Development of tolerance to the anticonvulsant effect of diazepam in dogs

In dogs the development of tolerance to the anticonvulsant effect of diazepam was followed by weekly determinations of the convulsive threshold for pentetrazole, 10-15 min after intravenous (i.v.) injection of 0.25 or 0.5 mg/kg diazepam. As soon as after 1 week of oral treatment with diazepam, 0.25 or 0.5 mg/kg three times daily (t.i.d.), the pentetrazole threshold showed a decline or even a fall to the control level in spite of unaltered or rising concentrations of diazepam and its active metabolites. Tolerance also developed when the dogs were treated with chlorazepate, 2 mg/kg t.i.d., between the weekly diazepam injections for threshold determination. The results favor a functional type of tolerance since there was no indication of a more rapid inactivation of diazepam. Treatment with desmethyldiazepam (2 mg/kg i.v. for threshold determination and oral treatment with the desmethyldiazepam precursor chlorazepate, 2 mg/kg t.i.d.) did not produce tolerance. In further experiments in dogs anesthetized, relaxed with suxamethonium and ventilated, a spike-wave activity in the EEG was induced and maintained by an injection and subsequent infusion of pentetrazole. Out of 6 dogs, receiving 4-5 i.v. injections of 0.25-0.5 mg/kg diazepam, 2 showed the phenomenon of acute tolerance, i.e. the effect of the drug on the spiking activity in the EEG became less from one injection to the next, and thus paralleled a situation which may be observed during treatment of clinical status epilepticus. No acute tolerance was observed in corresponding experiments with desmethyldiazepam.