International University for Sciences & Technology

Faculty of Pharmacy

Pharmacology 3

DIURETICS

Dr. Hala SARHAN

2024

Suggested reading:
 Lippincott Pharmacology (Karen Whalen ed.), 7TH ed. 2019, Chapter 17
 Lange Basic and Clinical Pharmacology (B. G. Katzung ed.), 15th ed. 2021, McGraw Hill 2021, Chapter 15
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 I. OVERVIEW

 Diuretics are drugs that increase the volume of urine excreted.

 Most diuretic agents are inhibitors of renal ion transporters 
decrease the reabsorption of Na+ at different sites in the nephron.
 Na+ and other ions enter the urine in greater than normal amounts
along with water  carried passively to maintain osmotic
equilibrium.
 Diuretics increase the volume of urine and often change its pH, as well
as the ionic composition of the urine and blood.
 Different classes of diuretics: ion transport inhibitors, osmotic
diuretics, aldosterone antagonists, carbonic anhydrase inhibitors.
 Diuretics are used for management of fluid retention (edema), or
for systemic effects in addition to their actions on kidney.
Examples, uses of thiazides in hypertension, carbonic anhydrase
inhibitors in glaucoma, aldosterone antagonists in heart failure.

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Summary of diuretic drugs.

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 II. Normal Regulation of Fluid and Electrolytes by the Kidneys

 16% to 20% of the blood plasma entering the kidneys is filtered from
the glomerular capillaries into Bowman's capsule.
 The filtrate, although normally free of proteins and blood cells,
contains most of the low molecular weight plasma components in
concentrations similar to that in plasma.
 These include glucose, sodium bicarbonate, amino acids, and other
organic solutes, as well as electrolytes, such as Na+, K+, and Cl−.
 The kidney regulates the ionic composition and volume of urine by
active reabsorption or secretion of ions and/or passive reabsorption of
water at five functional zones along the nephron: 1) the proximal
convoluted tubule ‫النبيب الملتوي القريب‬, 2) the descending loop of Henle ‫حلقة هنلي‬
‫الهابطة‬, 3) the ascending loop of Henle, ‫ حلقة هنلي الصاعدة‬4) the distal convoluted

tubule‫النبيب الملتوي البعيد‬, and 5) the collecting tubule and duct ‫النبيب الجامع والقناة‬.
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Major locations of ion and water exchange in the nephron, showing
sites of action of the diuretic drugs.
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 II. Normal Regulation of Fluid and Electrolytes by the Kidneys

A. Proximal Convoluted Tubule

 In the proximal convoluted tubule located in the cortex of the kidney,

almost all glucose, bicarbonate, amino acids, and other metabolites are
reabsorbed.

 Approximately 60-65% of the filtered Na+ and water are reabsorbed

from the lumen to the blood to maintain osmolar equality.

 Chloride enters the lumen of the tubule in exchange for an anion, such
as oxalate.

 The Na+ that is reabsorbed is pumped into the interstitium by the

Na+/K+-adenosine triphosphatase (ATPase) pump.

 Carbonic anhydrase in the luminal membrane and cytoplasm of the

proximal tubular cells modulates the reabsorption of bicarbonate.

 Diuretics working in the proximal convoluted tubule display weak

diuretic properties. 6
 The proximal tubule is the site of organic acid and base secretory
systems.
 The organic acid secretory system, secretes a variety of organic acids,
such as uric acid, some antibiotics, and diuretics, from the
bloodstream into the proximal tubular lumen.
 The organic acid secretory system is saturable, and diuretic drugs in
the bloodstream compete for transfer with endogenous organic acids
such as uric acid.
 The organic base secretory system is responsible for the secretion of
creatinine and choline.

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Proximal convoluted tubule cell.
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II. Normal Regulation of Fluid and Electrolytes by the Kidneys

B. Descending loop of Henle

 The remaining filtrate, which is isotonic, next enters the descending
limb of the loop of Henle and passes into the medulla of the kidney.

 The osmolarity increases along the descending portion of the loop

of Henle because of water reabsorption.

 This results in a tubular fluid with a three-fold increase in Na+

and Cl− concentration.

 Osmotic diuretics exert part of their action in this region.

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II. Normal Regulation of Fluid and Electrolytes by the Kidneys

C. Ascending loop of Henle

 The cells of the ascending tubular epithelium are unique in being
impermeable to water.
 Active reabsorption of Na+, K+, and Cl− is mediated by a
Na+/K+/2Cl− cotransporter.
 Both Mg2+ and Ca2+ are reabsorbed via the paracellular pathway 
the ascending loop dilutes the tubular fluid and raises the
osmolarity of the medullary interstitium.
  25% to 30% of the filtered sodium chloride is absorbed here.
 Because the ascending loop of Henle is a major site for salt
reabsorption drugs affecting this site, such as loop diuretics, have
the greatest diuretic effect.
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Ascending loop of Henle
cell. 11
 II. Normal Regulation of Fluid and Electrolytes by the Kidneys

D. Distal convoluted tubule

 The cells of the distal
convoluted tubule are also
impermeable to water ~ 5%
to 10% of the filtered sodium
chloride is reabsorbed via a
Na+/Cl− transporter, the target
of thiazide diuretics.
 Calcium reabsorption, under
the regulation of parathyroid
hormone, is mediated by an
apical ‫ قمي‬channel and then
transported by a Na+/Ca2+- Distal convoluted tubule cell.
exchanger into the interstitial
fluid
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II. Normal Regulation of Fluid and Electrolytes by the Kidneys

E. Collecting tubule and duct

 The principal cells of the collecting tubule and duct are responsible for
Na+, K+, and water transport. Intercalated cells affect H+ secretion.
 ~ 1% to 2% of the filtered sodium enters the principal cells through
epithelial sodium channels  are inhibited by amiloride and
triamterene.
 Inside the cell, Na+ reabsorption relies on a Na+/K+-ATPase pump to be
transported into the blood.
 Aldosterone receptors in the principal cells influence Na+ reabsorption
and K+ secretion.
 Aldosterone increases the synthesis of epithelial sodium channels and
Na+/K+-ATPase pump  increase Na+ reabsorption and K+ excretion.
 Antidiuretic hormone (ADH; vasopressin) binds to V2 receptors to
promote reabsorption of water through aquaporin channels.

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Collecting tubule and duct cells. E Na 14
channel = Epithelial sodium channel.
 III. Thiazides

 Thiazides are the most widely used diuretics because of their

antihypertensive effects.
 The efficacy of thiazides for hypertension is not entirely
dependent on their diuretic actions  They also reduce
peripheral vascular resistance with long-term therapy.
 Despite being sulfonamide derivatives, thiazides do not cause
hypersensitivity reactions in patients with allergies to
sulfonamide antimicrobials.
 All thiazides affect the distal convoluted tubule, and all have
equal maximum diuretic effects, differing only in potency.
 Thiazides are sometimes called “low ceiling diuretics”
because increasing the dose above normal therapeutic doses
does not promote further diuretic response.
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 III. Thiazides
A. Thiazides
 Chlorothiazide = the first orally active thiazide. Hydrochlorothiazide
and chlorthalidone are now used more commonly due to better
bioavailability.
 Hydrochlorothiazide is more potent, so the required dose is lower
than that of chlorothiazide.
 Chlorthalidone is twice as potent as hydrochlorothiazide.
 Chlorthalidone, indapamide, and metolazone are referred to as
thiazide-like diuretics because they lack the characteristic
benzothiadiazine chemical structurebut their mechanism of action,
indications, and adverse effects are similar to those of
hydrochlorothiazide.

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 III. Thiazides

1. Mechanism of action
 Thiazide and thiazide-like diuretics act mainly in the distal convoluted
tubule to decrease reabsorption of Na+ by inhibition of Na+/Cl−
cotransporter  increasing Na+ and Cl− concentration in the tubular
fluid.
 Thiazides must be excreted into the tubular lumen at the proximal
convoluted tubule to be effective  Therefore, decreasing renal
function reduces the diuretic effects.
 The efficacy of thiazides may be diminished with concomitant use of
nonsteroidal anti-inflammatory drugs (NSAIDs), such as
indomethacin, which inhibit production of renal prostaglandins 
reducing renal blood flow.

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 III. Thiazides
2. Actions
a. Increased excretion of Na+ and Cl−
 Thiazide and thiazide-like diuretics cause diuresis with increased Na+ and
Cl− excretion  excretion of very hyperosmolar urine.
This latter effect is unique, in comparison with other diuretic classes.

b. Decreased urinary calcium excretion

 Thiazide and thiazide-like diuretics decrease Ca2+ content of urine by
promoting its reabsorption in the distal convoluted tubule  where
parathyroid hormone regulates reabsorption.

c. Reduced peripheral vascular resístance

 Initial reduction in blood pressure results from a decrease in blood volume
 decrease in cardiac output.
 With continued therapy, blood volume returns to baseline.
 Antihypertensive effects result from reduced peripheral vascular resistance
caused by relaxation of arteriolar smooth muscle.
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 III. Thiazides

3. Therapeutic uses
a. Hypertension
 Current treatment guidelines for hypertension do not recommend any
thiazide preferentially.
b. Heart failure
 Thiazide diuretics such as Metolazone may be added in patients
resistant to loop diuretics, with careful monitoring for hypokalemia.
c. Hypercalciuria
 Thiazides can be useful in treating idiopathic hypercalciuria and
calcium oxalate stones in the urinary tract  they inhibit urinary Ca2+
excretion.
d. Diabetes insipidus
 Thiazides can be utilized as a treatment for nephrogenic diabetes
insipidus  The urine volume of such individuals may drop from 11 to
about 3 L/d when treated with thiazides.
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 III. Thiazides

4. Pharmacokinetics
 Thiazides are effective orally, with a
bioavailability of 60% to 70%.
 Chlorothiazide has a much lower
bioavailability (15% to 30%) and is the
only thiazide with an IV dosage form.
 Most thiazides take 1 to 3 weeks to
produce a stable reduction in blood
pressure and exhibit a prolonged half-life
(10 to 15 hours).
 Most thiazides are primarily excreted
unchanged in urine, except indapamide is
excreted in urine and bile.

Adverse effects commonly

observed with thiazides and 20
thiazide like medications.
 IV. Loop Diuretics

 Bumetanide, furosemide, torsemide, and ethacrynic acid have their

major diuretic action on the ascending loop of Henle .
 These drugs have the highest efficacy in mobilizing Na+ and Cl−
from the body  producing copious amounts of urine.
 Similar to thiazides, loop diuretics do not generally cause
hypersensitivity reactions in patients with allergies to sulfonamide
antimicrobials.
 Furosemide is the most commonly used of these drugs.
 The use of bumetanide and torsemide is increasing  because of
better bioavailability and more potentiality.
 Ethacrynic acid is used infrequently due to its adverse effect profile.

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 IV. Loop Diuretics

1. Mechanism of action
 Loop diuretics inhibit the co-transport of Na+/K+/2Cl− in the
luminal membrane in the ascending loop of Henle 
reabsorption of these ions into the renal medulla is decreased.
 Loop diuretics have the greatest diuretic effect of all
diuretics.
 By lowering the osmotic pressure in the medulla, less water is
reabsorbed from the descending loop of Henle  diuresis.
 Loop diuretics must be excreted into the tubular lumen at the
proximal convoluted tubule to be effective.
 NSAIDs inhibit renal prostaglandin synthesis and can reduce
the diuretic action of loop diuretics.

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 IV. Loop Diuretics
2. Actions
a. Diuresis
Loop diuretics cause diuresis, even with renal
failure.
Loop diuretics display a sigmoidal (“S”-
shaped) dose-response curve with three parts:
threshold effect, rapid increase in diuresis, a
ceiling effect.
A dose must be selected to cross the response
threshold, which is patient-specific:
Reducing the effective dose can result in no
Loop diuretic dose-response curve.
diuresis.
Increasing the effective dose may not cause
more diuresis because of the ceiling effect.

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 IV. Loop Diuretics

b. Increased urinary calcium excretion

Loop diuretics increase Ca2+ content of urine.
c. Venodilation
Loop diuretics cause acute venodilation and reduce left ventricular
filling pressures via enhanced prostaglandin synthesis.

3. Therapeutic uses
a. Edema
Treatment of pulmonary edema and acute/chronic peripheral
edema.
b. Hypercalcemia
c. Hyperkalemia

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 IV. Loop Diuretics

4. Pharmacokinetics
 Furosemide has unpredictable
bioavailability of 10% to 90% after
oral administration.
 Bumetanide and torsemide have
reliable bioavailability of 80% to
100%.
 The duration of action is
approximately 6 hours.

Adverse effects commonly

observed with loop diuretics.

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 V. Potassium-Sparing Diuretics

 Within this class, there are drugs with two distinct

mechanisms of action: aldosterone antagonists and
epithelial sodium channel blockers.
 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.
 These drugs should be used cautiously in renal
dysfunction because of increased risk of hyperkalemia.

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 V. Potassium-Sparing Diuretics

A. Aldosterone antagonists: spironolactone and eplerenone

1. Mechanism of action
 Spironolactone and eplerenone are synthetic steroids 
antagonize aldosterone receptors  inhibiting the Na+/K+-
exchange in the collecting tubule.
 Aldosterone antagonists prevent Na+ reabsorption and K+,
H+ secretion  causing diuresis.
 Eplerenone is more selective for aldosterone receptors and
causes less endocrine effects (gynecomastia) than
spironolactone, which also binds to progesterone and
androgen receptors.

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 V. Potassium-Sparing Diuretics

A. Aldosterone antagonists: spironolactone and eplerenone

2. Therapeutic uses
a. Edema
Aldosterone antagonists are particularly effective diuretics when used
in high doses for edema associated with secondary hyperaldosteronism.
b. Hypokalemia
Often given in conjunction with thiazides or loop diuretics to prevent
K+ excretion that occurs with those diuretics.
c. Heart failure
They are employed at lower doses to prevent myocardial remodeling
mediated by aldosterone  decreasing mortality associated with HF.
d. Resistant hypertension
e. Polycystic ovary syndrome
Spironolactone blocks androgen receptors and inhibits steroid
synthesis at high doses  helping to offset increased androgen levels.28
 V. Potassium-Sparing Diuretics

3. Pharmacokinetics
 Spironolactone and eplerenone are well absorbed orally.
 Spironolactone is extensively metabolized and converted to several
active metabolites.
 Eplerenone is metabolized by cytochrome P450 3A4.

4. Adverse effects
a. Hyperkalemia
b. Gynecomastia
Spironolactone, but not eplerenone, may induce gynecomastia in
approximately 10% of male patients .

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 V. Potassium-Sparing Diuretics

B. Triamterene and amiloride

 Triamterene and amiloride block epithelial sodium
channels, resulting in a decrease in Na+/K+ exchange.
 Their ability to block the Na+/K+-exchange site in the
collecting tubule does not depend on the presence of
aldosterone.
 These agents are not very efficacious diuretics.
 Both triamterene and amiloride are commonly used in
combination with other diuretics, for their potassium-
sparing properties.

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 VI. Carbonic Anhydrase Inhibitor

 Acetazolamide and other carbonic anhydrase inhibitors are more often

used for their other pharmacologic actions than for their diuretic effect,
because they are much less efficacious than thiazides or loop diuretics.
1. Mechanism of action
 Acetazolamide inhibits carbonic anhydrase located in cytoplasm and
on the membrane of the proximal tubular epithelium.
Carbonic anhydrase catalyzes the reaction of CO2 and H2O, leading
to H2CO3  spontaneously ionizes to H+ and HCO3− (bicarbonate).
 The decreased ability to exchange Na+ for H+ in the presence of
acetazolamide results in a mild diuresis.
 HCO3 − is retained in the lumen, with marked elevation in urinary pH
 the loss of HCO3− causes a hyperchloremic metabolic acidosis.
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Proximal convoluted tubule cell.
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 VI. Carbonic Anhydrase Inhibitor

2. Therapeutic uses
a. Glaucoma
b. Altitude sickness
3. Pharmacokinetics
Acetazolamide can be administered orally or intravenously. It is 90%
protein bound and eliminated renally.
4. Adverse effects
Metabolic acidosis (mild), potassium depletion, renal stone
formation, drowsiness, and paresthesia ‫ تنمل‬may occur.

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 VII. Osmotic Diuretics

 A number of simple, hydrophilic chemical substances are filtered through the

glomerulus, such as mannitol  result in diuresis.
 These filtered substances don’t undergo reabsorption  result in a higher
osmolarity of the tubular fluid  prevents further water reabsorption at the
descending loop of Henle and proximal convoluted tubule  resulting in
osmotic diuresis with little additional Na+ excretion (aquaresis).

These agents are not useful for treating conditions of Na+ retention.
They are used to maintain urine flow following acute toxic ingestion of
substances capable of producing acute renal failure.
 Osmotic diuretics are a mainstay of treatment for patients with increased
intracranial pressure.

 Mannitol is not absorbed orally and should be given intravenously.

 Adverse effects: dehydration and extracellular water expansion from the
osmotic effects in the systemic circulation.
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Urinary excretion from diuretic therapy.

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 Study Questions

Choose the ONE best answer.

1) An elderly patient with a history of heart pulmonary edema. Which treatment is indicated?
disease has difficulty breathing and is diagnosed with acute
A. Acetazolamide
B. Chlorthalidone
C. Furosemide
D. Spironolactone

2) A group of college students is planning a mountain climbing trip to the Andes. Which is most
appropriate for them to take to prevent altitude sickness?
A. A thiazide diuretic such as hydrochlorothiazide
B. An anticholinergic such as atropine
C. A carbonic anhydrase inhibitor such as acetazolamide
D. A loop diuretic such as furosemide

3) An alcoholic male has developed hepatic cirrhosis. To control the ascites and edema, which
should be prescribed?
A. Acetazolamide
B. Chlorthalidone
C. Furosemide
D. Spironolactone
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4) A 55-year-old male with kidney stones needs a medication to decrease urinary calcium excretion.
Which diuretic is best for this indication?
A. Torsemide
B. Hydrochlorothiazide
C. Spironolactone
D. Triamterene
5) A 75-year-old woman with hypertension and glaucoma is being treated with chlorthalidone,
amlodipine, lisinopril, and acetazolamide. In clinic today, she complains of acute joint pain and
redness in her great toe, which is diagnosed as gout. Which medication is most likely to have
caused the gout attack?
A. Amlodipine
B. Acetazolamide
C. Chlorthalidone
D. Lisinopril
6) Which is contraindicated in a patient with hyperkalemia?
A. Acetazolamide
B. Chlorothiazide
C. Ethacrynic acid
D. Eplerenone
7) A 59-year-old male patient in the intensive care unit has a metabolic alkalosis. Which therapy will
treat this condition?
A. Amiloride
B. Hydrochlorothiazide
C. Mannitol 37
D. Acetazolamide
8) A male patient is placed on a new medication and notes that his breasts have become enlarged
and tender to the touch. Which medication is the most likely taking?
A. Furosemide
B. Hydrochlorothiazide
C. Spironolactone
D. Triamterene
9) A patient with heart failure with reduced ejection fraction researched his medications on the
Internet and found he was taking two “diuretics,” bumetanide and spironolactone. He asks if this is a
mistake with his therapy. What is the best response?
A. Spironolactone is used to prevent hyponatremia.
B. Spironolactone is used to reduce heart structure changes and decrease the risk of death.
C. Bumetanide is used to decrease the potassium lost from spironolactone therapy.
D. This is a duplication error and one diuretic should be stopped.
10) Which diuretic has been shown to improve blood pressure in resistant hypertension or those
already treated with three blood pressure medications including a thiazide or thiazide-like
medication?
A. Indapamide
B. Furosemide
C. Mannitol
D. Spironolactone

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