Faculty Bibliography

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.

This report describes an adverse reaction to iodinated glycerol, an organic form of iodine prescribed as a mucolytic-expectorant. In a patient with a previous history of severe potassium iodide-induced hypothyroidism, administration of iodinated glycerol resulted in mild subclinical hypothyroidism. There is one report in the literature of goiter resulting from iodinated glycerol and physicians should be aware of the potential for hypothyroidism with this agent. Iodinated glycerol should be added to the list of iodine-containing organic compounds that interfere with thyroid function.

Two elderly patients, who were chronically receiving aspirin, developed lethargy, incontinence, and confusion after dosing with acetazolamide. Unbound plasma acetazolamide concentrations were elevated and plasma protein binding was reduced, suggesting an interaction with aspirin. In vitro studies demonstrated a concentration-dependent effect of salicylate on acetazolamide binding to serum proteins. At a therapeutic serum acetazolamide level of 8.0 micrograms/ml, the unbound percentage of acetazolamide in serum was 3.3% and increased to 11.0% and 30.0%, with serum salicylate levels of 200 and 386 micrograms/ml, respectively. Furthermore, the apparent association constant of acetazolamide for binding to serum proteins was decreased by 58% and 86% of its control value at these respective salicylate concentrations. The maximal binding capacity of serum for acetazolamide was not affected by salicylate. Pharmacokinetic studies in four volunteers showed that the plasma protein binding and renal clearance of acetazolamide were significantly reduced during chronic salicylate dosing. Salicylate appears to competitively inhibit the plasma protein binding of acetazolamide and simultaneously to inhibit acetazolamide renal tubular secretion. Caution is advised when acetazolamide and salicylate are used concurrently.

Influenza vaccine may inhibit hepatic metabolism of drugs and has been reported to prolong the prothrombin time in patients receiving warfarin by affecting the coagulation pathway. In a group of seven elderly residents of a long-term care facility who were receiving warfarin, prolongation of the prothrombin and partial thromboplastin times could not be shown up to 5 weeks after vaccination against influenza. The results were similar in nine elderly subjects who were not receiving warfarin.

Steady state theophylline concentrations were prospectively measured in 13 elderly institutionalized individuals following influenza vaccination. Vaccine-mediated increase in concentrations could not be identified. In seven individuals receiving warfarin, no change in prothrombin or partial thromboplastin times occurred following vaccination. No adverse drug reactions were observed. The following year 14 individuals receiving theophylline and 12 receiving warfarin were vaccinated without adverse drug reactions noticed. These data fail to support previous reports of influenza vaccine inhibition of theophylline metabolism or vaccine-enhanced anticoagulation and are consistent with recent reports on younger subjects.

A railroad accident in Somerville, Massachusetts, led to spillage of phosphorus trichloride liquid. Attempted clean-up with water led to the liberation of phosphorus trichloride, phosphoric acid, hydrochloric acid, and phosphorus oxides. Seventeen people exposed to this mixture were studied. Patients experienced eye irritation, lacrimination, nausea, vomiting, and dyspnea. Six patients had transient elevation of lactic dehydrogenase. Although all patients had normal chest roentgenographic findings, pulmonary function tests showed statistically significant decreases in vital capacity (p = 0.02), maximal breathing capacity (p = 0.02), forced expiratory volume in one second (p = 0.02), and maximal expiratory flow rate at 25 percent of vital capacity (p = 0.05) in those closest to the accident site. Further, patients exposed for less than one and a half hours had significantly greater maximal expiratory flow rates at 25 percent of vital capacity when compared with patients who had been exposed longer (p = 0.02). In seven patients, repeated pulmonary function tests one month later showed improvement, suggesting strongly that the acute effects may have been due to phosphorus trichloride toxicity.