Clorazepate in dogs: tolerance to the anticonvulsant effect and signs of physical dependence.
Dogs were treated with clorazepate, which is known to be completely metabolized to desmethyldiazepam. 2 mg/kg t.i.d. were given orally for 5-6 weeks, a dose regimen providing plasma concentrations of desmethyldiazepam in the range known to be therapeutic in man. The rate of development of tolerance to the anticonvulsant effect was followed by weekly determinations of the convulsive threshold for pentetrazole before, during and after cessation of treatment. The development of tolerance was not as clear and pronounced as that found after treatment with diazepam and clonazepam in earlier studies with dogs. The seizure threshold was elevated by a factor of 1.2-3.5 during the first 2 weeks of treatment; during the following weeks, tolerance developed in only 2 out of 6 dogs (decline of the pentetrazole threshold in spite of rising or unchanged plasma concentrations). 36 h after withdrawal of clorazepate, the convulsive threshold had fallen below the control values in all dogs, but 1 week later it had returned to the control level. One day after cessation of treatment, 2 out of 6 dogs showed withdrawal seizures, which, in 1 case, were lethal. This shows that severe withdrawal symptoms, even lethal seizures, may appear after abrupt discontinuation of chronic clorazepate treatment, in spite of the relatively low tolerance liability of clorazepate.
Scherkl
R
R
Department of Pharmacology and Toxicology, School of Veterinary Medicine, Free University of Berlin, Germany.
Kurudi
D
D
Frey
H H
HH
D000818:Animals; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D003009:Clorazepate Dipotassium; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D008297:Male; D010433:Pentylenetetrazole; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D019966:Substance-Related Disorders
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D003009:Clorazepate Dipotassium; D010433:Pentylenetetrazole