Carbonic anhydrase is present in many nephron sites, but the predominant location of this enzyme is the epithelial cells of the PCT (Figure 15–2), where it catalyzes the dehydration of H2CO3 to CO2 at the luminal membrane and rehydration of CO2 to TABLE 15–3 Carbonic anhydrase inhibitors used H2CO3 in the cytoplasm as previously described. By blocking orally in the treatment of glaucoma. carbonic anhydrase, inhibitors blunt NaHCO3 reabsorption and cause diuresis. Carbonic anhydrase inhibitors were the forerunners of mod-Dichlorphenamide 50 mg 1–3 times daily ern diuretics. They were discovered in 1937 when it was found that bacteriostatic sulfonamides caused an alkaline diuresis and hyperchloremic metabolic acidosis. With the development of newer agents, carbonic anhydrase inhibitors are now rarely used at sites other than the kidney. The ciliary body of the eye secretes as diuretics, but they still have several specific applications that are discussed below. The prototypical carbonic anhydrase inhibitor is HCO3− from the blood into the aqueous humor. Likewise, formation of cerebrospinal fluid (CSF) by the choroid plexus involves acetazolamide. HCO3− secretion. Although these processes remove HCO3− from the blood (the direction opposite of that in the proximal tubule), they are similarly inhibited by carbonic anhydrase inhibitors. The carbonic anhydrase inhibitors are well absorbed after oral administration. An increase in urine pH from the HCO3− diuresis is apparent within 30 minutes, is maximal at 2 hours, and persists
A. Glaucoma for 12 hours after a single dose. Excretion of the drug is by secretion in the proximal tubule S2 segment. Therefore, dosing must be The reduction of aqueous humor formation by carbonic anhyreduced in renal insufficiency. drase inhibitors decreases the intraocular pressure. This effect is valuable in the management of glaucoma in some patients, making it the most common indication for use of carbonic anhydrase inhibitors (see Table 10–3). Topically active agents, Inhibition of carbonic anhydrase activity profoundly depresses which reduce intraocular pressure without producing renal or HCO3− reabsorption in the PCT. At maximal safe inhibitor dos-systemic effects, are available (dorzolamide, brinzolamide).
age, 85% of the HCO3− reabsorptive capacity of the superficial PCT is inhibited. Some HCO3− can still be absorbed at other
B. Urinary Alkalinization nephron sites by carbonic anhydrase–independent mechanisms, Uric acid and cystine are relatively insoluble and may form stones so the overall effect of maximal acetazolamide dosage is only about in acidic urine. Therefore, in cystinuria, a disorder of cystine reab45% inhibition of whole kidney HCO3− reabsorption. Neverthesorption, solubility of cystine can be enhanced by increasing urinary less, carbonic anhydrase inhibition causes significant HCO3− losses pH to 7–7.5 with carbonic anhydrase inhibitors. In the case of uric and hyperchloremic metabolic acidosis (Table 15–2). Because − − acid, pH needs to be raised only to 6–6.5. In the absence of HCO3 of reduced HCO3 in the glomerular filtrate and the fact that − administration, these effects of acetazolamide last only 2–3 days,