Pharmacodynamic Interaction Between Midazolam and a Specific Benzodiazepine Antagonist in Humans

Abstract

The pharmacodynamic interaction between midazolam and the specific benzodiazepine antagonist Ro 15–1788 has been investigated in six healthy male volunteers. Hypnotic steady‐state concentrations of midazolam (55 ± 11 ng/mL; mean ± SD) have been achieved rapidly by an intravenous bolus of 0.07 mg/kg and maintained by an individual but constant infusion rate of 0.025 to 0.04 mg/kg/hr for eight hours. Following a two‐hour control period, the antagonist (2.5 mg) or the solvent were injected double‐blind in random order. Three hours later, the other medication was administered. Whereas plasma levels of midazolam remained constant throughout the complete eight‐hour trial (Clearance = 670 ± 96 mL/min) concentrations of Ro 15–1788 declined rapidly with an elimination half‐life between 0.7 and 1.8 hours and a total plasma clearance of 702 ± 235 mL/min. Concentrations of Ro 15–1788 approached the analytic limit of 2 ng/mL within three hours. The pharmacodynamic response to midazolam and the antagonist was assessed by a sedation index using visual analogue scales, reaction time (RT) measurements, and transformed Fourier analysis of the power spectrum of the recorded electroencephalogram (EEG). About 30 to 45 seconds following the injection of Ro 15–1788, hypnotic action of midazolam was completely reversed as visualized by return to alpha rhythm in the EEG, shortening of prolonged RT, and normalization of the elevated sedation index. The antagonistic action lasted for about two to three hours. The abrupt arousal from sleep was not associated with any unpleasant sensations, however, three subjects experienced a profound perspiration for about ten minutes following the injection of Ro 15–1788. In conclusion, a small intravenous bolus of 2.5 mg Ro 15–1788 reverses rapidly the hypnotic action of midazolam. The relative short duration of the antagonistic effect is due to the fast hepatic elimination of Ro 15–1788, which might be a suitable antidote of benzodiazepine‐induced oversedation in special clinical situations.

Possible interaction of fluoroquinolones with the benzodiazepine‐GABAA‐ receptor complex.

“…This pattern was known from different studies conducted with midazolam (Handel et al, 1988;Klotz et al, 1985), as well as other BZD (Sittig et al, 1982). Additionally, the increased sedation index and reported side effects such as fatigue and amnesia, indicate the typical agonist BZD action.…”

Lack of effect of nitrendipine on the pharmacokinetics and pharmacodynamics of midazolam during steady state.

“…flumazenil or CGS 8216) of convulsions, muscle relaxation, sedation or have been developed which by competitive bind-sleep (Polc et al, 1982). ing at the receptor site specifically can block the A candidate to be considered for such involveeffects of various BZD (Mohler & Richards, ment (Klotz et al, 1985). described that 45Ca2+ uptake into brain synaptosomes was increased by BZD, especially under depolarizing conditions (Paul et al, 1982;Mendelson et al, 1984a).…”

“…The study was performed under clinical relevant steady-state conditions and the protocol was almost identical to a previous study where the specific BZDantagonist flumazenil (Rol5-1788) reversed promptly the CNS-sedation induced by an infusion of midazolam (Klotz et al, 1985).…”

Effect of the Specific Benzodiazepine Antagonist Ro 15-1788 on Sleep

“…In the first clinical trials it was found that this drug could reverse the sedative-hypnotic effects of clonazepam, diazepam, flunitrazepam, midazolam, and other benzodiazepines rapidly ( see Hunkeler et al, 1981;Bonetti et al, 1982;Klotz et al, 1985). The very short duration of action corresponds weil to the elimination half-life time of about 0.97 ± 0.2 hours (Klotz et al, 1984).…”