Development of tolerance to the anticonvulsant effect of diazepam in dogs

Eur J Pharmacol. 1984 Sep 3;104(1-2):27-38. doi: 10.1016/0014-2999(84)90365-0.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants*
  • Diazepam / pharmacology*
  • Dogs
  • Drug Tolerance
  • Electrocardiography
  • Electroencephalography
  • Female
  • Male
  • Nordazepam / pharmacology
  • Pentylenetetrazole / antagonists & inhibitors
  • Pentylenetetrazole / pharmacology
  • Seizures / physiopathology
  • Time Factors

Substances

  • Anticonvulsants
  • Nordazepam
  • Diazepam
  • Pentylenetetrazole