ADAPTIVE-CHANGES IN THE PHARMACODYNAMICS OF MIDAZOLAM IN DIFFERENT EXPERIMENTAL-MODELS OF EPILEPSY - KINDLING, CORTICAL STIMULATION AND GENETIC ABSENCE EPILEPSY
A. Cleton et al., ADAPTIVE-CHANGES IN THE PHARMACODYNAMICS OF MIDAZOLAM IN DIFFERENT EXPERIMENTAL-MODELS OF EPILEPSY - KINDLING, CORTICAL STIMULATION AND GENETIC ABSENCE EPILEPSY, British Journal of Pharmacology, 125(4), 1998, pp. 615-620
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.