Carbonic Anhydrase Inhibitor
- Acetazolamide, the prototype Carbonic Anhydrase Inhibitors, inhibits carbonic anhydrase and in doing so reduces renal bicarbonate resorption in the proximal tubule. This leads to a direct increase in urinary bicarbonate excretion and secondarily to mild increases in sodium and potassium excretion. Because of its mild effects on electrolytes acetazolamide is a largely safe drug with few adverse side effects but in consequence is rarely used for its diuretic capacity.
- Effects on Bicarbonate
- The pharmacological effects of acetazolamide are due to its inhibitory effect on carbonic anhydrase in the proximal tubule. As discussed in Renal Bicarbonate Excretion, luminal and intracellular pools of carbonic anhydrase in the proximal tubule are critical for resorbing filtered bicarbonate and thus administration of acetazolamide results in significant increases in renal bicarbonate excretion. Because bicarbonate acts as a weak base this can lead to significant increases in urinary pH. Additionally, because bicarbonate is the primary weak base of the bicarbonate buffer, its wasting leads to a non-gap metabolic acidosis.
- Effects on Sodium and Potassium
- As discussed in renal bicarbonate excretion, bicarbonate resorption utilizes a luminal Na-H+ antiporter and in consequence the net process of bicarbonate resorption is linked to sodium resorption. Given this linkage between bicarbonate and sodium resorption, acetazolamide yields significant reductions in proximal tubule sodium resorption. However, the vast majority of this sodium is resorbed by later parts of the nephron and thus urinary sodium excretion is increased only mildly.
- The increased distal nephron sodium delivery caused by acetazolamide results in increased potassium secretion and thus carbonic anhydrase inhibitors typically result in moderate increases of urinary potassium excretion. The "Distal Tubular Flow Rate" section of the External Potassium Balance explains how increased sodium delivery to the distal nephron can yield increased potassium secretion.
- Although the renal effects of acetazolamide are profound, the drug does not significantly increase urinary sodium excretion and thus its clinical use as a diuretic is limited. Rather, acetazolamide is primarily used as a topical agent in chronic therapy for open-angle glaucoma as it reduces production of the aqueous humor. Additionally, it is used as a prophylactic for the symptomology of Mountain Sickness, possibly by its capacity to generate a metabolic acidosis.