Diuretics – Adverse effects


Diuretics are routinely used in the treatment of hypertension and congestive heart failure.  Several classes of diuretics exist, including thiazide diuretics (HCTZ, metolazone, chlorthalidone), loop diuretics (furosemide and bumetanide), carbonic anhydrase inhibitors (acetazolamide), osmotic diuretics (mannitol), and potassium sparing diuretics (spironolactone, amiloride, and triamterene).  The different classes have different mechanisms of action.  The thiazide diuretics inhibit Na-Cl cotransporters in the distal convoluted tubules of the kidney.  This leads to decreased reabsorption of sodium and chloride ions, leading to decreased free water reabsorption and diuresis.  Loop diuretics act in the ascending limb of the loop of henle.  They inhibit the Na-K-2Cl contransporter to inhibit sodium and chloride reabsorption.  This alters the interstitial osmolality leading to less water and sodium reabsorption causing dieresis.  Carbonic anhydrase inhibitors inhibit the enzyme carbonic anhydrase.   Carbonic anhydrase catalyzes the reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid.  This results in renal loss of the HCO3 ion.  This carries out sodium, water, and potassium.  Potassium sparing diuretics work in the cortical collecting duct to prevent sodium reabsorption, thereby preventing potassium secretion.  Spironolactone also inhibits aldosterone receptors in the cortical collecting duct, leading to decreased water and sodium reabsorption and decreased potassium excretion.  Diuretics have adverse effects, which mainly consist of electrolyte and metabolic abnormalities, with a few important unique adverse effects in the different classes.

Loop and thiazide diuretics can cause metabolic alkalosis due to increased excretion of chloride in proportion to bicarbonate.  This is more common with loop diuretics than thiazide diuretics.  They can also can cause hypokalemia, hyperglycemia and glucose intolerance, hyperlipidemia, hyponatremia, hyperuricemia, hypomagnesemia.  Thiazide diuretics can cause hypercalcemia while loop diuretics increase the excretion of calcium which can lead to hypocalcemia.  Moreover, loop and thiazide diuretics are sulfonamides and can lead to allergic reactions.  Loop diuretics also have the potential to cause ototoxicity and hearing loss.  Of note hypokalemia can cause ventricular arrhythmias and muscular weakness.

Spironolactone’s primary adverse effect is hyperkalemia, especially in elderly patients and those with chronic kidney disease.  Individuals at higher risk for hyperkalemia also include those on beta blockers, ACE inhibitors, angiotensin receptor blockers, and NSAIDs.  It also has antiandrogenic effects, including gynecomastia, hirsutism, and sexual dysfunction.

Acetazolamide is a sulfonamide and can lead to allergic reactions.   Other adverse reactions include paresthesias, tinnitus, taste alteration, and metabolic acidosis (especially in elderly and kidney disease).

Mannitol has complex effects on electrolytes.  It initially leads to hypertonic hyponatremia when it recruits water from cells.  Later as the extracellular fluid is excreted, hyperkalemic acidosis can develop.  After this hypernatremic dehydration may occur.


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  1. Domenic A Sica, Barry Carter, William Cushman, Lee Hamm Thiazide and loop diuretics. J Clin Hypertens (Greenwich): 2011, 13(9);639-43

  2. David H Ellison, Johannes Loffing Thiazide effects and adverse effects: insights from molecular genetics. Hypertension: 2009, 54(2);196-202