Acetazolamide Blood Concentrations are Excessive in the Elderly: Propensity for Acidosis and Relationship to Renal Function

Abstract

Elderly glaucoma patients are often treated with acetazolamide, a carbonic anhydrase inhibitor with clearance dependent on renal function. A high incidence of metabolic acidosis and other adverse effects have been noted among these patients but the reasons for this have not been explained. We hypothesized that commonly used doses of acetazolamide among the elderly result in excessive blood concentrations and that these concentrations are related to acid-base disturbances. We measured steady-state acetazolamide levels in plasma, plasma ultrafiltrate (unbound), and erythrocytes among 12 elderly subjects (79.2 +/- 7.6 years old). Mean plasma (18.9 +/- 10.9 micrograms/mL) and ultrafiltrate concentrations (1.0 +/- 0.7 microgram/mL) exceeded the therapeutic range (plasma 5-10 micrograms/mL; ultrafiltrate 0.25-0.50 microgram/mL) for glaucoma control by two fold and were elevated in 75% of subjects. Plasma and ultrafiltrate acetazolamide levels significantly correlated with the dose adjusted for creatinine clearance (r = 0.91, P less than 0.001; r = 0.89, P less than 0.001, respectively). Acidotic subjects (serum total carbon dioxide less than or equal to 22 mEq/L) tended to have higher plasma, ultrafiltrate, and erythrocyte acetazolamide levels compared with nonacidotic subjects. Serum total carbon dioxide levels were significantly correlated with erythrocyte acetazolamide concentrations (r = -0.75, P = 0.03). The ratio of erythrocyte acetazolamide concentration to creatinine clearance separated acidotic from nonacidotic subjects (P less than 0.01). These findings suggest that some of the adverse effects of acetazolamide can be avoided by reducing the dose to compensate for age-related reductions in renal drug clearance.

Immediate argon laser peripheral iridoplasty (ALPI) as initial treatment for acute phacomorphic angle-closure (phacomorphic glaucoma) before cataract extraction: a preliminary study

“…Furthermore, the systemic drugs may cause systemic side effects, such as paraesthesiae and drowsiness, or even confusion, loss of appetite, polydipsia and polyuria. More serious systemic side effects may also occur with carbonic anhydrase inhibitors, such as metabolic acidosis and electrolyte disturbance, 10,11 respiratory failure, 12 Stevens-Johnson Syndrome, 13 and blood dyscrasias. 14 Systemic hyperosmotic agents can cause metabolic disturbance such as acidosis, pulmonary oedema and congestive heart failure, acute renal failure, and even intracranial haemorrhage and anaphylactic reaction.…”

Pathogenic Mechanism, Prophylaxis, and Therapy of Symptomatic Acidosis Induced by Acetazolamide

“…5 In the preterm infant, acetazolamide toxicity is probably enhanced because the levels of CA I, CA III, and CA IV are low 29 and because their activity is normally reduced.…”

“…4 Few cases of symptomatic acidosis have been reported in the elderly, 5 in patients with renal 6 or liver failure, in diabetics 7 and more often in newborns. The pathogenic mechanism is still unknown.…”

Acetazolamide

“…As a result of these binding and clearance changes, the elderly people are predisposed to erythrocyte accumulation of acetazolamide, and so experience possibly greater concentration-dependent side effects. 4,5 In cases with advanced renal failure, plasma half-life is prolonged with values in the range of 26 hours. 6 …”