diazepam (nordiazepam). Clorazepate dipotassium re-quires biotransformation to an active form in the gas-trointestinal tract. The fastest absorption occurs in anacid environment, thus clorazepate dipotassium is mosteffective when administered on an empty stomach andmay be poorly absorbed in states of high gastric pH.
Empirically, the duration of action of benzodiaz-epines in small animals, especially dogs, appears shorterthan that in humans.
Thus, the timetable for elimina-tion half-lives of benzodiazepines in humans cannot re-liably be applied to other species. Other characteristicsof the pharmacokinetics appear to differ between hu-mans and dogs. For example, in humans but not indogs, clorazepate dipotassium sustained delivery (Tranxene SD
—Abbott Laboratories) produces pro-longed serum concentrations compared with the regu-lar formulation (Tranxene
Benzodiazepines have few side effects beyond the pre-viously mentioned sedation, cortical depression, andmuscle relaxation. They produce little respiratory de-pression even in overdoses, although they can potenti-ate the respiratory depression produced by other seda-tive hypnotics, such as the barbiturates. They have littleeffect on the cardiovascular system and apparently raiseseizure threshold, although benzodiazepine withdrawalcan be associated with seizures.In humans, intravenous use produces amnesia. Oraldosing, particularly of the rapidly absorbed lipid-solu-ble benzodiazepines, may also produce amnesia andinterferes with learning conditioned responses.
Chlor-diazepoxide administration, however, greatly facilitatesoperant conditioning of nervous pointer dogs.
Use of abenzodiazepine may therefore reduce the effectivenessof a behavior-modification program for some patients
but may facilitate associative learning by extremely anx-ious patients.Partial tolerance to all the aforementioned side effectsmay develop over time. In general, tolerance developsto the nonspecific sedative effects of a benzodiazepineduring long-term therapy, but tolerance to its anxiolyticeffects is less common.
Gradual withdrawal is recom-mended after long-term use of benzodiazepines in hu-mans and animals to avoid the discontinuation syn-drome. In one regimen for withdrawal, the daily dose isreduced by 25% per week.
In cats, there are reports of fatal idiopathic hepaticnecrosis in response to short-term oral administrationof benzodiazepines, especially diazepam.
This rarephenomenon has been confirmed to be a result of oralgeneric diazepam and at least four proprietary formula-tions.
Although questions about the dosage given toaffected cats and about their underlying medical statushave been raised,
the phenomenon does not appear tobe dose related and has occurred in cats with normalpretreatment hepatic enzyme assays.
There have beenspeculations that some cats produce toxic metabolitesfrom diazepam, possibly related to species-specific dif-ferences in hepatic metabolism.
All benzodiazepines are more effective than placebosfor the short-term treatment of generalized anxiety dis-order in human patients.
Trials comparing variousbenzodiazepines have failed to demonstrate consistentdifferences in efficacy among drugs of this class.
Sever-al benzodiazepines have other applications. Alprazolamis labeled for the treatment of panic disorder. Clon-azepam is labeled for treatment of epilepsy and is alsoused in the treatment of panic disorder. Flurazepam hy-drochloride and temazepam are marketed for insom-nia—likely more a marketing decision than a reflectionof unique pharmacologic profile. Because they are bio-transformed by conjugation, not oxidation, and havenonactive metabolites, lorazepam and oxazepam areused with success for agitated patients with compro-mised hepatic function.
Despite the widespread use of benzodiazepines inveterinary practice, there is a shortage of scientific datafor rational guidance of their use in animals. Hartevaluated the effect of diazepam (0.7 mg/kg orally)compared with other drugs and placebo in dogs.
Sev-en of 10 treated dogs (compared with controls) mildly increased behavioral measures of excitability and de-creased fearful responses. Chlordiazepoxide (1 mg/kgorally) given to a few dogs showed little effect on thesemeasures.
Numerous reviews have suggested the ben-zodiazepines to be effective at reducing the intensity of fearfulness and its associated anxiety in dogs,
al-though few studies have tested these effects.
Voithrecommends diazepam (0.55 to 2.2 mg/kg orally) forthunderstorm anxiety in dogs.
Beaver recommendschlordiazepoxide (0.5 to 5.0 mg orally) or diazepam(0.5 to 2.0 mg orally) for situations involving “frustra-tion” or social anxiety in cats.
The effects of benzodiazepines on aggressive behav-iors in animals are variable, possibly reflecting that dif-ferent brain centers mediate different types of aggres-sion.
Chlordiazepoxide reportedly has “taming” effectson wild cats and other zoo animals.
Marderreported improvement with diazepam treatment in a1-year-old dog exhibiting unpredictable aggressiontoward its owners as well as flank-chewing behavior.
Review articles generally indicate that benzodiazepinecan be used effectively to reduce fear-induced aggressive
November 1996Small Animal