Loop diuretics are the most potent type of diuretic, followed by thiazide diuretics.  Administration of either agent initially results in natriuresis.  However, continued use leads to significant volume depletion that counteracts the diuretic effect by decreasing glomerular filtration pressure.  Reduced pressure natriuresis also decreases distal tubule Na⁺ delivery, which is sensed by the macula densa and causes activation of the renin-angiotensin-aldosterone system.  Aldosterone then acts on the collecting tubule to enhance Na⁺ reabsorption and promote K⁺ and H⁺ loss.  Therefore, loop and thiazide diuretics cause hypokalemia and metabolic alkalosis secondary to volume contraction.

Loop diuretics function by inhibiting the absorption of solutes within the thick ascending limb of Henle's loop, a process that is critical for maintenance of the corticomedullary concentration gradient.  As a result, patients on loop diuretics are unable to maximally concentrate their urine and thus lose substantial amounts of both salt and water in the urine.  In contrast, patients taking thiazides have a normal corticomedullary concentration gradient and are better able to retain free water in response to increased vasopressin levels.  Thus, patients taking thiazide diuretics are more likely to retain free water and develop hyponatremia.

Thiazide diuretics can also lead to hypercalcemia secondary to increased proximal and distal tubule Ca²⁺ reabsorption.  In contrast, loop diuretics decrease Ca²⁺ reabsorption in the thick ascending limb and can cause hypocalcemia (Choice E).

(Choice A)  Acetazolamide induces a mild degree of natriuresis by inhibiting bicarbonate reabsorption in the proximal tubule.  The loss of bicarbonate in the urine also causes metabolic acidosis in addition to inducing natriuresis.

(Choices B and D)  Amiloride and spironolactone are potassium-sparing diuretics that induce a mild degree of natriuresis.  By decreasing Na⁺ reabsorption in the cortical collecting tubule, they reduce the luminal electronegative gradient, a major driving force for K⁺ and H⁺ secretion by principal and intercalated cells, respectively.  As a result, potassium-sparing diuretics can cause hyperkalemia and metabolic acidosis.

Educational objective:
Thiazide and loop diuretics cause significant volume depletion, activating the renin-angiotensin-aldosterone system, which can lead to hypokalemia and metabolic alkalosis.  Thiazide diuretics are more likely to cause hyponatremia and hypercalcemia; loop diuretics cause hypocalcemia.