Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo

Abstract

Eleven healthy volunteers received a single intravenous dose of diazepam (0.15 mg/kg), midazolam (0.1 mg/kg), and placebo by 1-minute infusion in a double-blind, three-way crossover study. Plasma concentrations were measured during 24 hours after dosage, and the electroencephalographic (EEG) power spectrum was simultaneously computed by fast-Fourier transform to determine the percentage of total EEG amplitude occurring in the 13 to 30 Hz range. Both diazepam and midazolam had large volumes of distribution (1.2 and 2.3 L/kg, respectively), but diazepam's half-life was considerably longer (33 versus 2.8 hours) and its metabolic clearance lower (0.5 versus 11.0 ml/min kg) than those of midazolam. EEG changes were maximal at the end of the diazepam infusion and 5 to 10 minutes after midazolam infusion. Percent 13 to 30 Hz activity remained significantly above baseline until 5 hours for diazepam but only until 2 hours for midazolam. For both drugs, EEG effects were indistinguishable from baseline by 6 to 8 hours, suggesting that distribution contributes importantly to terminating pharmacodynamic action. The relationship of EEG change to plasma drug concentration indicated an apparent EC50 value of 269 ng/ml for diazepam as opposed to 35 ng/ml for midazolam. However, Emax values were similar for both drugs (+19.4% and +21.3%, respectively).

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

“…When the effect of BZDs is quantified by electroencephalography (EEG), diazepam and midazolam have effective concentrations of 269 and 35 ng/ml, respectively, in 50% of the subjects (Greenblatt et al, 1989a). The spectrum of clinical CNS activity such as amnesia and sedation is similar with intravenous midazolam (0.05-0.15 mg/kg) and diazepam (0.1-0.3 mg/kg).…”

“…After administration of 0.15 mg/kg i.v. diazepam in healthy volunteers, the duration of diazepam effects, based on a statistically significant difference over the baseline EEG values, is 5 to 260 6 h compared with 2.5 h after administration of 0.1 mg/kg midazolam (Greenblatt et al, 1989a). However, larger doses of midazolam (0.2 mg/kg) may prolong the postoperative sedation (McClure et al, 1983).…”

Treatment of patients with cocaine‐induced arrhythmias: bringing the bench to the bedside

“…Although no comparative trials exist, diazepam and midazolam are generally preferable to lorazepam because of their rapid peak sedative effects [50,51]. Midazolam is particularly attractive because its short duration of effect more closely matches the toxicodynamics of cocaine and is therefore less likely to produce oversedation when cocaine has worn off.…”

Impairment State of Cognitive Performance and the Affecting Factors in Outpatients Following Gastrointestinal Endoscopy after Single-dose Diazepam

“…[17][18][19][20] From these published data, the plasma concentration of diazepam can be regarded as equivalent to the biophase concentration, even when the drug is at the distribution phase of its pharmacokinetic proˆle. Ndesmethyldiazepam, an active metabolite of diazepam, could not be detected during the study period.…”