BASIC PHARMACOLOGY OF DIURETIC AGENTS
CARBONIC ANHYDRASE INHIBITORS
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 H2CO3 in the cytoplasm as previously described. By blocking carbonic anhydrase, inhibitors blunt NaHCO3 reabsorption and cause diuresis.
Carbonic anhydrase inhibitors were the forerunners of modern diuretics. They were discovered in 1937 when it was found that bacteriostatic sulfonamides caused an alkaline diuresis and hyper-chloremic metabolic acidosis. With the development of newer agents, carbonic anhydrase inhibitors are now rarely used as diuretics, but they still have several specific applications that are discussed below. The prototypical carbonic anhydrase inhibitor is acetazolamide.
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 for 12 hours after a single dose. Excretion of the drug is by secre-tion in the proximal tubule S2 segment. Therefore, dosing must be reduced in renal insufficiency.
Inhibition of carbonic anhydrase activity profoundly depresses HCO3− reabsorption in the PCT. At its maximal safe dosage, 85% of the HCO3− reabsorptive capacity of the superficial PCT is inhibited. Some HCO3− can still be absorbed at other nephron sites by carbonic anhydrase–independent mechanisms, so the overall effect of maximal acetazolamide dosage is only about 45% inhibition of whole kidney HCO3− reabsorption. Nevertheless, carbonic anhydrase inhibition causes significant HCO3− losses and hyperchloremic metabolic acidosis (Table 15–2). Because of reduced HCO3− in the glomerular filtrate and the fact that HCO3− depletion leads to enhanced NaCl reabsorption by the remainder of the nephron, the diuretic efficacy of acetazolamide decreases significantly with use over several days.
At present, the major clinical applications of acetazolamide involve carbonic anhydrase–dependent HCO3− and fluid transport at sites other than the kidney. The ciliary body of the eye secretes HCO3− from the blood into the aqueous humor. Likewise, forma-tion of cerebrospinal fluid by the choroid plexus involves 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 reduction of aqueous humor formation by carbonic anhy-drase inhibitors decreases the intraocular pressure. This effect is valuable in the management of glaucoma, making it the most common indication for use of carbonic anhydrase inhibitors. Topically active agents, which reduce intraocular pressure without producing renal or systemic effects, are available (dorzolamide, brinzolamide).
Uric acid and cystine are relatively insoluble and may form stones in acidic urine. Therefore, in cystinuria, a disorder of cystine reab-sorption, solubility of cystine can be enhanced by increasing uri-nary pH from 7.0 to 7.5 with carbonic anhydrase inhibitors. In the case of uric acid, pH needs to be raised only to 6.0 or 6.5. In the absence of HCO3− administration, these effects of acetazol-amide last only 2–3 days, so prolonged therapy requires oral HCO3−. Excessive urinary alkalinization can lead to stone forma-tion from calcium salts , so urine pH should be fol-lowed during treatment with acetazolamide.
Metabolic alkalosis is generally treated by correction of abnor-malities in total body K+, intravascular volume, or mineralocorti-coid levels. However, when the alkalosis is due to excessive use of diuretics in patients with severe heart failure, replacement of intra-vascular volume may be contraindicated. In these cases, acetazol-amide can be useful in correcting the alkalosis as well as producing a small additional diuresis for correction of volume overload. Acetazolamide can also be used to rapidly correct the metabolic alkalosis that may appear following the correction of respiratory acidosis.
Weakness, dizziness, insomnia, headache, and nausea can occur in mountain travelers who rapidly ascend above 3000 m. The symp-toms are usually mild and last for a few days. In more serious cases, rapidly progressing pulmonary or cerebral edema can be life-threatening. By decreasing cerebrospinal fluid formation and by decreasing the pH of the cerebrospinal fluid and brain, acetazol-amide can increase ventilation and diminish symptoms of moun-tain sickness. This mild metabolic central and cerebrospinal fluid (CSF) acidosis is also useful in the treatment of sleep apnea.
Carbonic anhydrase inhibitors have been used as adjuvants in the treatment of epilepsy and in some forms of hypokalemic periodic paralysis. They are also useful in treating patients with CSF leak-age (usually caused by tumor or head trauma, but often idio-pathic). By reducing the rate of CSF formation and intracranial pressure, carbonic anhydrase inhibitors can significantly slow the rate of CSF leakage. Finally, they also increase urinary phosphate excretion during severe hyperphosphatemia.
Acidosis predictably results from chronic reduction of body HCO3− stores by carbonic anhydrase inhibitors (Table 15–2) and limits the diuretic efficacy of these drugs to 2 or 3 days. Unlike the diuretic effect, acidosis persists as long as the drug is continued.
Phosphaturia and hypercalciuria occur during the bicarbonaturic response to inhibitors of carbonic anhydrase. Renal excretion of solu-bilizing factors (eg, citrate) may also decline with chronic use. Calcium salts are relatively insoluble at alkaline pH, which means that the potential for renal stone formation from these salts is enhanced.
Potassium (K+) wasting can occur because the increased Na+ pre-sented to the collecting tubule (with HCO3−) is partially reab-sorbed, increasing the lumen-negative electrical potential in that segment and enhancing K+ secretion. This effect can be counter-acted by simultaneous administration of potassium chloride or a K+-sparing diuretic. Potassium wasting is theoretically a problem with any diuretic that presents increased Na+ delivery to the collect-ing tubule. However, the new adenosine A1-receptor antagonists appear to avoid this toxicity by blunting Na+ reabsorp-tion in the collecting tubules as well as the proximal tubules.
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 suppres-sion, and interstitial nephritis) may also occur.
Carbonic anhydrase inhibitor–induced alkalinization of the urine decreases urinary excretion of NH4+ (by converting it to rapidlyreabsorbed NH3) and may contribute to the development of hyperammonemia and hepatic encephalopathy in patients withcirrhosis.