Proximal Tubule

Mechanism Action Furosemide

FIGURE 28-2 NaHCO3 reabsorption in proximal tubule and mechanism of diuretic action of carbonic anhydrase (CA) inhibitors. A, antiporter; S, symporter; CH, ion channel. (The actual reaction catalyzed by carbonic anhydrase is OH- + CO2 ^ HCO3-; however, H2O ^ OH- + H+ ^ and HCO3- + H+ ^ H2CO3, so the net reaction is H2O + CO2 ^ H2CO3.) Numbers in parentheses indicate stoichiometry. BL and LM indicate basolateral and luminal membranes, respectively. The sizes of type for Na+, K+, and H+ reflect relative concentrations.

FIGURE 28-2 NaHCO3 reabsorption in proximal tubule and mechanism of diuretic action of carbonic anhydrase (CA) inhibitors. A, antiporter; S, symporter; CH, ion channel. (The actual reaction catalyzed by carbonic anhydrase is OH- + CO2 ^ HCO3-; however, H2O ^ OH- + H+ ^ and HCO3- + H+ ^ H2CO3, so the net reaction is H2O + CO2 ^ H2CO3.) Numbers in parentheses indicate stoichiometry. BL and LM indicate basolateral and luminal membranes, respectively. The sizes of type for Na+, K+, and H+ reflect relative concentrations.

excretion is observed. Although the proximal tubule is the major site of action of carbonic anhydrase inhibitors, carbonic anhydrase also is involved in secretion of titratable acid in the collecting duct system, which is a secondary site of action for these drugs.

EFFECTS ON URINARY EXCRETION Inhibition of carbonic anhydrase is associated with a rapid rise in urinary HCO3- excretion to -35% of filtered load. This, along with inhibition of titratable acid and NH4+ secretion in the collecting-duct system, results in an increase in urinary pH to -8 and development of a metabolic acidosis. However, even with a high degree of inhibition of carbonic anhydrase, 65% of HCO3- is rescued from excretion by poorly understood mechanisms. Inhibition of the transport mechanism described above results in increased delivery of Na+ and Cl-to the loop of Henle, which has a large reabsorptive capacity and captures most of the Cl- and a portion of the Na+. Thus, only a small increase in Cl-excretion occurs, HCO3-being the major anion excreted along with the cations Na+ and K+. The fractional excretion of Na+ may be as much as 5%, and the fractional excretion of K+ can be as much as 70%. The increased excretion of K+ in part reflects increased delivery of Na+ to the distal nephron, as described in the section on inhibitors of Na+ channels. Other mechanisms contributing to enhanced K+ excretion include flow-dependent enhancement of K+ secretion by the collecting duct, nonosmotic vasopressin release, and activation of the renin-angiotensin-aldosterone axis. Carbonic anhydrase inhibitors increase phosphate excretion but have little or no effect on the excretion of Ca2+ or Mg2+. The effects of carbonic anhydrase inhibitors on renal excretion are self-limiting, probably because the resulting metabolic acidosis decreases the filtered load of HCO3- to the point that the uncatalyzed reaction between CO2 and water is sufficient to achieve HCO3- reabsorption.

EFFECTS ON RENAL HEMODYNAMICS By inhibiting proximal reabsorption, carbonic anhydrase inhibitors increase solute delivery to the macula densa. This triggers TGF, which increases afferent arteriolar resistance and reduces renal blood flow (RBF) and GFR.

OTHER ACTIONS Carbonic anhydrase is present in a number of extrarenal tissues. Carbonic anhydrase in the ciliary processes of the eye mediates the formation of large amounts of HCO3- in aqueous humor. Inhibition of carbonic anhydrase decreases the rate of formation of aqueous humor and consequently reduces intraocular pressure (IOP). Acetazolamide frequently causes paresthesias and somnolence, suggesting a central nervous system (CNS) action of carbonic anhy-drase inhibitors. The efficacy of acetazolamide in epilepsy is due in part to the production of metabolic acidosis; however, direct actions of acetazolamide in the CNS also contribute to its anticonvulsant action. Owing to interference with carbonic anhydrase activity in erythrocytes, carbonic anhydrase inhibitors increase CO2 levels in peripheral tissues and decrease CO2 levels in expired gas. Large doses of carbonic anhydrase inhibitors reduce gastric acid secretion, but this has no therapeutic applications. Acetazolamide causes vasodilation by opening vascular Ca2+-activated K+ channels; however, the clinical significance of this effect is unclear.

ABSORPTION AND ELIMINATION The oral bioavailability, plasma t1/2, and route of elimination of the three available carbonic anhydrase inhibitors are listed in Table 28-2. Carbonic anhydrase inhibitors bind avidly to the enzyme; thus, tissues rich in this enzyme will have higher concentrations of drug following systemic administration.

TOXICITY, ADVERSE EFFECTS, CONTRAINDICATIONS, DRUG INTERACTIONS

Serious toxic reactions to carbonic anhydrase inhibitors are infrequent; however, these drugs are sulfonamide derivatives and, like other sulfonamides, may cause bone marrow depression, skin toxicity, sulfonamide-like renal lesions, and allergic reactions (see Chapter 43). With large doses, many patients exhibit drowsiness and paresthesias. Most adverse effects, contraindications, and drug interactions are secondary to urinary alkalinization or metabolic acidosis, including (1) diversion of ammonia of renal origin from urine into the systemic circulation, a process that may induce or worsen hepatic encephalopathy (the drugs are contraindicated in patients with hepatic cirrhosis); (2) calculus formation and ureteral colic owing to precipitation of calcium phosphate salts in an alkaline urine; (3) worsened metabolic or respiratory acidosis (the drugs are contraindicated in patients with hyperchloremic acidosis or severe chronic obstructive pulmonary disease); and (4) reduced urinary excretion of weak organic bases.

THERAPEUTIC USES The efficacy of carbonic anhydrase inhibitors as single agents for the treatment of edema is low. However, the combination of acetazolamide with diuretics that block Na+ reabsorption at more distal sites in the nephron causes a marked natriuretic response in patients with low basal fractional excretion of Na+ (<0.2%), who are resistant to diuretic monotherapy. Even so, the long-term usefulness of carbonic anhydrase inhibitors often is compromised by the development of metabolic acidosis.

Table 28-2

Inhibitors of Carbonic Anhydrase

Drug Relative Oral t1/2 Route of

(trade name) Structure Potency Availability (hours) Elimination

Acetazolamide CH3CONH S SO2NH2

Dichlorphenamide SO2NH2

(daramide) I 30 ID ID ID

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