces toxic gases, such as ammonia and
H2S. It is insoluble in water. It is stable, which is incompatible with strong oxidizing agent.

PHARMACODYNAMICS:
Mechanism of action:
Hydrochlorothiazide belongs to the thiazide class of diuretics. It reduces blood volume by acting
on the kidneys to reduce sodium (Na) reabsorption in the distal convoluted tubule. The major site
of action in the nephron appears on an electroneutral Na + Cl- co-transporter by competing for the
chloride site on the transporter. By impairing Na transport in the distal convoluted tubule,
hydrochlorothiazide induces a natriuresis and concomitant water loss. Thiazides increase the
reabsorption of calcium in this segment in a manner unrelated to sodium transport. Additionally,
by other mechanisms, HCTZ is believed to lower peripheral vascular resistance

SYNTHESIS OF HYDROCHLOROTHIAZIDE:
The route of synthesis is more or less identical with that for chlorothiazide described earlier
except that formaldehyde is used instead of formic acid in the final cyclization step from 3-
chloroaniline-4, 6-disulphonamide.

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CLINICAL USES:

1. Hydrochlorothiazide is frequently used for the treatment of hypertension, congestive

heart failure, symptomatic edema, diabetes insipidus, renal tubular acidosis, and the
prevention of kidney stones.
2. It is also sometimes used for hypercalciuria, Dent's disease and Ménière's disease.
3. Thiazides are also used in the treatment of osteoporosis. Thiazides decrease mineral bone
loss by promoting calcium retention in the kidney, and by directly stimulating osteoblast
differentiation and bone mineral formation.
4. It is frequently given together with losartan (an angiotensin II receptor antagonist) as
hydrochlorothiazide/losartan.
5. Its diuretic actions are similar to those of chlorothiazide but it is ten times more potent
than the latter. However, when the treatment is prolonged loss of K + causes hypokalemia
which may be prevented by supplementation with potassium salts.

DOSE:
 25 to 200 mg per day; usual, 50 mg 1 or 2 times daily.

FUROSEMIDE

INTRODUCTION:
Furosemide is a loop diuretic used in the treatment of congestive heart failure and edema. It is
most commonly marketed by Sanofi-Aventis under the brand name Lasix. It has also been used
to prevent Thoroughbred and Standardbred race horses from bleeding through the nose during
races. Along with some other diuretics, furosemide is also included on the World Anti-Doping
Agency's banned drug list due to its alleged use as a masking agent for other drugs.

STRUCTURE:

DESCRIPTION:
It is odorless white to slightly yellow crystalline powder which is almost tasteless. It is light
sensitive and air sensitive. It is slightly soluble in water. Furosemide may undergo hydrolysis at
sufficiently low pH. The pH of aqueous solutions should be maintained in the basic range to
prevent hydrolysis. Alcohol has been shown to improve the stability of Furosemide. It is
incompatible with strong oxidizing agents. Its melting point is 220 oC.

PHARMACODYNAMICS:
Mechanism of action:
Furosemide, like other loop diuretics, acts by inhibiting the luminal Na-K-2Cl symporter in the
thick ascending limb of the loop of Henle. The action on the distal tubules is independent of any

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inhibitory effect on carbonic anhydrase or aldosterone. It also abolishes the corticomedullary
osmotic gradient and blocks negative as well as positive free water clearance. Due to the large
NaCl absorptive capacity of the loop of Henle, diuresis is not limited by development of
acidosis, as it is with the carbonic anhydrase inhibitors.
By inhibiting the transporter, the loop diuretics reduce the reabsorption of NaCl and also
diminish the lumen-positive potential that derives from K + recycling. This electrical potential
normally drives divalent cation reabsorbtion in the loop, and by reducing this potential, loop
diuretics cause an increase in Mg2+ and Ca2+ excretion. Prolonged use can cause significant
hypomagnesemia in some patients. Since Ca2+ is actively reabsorbed in the distal convoluted
tubule, loop diuretics do not generally cause hypocalcemia. Additionally, furosemide is a
noncompetitive subtype-specific blocker of GABA-A receptors. Furosemide has been reported to
reversibly antagonize GABA-evoked currents of α6β2γ2 receptors at µM concentrations, but not
α1β2γ2 receptors. During development, the α6β2γ2 receptor increases in expression in cerebellar
granule neurons, corresponding to increased sensitivity to furosemide.

SYNTHESIS OF FUROSEMIDE:
2, 4-Dichloro-5-sulphamoyl benzoic acid may be prepared by reacting 2, 4-dichlorobenzoic acid
with chlorosulphonic acid at an elevated temperature and then carrying out the amidation. This
on treatment with furfuryl amine in the presence of sodium bicarbonate, affords nucleophilic
aromatic displacement of the highly activated chlorine at C-2, thereby yielding furosemide.
However, the protection of the chlorine atom at C-4 may be achieved by regulating the
temperature of the furfurylamination.

Diagram showing synthesis of furosemide

STRUCTURE ACTIVITY RELATIONSHIP:

These are;
1. If we substitute C6H5NH- or C6H5S- on position 04, its pharmacological activity will
increase.
2. Substitution at carbon-03 with any group, leads to lose in activity.

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CLINICAL USES:

1. Furosemide possesses relatively high efficacy, rapid onset of action, short duration of
action, and 1:10 ratio between the minimum and maximum diuretic dose.
2. It is used for the treatment of oedema associated with renal disease, nephrotic syndrome,
cirrhosis of the liver and congestive heart failure.
3. It has an edge over other commonly used diuretic agents specifically when a greater
diuretic potential is required.
4. It may also be employed towards the management of hypertension.
5. It is also sometimes used in the management of severe hypercalcemia in combination
with adequate rehydration.

DOSE:
 Oral, 40 to 600 mg per day; usual, 40 to 80 mg per day; I.M. or I.V., 20 to 40 mg.

ACETAZOLAMIDE

INTRODUCTION:
Acetazolamide, sold under the trade name Diamox, is a carbonic anhydrase inhibitor that is used
to treat glaucoma, epileptic seizures, Idiopathic intracranial hypertension (pseudotumor cerebri),
altitude sickness, cystinuria, periodic paralysis and dural ectasia. Acetazolamide is available as a
generic drug and is also a diuretic.

STRUCTURE:

DESCRIPTION:
It is white to yellowish white fine crystalline powder. It has no odour and taste. It is insoluble in
water. Its melting point is 256-261oC.

PHARMACODYNAMICS:
Mechanism of action:
Acetazolamide is a carbonic anhydrase inhibitor. Medically it may be used to treat conditions of
moderate to severe metabolic or respiratory alkalosis. It does this by interfering with bicarbonate
(HCO3-) reabsorption in the kidneys, thereby re-acidifying the blood (thus alkalinizing the urine).
Carbonic anhydrase (CA) catalyzes the first part of the following reversible reaction (the second
half happens spontaneously, favouring production of H+ + HCO3-), in which carbon dioxide
(CO2) and water (H2O) are converted to carbonic acid (H2CO3) and vice-versa:

CO2 + H2O -------CA------- H2CO3 --------------- H+ + HCO3-

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In the kidney tubules, locally secreted hydrogen ions normally combine with filtered bicarbonate
(HCO3-) to form carbonic acid (H2CO3). Carbonic acid in turn is normally acted upon by
carbonic anhydrase, leading to formation of CO 2. As CO2 rapidly leaves the tubules by diffusing
across cell membranes, the above reaction normally runs shifted strongly to the left (i.e.
reversed), and more bicarbonate can be continuously reabsorbed from the serum. However, in
the presence of acetazolamide, carbonic anhydrase is inhibited and carbonic acid levels build up.
The inhibition of carbonic anhydrase in turn leads to a slowing of the reverse reaction and a
decrease in the body's ability to reabsorb serum bicarbonate, resulting in urinary bicarbonate
wasting. This leads to a decreased ability to exchange Na+ for H+ in the presence of
acetazolamide (in proximal convoluted tubules of kidney) resulting in a mild diuresis. By
contrast, the H+ that is also present in the lumen is reabsorbed via an alternative pathway along
with Cl-; it then passes into the bloodstream, leading to hyperchloremic metabolic acidosis. This
effect can also be used for therapeutic correction of alkalosis seen in altitude sickness or other
forms of respiratory alkalosis.

SYNTHESIS OF ACETAZOLAMIDE:
Reaction between hydrazine hydrate and ammonium thiocyanate yields 1, 2-bis (thiocarbamoyl)
hydrazine which on treatment with phosgene undergoes molecular rearrangement through loss of
ammonia to yield 5-amino-2-mercapto-1, 3, 4-thiadiazole. This on acylation gives a
corresponding amide which on oxidation with aqueous chlorine affords the 2-sulphonyl chloride.
The final step essentially consists of amidation by treatment with ammonia.

Diagram showing synthesis of acetazolamide

STRUCTURE ACTIVITY RELATIONSHIP:

These are;
1. Sulfamoyl group is essential for the carbonic anhydrase, inhibitory activity in vitro and
dieresis vivo.
2. If we substitute sulfamoyl nitrogen, it will lead to loss in activity.

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CLINICAL USES:
1. Acetazolamide is employed effectively for adjunctive treatment of drug-induced oedema,
oedema caused by congestive heart failure, petit mal and other centrencephalic epilepsies.
2. It has also been used to lower the intraocular pressure prior to surgery in acute conditions
of angle-closure glaucoma, besides open angle and secondary glaucoma.
3. Acetazolamide is also used to decrease the production of cerebrospinal fluid in idiopathic
intracranial hypertension as well as hydrocephalus to delay surgical intervention[5] and
has shown efficacy in some forms of periodic paralysis.
4. It's been demonstrated in drug trials to relieve symptoms associated with dural ectasia in
individuals with Marfan's Syndrome.
5. To reduce the incidence of Acute Mountain Sickness acetazolamide is sometimes taken
prophylactically.

DOSE:
 Usual, 250 mg 2 to 4 times per day.

ETHACRYNIC ACID

INTRODUCTION:
Etacrynic acid or ethacrynic acid, trade name Edecrin, is a loop diuretic used to treat high
blood pressure and the swelling caused by diseases like congestive heart failure, liver failure, and
kidney failure. Unlike the other loop diuretics, etacrynic acid is not a sulfonamide and thus, its
use is not contraindicated in those with sulfa allergies.
Etacrynic acid is a phenoxyacetic acid derivative containing a ketone and a methylene group. A
cysteine adduct is formed with the methylene group and this is the active form.

STRUCTURE:

DESCRIPTION:

It is white powder, which is insoluble in water. Ethacrynic acid may react vigorously with strong
oxidizing agents. It can react exothermically with reducing agents (such as alkali metals and
hydrides) to release gaseous hydrogen. It may react exothermically with acids. It reacts
exothermically with all bases both organic (for example, the amines) and inorganic. Its melting
point is 125 oC.

PHARMACODYNAMICS:
Mechanism of action:
Ethacrynic acid acts by inhibiting sodium-potassium-chloride cotransport in the ascending loop
of Henle. Loss of potassium ions is less marked but chances of hypochloremic alkalosis are

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greater. Thus decreases reabsorption of NaCl. Ethacrynic acid increases renal blood flow and
causes redistribution of blood flow within renal cortex.

SYNTHESIS OF ETHACRYNIC ACID:

2, 3-Dichloro-phenoxy acetic acid undergoes Friedal Craft’s reaction with 4-butyryl chloride to
yield the corresponding 4-butyryl analogue. This is subsequently subjected to Mannich reaction
with formaldehyde and dimethylamino thereby introducing the methylene group caused by
thermal decomposition, yields the official compound.

Diagram showing synthesis of Ethacrynic acid

CLINICAL USES:

1. Ethacrynic acid is normally used in the treatment of fluid retensive conditions due to
congestive heart failure, cirrhosis of the liver, renal disease, and the nephrotic syndrome.
2. It is invariably employed for the control and management of ascites due to lymphoedema,
idiopathic oedema and malignancy.
3. It is also recommended through i.v. in an emergency situation of acute pulmonary
oedema.

DOSE:
 50 to 200 mg per day ; 50 mg 2 times daily or 2 times every alternate day ; I.V. 100 mg
per day in divided doses.

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