In addition to potassium wasting, carbonic anhydrase inhibitors can lead to phosphorus wasting, and even symptomatic hypophosphatemia has been reported with these agents. Therefore, both serum potassium and serum phosphorus should be monitored in patients who are being treated chronically with these agents.
D. Other Toxicities
Drowsiness and paresthesias are common following large doses of acetazolamide. Carbonic anhydrase inhibitors may accumulate in patients with renal failure, leading to nervous system toxicity. Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) may also occur.
Carbonic anhydrase inhibitor–induced alkalinization of the urine decreases urinary excretion of NH4+ (by converting it to rapidly reabsorbed NH3) and may contribute to the development of hyperammonemia and hepatic encephalopathy in patients with cirrhosis.
In the normal individual, the proximal convoluted tubule reabsorbs almost all of the glucose filtered by the glomeruli. Ninety percent of the glucose reabsorption occurs through SGLT2 (Figure 15–2), but inhibiting this transporter using the currently available drugs will result in glucose excretion of only 30–50% of the amount filtered. Although we have known about the proximal tubule sodium/glucose cotransporter for many years, the inhibitors of this transport channel were developed only recently. Four SGLT2 inhibitors (dapagliflozin, canagliflozin, empagliflozin, and ipragliflozin [available in Japan]) are currently available. Angiotensin II has been shown to induce SGLT2 production via the AT1 receptor. Thus, blockade of the renin-angiotensinaldosterone axis may result in lower SGLT2 availability.
The SGLT2 inhibitors are rapidly absorbed by the gastrointestinal (GI) tract. The elimination half-life of dapagliflozin is 10–12 hours, and up to 70% of the given dose is excreted in the urine in the form of 3-O-glucuronide (only around 2% of the drug is excreted unchanged in the urine). Although the drug levels are higher with more severe renal failure, urinary glucose excretion would also decline as chronic kidney disease worsens. The dose of canagliflozin is recommended not to exceed 100 mg/d with an estimated GFR of 45–59. The drugs are not recommended in patients with more severe renal failure or advanced liver disease. Drug-drug interactions are a consideration with these drugs. For example, concomitant rifampin administration reduces the total exposure to dapagliflozin by 22%.