Physostigmine reversal of midazolam-induced electroencephalographic changes in
healthy subjects.
Author(s): Ebert U, Oertel R, Kirch W.
Affiliation(s): Institute of Clinical Pharmacology, Faculty of Medicine, Technical University
Dresden, Germany. uebert@rcs.urz.tu-dresden.de
Publication date & source: 2000, Clin Pharmacol Ther. , 67(5):538-48
OBJECTIVE: Midazolam is a water-soluble benzodiazepine. Flumazenil is a potent
antagonist of midazolam-induced sedation. Physostigmine has also been shown to
reverse benzodiazepine sedation in anecdotal reports. The aim of this study was
to quantitatively characterize the reversal of midazolam-induced changes in
electroencephalogram (EEG) by physostigmine compared to flumazenil and placebo.
METHODS: Twelve healthy male subjects received 5 mg midazolam as an intravenous
infusion over 15 minutes. Fifteen minutes after the end of infusion, single doses
of either 0.4 mg flumazenil, 0.5 mg physostigmine, or placebo (physiologic saline
solution) were administered as intravenous injections in a randomized crossover
fashion. Midazolam serum concentrations were measured using liquid
chromatography-tandem mass spectrometry. The time from the start of injection
until awakening was noted and the EEG was measured.
RESULTS: Four subjects were excluded from further pharmacokinetic and
pharmacodynamic analysis because no midazolam-induced changes on EEG alpha power
could be observed in each of the three study periods. The pharmacokinetics of
midazolam were not influenced by flumazenil or physostigmine. Midazolam induced a
decrease in EEG alpha power (7.50 to 11.25 Hz) compared with baseline (P < .05).
After injection of flumazenil and physostigmine, an increase in EEG alpha power
was observed, whereas placebo did not affect alpha power. Subjects opened their
eyes 25.2 +/- 1.1 minutes after the placebo injection was begun, whereas subjects
awoke after 6.2 +/- 2.7 minutes and 15.4 +/- 3.4 minutes after they received
flumazenil and physostigmine, respectively (mean +/- SEM; P < .001).
CONCLUSION: Physostigmine and flumazenil antagonized midazolam-induced sedation.
This suggests that a reversible central anticholinergic mechanism may be involved
in the sedative action of midazolam.
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