Pharmacodynamic interactions of diazepam and intravenous alcohol at pseudo steady state.

van Steveninck AL, Gieschke R, Schoemaker HC, Pieters MS, Kroon JM, Breimer DD, Cohen AF

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.