Dennis J. Chapron

Toxic interaction between acetazolamide and salicylate: Case reports and a pharmacokinetic explanation

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 µg/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 µg/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.

Imipramine Disposition in Alcoholics

The disposition of orally administered imipramine (IMI) was studied in 11 depressed alcoholic and 12 depressed nonalcoholic male inpatients. Subjects received 50 mg three times daily for at least 10 days to ensure steady state. Following a temporary discontinuation of therapy, several blood samples were drawn over a 40-hour period. Imipramine, desipramine, and their 2-hydroxylated metabolites were measured in plasma using a high performance liquid chromatography assay. Eight hours following the last dose, alcoholics had significantly lower IMI (50 ± 41 versus 106 ± 46 ng/ml; p<0.005) and 2-hydroxyimipramine (12.8 ± 7.5 versus 22.6 ± 9.8 ng/ml; p< 0.01) levels than controls. The mean terminal half-lives in the two groups were nearly identical (16.3 ± 6.7 hours in alcoholics versus 17.1 ± 5.4 hours in controls). Beck Depression Inventory scores were significantly reduced during IMI therapy (p<0.001) in the nonalcoholic controls, whereas no change was observed in the alcoholic group. These results are consistent with either a decrease in oral bioavailability of IMI in alcoholics or, assuming complete absorption, an increase in intrinsic clearance of 2.5 fold (2444 ± 1151 versus 986 ± 438 ml/min; p<0.005) over the clearance found in control subjects. The latter seems a more likely result of chronic ethanol intake. The fact that lower levels of IMI in the alcoholic group were accompanied by a lack of efficacy in relieving depressive symptomatology suggests that whether through an effect on bioavailability or intrinsic clearance, ethanol consumption is an important consideration when recommending tricyclic therapy.

Kinetic discrimination of three sulfamethazine acetylation phenotypes

The relationship between sulfamethazine disposition kinetics and acetylator phenotype was studied in 19 healthy subjects. Various kinetic parameters for sulfamethazine and its N4‐acetylated metabolite were determined after a dose of a rapidly absorbed oral solution. When plotted on a frequency distribution histogram, the results exhibited a well‐defined trimodal pattern for acetylation clearance values and overall elimination or metabolic rate constants. These data were consistent with the well‐recognized acetylation polymorphism for sulfamethazine, except that they clearly subdivided the previously acknowledged “fast” acetylator mode into intermediate and rapid acetylator groups. The apparent distribution volume and renal clearance for sulfamethazine and acetylsulfamethazine did not differ significantly among the 3 phenotypes. Of special interest was the observation that rapid acetylators initially produce much greater amounts of acetyl metabolite than intermediate acetylators. The potential clinical implications of identifying rapid and intermediate acetylators are discussed in view of evidence showing that acetyl metabolites may be pharmacologically active or function as intermediates in toxic metabolic pathways.

Tetracycline absorption in elderly patients with achlorhydria

Five elderly achlorhydric patients and five controls took 250 mg tetracycline as a capsule or as an oral solution. Venous blood samples drawn during the 12‐hr period following administration and urine collected for 72 hr post‐dosing were assayed fluorometrically for tetracycline. There were no differences between the two groups in either rate or extent of tetracycline absorption. The mean apparent first‐order rate constant (ka) for absorption of drug from capsules was 0.58 ± 0.17 hr−1 for patients and 0.65 ± 0.21 hr−1 for controls. The mean extent of absorption for capsule dosage forms relative to an oral solution was 1.0 ± 0.20 for patients and 1.0 ± 0.24 for controls. Concurrent administration of 2 gm of sodium bicarbonate to 2 of the normal subjects resulted in no impairment of either the rate or extent of tetracycline absorption from capsules, suggesting that the effect of elevated gastric pH on tetracycline bioavailability may relate to formulation.

Observations on Lithium Disposition in the Elderly

The disposition kinetics of lithium were studied in six elderly women who had been maintained on this medication for several years. Lithium administration was stopped abruptly. Plasma, whole blood, and erythrocyte half‐lives were then measured, as well as renal plasma clearance and distribution volume. Half‐life values in whole blood and in its components were found to be similar. The plasma lithium half‐life approximated that in younger schizophrenics, but appeared prolonged when compared with half‐lives reported for young normal volunteers. Renal plasma clearance and distribution volume of lithium appeared substantially reduced when compared with published values. The data are consistent with altered lithium disposition in the aged.

Renal response to furosemide in very low birth weight infants during chronic administration.

Renal response to furosemide following initial and chronic doses was investigated in premature infants with bronchopulmonary dysplasia. Seven infants (mean birth weight = 890 +/- 216 g, mean gestational age at birth = 27.7 +/- 2.6 weeks, mean postnatal age at the start of diuretic therapy = 2.7 +/- 0.9 weeks) were studied. Twelve-hour urine collections were performed after the initial dose, and following chronic doses after 1 week and 3 weeks of therapy. Volume of each urine sample was measured and concentrations of furosemide, sodium and creatinine determined. Linear dose-response relationships were found between the logarithm of the urinary furosemide excretion rate and diuretic/natriuretic response (urine output and urinary sodium excretion rate). The furosemide excretion rate required to achieve midrange diuretic and natriuretic responses was significantly greater during chronic dosing than following initial doses, indicating a decrease in renal responsiveness to drug with sustained use. Increasing postconceptional age was associated with a decrease in initial responsiveness to furosemide. These data demonstrate that in premature infants renal sensitivity to furosemide decreases with chronic use as well as with increasing postconceptional age at the start of therapy. The decrease in renal sensitivity to drug with chronic use is of much greater magnitude, and appears to represent renal compensation for drug-induced diuresis and natriuresis.

Unmasking the Significant Enzyme-Inducing Effects of Phenytoin on Serum Carbamazepine Concentrations during Phenytoin Withdrawal

OBJECTIVE: We report on two patients who appeared to exhibit profound induction of carbamazepine metabolism during cotherapy with phenytoin. Gradual withdrawal of phenytoin confirmed this impression. DESIGN: Two case studies. RESULTS: Two patients receiving carbamazepine and phenytoin as combination anticonvulsant therapy were admitted for comprehensive rehabilitation. A 23-year-old man had therapeutic serum phenytoin concentrations, but his serum carbamazepine concentrations were so low that they were nonquantifiable. Doubling the daily carbamazepine dosage did not yield quantifiable serum concentrations. When the daily phenytoin dosage was tapered from 500 to 200 mg, the carbamazepine concentration rose to 10.0 μg/mL. No further changes in serum carbamazepine concentrations were observed when the phenytoin was discontinued. A 49-year-old man was receiving large daily dosage of phenytoin (600 mg) and carbamazepine (2300 mg). In the process of tapering and discontinuing phenytoin, the patient became lethargic and confused. These signs and symptoms suggested carbamazepine toxicity. The patient was eventually stabilized on a carbamazepine dosage of 1200 mg/d, which produced a serum concentration of 8.4 μg/mL. When this patient had been receiving concurrent phenytoin therapy, approximately twice as much carbamazepine (2300 mg) was required to maintain a similar serum concentration. CONCLUSIONS: Phenytoin is a potent inducer of carbamazepine metabolism. Whenever phenytoin dosages are tapered and discontinued in patients receiving these medications concomitantly, frequent serum carbamazepine monitoring is recommended during the ensuing deinduction phase.

Estimating steady state desipramine levels in noninstitutionalized elderly patients using single dose disposition parameters.

Clearances calculated from single oral dose data have been utilized to predict steady state levels of desipramine in 12 noninstitutionalized depressed elderly patients. Observed steady state plasma levels correlated very well (r = 0.967, p <0.0005) with those predicted from single dose clearances, but not with plasma levels obtained 20 hours after a single oral dose (r = 0.24,p > 0.2). The mean half-life of desipramine (20.9 hours) in this group of elderly (mean age, 72 years) was considerably less than values of “apparent disappearance” half-life previously reported for elderly patients receiving imipramine. The single dose clearance technique yielded a precise criterion for quantitating early compliance with and adjusting drug dosing regimens.

Gastric Retention of Enteric-Coated Magnesium Chloride Tablets

OBJECTIVE: To describe a patient with gastric retention of enteric-coated magnesium chloride tablets. Potential drug and disease etiologies accounting for failure to empty this dosage form are discussed. DESIGN: Single case report. CASE SUMMARY: A seriously ill patient with metastatic small-cell lung cancer accumulated 21 enteric-coated magnesium chloride tablets in his stomach during a four-day administration period. The patient had gastroscopic evidence of mild pylorospasm and suspected gastric motor dysfunction. The latter may have been the result of several factors including concurrent use of oxycodone, vagal dysfunction from chronic alcoholism and cisplatin-based chemotherapy, and possibly a paraneoplastic neuromuscular syndrome involving the gastrointestinal tract. CONCLUSIONS: Enteric-coated tablets are indigestible solids, often of considerable size. Strong antral contractions, associated with phase 3 of the interdigestive migrating myoelectric complex, are usually required to carry such dosage forms through a normal pyloric channel and into the duodenum. Seriously ill patients who may have gastric hypomotility or pyloric channel narrowing are probably not good candidates for therapy with large enteric-coated dosage forms.

Lymphopenic effect of carbamazepine in a patient with chronic lymphocytic leukemia.

Objective: To report a dramatic and reproducible suppressive effect of carbamazepine on circulating lymphocytes in an elderly woman with chronic lymphocytic leukemia. Case Summary: An elderly woman taking phenytoin for a stroke-associated seizure disorder had lymphocyte count of 28 800 × 106 cells/L. Speculating an unusual lymphadenopathic effect of the phenytoin therapy, carbamazepine therapy was substituted. After 15 weeks of carbamazepine treatment, the lymphocyte count declined to 3200 × 106 cells/L. Because of severe diarrhea, carbamazepine therapy was stopped and phenytoin therapy was reinstituted. At the end of 4 months of phenytoin treatment, the lymphocyte count had increased to 23 200 × 106 cells/L. Phenytoin therapy was discontinued and carbamazepine therapy was begun. The lymphocyte count decreased to 10 700 × 106 cells/L. Severe diarrhea recurred and phenytoin treatment was reinstituted. Over 12 days the lymphocyte count increased to 28 900 × 106 cells/L. Phenytoin therapy was stopped and valproic acid therapy was started. The lymphocyte count continued to increase during valproic acid therapy, reaching a peak of 114 300 × 106 cells/L. Discussion: In this patient with chronic lymphocytic leukemia, carbamazepine therapy had a significant and reproducible lymphopenic effect that was readily reversible upon discontinuation of the drug. Unfortunately, this effect was associated with severe diarrhea, preventing further attempts at exploiting this potentially beneficial action. Conclusions: Carbamazepine had a reproducible suppressive effect on lymphocyte counts in an elderly patient with chronic lymphocytic leukemia. This unique observation raises the possibility that carbamazepine therapy may have a useful effect in patients with chronic lymphocytic leukemia.