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Behavioral Pharmacotheraphy.part 2.Anxiolytics and Mood Stabilizers

Behavioral Pharmacotheraphy.part 2.Anxiolytics and Mood Stabilizers

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Vol.18, No. 11November 1996Continuing Education Article
V
FOCAL POINTKEY FACTS
#
Anxiolytics and mood stabilizersthat are commonly used inhuman psychiatry may be usefulin veterinary behavioral medicine.
BehavioralPharmacotherapy.Part II. Anxiolytics andMood Stabilizers
*
The Veterinary Behavior ClinicMoore Regional HospitalSouthern Pines, North CarolinaPinehurst, North Carolina
Barbara S. Simpson, PhD, DVMDale M. Simpson, MD, PhD
M
any drugs that have long been used in human psychiatry are beingtested in veterinary behavioral medicine. Part I of this two-part pre-sentation discussed antipsychotic drugs and antidepressants. Most of the drugs described in this presentation (Table I) have not been approved foruse in animals. Their use in companion animals is extralabel.
 Although the human psychiatric literature serves as a useful reference, drugs tested and labeled  for human psychiatric problems may have different effects, side-effect profiles, or tox- icities in companion animals.
ANXIOLYTICS
Drugs with antianxiety properties include benzodiazepines, azapirones, bar-biturates, and antihistamines. The benzodiazepines have become the standarddrug class of choice for the treatment of anxiety in humans. A specific aza-pirone, buspirone hydrochloride, offers a pharmacologically distinct alternativeto these drugs. The anxiolytic effect of the barbiturates is associated with asignificant degree of cortical depression; the anxiolytic effects of the anti-histamines, although real, appear to be a nonspecific effect associated with thesedating properties of some of these drugs. Only the benzodiazepines and bus-pirone hydrochloride are considered in the sections below. Other drugs that were described in Part I, such as certain tricyclic antidepressants and the atypi-cal antidepressants trazodone hydrochloride and nefazodone hydrochloride,may also be useful in the treatment of some anxiety states.
Benzodiazepines
Benzodiazepines have become synonymous with
anxiolytics,
and the vast
*Part I of this two-part presentation appeared in the October 1996 issue (Vol. 18, No.10) of 
Compendium.
I
Benzodiazepines should bediscontinued gradually.
I
Fatal idiopathic hepatic necrosishas reportedly followed short-term oral administration ofdiazepam to cats.
I
If fear or anxiety is restrainingaggression, an anxiolytic drugwill release the expression ofaggression.
I
Pet owners need to understandthat behavior problems areseldom cured but frequentlyimproved by pharmacologictreatment.
I
Target behaviors are defined andquantified before drug treatmentbegins.
 
majority of pharmacologic treatments for anxiety inhumans involve benzodiazepines.
1
The most commonly used benzodiazepines are diazepam, lorazepam, alpra-zolam, chlorazepate dipotassium, oxazepam, chlor-diazepoxide, and clonazepam. Several others (e.g.,temazepam and flurazepam hydrochloride) are labeledonly as sleeping pills. All benzodiazepines have greatstructural similarity and appear to work throughthesame mechanisms but differ widely with regard topharmacodynamics and pharmacokinetics. With theexception of clonazepam, all commonly used benzodi-azepines are available in generic form and are inexpen-sive. They are extremely safe in overdosage and have alimited number of side effects.
1
Pharmacology and Mode of Action 
Benzodiazepines have been available since chlor-diazepoxide was introduced in 1960.
1
There are now atleast 39 benzodiazepines on the market.
1
These drugsare believed to act by binding to
γ 
-aminobutyric acid(GABA) receptors in the central nervous system, thuspromoting the inhibitory activity of GABA. Theiranxiolytic properties seem to result from GABAergicactivity at the levels of the cerebral cortex and limbicsystem. GABA receptors are widely distributed, so ef-fects at other sites explain the side effects of benzodi-azepines. For example, the sedating effects result fromGABA activity in the reticular activating system, mus-cle-relaxing effects result from GABA effects at the levelof the spinal cord, and anticonvulsant effects are medi-ated by GABA circuits at multiple levels of the centralnervous system.
1
The benzodiazepines are lipid soluble and are thus well absorbed from the gastrointestinal tract and passeasily into the brain. In humans, they reach peak plasma levels from 0.5 to 6 hours, depending on theabsorption rate of each particular drug and othervariables, such as the amount of food in the patient’sstomach. After a single dose of a benzodiazepine, its be-havioral action is reduced primarily by drug distribu-tion. Diazepam, for example, is rapidly absorbed anddistributed following a single oral dose. Even thoughdiazepam has a long elimination half-life, its durationof behavioral action is relatively brief.
2
In human psychopharmacology, these drugs are clas-sified according to whether the elimination half-lives of the parent compound and active metabolites in humansare short (<6 hours), intermediate (6 to 20 hours),orlong (>20 hours).
1
The half-life determines the time re-quired to achieve a steady-state concentration (approxi-mately four half-lives). Until a drug reaches steady state, it is accumulating and the optimal dosage for aparticular patient cannot be determined.
2
Drugs withelimination half-lives greater than 24 hours may be ad-ministered once a day. Drugs with shorter half-livesshould be given more often.The intermediate–half-life benzodiazepines loraz-epam, oxazepam, and temazepam are metabolized by conjugation to inactive glucuronides, sulfates, andacetylated substances. They have no active metabolitesand are often used for elderly patients or those withcompromised hepatic function. Alprazolam, anotherintermediate–half-life benzodiazepine, undergoes ox-idation but has no clinically important metabolites.Only lorazepam and midazolam are reliably absorbedafter intramuscular injection.
2
Long–half-life benzodiazepines include diazepam,chlordiazepoxide, clorazepate dipotassium, and clon-azepam. All are biotransformed by hepatic oxidativereactions to at least one active metabolite, desmethyl-
Small Animal
The Compendium 
November 1996
GABA
I
ELIMINATION HALF-LIFE
I
DURATION OF BEHAVIORAL ACTION
TABLE IAnxiolytics and Mood Stabilizers Used in Veterinary Behavioral Medicine
Potential Applications Indications inin VeterinarDrug ClassExamplesHuman PsychiatryBehavioral Medicin
 Anxiolytics
BenzodiazepinesDiazepam, clorazepateAnxiety disordersAnxiety disorders, urinealprazolammarking by cats AzapironesBuspirone hydrochlorideAnxiety disordersAnxiety disorders, urinemarking by cats
Mood stabilizers
Lithium, carbamazepine,Bipolar disorders, seizureAggressive behaviorsvalproic acid
 
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.
3
Empirically, the duration of action of benzodiaz-epines in small animals, especially dogs, appears shorterthan that in humans.
4
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
®
—Abbott Laboratories).
4
Side Effects 
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.
2
Chlor-diazepoxide administration, however, greatly facilitatesoperant conditioning of nervous pointer dogs.
5
Use of abenzodiazepine may therefore reduce the effectivenessof a behavior-modification program for some patients
6
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.
7
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.
7
In cats, there are reports of fatal idiopathic hepaticnecrosis in response to short-term oral administrationof benzodiazepines, especially diazepam.
8,9
This rarephenomenon has been confirmed to be a result of oralgeneric diazepam and at least four proprietary formula-tions.
9
 Although questions about the dosage given toaffected cats and about their underlying medical statushave been raised,
10
the phenomenon does not appear tobe dose related and has occurred in cats with normalpretreatment hepatic enzyme assays.
8,9
There have beenspeculations that some cats produce toxic metabolitesfrom diazepam, possibly related to species-specific dif-ferences in hepatic metabolism.
Applications 
 All benzodiazepines are more effective than placebosfor the short-term treatment of generalized anxiety dis-order in human patients.
7
Trials comparing variousbenzodiazepines have failed to demonstrate consistentdifferences in efficacy among drugs of this class.
7
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.
3
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.
11
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.
11
Numerous reviews have suggested the ben-zodiazepines to be effective at reducing the intensity of fearfulness and its associated anxiety in dogs,
6,12,13
al-though few studies have tested these effects.
14
Voithrecommends diazepam (0.55 to 2.2 mg/kg orally) forthunderstorm anxiety in dogs.
6
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.
15
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.
15
Chlordiazepoxide reportedly has “taming” effectson wild cats and other zoo animals.
11,16,17
Marderreported improvement with diazepam treatment in a1-year-old dog exhibiting unpredictable aggressiontoward its owners as well as flank-chewing behavior.
12
Review articles generally indicate that benzodiazepinecan be used effectively to reduce fear-induced aggressive
The Compendium 
November 1996Small Animal
SEDATION
I
WITHDRAWAL SEIZURES
I
AMNESIA
I
FEAR

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