Page 275 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 15 Diuretic Agents 261

ventilation and diminish symptoms of mountain sickness. This Contraindications
mild metabolic central and CSF acidosis is also useful in the treat-
ment of sleep apnea. Carbonic anhydrase inhibitor–induced alkalinization of the urine
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decreases urinary excretion of NH (by converting it to rapidly
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E. Other Uses reabsorbed NH ) and may contribute to the development of
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hyperammonemia and hepatic encephalopathy in patients with
Carbonic anhydrase inhibitors have been used as adjuvants in the cirrhosis.
treatment of epilepsy and in some forms of hypokalemic periodic
paralysis. They are also useful in treating patients with CSF leakage
(usually caused by tumor or head trauma, but often idiopathic). SODIUM GLUCOSE
By reducing the rate of CSF formation and intracranial pressure, COTRANSPORTER 2 (SGLT2)
carbonic anhydrase inhibitors can significantly slow the rate of
CSF leakage. They also increase urinary phosphate excretion dur- INHIBITORS
ing severe hyperphosphatemia. Finally, acetazolamide may have a
role in the treatment of Meniere’s disease, nephrogenic diabetes In the normal individual, the proximal convoluted tubule reab-
insipidus, idiopathic intracranial hypertension, and Kleine-Levin sorbs almost all of the glucose filtered by the glomeruli. Ninety
syndrome (episodes of hypersomnia and cognitive and behavioral percent of the glucose reabsorption occurs through SGLT2
abnormalities). (Figure 15–2), but inhibiting this transporter using the currently
available drugs will result in glucose excretion of only 30–50% of
Toxicity the amount filtered. Although we have known about the proximal
tubule sodium/glucose cotransporter for many years, the inhibi-
A. Hyperchloremic Metabolic Acidosis tors of this transport channel were developed only recently. Four
Acidosis predictably results from chronic reduction of body SGLT2 inhibitors (dapagliflozin, canagliflozin, empagliflozin,
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HCO stores by carbonic anhydrase inhibitors (Table 15–2) and and ipragliflozin [available in Japan]) are currently available.
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limits the diuretic efficacy of these drugs to 2 or 3 days. Unlike the Angiotensin II has been shown to induce SGLT2 production
diuretic effect, acidosis persists as long as the drug is continued. via the AT receptor. Thus, blockade of the renin-angiotensin-
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aldosterone axis may result in lower SGLT2 availability.
B. Renal Stones
Phosphaturia and hypercalciuria occur during the bicarbonaturic Pharmacokinetics
response to inhibitors of carbonic anhydrase. Renal excretion of The SGLT2 inhibitors are rapidly absorbed by the gastroin-
solubilizing factors (eg, citrate) may also decline with chronic use. testinal (GI) tract. The elimination half-life of dapagliflozin is
Calcium phosphate salts are relatively insoluble at alkaline pH, 10–12 hours, and up to 70% of the given dose is excreted in the
which means that the potential for renal stone formation from urine in the form of 3-O-glucuronide (only around 2% of the
these salts is enhanced.
drug is excreted unchanged in the urine). Although the drug levels
C. Renal Potassium Wasting are higher with more severe renal failure, urinary glucose excretion
would also decline as chronic kidney disease worsens. The dose of
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Potassium wasting can occur because the increased Na pre- canagliflozin is recommended not to exceed 100 mg/d with an esti-
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sented to the collecting tubule (with HCO ) is partially mated GFR of 45–59. The drugs are not recommended in patients
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reabsorbed, increasing the lumen-negative electrical potential with more severe renal failure or advanced liver disease. Drug-drug
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in that segment and enhancing K secretion. This effect can interactions are a consideration with these drugs. For example,
be counteracted by simultaneous administration of potassium concomitant rifampin administration reduces the total exposure to
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chloride or a K -sparing diuretic. Potassium wasting is theoreti- dapagliflozin by 22%.
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cally a problem with any diuretic that increases Na delivery to
the collecting tubule. Clinical Indications and Adverse
In addition to potassium wasting, carbonic anhydrase inhibitors
can lead to phosphorus wasting, and even symptomatic hypophos- Reactions
phatemia has been reported with these agents. Therefore, both Currently, the only indication for the use of these drugs is as
serum potassium and serum phosphorus should be monitored in third-line therapy for diabetes mellitus (see Chapter 41). SGLT2
patients who are being treated chronically with these agents. inhibitors will reduce the hemoglobin A by 0.5–1.0%, similar to
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other oral hypoglycemic agents. Even though SGLT2 inhibitors
D. Other Toxicities are not indicated for other diagnoses, they do have other minor
Drowsiness and paresthesias are common following large doses effects. SGLT2 inhibitors will result in an average weight loss of
of acetazolamide. Carbonic anhydrase inhibitors may accumulate 3.2 kg versus a weight gain of 1.2 kg with glipizide. It is not clearly
in patients with renal failure, leading to nervous system toxicity. established how much of this is due to the diuretic effect, but it is
Hypersensitivity reactions (fever, rashes, bone marrow suppres- notable that SGLT2 inhibitors also induce a drop in systolic blood
sion, and interstitial nephritis) may also occur. pressure by an average of 5.1 mm Hg, compared with an increase