Loop Diuretics

MOA • Act in ascending limb of loop of Henle

• Inhibit Na+/K+/Cl- co-transporter of the luminal membrane
– Reabsorption of Na+, K+, Cl- is decreased

Metabolism • Bioavailability of 64% (tablets) and 60% (oral solution) with more rapid absorption from oral solution
• Duration of action only 1-4 hrs
• 91-99% PPB
• Liver metabolism (Glucuronate)
• Excreted in urine (+ unchanged drug)

Uses – Acute pulmonary oedema

– Reduce acute pulmonary edema of congestive heart failure
– Rapid onset of action useful in emergency situations for rapid, intense diuresis
– Chronic heart failure
– Nephrotic syndrome
– Renal failure
– Hypertension complicated by renal impairment
– Cirrhosis of the liver complicated by ascites
– Hypercalcaemia
– Stimulate tubular Ca2+ secretion, reducing Ca2+ concentration in blood.

Side Effects – Hypokalemia (reduced K+ level) – induced by large Na+ levels in DCT
– Hypomagnesaemia (reduced Mg2+ level)
– Hypochloraemic metabolic alkalosis (increased H2CO3 and CO2 concentrations with accompanying low Cl- levels)
– Acute hypovolemia - severe & rapid decrease in blood volume; possibility of hypotension, shock, cardiac
arrhythmias
– Ototoxicity (ear damage) – Can be permanent with chronic use
– Hyperuricemia (High uric acid levels) – can initiate gout attacks
– Dehydration/hyponatraemia (low Na+ levels)

Examples – Furosemide (Frusemide; Lasix)

– Bumetanide (Bumex)
– Piretanide
– Torasemide (Torsemide)
Notes • Referred to as High-ceiling diuretics
• Most powerful Diuretic
• “Torrential Urine Flow”
• Most efficacious of the diuretics because ascending limb accounts for reabsorption of 30-40% of filtered NaCl
 Thiazides
MOA – Act in distal tubule
– Decrease reabsorption of Na+ by inhibition of Na+/Cl- co-transporter
– Increase concentration of Na+ & Cl- in tubular fluid
– N.B. Significant loss of K+
– Thiazide diuretics decrease Ca2+ content of urine
• Promote the reabsorption of Ca2+
• Contrast with loop diuretics

Metabolism • Varying degrees of kinetics

Uses – Hypertension
• Effective in reducing systolic & diastolic BP for extended periods.
• After 3-7 days, BP stabilizes at reduced level
• Can be maintained by daily dose of thiazide
– Congestive heart failure (mild/moderate)
• Reduces extracellular volume
– Prevent stones in idiopathic hypercalciuria
• Due to decreased excretion of Ca2+
– Nephrogenic diabetes insipidus

Side Effects – Hypotension

– Hypokalemia (↓ K+)
– Hypomagnesemia (↓ Mg2+)
– Hypochloraemic metabolic alkalosis
– Hyperuricemia (↑ Uric acid)
– Impaired carbohydrate tolerance
– Hyperlipemia
– Hyponatremia
– Allergic reactions

Examples – Bendroflumethiazine (Naturetin)

– Chlorothiazide & Hydrochlorothiazide
– Chlorthalidone
Notes • Most widely used diuretics
• Act on distal tube
• Moderately powerful diuresis
• Long-term vasodilator effect
 K+ - Sparing Diuretics
1. Inhibition of epithelial Na+ channels
• e.g. Triamterene, amiloride

– Actions independent of aldosterone

– inhibition of sodium reabsorption at the distal convoluted tubule, cortical collecting tubule and
collecting duct
– Reduced potassium and hydrogen secretion and subsequent excretion.
– Not metabolized by the liver
• Excreted as unchanged drug in urine and stool

1. Inhibition of aldosterone
MOA & Metabolism
• e.g. Spironolactone, Potassium canrenoate

– Competitive aldosterone antagonist

– Competes with aldosterone for intracellular receptors
Prevents translocation of receptor complex into nucleus, preventing transcription, translation
of mediator proteins
– These mediator proteins normally stimulate the Na +-K+ exchange sites of distal tubule
– Prevents Na+ reabsorption and K+ and H+ secretion
– Metabolized to active metabolite (Canrenone)
Both exert diuretic effect

Uses – With K+- losing diuretics (Loop diuretics or Thiazides) to prevent K + loss
– Heart failure
– Spironolactone counteracts Secondary aldosteronism associated with diuretic electrolyte loss

Side Effects – Hyperkalemia

– Metabolic acidosis
– Spironolactone
• Gynecomastia
– development of breasts on men.
• Menstrual cycle irregularities

Notes • Act on late distal tubule and the collecting duct.

• Inhibit Na+ reabsorption, K+ secretion, and H+ secretion
 Osmotic Diuretics
MOA – Act by altering the osmolarity of the urine
– Act on water-permeable areas of nephron
• Proximal tubule
• Descending limb
• Collecting duct
– Hydrophilic substances filtered through glomerulus, ability to carry water with them into tubular fluid,
not reabsorbed
– Results in ↑ urinary output with little Na + excretion

Uses • Limited therapeutic applications:

– Decreasing intracranial pressure (cerebral oedema)
– Decreasing intraocular pressure (Glaucoma)
– Prevention of acute renal failure

Side Effects – Consequential S/E’s related to shift in fluids

– E.g. Expansion of extracellular fluid
– May lead to aggravation of cardiac de-compensation.

Examples Mannitol
Notes • Pharmacologically inert substances
 Carbonic Anhydrase Inhibitors
MOA • Acts to prevent Carbonic Anhydrase in the proximal tubule (also effect on the collecting duct)
CO2+H2O à H2CO3 à H+ +HCO3-
• Increased excretion of bicarbonates
– Leads to increased excretion of Na+, K+, and H2O.
– Causes alkalization of urine (metabolic acidosis)

Metabolism • 100% bioavailability

• Eliminated unchanged in urine

Uses • Not clinically relevant

– Can be used in the treatment of:
• Glaucoma
– Reduces elevated intraocular pressure. Decreases the production of aqueous humor,
probably by blocking CA in the cilary body of eye.
• Edema
– E.g. Acute mountain sickness
– Given nightly 5 days before ascent above 10,000ft prevents weakness, breathlessness,
dizziness, nausea and cerebral & pulmonary edema

Side Effects – Metabolic acidosis (transient)

– Hypokalemia

Examples Acetazolamide
Notes • Limited effectiveness as diuretics
• Self-limiting diuretic
– Action proportional to the amount of bicarbonate