Pharmacodynamic interactions of diazepam and intravenous alcohol at pseudo steady state

Abstract

Pharmacodynamic interactions of low doses of diazepam and alcohol were investigated in a double blind, randomised, 2 x 2 factorial, cross-over study in eight healthy volunteers. Alcohol or glucose 5% were administered intravenously at rates calculated to maintain breath alcohol levels of 0.5 g/l from 1.5 to 5.5 h after starting the alcohol infusion. Diazepam 5 mg or placebo were administered orally at 1.5 h. Evaluation of pharmacodynamic interactions was performed for the average results of tests performed at 2, 3.5 and 5 h. Plasma concentrations of (desmethyl-) diazepam and breath alcohol levels were measured for pharmacokinetic analysis. Breath alcohol reached pseudo steady state levels of 0.38 g/l (range: 0.24-0.57) after alcohol alone and 0.37 g/l (range: 0.27-0.52) in combination with diazepam. Alcohol effects were demonstrated for latency of saccadic eye movements, smooth pursuit eye movements and subjective drug effects. Diazepam impaired smooth pursuit and saccadic eye movements, adaptive tracking, digit symbol substitution and body sway. The effects of combined alcohol and diazepam were mostly additive without significant synergistic interactions. However, in two subjects large supra-additive effects occurred at 3.5 h following alcohol+diazepam, which were not explained by increased drug levels. The design and methods used in this study proved advantageous in evaluating low dose pharmacodynamic interactions. Despite the absence of significant synergistic interactions, unanticipated impairment of performance may occur in susceptible individuals when taking combined low doses of alcohol and diazepam.

Effects of ethanol at four phases of the menstrual cycle

“…Qualitatively, ethanol increased ratings of both sedative-like effects [ARCI PCAG (sedation), SSQ "unpleasant sedation" and "pleasant sedation"] and some stimulant-like effects (ARCI A scale), similar to results from previous studies (Holdstock and de Wit 1998). Consistent with the known actions of ethanol on eye movements (Baloh et al 1979;Lehtinen et al 1979;Jantti et al 1983;Stapleton et al 1986;van Steveninck et al 1993;Gale et al 1996;Blekher et al 1997;Holdstock and de Wit 1999), the eye movement measures proved very sensitive to the impairing effects of ethanol: PSEV was decreased after 0.2, 0.4, and 0.6 g/kg ethanol, whereas latency and SPG were impaired after 0.4 g/kg and 0.6 g/kg. Thus, the measures we used were sensitive but did not alter with menstrual cycle phase.…”

Central nervous system effects of alcohol at a pseudo‐steady‐state concentration using alcohol clamping in healthy volunteers

“…The 'Neurocart' is a battery of sensitive tests for a wide range of CNS domains that has been developed at CHDR to examine different kinds of CNS-active drugs [7][8][9]. The following tests were performed twice at baseline, and repeated hourly during the plateau and wash-out phases in a quiet room with ambient illumination, in the following order.…”

“…Visual analogue scales (VAS), as originally described by Norris [13], have been used previously to quantify subjective effects of a variety of sedative agents [8,9,14,15]. In the current study alertness, mood and calmness were derived from a VAS previously described by Bond and Lader [16].…”

“…These results correspond to literature findings. Effects on postural stability, subjective assessments (visuo-) motor control and oculomotor coordination or attention are frequently observed after alcohol administration [8,9]. Some of these effects fluctuated significantly during the plateau phase, despite relatively constant alcohol levels.…”

Effects of Fentanyl and Low Doses of Alcohol on Neuropsychological Performance in Healthy Subjects

“…There are only few studies applying alcohol by intravenous infusion. Using low doses of alcohol (up to 0.04% BAC) no effects on psychomotor performance were reported [30,31]. At a BAC of 0.15%, Fluckinger et al [32] measured a marked impairment of psychomotor performance.…”