Electroencephalographic effects of benzodiazepines. II. Pharmacodynamic modeling of the electroencephalographic effects of midazolam and diazepam

Abstract

The comparative pharmacodynamics of midazolam and diazepam were examined by use of the electroencephalogram as a measure of drug effect on the central nervous system. Intravenous doses of 7.5, 15, and 25 mg midazolam and 15, 30, and 50 mg diazepam were given on repeated occasions to three volunteers. Arterial plasma concentration and electroencephalogram voltage were related with nonparameteric and parametric pharmacodynamic models. The peak increases in voltage (maximal effect) and the slopes of the plasma concentration versus effect curve were similar for both drugs. The half-time of blood:brain equilibration was significantly longer for midazolam than diazepam (4.8 minutes versus 1.6 minutes). Midazolam was found to have an intrinsic steady-state potency that was approximately five times greater than that of diazepam (152 ng/ml versus 958 ng/ml).

Pharmacological alteration of sleep and dreams ? a clinical framework for utilizing the electrophysiological and sleep stage effects of psychoactive medications

“…Such EEG frequency effects are not well described for all CNS active compounds, but are increasingly being used to characterize the expected behavioural effects of medication (Javanoviv, 1974;Herrmann and Schaerer, 1986;Buhrer et al, 1990). Although benzodiazepines, and antidepressants show some drug specific variations, chemically similar agents produce consistent changes in EEG frequency and spindle effects (Tables 1 and 2) (Herrmann, 1982;Kupfer, 1988;Pagel, 1993).…”

Midazolam premedication and thiopental induction of anaesthesia: interactions at multiple end-points

“…In the bolus studies, midazolam effect-site concentrations are likely to still be increasing at the end-point under investigation, while in our study they are likely to be decreasing slowly during all end-points. [11][12][13][14] Thiopental effect-site concentrations, which are increasing for both designs, increase more slowly in an infusion model, but with smaller differences in plasma concentrations. [11][12][13][14] We chose an infusion induction titration design because multiple end-points can be studied in the same patient and session, and because for thiopental, such a model is demonstrably efficient at deriving timing and bolus dose results relevant to clinical use.…”

“…[11][12][13][14] Thiopental effect-site concentrations, which are increasing for both designs, increase more slowly in an infusion model, but with smaller differences in plasma concentrations. [11][12][13][14] We chose an infusion induction titration design because multiple end-points can be studied in the same patient and session, and because for thiopental, such a model is demonstrably efficient at deriving timing and bolus dose results relevant to clinical use. 2 The design allows conclusions about clinically important end-point timing not available from bolus administration studies (end-points sought in fixed time windows).…”

Pharmacotherapy of insomnia: Practice and prospects

“…Sophisticated pharmacokinetic-pharmacodynamic modelling experiments with hypnotic drugs have been conducted, usually focusing on the EEG as pharmacodynamic effect measure [94][95][96]. This type of experiments yield pivotal information on the comparative potency of drugs and the role of drug metabolites but their value in the clinical application of hypnotics has not yet been demonstrated.…”