Diuretics: Mechanism of action

Sulfonamide derivatives

Carbonic anhydrase inhibitors, such as acetazolamide, work at the proximal convoluted tubules to block the cleavage and subsequent resorption of bicarbonate to water and carbon dioxide. This leads to bicarbonate loss in the urine and mild diuresis. As such, there is urine alkanization that can lead to potassium wasting and deposition of calcium salts. Furthermore, in states of hepatic impairment, this can reduce the renal clearance of ammonia by decreasing the ammonia to ammonium ion conversion and promote hepatic encephalopathy.

Loop diuretics, such as furosemide, bumetanide and torsemide, act at the thick ascending loop of Henle to inhibit the NKCC2 co-transporter (Na/K/2Cl co-transporter). Inhibition of the NKCC2 transporter leads to sodium diuresis and can be very effective at removing edematous volumes. Indications for loop diuretics include heart failure, hypertension, acute pulmonary edema, and hyperkalemia. Intraoperatively, they may be used for renal protection periods of renal ischemia; however, there is little evidence to support efficacy. Loop diuretics can lead to hypovolemia, hypokalemic metabolic acidosis, hypocalcemia, ototoxicity, and nephrotoxicity. Ethacrynic acid is a phenoxyacetic acid derivative that acts as a loop diuretic that can be substituted in cases of severe sulfonamide allergies.

Thiazide diuretics, such as hydrochlorothiazide and chlordiazepoxide, act at the distal convoluted tubule to inhibit the NCC co-transporter (Na/Cl cotransporter). Inhibition of the NCC co-transporter on the luminal side of DCT cells decreases sodium and chloride resorption. This in effect promotes interstitial calcium-sodium exchange transport and increased calcium resorption. The major indication for thiazide use is hypertension. Side effects may include increased uric acid or lipid levels as well as dilutional hyponatremia, and hypokalemic metabolic acidosis.

Non-sulfonamide derivatives

Aldosterone antagonists, such as spironolactone and eplerenone, act at the cortical collecting tubule to indirectly inhibit ENaC and the Na/K ATPase on interstitial membranes. Aldosterone antagonists competitively antagonize the intracellular aldosterone receptor to downregulate the expression of genes leading to the luminal expression of the epithelial sodium ion channel (ENaC). Aldosterone antagonists are commonly used in heart failure and hyperaldosteronism. Side effects may include antiandrogenic effects such as gynecomastia.

Potassium sparing diuretics, such as amiloride and triamterene, act at the cortical collecting tubule to directly inhibit ENaC and sodium resorption.

An important side effect of both aldosterone antagonists and potassium sparing diuretics is hyperkalemia.

Osmotic diuretics, such as glycerin, urea and mannitol, are filtered across the glomerulus but are poorly resorbed from the lumen. By increasing intraluminal osmolarity, less solute and water is resorbed by the kidney leading to diuresis. Their major site of action is the proximal convoluted tubule; however, these will decrease water resorption both at the descending loop and collecting tubule. Mannitol is often used in the perioperative period to help reduce intracranial pressure and brain volume during neurosurgery. Side effects may include increased serum osmolarity and if given as a rapid bolus, osmotic diuretics can lead to increased ICP.

ADH Antagonists, such as tolvaptan and conivaptan, are antidiuretic hormone antagonists. These act as at the vasopressin-2 (V2) receptor of the collecting tubule leading to a decrease in the intracellular cascade (V2 -> adenylyl cyclase activation -> increase cAMP -> AQP2 insertion) and subsequent downregulation of insertion of aquaporin 2 channel into the luminal membrane. Conivaptan also has some V1alpha receptor affinity. Traditionally, ADH antagonists are used in states of central SIADH, refractory hypervolemia in heart failure and severe hyponatremia. Demeclocycline (and to some extent lithium) also inhibit the insertion of AQP2 into the luminal membrane via another as yet unspecified mechanism.

Updated definition 2020:

• Osmotic Diuretics:
• Example(s): Mannitol
• MOA: agents are filtered at the glomerulus and undergo limited or no reabsorption in the proximal tubule. Their presence in the proximal tubule limits passive water reabsorption that normally follows active sodium reabsorption. Their major effect is increasing water excretion but, in large, doses, they can also act to increase electrolyte excretion

• Loop Diuretics:
• Example(s): Furosemide (Lasix), Bumetanide (Bumex), Ethacrynic Acid (Edecrin), Torsemide (Demadex)
• MOA: inhibit Na+ and Cl- reabsorption in the thick ascending limb of the loop of Henle by competing with Cl- for its binding site on the Na+-K+-2Cl- luminal carrier protein. With maximal effect, they can promote excretion of 15-20% of the filtered sodium load. Also increase urinary calcium and magnesium excretion.

• Thiazide and Thiazide-Like Diuretics:
• Example(s): Hydrochlorothiazide, Chlorthalidone (Thalitone), Metolazone, Indapamide (Lozol)
• MOA: Compete for the Cl- site on the luminal Na+-Cl- carrier protein in the distal collecting tubule which inhibits sodium reabsorption at this site and impairs the diluting (but not concentrating) ability.

• Potassium Sparing Diuretics:
• Aldosterone Antagonists
• Example(s): Spironolactone (Aldactone), Eplerenone (Inspra)
• MOA: directly antagonize the aldosterone receptor in the collecting tubule and inhibit aldosterone-mediated Na+ reabsorption and K+ secretion
• Noncompetitive Potassium Sparing Diuretics
• Example(s): Triamterene (Dyrenium), Amiloride (Midamor)
• MOA: inhibit Na+ reabsorption and K+ secretion by decreasing the number of open sodium channels in the luminal membrane of collecting tubules. These are NOT dependent on aldosterone activity.

• Carbonic Anhydrase Inhibitors:
• Example(s): Acetazolamide (Diamox)
• MOA: weak diuretics that interfere with Na+ reabsorption and H+ secretion in proximal tubules. Also act to impair HCO₃– reabsorption.