PHARMACEUTICAL CHEMISTRY -2

Lecture 6
Diuretics

Asmaa Mohamed Atta, PhD

Cardiovascular drugs
Antihypertensive drugs

Antianginal drugs

Antiarrhythmic

Anti-hyperlipidemic

Anticoagulants
 Hypertension
 Hypertension is the most common
cardiovascular disease and is the major risk
factor for coronary artery disease, heart failure,
stroke, and renal failure.
 The onset of hypertension is defined as having a
blood pressure of 140/90 mm Hg or greater.
 Although hypertension may occur secondary to
other disease processes, more than 90% of
patients have essential hypertension
(hypertension with no identifiable cause).
 Therapy using antihypertensive agents evolved
rapidly between 1950 and 1960.
 During that time, several drugs for the treatment
and control of hypertensive disease were
discovered.
Antihypertensive drugs
Angiotensin-converting
enzyme inhibitors

Calcium channel Angiotensin receptor

blockers antagonists

Classification of
antihypertensive drugs

Vasodilator Diuretics

Sympatholytic
drugs
 Diuretics
 Diuretics are chemicals that increase the
rate of urine formation.
 By increasing the urine flow rate, diuretic
usage leads to increased excretion of
electrolytes (especially sodium and
chloride ions) and water from the body
without affecting protein, vitamin, glucose,
or amino acid reabsorption.
 These pharmacologic properties have led to
the use of diuretics in the treatment of
edematous conditions resulting from a
variety of causes (e.g., congestive heart
failure, nephrotic syndrome, and chronic
liver disease) and in the management of
hypertension.
 Diuretics
Osmotic diuretics

Carbonic anhydrase inhibitors Diuretics

Thiazide Diuretics

High-Ceiling or Loop Diuretics

Potassium-Sparing Diuretics
Diuretics
 Osmotic Diuretics
Mechanism of action
 Osmotic diuretics are low molecular weight compounds
that are freely filtered through the Bowman’s capsule
into the renal tubules.
 Once in the renal tubule, osmotic diuretics have a
limited reabsorption because of their high water
solubility.
 These agents increase intraluminal osmotic pressure,
causing water to pass from the body into the tubule
 Osmotic diuretics increase the volume of urine and the
excretion of water and almost all of the electrolytes.
Therapeutic Applications
 Prophylaxis of acute renal failure, in which these drugs inhibit water reabsorption and
maintain urine flow.
 Used to acutely reduce increased intracranial or intraocular pressure.
 Osmotic Diuretic
Mannitol Isosorbide

 Most commonly used as an osmotic  Used orally to cause a

diuretic (administrated IV). reduction in intraocular
 Filtered at the glomerulus and is poorly pressure in glaucoma
reabsorbed by the kidney tubule. cases.
 The osmotic effect of mannitol in the
tubule inhibits the reabsorption of water.
 Also used to reduce intracranial pressure.
 Carbonic anhydrase inhibitors Diuretics
Mechanism of action
 Induce diuresis by inhibiting the formation of
carbonic acid within proximal and distal
tubular cells to limit the number of hydrogen
ions available to promote sodium
reabsorption.

Uses
 Most commonly used in the treatment of
glaucoma (inhibit carbonic anhydrase in the
eye).
 With prolonged use, the urine becomes more
alkaline and the blood becomes more acidic
(lose their effectiveness as diuretics).
 Carbonic anhydrase inhibitors Diuretics
Acetazolamide Methazolamide

 The first of the carbonic anhydrase  One of the active hydrogens in

inhibitors. the thiadiazole ring has been
 Thiadiazole derivative. replaced by a methyl group
 The sulfonamide portion of an decreases polarity permits
active diuretic molecule could not a greater penetration into the
be monosubstituted or disubstituted. ocular fluid.
 Thiazide Diuretics
Mechanism of action
 The major site of action is mainly in the distal convoluted tubule to decrease
the reabsorption of Na+ and Cl– ions by inhibition of a Na+/ Cl– symporter.
 As a result, these drugs increase the concentration of Na+ and Cl– in the tubular
fluid.

Uses
 Commonly are used in the treatment of hypertension.
 Used to treat edemas caused by cardiac disease, hepatic or renal disease.

Adverse effect
Hypokalemia is the most frequent problem with the thiazide diuretics.
Because thiazides increase Na+ in the filtrate arriving at the distal tubule, more K+
is also exchanged for Na+, resulting in a continual loss of K+ from the body with
prolonged use of these drugs.
Thiazide Diuretics
 Thiazide Diuretics
Structure activity relationship

Benzothiadiazine-1,1 dioxide -7-sulphonamide

 Replacement or removal of the sulfonamide group at position 7 yields compounds
with little or no diuretic activity.
 An electron-withdrawing group is necessary at position 6 for diuretic activity.
 Saturation of the double bond to give a 3,4-dihydro derivative produces a diuretic
that is 10-fold more active than the unsaturated derivative.
 Substitution with a lipophilic group at position 3 gives a marked increase in the
diuretic potency.
 Alkyl substitution on the 2-N position also decreases the polarity and increases
the duration of diuretic action.
 Thiazide Diuretics
Chlorothiazide Hydrochlorothiazide

6-chloro-2H-benzo[e] [1,2,4] 6-chloro-3,4-dihydro-2H benzo[e]

thiadiazine-7-sulfonamide 1,1- [1,2,4]thiadiazine-7-sulfonamide
dioxide 1,1-dioxide
 Thiazide-like Diuretics
 This is a structurally diverse group of sulfonamide derivatives that do not contain
benzothiadiazine rings.
 Nevertheless, they have the same mechanism of action and similar therapeutic activities and
adverse effects as the thiazide diuretics.

1- Phthalimidine derivatives

Chlorthalidone

1-oxo-isoindoline

 Has a long duration of action (48 to 72 hours).

 Thiazide-like Diuretics
2- Indoline
Indapamide

methylindoline group
chlorobenzamide

 It contains a polar chlorobenzamide moiety and a nonpolar lipophilic

methylindoline group.
 Uses of indapamide include the treatment of essential hypertension and edema
resulting from congestive heart failure.
 High-Ceiling or Loop Diuretics
Mechanism of action
 Site of action is believed to be on the thick ascending limb of the loop of Henle,
where they inhibit the luminal Na+/ K+/2Cl− symporter.
 Therefore, reabsorption of these ions is decreased and less water is reabsorbed
from water permeable segments, like the descending loop of Henle, causing
diuresis.
 These agents have the greatest diuretic effect of all the diuretics because the
ascending limb accounts for reabsorption of 25% to 30% of filtered NaCl.
 High-ceiling diuretics are characterized by a quick onset and short duration of
activity.
 Their diuretic effect appears in approximately 30 minutes and lasts for
approximately 6 hours.
 Adverse effects: clinical toxicity of loop diuretics primarily involves
abnormalities of fluid and electrolyte balance (hypokalemia, hypomagnesemia,
hyperuricemia and hypocalcemia).
High-Ceiling or Loop Diuretics
 High-Ceiling or Loop Diuretics
Furosemide
Furan ring

5-Sulfamoylanthranilic
acid

 Derivative of anthranilic acid or o-aminobenzoic acid.

 Furosemide has a saluretic effect 8- to 10-fold that of the thiazide diuretics;
however, it has a shorter duration of action (∼6 to 8 hours).
 It is effective for the treatment of hypertension and edemas connected with
cardiac, hepatic, and renal sites.
 Orally effective but may be used parentally when a more prompt diuretic effect
is desired.
 High-Ceiling or Loop Diuretics
Bumetanide
The phenoxy group is an electron-withdrawing group
similar to the chloro substitution.

 The minor variations from furosemide produced a compound with a mode of

action similar to that of furosemide, but with a marked increase in diuretic
potency.
 Bumetanide is approximately 50-fold more potent than furosemide but has same
short duration of action.
 High-Ceiling or Loop Diuretics
Torsemide

sulfonylurea moiety

 The oral bioavailability of torsemide is very good (∼80%), and absorption is not
affected by the presence of food in the gastrointestinal tract.
 Potassium-Sparing Diuretics
 Potassium-sparing diuretics act in the collecting tubule to inhibit Na+ reabsorption
and K+ excretion.
 Potassium levels must be monitored in patients treated with potassium-sparing
diuretics.
 Within this class, there are drugs with two distinct mechanisms of action:
aldosterone antagonists (Mineralocorticoid Receptor Antagonists) and epithelial
sodium channel blockers.

Epithelial sodium Aldosterone

channel blockers antagonist

Potassium
sparing
diuretics
Potassium-Sparing Diuretics
 Potassium-Sparing Diuretics
I- Sodium channel inhibitors
Mechanism of action
 Exert a diuretic effect by blocking sodium channel in the late distal convoluted
tubule and collecting duct.
 Sodium channel inhibitors block the reabsorption of sodium ion and inhibit the
secretion of potassium ion.
 The net result is increased sodium and chloride ion excretion in the urine and
almost no potassium excretion.
 Two drugs in this class of diuretics are triamterene and amiloride which exert a
mild diuretic effect and are usually used in combination with thiazides or loop
diuretics (used to offset the effect of other diuretics that result in loss of
potassium).

Adverse effect: the most serious side effect is hyperkalemia.

 Potassium-Sparing Diuretics
I- Sodium channel inhibitors
Pteridines
Triamterene

pteridine

6-phenylpteridine-2,4,7-triamine

 Triamterene is extensively metabolized to 4′-hydroxytriamterene and its sulfate

conjugate, both of which (major metabolite) are still active as diuretics.
 Triamterene is useful in combination with a thiazide or loop diuretic in the
treatment of edema or hypertension.
 Potassium-Sparing Diuretics
I- Sodium channel inhibitors
Aminopyrazines
Amiloride

 Aminopyrazine structurally related to triamterene as an open-chain analog.

 Amiloride combined with a thiazide or loop diuretic is used to treat edema or
hypertension.
 Potassium-Sparing Diuretics
II- Mineralocorticoid Receptor Antagonists
 The adrenal cortex secretes a potent mineralocorticoid called aldosterone which
promotes salt and water retention and potassium and hydrogen ion excretion.
 Aldosterone exerts its biologic effects through binding to the mineralocorticoid
receptor (MR).
 Mineralocorticoid receptor antagonists antagonize the effects of aldosterone.
 Potassium-Sparing Diuretics
II- Mineralocorticoid Receptor Antagonists

Spironolactone

Aldosterone

 Competitively inhibits aldosterone binding to the MR, thereby interfering with

reabsorption of sodium and chloride ions and the associated water.
 MR antagonist activity is dependent on the presence of a γ-lactone ring on C-17
and a substituent on C-7 (acetylthio group) in spironolactone and structurally
related compounds.
 Potassium-Sparing Diuretics
II- Mineralocorticoid Receptor Antagonists
Spironolactone
USES:
1. Coadministrated with a potassium depleting diuretic
(e.g., a thiazide or loop diuretic) to prevent or treat
diuretic-induced hypokalemia.
2. The drug of choice for treating edema resulting from
cirrhosis of the liver.
Adverse effect:
1. Hyperkalemia, which can be fatal.
2. Sexual side effects can also occur and are due to
nonselective binding of spironolactone to the
androgen receptor, glucocorticoid receptor, or
progesterone receptor.