Modelling acute tolerance to the EEG effect of two benzodiazepines |
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| Authors: | Ihmsen Harald Albrecht Sven Hering Werner Schüttler Jürgen Schwilden Helmut |
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| Affiliation: | Department of Anaesthesiology, Friedrich-Alexander-University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany. harald.ihmsen@kfa.imed.uni-erlangen.de |
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| Abstract: | AIMS: We studied the development of acute tolerance to the EEG effect of midazolam and the new benzodiazepine Ro 48-6791. METHODS: Nine young (24-28 years) and nine elderly (67-81 years) male volunteers received midazolam and Ro 48-6791 computer-controlled, targeting linearly increasing plasma concentrations for 30 min (targeted slopes: 40 and 20 ng ml-1 min-1 for midazolam, 3 and 1.5 ng ml-1 min-1 for Ro 48-6791, for young and elderly, respectively) and a constant concentration for the following 15 min. After recovery, the same infusion scheme was repeated. Plasma concentrations of midazolam, Ro 48-6791 and its metabolite Ro 48-6792 were determined from arterial blood samples. The hypnotic effect was assessed using the median frequency of the EEG power spectrum. RESULTS: The concentration-effect relationship in each infusion cycle could be described by a sigmoid Emax model. The half-maximum concentration EC50 was higher in the second infusion cycle compared with the first one (midazolam, 47% (2.3-91.6%) and 37% (5.3-69.5%); Ro 48-6791, 22% (-2.8% to 44.6%) and 43% (3.4-82.4%) for young and elderly; mean and 95% confidence interval). The complete time course of the EEG median frequency could be described by an interaction between the parent drug in an effect compartment and a hypothetical competitive drug in an additional tolerance compartment. For Ro 48-6791, the use of its metabolite Ro 48-6792 as competitive compound also gave appropriate results. CONCLUSION: Midzolam and Ro 48-6791 showed acute tolerance to the EEG effect which might be caused by competitive interaction with the metabolite. |
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| Keywords: | benzodiazepines electroencephalogram pharmacodynamics tolerance |
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