DIURETICS 1 Diuretic Drugs

DIURETICS
Introduction:
Diuretics are the chemicals that increase the rate of urine formation. By increasing the urine
formation, the diuretics lead to increased excretion of electrolytes (especially sodium and chloride)
along with water from the body. The increased excretion of water and electrolytes by the kidneys
is dependent on three different processes, viz., glomerular filtration, tubular reabsorption (active
and passive) and tubular secretion.
Diuretics increase the rate of urine flow and sodium excretion, and are used to adjust the volume
or composition of body fluids in a variety of clinical situations, including hypertension, heart
failure, renal failure, nephritic syndrome, diabetes insipidus, edema and cirrhosis. The normal fluid
filtration in human body is 180 liters, and about 1.5 litters of urine is formed in 24 hrs.
The diuretics act primarily by inhibiting tubular reabsorption in the nephrons; just 1% decrease in
tubular reabsorption would produce more than double urine output.
Diuretic that increases the excretion of;
 Sodium (Na+) is called Natriuretic agent
 Chloride (Cl‾) is called Chloruretic agent
 Potassium (K+) is called Kaliuretic agent
 Bicarbonate (HCO3‾) is called Bicarbonateuretic agent
 Calcium (Ca2+) is called Calciuretic agent
 Sodium chloride (NaCl) is called Soluretic agent
 Uric acid is called Uricosuric agent.
DIURETICS 2 Diuretic Drugs

CLASSIFICATION OF DIURETICS:
A. Classification of Diuretics based on Site/Mechanism of Action:
1. Site-I Diuretics (Acting on Proximal Tubule):
Carbonic anhydrase (CA) inhibitors such as Acetazolamide.
2. Site-II Diuretics (Loop Diuretics):
Such as Furosemide, Bumetanide, Ethacrynic acid.
3. Site-III Diuretics (Acting of Distal Convoluted Tubule):
Thiazide diuretics such as Chlorthiazide, Hydrochlorthiazide.
4. Site-IV Diuretics (Acting on Collecting Tubule):
Potassium sparing diuretics such as Amiloride, Triamterene, Spironolactone.
5. Miscellaneous Diuretics:
Mannitol, Urea, Theophylline, Indapamide, Clopamide, Metolazone, Chlorthalidone.
B. Chemical Classification of Diuretics:
1. Mercurial Diuretics: Mercaptomerin, Meralluride, Mersalyl, Chloromerodrin.
2. Non-Mercurial Diuretics:
i. Thiazide and Hydrothiazide Diuretics:
Chlorthiazide, Flumethiazide, Hydrochlorothiazide, Bendroflumethiazide, Cyclothiazide,
Trichloromethiazide, Methyclothiazide.
ii. Sulphonamide Diuretics (CAse Inhibtors):
Acetazolamide, Methazolamide, Dichlorophenamide, Disulfamide, Chlorthalidone,
Metolazone, Indapamide, Clopamide.
iii. Aldosterone Inhibitors: Spironolactone, Canrenone.
iv. Aminopteridines: Triamterene.
v. Pyrazinoyl Guanidines: Amiloride.
vi. Sulfamoyl Benzoic Acid Derivatives: Furosemide, Bumetanide.
vii. Phenoxyacetic Acid Derivatives: Ethacrynic acid.
viii. Purine or Xanthine Derivatives: Caffeine, Theophylline, Theobromine, Aminophylline.
ix. Osmotic Diuretics: Urea, Sucrose, Mannitol, Trometamol, Sodium acid phosphate,
Potassium acetate, Glycerin.
x. Acidic Diuretics: Ammonium chloride.
xi. Uricosuric Diuretics: Indacrinone.
DIURETICS 3 Diuretic Drugs

MERCURIAL DIURETICS
Chemistry/Structure/Examples:
Most mercurial diuretics have the same general structure, which is a chain of at least three carbon
atoms with one atom of mercury at one end of the chain.

Where, X = hydroxyl, halide or heterocyclic moiety.

Y = Substituted side chain or aromatic function
R = Methyl group or alkyl ether chain.

Generic name Y R X

Mercaptomerin

Meralluride

Mersalyl Theophylline

Chloromerodrin

SAR of Mercurial Diuretics:

 Mercury is essential for activity.

 The group R is hydrophilic in nature, which determines the distribution and late excretion
of the compound.
 The nature of α-substituent affects the toxicity of the compound, irritation at the site of
injection, and rate of absorption.
DIURETICS 4 Diuretic Drugs

Mode/Mechanism of Action of Mercurial Diuretics:

 These drugs primarily inhibit Na-K-Cl cotransporter in the ascending limb of loop of Henle
and produce acidic urine. It involves interactions with sulphhydryl enzymes in kidney
tubules.
 There is slight effect in the distal tubule where inhibition of chloride reabsorption also
occurs.
MERCAPTOMERIN:

Uses:
It is used for the treatment of congestive heart failure due to edema, chronic nephritis, liver
diseases, and nephrotic edema.
Synthesis of Mercaptomerin:

MERALLURIDE:

Uses:
Meralluride is employed for the treatment of edema secondary to congestive heart failure,
glomerulonephritis and hepatic cirrhosis.
DIURETICS 5 Diuretic Drugs

Synthesis of Meralluride:

THIAZIDE & HYDROTHIAZIDE DIURETICS

Chemistry/Structure/Examples of Thiazide Diuretics:
A major breakthrough in diuretic therapy was the introduction of chlorothiazide as a reliable, oral
and non-mercurial diuretic in 1955 by Nouello and Spagne in the research laboratories of MSD. A
number of benzothiadiazines were subsequently synthesized and found to possess varying degree
of diuretic actions.
Thiazide diuretics have a benzothiadiazine-1,1-dioxide nucleus with general structure shown
below.

Generic name R1 R2
Chlorothiazide
(Chlorthiazide)
Benzthiazide

Flumethiazide
DIURETICS 6 Diuretic Drugs

Chemistry/Structure/Examples of Hydrothiazide Diuretics:

Hydrothiazides are derived from thiazide diuretics by saturation of double bond between positions
3 & 4 of benzothiadiazine nucleus. Thus they are benzodihydrothiadiazine-1,1-dioxide derivatives
and have following general structure.

Generic name R1 R2 R3

Hydrochlorothiazide

Bendroflumethiazide

Cyclothiazide

Trichloromethiazide

Methyclothiazide

Mode/Mechanism of Action of Thiazide Diuretics:

 Thiazide diuretics act mainly to block sodium and chloride reabsorption at the first portion of
the distal tubules. Thiazides inhibit a Na+–Cl‾ symport in the luminal membrane of the
epithelial cells in the distal convoluted tubule. Thus, thiazides inhibit NaCl reabsorption in the
distal convoluted tubule, and may have a small effect on the NaCl reabsorption in the proximal
tubule.
DIURETICS 7 Diuretic Drugs

 Thiazides enhance Ca++ reabsorption in the distal convoluted tubule by inhibiting Na+ entry
and thus enhancing the activity of Na+–Ca++ exchanger in the basolateral membrane of
epithelial cells.
 They also have a mild anti-carbonic anhydrase effect. The resulting diuretics are accompanied
by increased excretion of potassium, bicarbonates, chloride, and water.
 The anti-hypertensive action of the thiazide is attributable to two factors:
 depletion of sodium and subsequent reduction in plasma volume, and
 a decrease in peripheral resistance.
SAR of Thiazide Diuretics:

 The position 2 can tolerate the presence of relatively small alkyl groups such as –CH3. For
example, methylchlorthiazide derived from chlorothiazide also shows sufficient diuretic activity.
 Substituents in the 3-position play a dominant role in determining the potency and duration of
action of thiazide diuretics.
 Loss of the carbon-nitrogen double bond between the 3- and 4-position of nucleus increases
the diuretic potency approximately 3–10 fold. This has resulted in hydrothiazide diuretics.
 Direct substitution of the 4-, 5-, or 8-position with an alkyl group usually results in diminished
diuretic activity.
 Substitution of the 6-position with an activating group is essential for diuretic activity. The
best substituents include –Cl, –Br, –CF3 and –NO2 groups.
 The free sulphamoyl (–SO2NH2) group in the 7-position is essential for diuretic activity.
 Hydrogen atom at the position-2 is more acidic due to the presence of neighboring electron
withdrawing the sulphonyl group. This can result in water-soluble sodium salts.
Uses of Thiazide Diuretics:
 Treatment of hypertension and reduce the risk of death, stroke, heart attack, and heart failure
due to hypertension.
 As adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and
renal dysfunction, and corticosteroid and estrogen therapy
 Prevents the formation and recurrence of calcium stones & nephrolithiasis in hypercalciuric patients.
 Nephrogenic diabetes insipidus.
Side Effects/ADRs/Contraindications of Thiazide Diuretics:
 Side effects and ADRs may include; hypokalemia, hyperglycemia, hyperlipidemia,
hyperuricemia, hypercalcemia, hyponatremia, hypomagnesemia and hypocalciuria.
 Contraindications include; hypotension, allergy to sulphur-containing medications, gout,
kidney failure, Lithium therapy, hypokalemia and diabetes.
 Thiazide diuretics should be avoided in pregnancy.
DIURETICS 8 Diuretic Drugs

Synthesis of Chlorothiazide (Chlorthiazide), Hydrochlorothiazide, Trichlormethiazide:

CARBONIC ANHYDRASE INHIBITORS (Sulphonamide Diuretics)

Chemistry/Structure/Examples of Carbonic Anhydrase Inhibitors:
In early 1940s, attempts were made towards the synthesis and subsequent screening of
sulphonamides possessing carbonic anhydrase inhibitory characteristics of sulphanilamide which
resulted in the production of a variety of heterocyclic sulphonamides showing diuretic activity.
Mostly, they are either Heterocylic Sulphonamides or Meta-Disulphamoyl Benzene derivatives.
Examples: Acetazolamide, Methazolamide, Dichlorophenamide, Disulfamide, Chlorthalidone,
Metolazone, Indapamide, Clopamide.
DIURETICS 9 Diuretic Drugs

Mode/Mechanism of Action of Carbonic Anhydrase Inhibitors:

 Carbonic anhydrase (CA) inhibitors are mild diuretics that decrease the acidity of urine.
 This class of diuretics inhibits carbonic anhydrase enzyme in the membrane and cytoplasm of
the epithelial cells. The primary site of action is in proximal tubules.
 Carbonic anhydrase is an enzyme present in the renal tubular cells, and catalyzes the hydration
of CO2 produced metabolically in the cells of the renal tubules. Thus CO2 is converted
immediately to carbonic acid by the enzyme. Carbonic acid spontaneously ionizes to H+ and
HCO3‾ ions.

 Due to inhibition of carbonic anhydrase, there is lack of H+ ions in the tubular cells and
therefore secretion of H+ from tubular epithelial cells to tubular lumen in exchange for Na+
(Na+–H+ antiport), and reabsorption of Na+ from tubular lumen back to tubular cells is
inhibited.
 This leads to increased urinary secretion of Na+ accompanied by HCO3‾ ions. A one Na+ ion
retains two water molecules with it, so it will lead to diuresis.

 The increase in Na+ concentration in the tubular fluid may be compensated partially by
increased NaCl reabsorption in later segments of the tubule. Thus, the diuretic effect of the
carbonic anhydrase inhibitors is mild.
DIURETICS 10 Diuretic Drugs

SAR of Carbonic Anhydrase Inhibitors:

SAR of carbonic anhydrase inhibitors can be divided into two parts; Heterocylic Sulphonamides
and Meta-Disulphamoyl Benzene derivatives.
1. Heterocylic Sulphonamides:

 The C-2 sulphamoyl group is absolutely essential for the activity.

 The sulphamoyl nitrogen must remain unsubstituted for diuretic activity.
 Substitution of a methyl group on one of acetazolamide’s ring nitrogens yields Methazolamide,
a product that retains carbonic anhydrase inhibitory activity.
 The moiety to which the sulphamoyl group is attached must possess aromatic character.
 The heterocyclic sulphonamides with higher partition coefficient and lowest Pka value have
greatest CAse inhibitory and diuretic activites. Example–Acetazolamide, Methazolamide.
2. Meta-Disulphamoyl Benzene derivatives:

 m-Disulphamoyl benzene itself does not show diuretic activity. However, properly substituted
m-sulphamoyl benzene exhibits diuretic activity.
 The unsubstituted sulphamoyl moiety is essential for the activity; any substitution leads to
affect the potency of the compound.
 The sulphamoyl moiety can be replaced with similar electrophilic groups (e.g. carboxyl,
carbamoyl) that may increase the potency of the compound. Example–Dichlorphenamide.
 Maximum diuretic activity is obtained when position-4 is substituted by Cl, Br, CF3, or NO2
group.
 Substitution of amino group at position-6 increases saluretic activity, but decreases CAse
inhibitory activity. Example–Chloraminophenamide.
Uses of Carbonic Anhydrase Inhibitors:
 Treatment of cystinuria, and enhanced excretion of uric acid and other organic acids.
 Useful in metabolic alkalosis condition.
 Adjuvant treatment of edema due to congestive heart failure and drug-induced edema.
 Used for the treatment of glaucoma.
 Also used for epilepsy and acute altitude sickness (acute mountain sickness).
DIURETICS 11 Diuretic Drugs

Synthesis of Acetazolamide:

Synthesis of Dichlorophenamide (Diclofenamide):

LOOP DIURETICS (High Ceiling Diuretics)

Chemistry/Structure/Examples of Loop Diuretics:
Two major classes of loop diuretics are:
1. Sulphamoyl benzoic acid derivatives such as furosemide and bumetanide, and
2. Non-sulphonamide loop diuretics such as ethacrynic acid (a phenoxyacetic acid derivative).
DIURETICS 12 Diuretic Drugs

Mode/Mechanism of Action of Loop Diuretics:

 Loop diuretics inhibit reabsorption of NaCl and KCl by inhibiting the Na+–K+–2Cl symport in
the luminal membrane of the thick ascending limb (TAL) of loop of Henle. As TAL is
responsible for the reabsorption of 35% of filtered sodium, and there are no significant
downstream compensatory reabsorption mechanisms, loop diuretics are highly efficacious and
are thus called high ceiling diuretics.
 As the Na+–K+–2Cl symport and sodium pump together generate a positive lumen potential
that drives the reabsorption of Ca++ and Mg++, inhibitors of the Na+–K+–2Cl symport also
inhibit reabsorption of Ca++ and Mg++ ions.
 By unknown mechanisms (possibly prostaglandin-mediated), loop diuretics also have direct
effects on vasculature including increase in renal blood flow and increase in systemic venous
capacitance.

SAR of Loop Diuretics (Sulphamoyl Benzoic Acid Derivatives):

They are either 5-sulphamoyl-2-amino benzoic acid or 5-sulphamoyl-3-amino benzoic acid
derivatives.

5-sulphamoyl-2-amino benzoic acid derivatives 5-sulphamoyl-3-amino benzoic acid derivatives

(Example–Furosemide) (Example–Bumetanide)
DIURETICS 13 Diuretic Drugs

 The acidic carbonyl group at C-1 provides optimal diuretic activity.

 The substitution of activating group (X) in the position-4 by Cl, alkoxy, aniline, benzyl, or
benzoyl group at position-4 increases the diuretic activity.
 The presence of sulphamoyl group in the position-5 is essential for activity.
 The two series of 5-sulphamoyl benzoic acid derivatives differ in the nature of the functional
group that is substituted in 2nd and 3rd position.
 The presence of furfuryl methyl, benzyl, and thienyl methyl group at 2nd amino group of 5-
sulphomoyl-2-amino benzoic acid gives maximum diuretic activity.
 The wide range of alkyl group can be substituted at 3rd amino group of 5-sulfamoyl-3-amino
benzoic acid without modifying the optimal diuretic activity.
 A molecule with a weakly acidic group to direct the drug to the kidney and an alkylating moiety
to react with sulfhydryl groups and lipophilic groups provide the best combination of a diuretic
in the class.
Uses of Loop Diuretics:
 Acute pulmonary edema.
 Chronic congestive heart failure when decrease of extracellular fluid volume is desirable to
reduce venous and pulmonary edema.
 Treatment of hypertension when patients do not response satisfactorily to thiazide diuretics
and anti-hypertensive drugs.
 Hypercalcaemia.
 Treatment of hyperkalemia in combination with isotonic NaCl administration.
 Used in acute renal failure to increase the urine flow and K+ secretion.
 Treatment of toxic ingestions of bromide, fluoride, and iodide (with simultaneous saline
administration)

Synthesis of Ethacrynic Acid:

DIURETICS 14 Diuretic Drugs

Synthesis of Furosemide:

POTASSIUM SPARING DIURETICS

Potassium-sparing diuretics are mild diuretics that inhibit sodium reabsorption in the late distal
tubule and, thus, indirectly spare potassium excretion. They tend to cause bicarbonate loss, but not
chloride.
They can be divided into two groups;
1. Sodium Channel Inhibitors such as
a. Pyrazinoyl Guanidines such as Amiloride.
b. Aminopteridines such as Triamterene.
2. Aldosterone Antagonists such as Spironolactone, Canrenone.
Uses of Potassium Sparing Diuretics:
 Used in combination with loop diuretics and thiazides in treatment of edema and hypertension.
 Na+ channel inhibitors are mainly used in combination with other classes of diuretics such as
loop diuretics and thiazides in order to enhance Na+ excretion and to counteract K+ wasting
induced by these diuretics.
 Pseudo-hyperaldosteronism (Liddle’s syndrome).
 Treatment of edema associated with secondary hyperaldosteronism (such as cardiac failure,
hepatic cirrhosis, and nephrotic syndrome). Spironolactone is the diuretic of choice in patients
with hepatic cirrhosis.
 Amiloride is used to treat Lithium-induced nephrogenic diabetes insipidus by blocking Li+
transport into tubular epithelial cells.
 Amiloride also inhibits Na+ channel in airway epithelial cells, and is used to improve
mucociliary clearance in patients with cystic fibrosis
SODIUM CHANNEL INHIBITORS:
DIURETICS 15 Diuretic Drugs

Mode/Mechanism of Action of Sodium Channel Inhibitors:

 They inhibit the sodium channel in the luminal membrane of the collecting tubule and
collecting duct.
 This sodium channel is critical for Na+ entry into cells down the electrochemical gradient
created by sodium pump in the basolateral membrane, which pumps Na+ into interstitium.
 This selective transepithelial transport of Na+ establishes a luminal negative transepithelial
potential, which in turn drives secretion of K+ into the tubule fluid.
 These interfere with the sodium absorption in the late distal tubules and cortical collecting
ducts, thereby promoting sodium excretion while conserving potassium.

Synthesis of Triamterene:
DIURETICS 16 Diuretic Drugs

ALDOSTERONE ANTAGONISTS:

Mode/Mechanism of Action of Aldosterone Antagonists:

 Aldosterone, by binding to its receptor in the cytoplasm of epithelial cells in collecting tubule
and collecting duct, increases expression and function of Na+ channel and sodium pump, and
thus enhances sodium reabsorption.
 Spironolactone competitively inhibits the binding of aldosterone to its receptor and abolishes
its biological effects. Hence, it is effective only when aldosterone is present.

Synthesis of Canrenone and Spironolactone:

DIURETICS 17 Diuretic Drugs

Spironolactone
Canrenone

XANTHINE DIURETICS (Purine Diuretics)

Chemistry/Structure/Examples of Xanthine Diuretics:
These are the structural analogues of the parent compounds of purine and xanthine. The Xanthines
(caffeine, theophylline, and theobromine) are natural components of tea (Camellia sinensis).

Generic name R R1

Caffeine

Theophylline

Theobromine

Aminophylline
DIURETICS 18 Diuretic Drugs

Mode/Mechanism of Action of Xanthine Diuretics:

 The Xanthines (caffeine, theophylline, and theobromine) have a weak diuretic activity.
 They have been known for their diuretic action, but currently it is rarely used.
 Aminophylline (theophylline ethylene diamine) is the most used member.
 Theophylline exerts its diuretic action by inhibition of Na+ reabsorption in the proximal
convoluted tubule.
 These drugs stimulate cardiac function thereby increasing renal plasma flow, promoting a
higher glomerular filtration rate and promote urine formation.
Uses of Xanthine Diuretics:
 Caffeine is used as CNS stimulant and causes wakefulness. The diuretic action of caffeine is
weaker than theophylline. Caffeine is used along with ergotamine in the treatment of migraine.
 Theophylline has a mild diuretic action. It is used in the treatment of reversible airways
obstruction.
 Theobromine is used as diuretic and used in the treatment of angina pectoris and hypertension.
It is also used in the treatment of reversible airways obstruction.
 It is used in the treatment of bronchial asthma and in the treatment of reversible airways
obstruction.
Synthesis of Caffeine and Theophylline:

Theophylline