Diuretics

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Normal regulation of fluid and electrolytes by the
kidneys
• Approximately 16-20% of the blood plasma is filtered from the glomerular
capillaries into Bowman’s capsule

• The filtrate is normally protein-free, contains most of the low molecular

weight plasma components in conc. similar to that in the plasma.

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Composition of the filtrate:

• Glucose
• Sodium bicarbonate
• Amino acids
• Organic solutes and metabolites
• Electrolytes such as: Na+, K+, Cl-and Ca2+
• Water

Water is curried passively to regulate osmotic equilibrium.

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Nephron

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 Proximal convoluted tubule (PCT)

• Located in the cortex of the

kidney
• Reabsorbs:
- All the glucose
- Bicarbonate (HCO3-)
- Amino acids
- Metabolites
- ⅔ of Na+
- Cl-
- Water follows passively to
maintain osmolar equality
- Accetazolamide: blocks carbonic
anhydrase

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Proximal convoluted tubule (PCT)

• PCT is the site for secretory systems of organic acid & base

• Secrete: uric acid, some antibiotics & diuretics

• Diuretic drugs in the blood compete for the transfer with

endogenous organic acids such as uric acid

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 Descending loop of Henle

• Passes into the

medulla of the kidney

• Reabsorbs water form

the isotonic filtrate
resulting in 3-fold
increase in salt
concentration.

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 Ascending loop of Henle

• Impermeable to water

• It is a diluting region of the nephron

• Actively reabsorbs: Na+, K+ and Cl- by

Na+/K+/2Cl- cotransporter.

• Both Ca2+ and Mg2+ enter the interstitial fluid via

the paracellular pathway.

• 25-30% of the tubular NaCl is reabsorbed there

(site of action of loop diuretics)
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 Distal convoluted tubule (DCT)

• Also Impermeable to water

• Reabsorbs about 10% of luminal NaCl via Na+/Cl- cotransporter

(that is sensitive to Thiazide diuretic)

• Ca2+ reabsorption is mediated via a channel and is then

transported via Na+/Ca2+ exchanger into the interstitial fluid

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 Collecting tubule and duct

• Na+ enters the cell via Na+ channels

(inhibited by Amiloride and
Triametrene).

• Once inside the cells, Na+ is transported

to the blood via Na+/K+ ATPase pump.

• Aldosterone increases the synthesis of

Na+ channels and Na+/K+ ATPase pump.

• Antidiuretic hormone (ADH;

vasopressin) promotes the
reabsorption of water from there.

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 Diuretics
• Thiazides (Chlorothiazide, Hydrochlorothiazide) & Thiazide-like
diuretics (Indapamide, Metolazone)

• Loop (high ceiling) diuretics: Furosemide, Bumetanide, Torsemide,

Ethacrinic acid

• Potassium-sparing diuretics:
- Aldosterone antogonists (Spironolactone, Eplerenone)
- Amiloride, Triametrene

• Carbonic anhydrase inhibitors: Acetazolamide

• Osmotic diuretics: Mannitol

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 Thiazides & Thiazide-like diuretics

• Thiazides (Chlorothiazide, Hydrochlorothiazide) & Thiazide-like

diuretics (Indapamide, Metolazone)

• Also called “low ceiling diuretics” because increasing the dose above
the normal therapeutic doses does not promote the response further.

• Most widely used diuretic

• All have equal maximum diuretic effects

• Differ only in potency

• Sulfonamide derivatives
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 Mechanism of action of Thiazide diuretics

• Thiazides are secreted by the organic acid secretory system of the

kidneys.

• Act at the cortical region of the ascending loop of Henle and the
DCT.

• They inhibit Na+/Cl- cotransporter, thus increases the conc. of NaCl

in the tubular fluid.

• In order to be functional, Thiazides must be excreted in the tubular

lumen, therefore their efficiency is reduced with renal failure.

• Unlike Thiazides, Metolazone and Indapamide can be used for

patients with renal failure. 13
Actions of Thiazide diuretics

1. Increase excretion of Na+ and Cl-

and produce hyperosmolar urine.

2. Increase loss of K+ : Greater amount

of Na+ reaches the DCT and
collecting duct:
 thus more K+ is exchanged for
Na+
 Resulting in hypokalemia with
prolonged use.

3. Increase loss of Mg 2+: Unknown

mechanism

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Actions of Thiazide diuretics

4. Promote Ca2+ reabsorption in the DCT, decrease urinary Ca2+ excretion

5. Reduce peripheral vascular resistance: unknown mechanism

6. NSAIDs can reduce the diuretic action of Thiazides via inhibition of renal
prostaglandin synthesis.

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Therapeutic uses of Thiazide diuretics

1. Mild to moderate hypertension: reduce blood volume and peripheral

vascular resistance.

2. Heart failure: used additionally to loop diuretics if additional diuresis

is required.

3. Idiopathic hypercalciuria: beneficial for patients with calcium oxalate

stones in the urinary tract

4. Nephrogenic diabetes insipidus: can produce hyperosmolar urine.

Urine volume can drop from 11 L/d to 3 L/d.

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Adverse effects of Thiazide diuretics

1. Hypokalemia:
- Requires K+ supplements or the addition of K+ sparing diuretics
- Can predispose patients taking Digoxin to ventricular arrhythmias

2. Hyponatremia: due to increased ADH release in response to

hypovolemia.

3. Hyperuricemia:
- Due to competition for the organic acid secretory system.
- Cause gout attacks in predisposed patients

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Adverse effects of Thiazide diuretics

4. Volume depletion: can cause orthostatic hypotension or light

headedness

5. Hypercalcemia

6. Hyperglycemia: due to impaired release of insulin and tissue

uptake of glucose.

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Loop (High-ceiling) diuretics

• Furosemide, Bumetanide, Torsemide, Ethacrinic acid

• They have the highest efficacy in mobilizing Na+ & Cl- from the body.

• They function in the ascending loop of Henle

• They inhibit Na+/K+/2Cl- cotransporter, thus reduce the reabsorption of

these electrolytes

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Actions of Loop (High-ceiling) diuretics

• They act promptly even in patients with poor renal function

• They increase Na+, K+ and Ca2+ renal excretion

• Hypocalcemia does not occur because Ca2+ is reabsorbed in the DCT.

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Actions of Loop (High-ceiling) diuretics

• They can enhance renal blood perfusion via induction of prostaglandin

synthesis

• NSAIDs can reduce the diuretic action of loop diuretics

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Therapeutic uses of Loop (High-ceiling) diuretics
- They are administered orally or parenterally

1. Drug of choice for pulmonary edema

2. Drug of choice for acute/chronic peripheral edema associated with

heart failure or renal impairment

3. Drug of choice for emergency pulmonary edema

4. Used along with hydration to treat hypercalcemia

5. Treatment of hyperkalemia

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Adverse effects of Loop (High-ceiling) diuretics

1. Ototoxicity: reversible or permanent hearing loss

2. Hyperuricemia causing or exacerbating gout attacks

3. Acute hypovolemia, with possibility of hypotension, shock and

arrhythmias

4. Hypokalemic alkalosis: High Na+ content in the urine reaching the DCT
increases secretion of K+ and H+ by the duct, causing hypokalemic
metabolic alkalosis

5. Hypomagnesemia: with chronic use

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 Potassium-sparing diuretics

- Act in the collecting tubule to inhibit Na+ reabsorption and K+ excretion

• Two distinct mechanisms of action:

1. Aldosterone antagonists:
Spironolactone & Eplerenone

2. Sodium channel blockers:

Amiloride & Triametrene

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1) Aldosterone antagonists

• Spironolactone & Eplerenone

• Synthetic steroid

• Antagonizes the effect of Aldosterone at the intracellular cytoplasmic

receptor

• Prevents the expression of genes controlling the synthesis of epithelial

Na+ channels and Na+/K+ ATPase.

• Action: Retention of K+ and excretion of Na+

• The effect of these drugs can be diminished by concomitant treatment

with NSAIDs.
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 Therapeutic Uses of Aldosterone antagonists
• Diuretic: Used in conjunction with Thiazides or loop diuretics to prevent
hypokalemia.

• Edema due to secondary hyperaldosteronism, which is associated with hepatic

cirrhosis and nephrotic syndrome

• Ascitis: accumulation of fluids in the abdominal cavity (a complication of hepatic

cirrhosis)

• Heart failure: Aldosterone antagonists prevent cardiac remodeling, and reduces

mortality rate.

• Resistant hypertension

• Polycystic ovarian syndrome: Spironolactone blocks androgen receptors and

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prevents steroid synthesis
Adverse effects of Aldosterone antagonists

• Gynecomastia in males

• Menstrual disturbances in females

• Hyperkalemia

• Mental confusion
• Gastric upset and nausea

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2) Sodium channel blockers

• Amiloride & Triametrene

• Block Na+ channels resulting in decreased Na+/K+ exchanger activity

• Used in conjunction with Thiazides or loop diuretics to prevent hypokalemia.

• Side effects:
1. increased uric acid
2. renal stones
3. K+ retention

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Carbonic anhydrase inhibitor (CAI)
• Acetazolamide, Dorzolamide, Brinzolamide
• Decreased ability to exchange Na+ causes mild diuresis

CAI
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Therapeutic uses of Carbonic anhydrase inhibitor (CAI)

• Open-angle glaucoma:
 Dorzolamide and Brinzolamide
 Applied topically to reduce aqueous humor production by the ciliary
body

• Mountain sickness: Acetazolamide

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Osmotic diuretics

• Mannitol and Urea

• Mechanism of action: hydrophilic chemicals that are filtered through the

glomerulus and does not undergo significant reabsorption, resulting in
higher osmolarity of the tubular fluid and prevents further water
reabsorption.

• Clinical use:
- Increased intracranial pressure
- Acute renal failure due to shock, drug toxicity and trauma
- Acute Angle-Closure Glaucoma

• Side effects: hypo- or hypernatremia

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