‫بسم هللا الرحمن الرحيم‬

Diuretics
• A diuretic provides a means of forced diuresis which elevates the rate of urination.
• There are several categories of diuretics.
• All diuretics increase the excretion of water from bodies, although each class does so
in a distinct way.
Medical uses

• Diuretics are used to treat edema, heart failure, liver cirrhosis,

hypertension and certain kidney diseases.
• Some diuretics, such as acetazolamide, help to make the urine more
alkaline and are helpful in increasing excretion of substances such as
aspirin in cases of overdose or poisoning.
Sites of actions of diuretics
 Diuretics

Loop K-sparing CA Osmotic

Thiazides
diuretics diuretics inhibitors diuretics
High ceiling loop diuretics
1- High ceiling loop diuretic
• They are diuretics that may cause a substantial
diuresis – up to 25% of the filtered load of Na+ and
water.
• Loop diuretics act on the ascending loop of Henle in
the kidney.
• They are primarily used in medicine to treat
hypertension and edema.
• loop diuretics are effective in patients with impaired
kidney function.

Mechanism of action
❑ Loop diuretics act on the Na+-K+-2Cl- symporter
(cotransporter) in the thick ascending limb of the loop
of Henle.
❑ Loop diuretics also inhibit Mg++ and Ca++ reabsorption.
Side Effects:
• volume depletion, hyponatremia, hypokalemia, hypochloremia, hypocalcemia and
hypomagnesemia.
• Ototoxcity, especially with ethacrynic acid
• Hypotension
• Hyperuricemia, hyperglycemia, increase triglyceride and cholesterol levels.
• the hypokalemia produced by high ceiling diuretics can increase the likelihood
of ventricular arrhythmias.
 High ceiling loop diuretic

Sulphonamide derivatives:

Phenoxy acetic acid derivatives:

Furosemide; Lasix: 4-chloro-2-(furan-2-ylmethylamino)- 5-sulfamoylbenzoic acid.
It is a loop diuretic used in the treatment of congestive heart failure and edema.

When taken orally, it begins working within an hour, while intravenously, it begins working
within 5 min.

Serious side effects include electrolyte abnormalities, low blood pressure, and hearing loss.
Common side effects of furosemide injection include hypokalemia , hypotension, and dizziness.
Bumetanide (Bumex or Burinex) 3-butylamino-4-phenoxy-5-sulfamoyl-benzoic acid

• It is used in people in whom high doses of furosemide are ineffective.

• Furosemide is incompletely absorbed in the intestine (60%).
• Bumetanide is almost completely absorbed (more than 80%).

Bumetanide is 40 times more potent than furosemide (for patients with normal renal
function).
Ethacrynic acid: [2,3-dichloro-4-(2-methylenebutanoyl)phenoxy]acetic acid

Unlike the other loop diuretics, ethacrynic acid is not a sulfonamide and thus, its use is
not contraindicated in those with sulfa allergies.
Ethacrynic acid is a phenoxyacetic acid derivative containing a ketone and a
methylene group.
Thiazide diuretics
 Thiazide-type diuretics

Thiazide chlorothiazide hydrochlorothiazide bendroflumethiazide

• Act on the distal convoluted tubule and

inhibit the Na+, Cl- symporter.
• The short-term anti-hypertensive action is
based on the fact that thiazides decrease
preload, decreasing blood pressure.
• The long-term effect is due to an unknown
vasodilator effect that decreases blood
pressure by decreasing resistance.
Effects on Electrolytes:
➢ Na+, Cl-, K+ and Mg2+ excretion is enhanced.
➢ In the long term, uric acid excretion is reduced.
➢ Ca2+ excretion is decreased.

Side Effects:
• volume depletion, hypokalemia, hyponatremia, hypochloremia, hypercalcemia,
hyperuricemia and hypomagnesemia.
• Hyperglycemia.
• Increases plasma levels of LDL cholesterol, and triglycerides.
• The hypokalemia resulting from thiazides increases the likelihood of ventricular
rhythm disturbances.
 SAR of Thiazide diuretics
5 4
R
2 6 N R
1

7 N
H
H
N
2OS
2 S2
8
O1O

• Weakly acidic gp at position 1 (sulphur-1, 1 dioxide) is required for activity.

• Hydrogen atom at the 2-N is most acidic due to presence of electron-withdrawing group.
• Alkyl gp at position 2 decreases the polarity and increases the duration of action.
• Substitution of a lipophillic group at 3 position increases the potency.
• R1= H, CH2C6H5, Cyclopentylmethyl, …..
• Saturation of double bonds give 3, 4-dihydro derivatives (hydrochlorothiazide) which is 10-
folds more active than the unsaturated compounds.
• Electron withdrawing gp at position 6 increases the activity (Cl, Br, CF3)
• Sulfamoyl gp at position 7 is essential for activity and provides additional acidity to the drug
A thiazide-like diuretic is a sulfonamide diuretic that has similar physiological
properties to a thiazide diuretic, but does not have the chemical properties of a
thiazide, lacking the benzothiadiazine molecular structure.

Examples include metolazone and chlorthalidone.

Potassium-sparing diuretics
3- Potassium-sparing diuretics

They do not promote the secretion of K+ into the urine; thus,

K+ is spared and not lost as much as in other diuretics.
Mechanism of action
They are competitive antagonists that compete with
aldosterone for intracellular cytoplasmic receptor sites, or by
directly blocking sodium channels.
Indications
Used in combination with other diuretic drugs (e.g. loop
diuretics) that would otherwise tend to lower the potassium
levels to potentially dangerous low levels (hypokalemia).
The combination helps maintain a normal reference range
for potassium.
Adverse effects
They may raise potassium levels beyond the normal range
(hyperkalemia), which risks potentially fatal arrhythmias.
There are two types of potassium sparing diuretics.
1) Aldosterone Antagonists - spironolactone, eplerenone and canrenone
2) Renal epithelial Na+ channel inhibitors - amiloride, triamterene
Aldosterone antagonists:

Epithelial sodium channel blockers:

Aldosterone antagonists
aldosterone interacts with a mineralocorticoid receptor to enhance the expression of
the Na+, K+-ATPase and the Na+ channel involved in Na+ transport in the distal tubule .
Spironolactone and eplerenone bind to the intracellular receptor blocking the actions
of aldosterone.

Spironolactone has limited efficacy alone but is often given with other diuretics to:
1- enhances the diuretic effect
2- counteracts the K+ loss seen with these diuretics.
Due to its steroid structure, spironolactone can cause antiandrogen effects such
as gynecomastia and impotence in men as well as menstrual irregularities and hair
growth in women.

Eplerenone: Is an analog of spironolactone.

It has lower affinity compared to spironolactone for the mineralocorticoid receptor.
However, eplerenone has little affinity for androgen receptor. Therefore it is void of the
unpleasant steroid hormone-like effects (gynecomastia, hair growth).
Carbonic Anhydrase Inhibitors
4- Carbonic Anhydrase Inhibitors
• This results in bicarbonate retention in the urine and decreased sodium absorption.

• Carbonic anhydrase (CA) catalyzes the first part of

the following reversible reaction, in which carbon
dioxide (CO2) and water (H2O) are converted to
carbonic acid (H2CO3) and vice-versa:
CO2 + H2O <--CA--> H2CO3 <--> H+ + HCO3-
• 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 CO2.
• 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.
 Carbonic Anhydrase Inhibitors include acetazolamide and methazolamide.

• 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+

• 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.
 Acetazolamide (Diamox),

• It is used for glaucoma.

• It reduce the formation of aqueous humor and so reduces the intramolecular
pressure.
• It can act as a mild diuretic by reducing Na and bicarbonate reabsorption in the
proximal tubule.

N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide
Methazolamide
It has a longer elimination half-life than acetazolamide and is less associated with
adverse effects to the kidney

N-(3-Methyl-5-sulfamoyl-1,3,4-thiadiazol-2(3H)-ylidene)acetamide

• It is more potent carbonic anhydrase inhibitor than acetozolamide, but is rarely used
as diuretic.
• It is used in treatment of glaucoma, because it displays improved penetration into the
eye.
 SAR of 1, 3, 4 Thiadiazole-5-sulphonamide
4 3
N N
R
1
H
2N 5
S 2 N
S
O 1 R
O 2

• R1= H, alkyl, phenyl

• R2= O=C-CH3
• Increasing number of carbons in acyl gp leads to retention of activity but side
effects will increase
• Methyl gp on N at position 3 gives active compound (Methazolamide)
• CH3 gp decreases polarity so permits greater penetration into the ocular fluid.
• At position 5, unsubstituted sulphamoyl gp is essential for CA inhibitory activity.
• SO2NH2 gp is necessary for binding with Zn ion of CA enzyme.
Osmotic diuretics
5- Osmotic diuretics
• Compounds such as mannitol are filtered in the glomerulus, but cannot be
reabsorbed. Their presence leads to an increase in the osmolarity of the filtrate. To
maintain osmotic balance, water is retained in the urine.

• Glucose, like mannitol, is a sugar that can behave as an osmotic diuretic.

Thank you