Rate of Increase of Plasma Lorazepam Concentrations; Absence of Influence upon Subjective and Objective Effects

Abstract

This study was designed to investigate the relationship between subjective and objective effects of a benzodiazepine on the one hand, and the rate of increase of plasma concentration on the other. The pharmacokinetic variables of 10 normal volunteers were calculated following a single intravenous bolus injection of 1 mg of lorazepam, a benzodiazepine devoid of active metabolites. In six of the subjects rates of infusion could be calculated in order to achieve the same plasma concentration after 1 hour and 2 hours. In the main study, lorazepam was infused at two different rates on two separate occasions, with a third placebo infusion occasion. A balanced crossover design was used with single-blind procedures. Plasma concentrations, subjective ratings, quantified EEG recordings, and psychological performance tests were estimated before and at 1, 2, and 3 hours after the start of the infusions. The peak plasma concentrations achieved were the same at the end of the two drug infusions. EEG and some performance tests paralleled the plasma concentrations fairly closely, but subjective effects did not reach their maximum until the 3-hour point and were significantly greater after the 2-hour than after the 1-hour infusion. Drug doses, rate of penetration into the brain, and duration of exposure to the increasing concentrations of lorazepam seem more relevant factors for the time course and the intensity of the various initial effects of the drug than the rate of increase of plasma levels.