DIURETICS

DR J TUSIIMIRE | BPH 3203

PHARMACY DEPT, FOM, MUST
 Diuretics

Are chemicals that increase the rate of urine formation

Primarily act by direct inhibition of Na+ transport along the nephron

2o indirect actions may occur as a result of 1o diuretic actions

Are X-teristic of each class and determined by locus of diuretic action and
downstream nephron response

Both 1o and 2o X-tics determine the electrolyte secretion pattern

E.g. Some combination of natriuretic, chloruretic, saluretic, kaliuretic,
bicabonuretic or calciruretic properties
Therapeutic classes
 Carbonic anhydrase inhibitors
(CAIs)
Discovered shortly after the introduction
of sulphanilamide as an antibacterial

Observed that sulphanilamide also

produced systemic acidosis and an
alkaline urine (HCO3− excretion)

It was shown that this activity was a

result of renal carbonic anhydrase (CA)
inhibition
Mechanism of action of CAI’s
Acetazolamide

N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide
 Methazolamide

N-[3-methyl- 5-sulfamoyl -1,3,4-thiadiazole-2-yl-]acetamide

 SAR’s of CAI’s

The free sulfamoyl group is important for diuretic activity. Mono- and di-
substitutions of the -SO2NH2 hydrogens diminish/abolish the activity

Substitution of the methyl group on one of the ring nitrogens (Methazolamide)

retains the activity

The heterocyclic sulphonamides having highest partition coefficients and

lowest pKa values have greatest CA inhibitory and diuretic activity

Meta-disulfamoyl benzene derivatives have activity only when substituted

with chlorine or methyl groups
Methazolamide
Dichlorphenamide

4,5-Dichloro-1,3-benzenedisulfonamide
Synthesis of acetazolamide
 Synthesis of acetazolamide

Synthesis of acetazolamide is based on the production of 2-amino-5-

mercapto-1,3,4-thiadiazole, which is synthesised from the reaction
between ammonium thiocynate and hydrazine to form 1,2-
bis(thiocarbamoyl)hydrazine

The 1,2-bis(thiocarbamoyl)hydrazine cyclises into the thiadiazole

upon reacting with phosgene

Acylation with acetic anhydride gives 2-acetylamido-5-mercapto-1,3,

4-thiadiazole. Oxidative chlorination followed by reaction with
ammonia to give acetazolamide
Thiazide diuretics

The compounds in this group are mostly analogues of 1,2,

4-benzothiadiazine-1,1-dioxide
Examples
Mechanism of action

They reduce the reabsorption of electrolytes from the renal

tubules, thereby increasing the excretion of sodium and chloride
ions, and consequently of water.

They also reduce carbonic anhydrase activity but this effect is

small.

The thiazides also have a hypotensive (antihypertensive) action.

Chlorthiazide
Synthesis of chlorthiazide
Hydrochlorothiazide
Hydroflumethiazide
Methyclothiazide
 SARs of thiazides

Thiazides having benzothiadiazine-1,1-dioxide with weakly acidic

character have good activity.

Presence of electron withdrawing groups (e.g. Cl) at C-6 is necessary

for good diuretic activity.

Substitution with CF3 at C-6 yields more lipid soluble derivatives with
larger diuretic action than the chloro-substituted compounds.

Presence of electron releasing groups like methyl or methoxy at C-6

reduces the diuretic activity.
 SARs of thiazides cont’d

Removal or replacement of sulphonamide at C-7 reduces the diuretic

activity.

Saturation of double bond between 3&4 produces compounds having

up to 10 times more diuretic activity than unsaturated analogues.
Introduction of lipophilic groups such as aryl alkyl, halo alkyl, thio ether
enhances the diuretic activity and increases the duration of action.

Alkyl substitution at N2 lowers the polarity and enhances the duration

of action.
 Loop Diuretics/ High Ceiling
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.

2Cl- 2Cl-
 Loop Diuretics

TAL responsible for 35% reabsorption of filtered sodium.

Therefore loop diuretics are highly efficacious or “High

Ceiling Diuretics”.

The Na+/K+/2Cl– symport and sodium pump together

generate a positive lumen potential that drives the
reabsorption of Ca++ and Mg++.

Therefore, Ca++ and Mg++ inhibited as well.

 Chemistry

There are two major chemical classes of loop diuretics:

1. Organomercuricals

2. 5-Sulfamoyl-2-aminobenzoic acid (5-S-2-ABA)& 5-Sulfamoyl-3-

aminobenzoic acid (5-S-3ABA) derivatives.

3. 4-Amino-3-pyridinesulfonoylureas

4. Phenoxyacetic acids
5-Sulfamoyl-2-aminobenzoic acid
derivatives

Furosemide
4-Chloro-N-fufuryl-5-sulphamoylanthracillic acid
5-sulfamoyl-3-aminobenzoic
acid derivatives
Bumetanide
3-butylamino-4-phenoxy-5-sulphamoylbenzoic acid
SAR’s

The substituent at C1 must be acidic…the carboxyl group gives

optimal activity.
A sulfamoyl group in the C5 is a pre-requisite for optimal high ceiling
diuretic activity.
The activating group in the C4 position can be Cl- or CF3 as was with
thiazide diuretics.
Phenoxy, alkoxy, anilino, benzyl or benzoyl groups substituted at 4th
position decreases diuretic activity.
Furfuryl, benzyl and thienyl methyl group at 2-position increases the
activity.
4-Amino-3-pyridinesulfonoylureas
Torsemide

Assignment:

Draw the structure of Torsemide

Understand and Justify its chemical Class

Give the systematic Name of Torsemide

Phenoxyacetic acid derivatives
Ethacrynic Acid

2,3-Dichloro-4-(2-methylenebutyryl) phenoxyacetic
acid
 Mechanism of Action

Reacts with sulfhydryl containing nucleophiles to form sulphydryl

conjugates of ethacrynic acid.
 Structure Activity Relationship

Optimal activity is achieved in phenoxyacetic acid derivatives when….

a) An oxyacetic acid is placed at C1 position of benzene ring
b) A sulfhydryl–reactive acrylol moiety is located para to the
oxyacetic acid group
c) Activating groups (i.e., Cl-) occupy either C3 or C2 and C3
d) Alkyl substituents of two or four positions occupy the position
alpha (α) to carbonyl on the acryloyl moiety
e) Hydrogen atoms occupy the terminal position of the carbon-
carbon double bond of the acryloyl moiety
Potassium sparing diuretics

Spironolactone
It inhibits the re-absorption of 2-3% of the filtered load
sodium by competitively inhibiting the action of
aldosterone.
So the passage of luminal fluid sodium in to and
potassium, hydrogen ions out of the late distal
convoluted tubule and the early collecting tubule cell is
enhanced.
So they enhance the water, sodium and chloride excretion.
Triamterene & Amiloride

These drugs plug the sodium channels in the luminal

membrane of the principal cell at site IV and there by
inhibiting the electrogenic entry of 2-3% of the filtered load
sodium in these cells.

They decrease the antiluminal membrane bound Na+/K+-

ATPase activity, lead to decrease in cellular extrusion of
sodium and in the cellular uptake of potassium at site-IV.
Aldosterone Antagonists
Sodium Channel Inhibitors
Triamterene cont’d
Structures (3)
Synthesis of amiloride
Other diuretics

Mannitol
Is D-mannitol, a hexahydric alcohol
Forms white, crystalline powder of free flowing
granules
Freely soluble in water
Solutions sterilised by autoclaving
 Urea

It is the diamide of carbonic acid, H2NCONH2

It forms white, crystalline powder or transparent crystals
It is odourless or almost odourless, but may gradually
develop a slight odour of ammonia upon long standing
It is slightly hygroscopic and is stored in well-closed
containers
It is freely soluble in water
Sterilised by filtration