Central effects during the continuous osmotic infusion of a benzodiazepine (triazolam).

Abstract

The effects of relatively constant plasma levels of a rapidly eliminated benzodiazepine (triazolam) were studied in young healthy males to determine whether tolerance to certain effects may develop over a relatively short period of time. The drug was given over a period of 30 h (2 days and 1 night) at zero‐order rate using a rectal osmotic pump. Performance was measured at 2 hourly intervals during the day and was continuously impaired during the infusion, though there was a rapid recovery when the infusion ceased. All tasks were affected, in particular mental arithmetic and letter cancellation, but there was some improvement in performance during the second day. The normal circadian improvement in performance may have contributed to this effect, but some degree of tolerance to the effect of the drug cannot be excluded. Overnight there was a marked reduction in wakefulness, suppression of slow wave sleep, and delay to the onset and reduction in the duration of rapid eye movement sleep. During the night after infusion there was less slow wave sleep and increased wakefulness. The experimental design may prove useful in the study of tolerance to drugs.

Anticonvulsant Pharmacodynamics and Disposition of Triazolam in Rats††These results were presented, in part, at the Seventh Annual Meeting of the American Association of Pharmaceutical Scientists, San Antonio, TX, November 1992.

“…2,3,34,46,47 Characterized by a rapid onset of action and a very potent anticonvulsant activity, a parenteral formulation of TZ could potentially be useful in the treatment of status epilepticus; however, the low hydrosolubility, as seen with other benzodiazepines, could be a limiting factor in the development of such a formulation. As discussed earlier, no previous animal study evaluating TZ pharmacokinetics and pharmacodynamics could be found in the literature; that is, the available clinical data are limited to relationships between deleterious effects of the drug, such as decrease in memory or in performance on various psychometric tests, and TZ concentrations.…”

Pharmacokinetics of temazepam compared with other benzodiazepine hypnotics—some clinical consequences

“…The elimination of brotizolam was also decreased in patients with liver cirrhosis (8). Age also affects the kinetics of loprazolam: elimination in the elderly was 20 hours as compared with 11 hours in the young It has been shown for triazolam, midazolam and brotizolam that no significant quantities of active metabolites are present in plasma, even during or after continuous administration (47,49,56).…”