For reasons that are not well established, but perhaps because of the tendency toward acidosis with these drugs, carbonic anhydrase inhibitors are also useful for treating epilepsy (especially absence seizures in children). An effective prophylactic dose of acetazolamide is 125 mg twice daily to be taken a day before ascent and continued for 2 days after the highest sleeping altitude. This phenomenon reflects the fact that approximately one third of proximal tubule Na+ reabsorption occurs in exchange for H+ (through the Na+-H+ antiporter) and thus depends on the activity of carbonic anhydrase (see Chapter 8). Rap1B, on the other hand, appeared important in dynamic reformation of the barrier integrity following pathologic stress. Carbonic anhydrase inhibitors, such as acetazolamide, decrease proximal tubular reabsorption of HCO3− in the kidney by noncompetitive inhibition of luminal and cellular carbonic anhydrase. However, larger clinical trials have shown a smaller benefit. Activation of the Rap1 isoform, Rap1A, was found to enhance RPE barrier integrity through reorganization of cortical F-actin. Carbonic anhydrase inhibitors are IOP-lowering sulfonamide derivatives which inhibit the activity of CA in the ciliary processes of the eye, thus reducing aqueous humor formation and consequently decreasing IOP. Pharmacotherapeutic group: Carbonic anhydrase inhibitors. An open-label study of acetazolamide in 6 people with SCA6 for 88 weeks demonstrated improvements in postural sway and ratings of ataxia. By inhibiting the reaction catalysed by this enzyme in the renal tubules, acetazolamide increases the excretion of bicarbonate and of cations, chiefly sodium and potassium, and so promotes alkaline diuresis. Studies are underway to better understand mechanisms of the Rap1 isoforms. Carbonic anhydrase inhibitors (CAIs) act primarily in the proximal tubule; an additional, albeit modest, effect along the distal nephron is also observed. Continuous administration of acetazolamide is … There is also a role for these agents in treating glaucoma because CA inhibitors reduce intraocular pressure by inhibiting the formation of aqueous humor. Carbonic anhydrase inhibitors also suppress aqueous humor formation in the eyes and can be used to reduce intraocular pressure in open-angle glaucoma and before surgery in cases of angle-closure glaucoma. Acetazolamide, a carbonic anhydrase inhibitor that induces a metabolic acidosis, thereby increasing ventilation, has been studied primarily in patients with central sleep apnea secondary to high altitude exposure or heart failure, who often have unstable ventilatory control (i.e., high loop gain). The lack of proton secretion into the tubules as a consequence of CA inhibition may be used to alkalinize the urine to enhance elimination of weak acids, such as uric acid and cystine. Cuffaro D 1, Nuti E 1, Rossello A 1. Pharmacology: Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye.It catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. It has fewer renal effects and therefore is preferred for treatment of glaucoma. Bruce M. Koeppen MD, PhD, Bruce A. Stanton PhD, in Renal Physiology (Fifth Edition), 2013. In the kidney, the control of bicarbonate ions influences the water content of the cell. Carbonic anhydrase inhibitors are IOP-lowering sulfonamide derivatives which inhibit the activity of CA in the ciliary processes of the eye, thus reducing aqueous humor formation and consequently decreasing IOP. Systemic CAIs provide an approximately 40% IOP reduction, and their effect develops rapidly. With CA on the luminal membrane also inhibited, the formation of bicarbonate from carbonic acid in the lumen is slowed, as is the diffusion of CO2 into the tubular cells. The first-generation CAIs, used since the 1950s, were systemically administered, but they had a large number of side effects. As hyperchloremic metabolic acidosis develops, the filtered load of HCO3− decreases and the effect of carbonic anhydrase inhibitors on HCO3− reabsorption is limited. This debate reflects our imperfect understanding of aqueous humor formation and the contradictory results of studies performed in different animal species. Copyright © 2020 Elsevier B.V. or its licensors or contributors. Indeed, some side effects of acetazolamide can even be lethal. Stephen P. DiBartola, in Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice (Third Edition), 2006. At present, acetazolamide can be considered for patients with CSA, though close clinical monitoring is warranted. Its effectiveness is limited by the development of hyperchloremic metabolic acidosis. Hypokalemia is caused by increased sodium delivery to the distal nephron and its reabsorption there in exchange for potassium. Similarly, some patients with OSA also have been shown to have an elevated loop gain.146 In one study of patients with OSA treated with CPAP, administration of acetazolamide for 7 days reduced the mean loop gain by 41% and the mean AHI by 41%.147 However, difficulties with tolerability of acetazolamide may preclude its long-term use, because patient-reported side effects have included paresthesias, altered taste, nocturia, and hypokalemia (when it is used in combination with a diuretic), with the need to monitor serum bicarbonate levels over time.