ADAPTIVE-CHANGES IN THE PHARMACODYNAMICS OF MIDAZOLAM IN DIFFERENT EXPERIMENTAL-MODELS OF EPILEPSY - KINDLING, CORTICAL STIMULATION AND GENETIC ABSENCE EPILEPSY

1 The objective of this investigation was to determine quantitatively whether experimental epilepsy is associated with a change in the pharm acodynamics of benzodiazepines in vivo. For that purpose the pharmacod ynamics of midazolam were quantified by an integrated pharmacokinetic- pharmaco dynamic approach in three different models of experimental ep ilepsy: amygdala kindling, cortical stimulation and genetic absence ep ilepsy. 2 The time course of the EEG effect was determined in conjunct ion with the decline of drug concentrations after intravenous administ ration of 10 mg kg(-1) midazolam. The pharmacokinetics of midazolam we re most adequately described by a bi-exponential equation. No influenc e of epilepsy on the pharmacokinetics of midazolam was observed. 3 The increase in beta activity (11.5-30 Hz) of the EEG as derived by Fast Fourier Transformation analysis was used as pharmacodynamic endpoint. For each individual rat the increase in beta activity was directly rel ated to the concentration in blood on the basis of the sigmoidal E-max pharmacodynamic model. In all three models a significant reduction in the maximal effect was observed, in amygdala kindling 28%, in the cor tical stimulation model 49% and in genetic absence epilepsy 37%. No di fferences in the other pharmacodynamic parameters, E-0, EC50,u and Hil l factor, were observed. 4 It is inferred that in three different mode ls of epilepsy there is a similar change in GABAergic functioning whic h is associated with a significant reduction in the intrinsic activity of midazolam in vivo. These models provide therefore a useful basis f or further studies on the mechanism of epilepsy-induced changes in pha rmacodynamics of anti-epileptic drugs.