Chronic administration of and dependence on halazepam, diazepam, and nordiazepam in the dog.
Halazepam administered chronically to dogs in oral doses of 180 and 450 mg/kg/day produced physical dependence which was revealed by a flumazenil precipitated abstinence syndrome and measured by the Nordiazepam Precipitated Abstinence Scale score (NPAS) (McNicholas et al., 1988; Sloan et al., 1990). This abstinence as measured by the NPAS score was more severe in diazepam- and halazepam-dependent than in nordiazepam-dependent dogs whereas the incidence of precipitated clonic seizures was greater in the diazepam- and nordiazepam-dependent than in the halazepam-dependent dogs. Pharmacokinetic studies showed that in the dog the major conversion of halazepam, like diazepam, was to nordiazepam and an oxazepam conjugate. Appreciable quantities of oxazepam, 3-OH halazepam and its conjugated metabolite were also identified in plasma. The NPAS score obtained in the halazepam-dependent dogs, however, was greater than the NPAS score obtained in nordiazepam-dependent dogs who had nordiazepam plasma levels over three times higher than those obtained in the halazepam-dependent dogs. Further, the precipitated abstinence observed in the halazepam-, diazepam- and nordiazepam-dependent dogs differed in qualitative as well as in quantitative aspects including marked differences in the time course of abstinence signs. These data argue that the different dependencies produced by halazepam, diazepam and nordiazepam are not due solely to either the parent compound or to a single metabolite but most likely to their combined effects.
Department of Anesthesiology, University of Kentucky, College of Medicine, Lexington 40536.
J W
JW
Sloan
W R
WR
Martin
E
E
Wala
K M
KM
Dickey
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics / Q000633:toxicity; D001569:Benzodiazepines; D001570:Benzodiazepinones / Q000493:pharmacokinetics / Q000633:toxicity; D001921:Brain / Q000378:metabolism; D003975:Diazepam / Q000493:pharmacokinetics / Q000633:toxicity; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D009460:Neurologic Examination; D003708:Nordazepam / Q000493:pharmacokinetics / Q000633:toxicity; D013375:Substance Withdrawal Syndrome / Q000097:blood / Q000209:etiology; D019966:Substance-Related Disorders / Q000097:blood / Q000523:psychology*
D014151:Anti-Anxiety Agents; D001570:Benzodiazepinones; D001569:Benzodiazepines; C010175:halazepam; D005442:Flumazenil; D003708:Nordazepam; D003975:Diazepam