Paradoxical Effect of Acetazolamide in the Kidneys and Lungs

Acetazolamide is a carbonic anhydrase inhibitor and is frequently used to treat hypercarbia and metabolic alkalosis. Acetazolamide affects three major organs of the body: the brain, lungs, and kidneys. It is imperative to understand the paradoxical effect of acetazolamide in kidneys and lungs.

In the kidneys, acetazolamide increases hydrogen ion retention and bicarbonate excretion, causing metabolic acidosis over several hours. This also has a secondary effect: metabolic acidosis further increases respiratory drive.

In the lungs, acetazolamide blocks the reciprocal conversion of bicarbonate to CO2 in pulmonary capillaries and impairs the lungs' ability to excrete the CO2. The intended effect is to increase minute ventilation and thereby reduce hypercarbia. But the patients who are not able to increase their ventilation, like patients on ventilators, and, to make it worse, on neuromuscular blockade, may have further deterioration in hypercarbia.

Clinical significance: In the ICU, acetazolamide may 'fire back' if the patient's kidneys are not working well and the patient is on a ventilator. Therefore, it should be used with much greater caution.

Centrally, acetazolamide blocks the CO2 conversion to bicarbonate in tissue capillaries and acutely raises the local tissue partial pressure of carbon dioxide (PCO2). This locally elevated PCO2 and lower pH in the brain increase the central ventilatory drive and lower PaCO2. This central effect, combined with its pulmonary effect, makes acetazolamide an effective prophylactic and therapeutic agent for acute and chronic mountain sickness in healthy individuals.

#pulmonary

#acid-base

References:

1. Swenson ER, Hughes JM. Effects of acute and chronic acetazolamide on resting ventilation and ventilatory responses in men. J Appl Physiol (1985) 1993; 74:230.

2. Richalet JP, Rivera M, Bouchet P, et al. Acetazolamide: a treatment for chronic mountain sickness. Am J Respir Crit Care Med 2005; 172:1427.

3. Alkhuzaee FS, Aldardeer NF, Althobaiti OA, Aljuaid AS, Alshehri AM. Acetazolamide for the Management of Diuretic-Induced Chloride Depletion Alkalosis: A Systematic Review. J Clin Med. 2025 Feb 7;14(4):1041. doi: 10.3390/jcm14041041. PMID: 40004571; PMCID: PMC11857046.

4. Van Berkel MA, Elefritz JL. Evaluating off-label uses of acetazolamide. Am J Health Syst Pharm. 2018 Apr 15;75(8):524-531. doi: 10.2146/ajhp170279. PMID: 29626002.