Benzodiazepine pharmacodynamics: evidence for biophase rate limiting mechanisms

Pharmacokinetics do not adequately reflect recovery from cognitive neuromotor impairment induced by most benzodiazepines. This paper examines across time the nature of the relationship of effect to serum concentration of three benzodiazepines. Using the same protocol lorazepam, alprazolam, diazepam and placebo were administered to eight healthy males at doses of 0.057, 0.029, 0.286 and 0.000 mg/kg, body weight, respectively for the first study and at 0.028, 0.014, 0.143 and 0.000 mg/kg, respectively, for the second study. After each dose administration multiple measurements were made over a period of 5.5-11.5 h using two different psychomotor performance tests. Serum drug concentrations were also measured. The profiles for diazepam and alprazolam effects demonstrate a stepwise decrement in the slopes of the concentration versus response curves across time, illustrating the rapid development of acute tolerance. In contrast, lorazepam induced a remarkably constant relationship between concentration and effect across testing intervals.