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Animal Behaviour - Psychopharmacological Agents Used in Practice

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Drug therapy in animal behaviour is advocated when behavioural responses are extreme, deeply ingrained, or occur at very low thresholds, making behavioural therapy difficult to initiate. It is also used when there's a strong organic basis (e.g. neurological disorders) or when rapid improvement is necessary to maintain client motivation and compliance.

When would drug therapy be advocated?

Behavioural response extreme and well established

Difficult to start any form of behavioural therapy due to response at a low threshold

Strong ‘organic’ component (eg. neuro pathologies)

Rapid changes are needed for client compliance/motivation

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Key Terms

Term
Definition

When would drug therapy be advocated?

Behavioural response extreme and well established

Difficult to start any form of behavioural therapy due to response at a low threshold

What 3 things should be considered when thinking about drug use?

Possible side effects/costs/risk of misuse v pros.

Owner aware that drugs are an adjunct not alternative?

Non-specific action of drugs ...

Why is off-label drug usage common with behavioural drugs?

Few licensed in the species we need them for.

ensure sufficient quality scientific evidence to support use

ensure owner has given infor...

What are the six main NTs behavioural drugs will work on?

Ach (Achetylcholine)

DA (Dopamine)

NA (Noradrenaline)

GABA (Gama-aminobutyric acid)

5-HT (Serotonin)

Melatonin

List the 8 classes of anxiolytic drug

Benzodiazepenes

B Blockers

Azapirones

Barbituates

Antihistamines

Tri-Cyclic Antidepressants (TCAs)

Selective se...

List the anxiolytic medications useful for SHORT TERM use.

Benzodiazepenes (Diazepam, Alprazolam)

- B Blockers (Propanolol)

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TermDefinition

When would drug therapy be advocated?

Behavioural response extreme and well established

Difficult to start any form of behavioural therapy due to response at a low threshold

Strong ‘organic’ component (eg. neuro pathologies)

Rapid changes are needed for client compliance/motivation

What 3 things should be considered when thinking about drug use?

Possible side effects/costs/risk of misuse v pros.

Owner aware that drugs are an adjunct not alternative?

Non-specific action of drugs -> Disinhibitoin risk?

Why is off-label drug usage common with behavioural drugs?

Few licensed in the species we need them for.

ensure sufficient quality scientific evidence to support use

ensure owner has given informed written consent

use in accordance with published guidelines

What are the six main NTs behavioural drugs will work on?

Ach (Achetylcholine)

DA (Dopamine)

NA (Noradrenaline)

GABA (Gama-aminobutyric acid)

5-HT (Serotonin)

Melatonin

List the 8 classes of anxiolytic drug

Benzodiazepenes

B Blockers

Azapirones

Barbituates

Antihistamines

Tri-Cyclic Antidepressants (TCAs)

Selective serotonin reuptake inhibitors

Monoamine oxidase inhibitors

List the anxiolytic medications useful for SHORT TERM use.

Benzodiazepenes (Diazepam, Alprazolam)

- B Blockers (Propanolol)

List the anxiolytic medications useful for LONG TERM use.

Azapirones (Buspirone)

TCAs (Amytriptaline, clomipramine (Clomicalm), Imipramine, Doxepin, Desiprsamine, Nortriptyline

SSRIs (Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (Zoloft), Citalopram, Fluvoxamine)

MAO inhibitors (Selegiline, MAO-B inhibitor)

What is another name for Diazepam? What is it commonly used for?

Valium

Seizure medication in dogs and cats

What is the main effect of the benzodiazepines?

Facilitate the INHIBITORY effect of GABA in the CNS -> dampen excitation in the brain

Why are benzodiazepines well formulated to affect the CNS? What repercussions does this have?

They are highly lipophilic.

Pharmacokinetics/dynamics affected depending on obesity level of dog

- fat dog -> absorption and slow release

- skinny dog -> rapid ^conc and then vconc

What side effects are associated with benzodiazepines and how soon is their onset?

Very quick onset

sedation

ataxia

mm relaxation

^apetite esp in cats

paradoxical excitement in 10-20% cases

memory deficits

hepatic necrosis in cats (rare)

Why are benzodiazepines not good to give in conduction with behaviour therapy?

Block consolidation of memory so will not learn new things

How might these effects change with time?

Tolerance to sedation and ataxia after a few days

How can these side effects be predicted?

Give test doses to evaluate reaction

What are benzodiazepines useful for in behavioural medicine?

Anxiolytic

Amnesic if given ~1 hour before event

What are the potential problems associated with benzo use?

Disinhibition of aggression

Interference with learning

Risk of fatal liver failure in cats

Human abuse potential

Addictive properties/dependence

Teratogenic properties

Drug interactions

How should benzos be stopped?

Gradually

- suddenly stopping -> recurrence, extreme nervousness, seizures

What is the half life of diazepam in dogs?

Hours (v short)

What is the greatest risk associated with the use of diazepam in cats? Other risks?

Hepatic necrosis

Reduced depth perception (do not let outside!)

Apetite stimulant

What is the efficacy of diazepam like?

Varied - dose adjusted to effect

Sometimes dose required causes unacceptable level of ataxia

How does alprazolam compare to diazepam?

Higher potency

Better retrograde amnesia (NB: no anxiolytic effect until given obviously)

Longer half life - 12 hrs, peak levels in 1-2hrs

Increased friendliness in cats (but still loss of depth perception and ataxia)

How do B-blockers work?

Selective blocking of b1 and/or b2 adrenergic receptors in myocardium, bronchi and vascular smooth muscle

Reduced sympathetic response in a fearful situation -> v feeling of anxiety feedback loop

Possibly also central activity

When would B-Blockers be useful in a behavioural therapy programme?

When animal is too hyper-reactive to even begin training.

Only mild anxiolytics but no cognitive impairment

What are the potential side effects of B-blockers?

Bradicardia

Hypotension

Lethargy

Depression

Hypoglycaemia

Bronchoconstriction

Syncope

Diarrhoea

What is syncope?

Fainting

Where are B-blockers contra-indicated?

Hypotension

Heart failure

Bronchospastic disease

Bradycardia

What type of drug is Propanolol?

Non-selective B-blocker (b1+b2)

| Metabolised in liver

What is the half life of propanolol in dogs?

0.77-2hours

What four mechanisms of actions do azapirones have?

Serotonergic, noradrenergic, dopaminergic and cholinergic

| "Dirty"

What is the only azapirone used in behavioural therapy?

Buspirone

What is buspirone's main mechanism of action?

Partial 5-HT1a agonist at PRE and POST synaptic receptors.

| Mixed ag/ant properties on DA receptors

How is buspirone excreted?

Inactive metabolite in the urine

Why will buspirone have varying effects in individual animals?

As it acts on PRE and POST synaptic receptors, effects will depend on number of receptors in individual animal.

if more PRE synaptic receptors to be affected, will DEcrease activity

if more POST synaptic receptors to be affected, will INcrease activity

How and why do effects of buspirone differ in the short and long term?

Short term: ^ likelihood of 5-HT impulses

| Long term: Downregulation of post synaptic receptors -> v likelihood of 5-HT impulses

How commonly is buspirone used?

RARELY

some success reported in feline spraying but high relapse rate, no placebo controlled trials

poor efficacy in specific fears

How quickly does Buspirone act?

Slow onset of action (1-3 weeks)

| Short half life - BID/TID

What are the side effects of buspirone?

GI disturbance, irritability, ^aggression, paradoxical excitability, humans - headaches, dizziness, insomnia, bradycardia, cramps, stereotypic behaviours

What makes buspirone a good choice of drug? (despite not commonly used)

Wide safety margin

No sedative/hypotic effect

No withdrawal phenomenon

No abuse potential

Give examples of TCAs

Amitryptaline

Clomipramine (licensed for dogs)

Imipramine

Doxepin

Desipresamine

Noritryptaline

How do TCAs work?

Block reuptake of 5HT and NA (different compounds block each to a different degree)

Most have active metabolites

Which behaviour problems are TCAs advocated for?

Wide variety - compulsive disorders, separation anxiety, urine marking

How long does it take for TCAs to reach therapeutic levels?

Long time - 2-4 weeks

What are the side effects of TCAs and when do they begin?

RAPID ONSET (despite therapeutic action slow onset)

mild transient sedation

Anticholinergic effects (urinary retention, constipation, dry mouth)

Antihistiminic effects - Hypotension, motor incoordination, cardiac conduction disturbance (in healthy animals this is not pathological), agranulocytosis (rare)

When may the antihistaminic effects of TCAs be useful? Which TCA is particularly antihistaminic?

Itching/scratching based problems

Cystitus

amytriptaline good

Which two drugs should NEVER be given together?

Clomipramine and Selegeline

inexact with MAObs -> SEROTONIN SYNDROME

hyperthermia, rigidity, myoclonus, confusion, delerium, coma - fatal

What conditions are TCAs contraindicated for?

Heart disease

Hypertension

Hypothyroidism

Epilepsy (lowers seizure threshold)

Concurrent use with MAOBs

Other potential problems

- bitter taste

- potential for human misuse

- OD fatal with no antidote

When is amitryptaline usually used?

Greater NA and H1/2 effects required

FLUTD (although beware urine retention due to Anticholinergic side effects)

Pyschogenic alopenia

ALD in dogs

What is the most common use of Clomipramine?

Clomicalm - licensed for separation anxiety in dogs

multi centre, palcebo controlled, blinded trial

Main effect 5HT

used in cats off label but tolerated less well than dogs, side effects worse and more variable

Give examples of` SSRIs

Fluoxetine (Prozac)

Paroxetine (Paxil)

Sertraline (Zoloft)

Citaloproam

Fluvoxamine (also NA effects -> anxiety)

What are SSRIs most commonly used for?

Fear responses - sudden, immediate and unconsidered, sometimes anxiety

sometimes compulsive disorders

Which response is NA responsible for?

Panic/stress

What is serotonins role?

Anti depressive, antianxiety

What is the time until therapeutic onset of SSRIs?

Long - 3/4 weeks

What may occur with short term SSRI use?

^anxiety due to v 5HT (negative feedback of serotinergic auto receptors)

with longterm use v anxiety due to receptor (up?) regulation and ^ [5HT]

How may the initial antigenic properties of SSRIs be combatted?

Short course benzodiazepenes

Where other than the CNS are serotinergic pathways found? How does this impact side effects?

The gut

-GI irritability

(can be reduced by gradual increase of dose)

What other side effects of SSRIs?

Insomnia, sedation, potential for human misuse

Which SSRI is licensed for separation anxiety?

Fluoxetine "Reconcile" (USA)

long half life active metabolite

rapid onset side effects

GI irritation, inappetance , lethargy, nervousness

What kind of molecule are all NTs?

Monoamines

How do MAO inhibitors work?

Prevent mono amine oxidase working to break down generalised NTs in synaptic clefts -> ^[NT]

NTs include NA, Adrenaline, DA, 5HT, tyramine

What are the 2 different forms of MAO inhibitors?

MAO a - inhibtis all monoamines, has dietary requirements - no tyramine containing foods (not used in dogs therefore)

MAO b - inhibits all monoamines except 5HT, NO dietary requirements

Give an example of a MAOb inhibitor. Is it licensed?

Selegeline

licensed in Europe (disorders of emotional origin) and USA(cognitive dysfunction=alzheimers)- different purposes

some evidence of neuroprotective effect

What should Selegeline never be given in conjunction with?

SSRIs, TCAs or St Johns Wort- Serotonin syndrome can be fatal

Remember long half life (20d!)

Give 4 antipsychotics/neuroleptics (=tranquillisers/anti-scizophrenics)

ACP (acepromazine)

Chlorpromazine

Haloperidol (parrots feather plucking, lots of side effects)

Risperidone

How do antipsychotics work?

Block DA receptors (and newer compounds may also have 5HT antag)

Are antipyschotics used regularly in animals?

No because of side effects

| Although still used a bit in Europe

What are the side effects of antipsychotics?

^PRL (-> milk production)

Seizures

Sedatino and anticholinergic effects

Extra-pyramidal symptoms eg. muscle tremor (due to blocking of DA receptors in basal nuclei, controlling motor function) - seen more in high potency neuroleptics eg. haloperidol

Give some examples of low potency antipsychotics

Chlorpromazine, acepromazine

| - low specificity, hence many side effects

Give some examples of high potency antipsychotics

Haloperidol, azaperone (eg. Suicalm, give to pigs before mixing)

more specific

less sedation but greater risk of extra-pyramidal effects

Give some examples of atypical neuroleptics/antipsychotics

Clozapine, ripseridone

| - newer, potentially better, less side effects

Is ACP recommended for tranquillising anxious animals?

NO - provides motor sedation but no anxiolytic effect

Give some examples of anticonvulsants

RARELY USED (Antiepileptics)

Phenobarbitone (Epiphen)

Phenytoin (Epanutin)

Primidone (Mysolene)

Carbamazepine (Tegretol)

When may carbamazepine be used?

Peripheral sensory neuropathy/ectopic firing

eg. Burmese cats with facial pain where scratching -> neuralgia

erratic absorption so best administered with food

What types of partial seizures are possible?

Anywhere in the brain eg. visual (fly snapping)

Motor/central brain (absent seizure)

Amygdala/limbic system (sudden emotional response/jump up)

Which drug is advocated for use with motor partial seizures? What must be wary of?

Phenobarbitone

(used to be used more widely but effect due to sedation only)

regular blood monitoring to check hepatotoxicity

What is the action of Phenytoin?

Reduces spread of focal seizures

| - used extensively in humans

How does the pharmacokinetics of phenytoin differ in cats and dogs?

Dogs - metabolised very rapidly, high and frequent dosing needed

Cats - metabolised slowly, problems with toxicity

What is the effect of progestagens?

Anti-testosterone, secondary sedative effect - non-specific

Are progestagens advocated? What are the side effects?

NO

common and severe side effects

- ^apetetie, weight gain

- hyperglyceamia

- diabetes

- lethargy

- poor cognitive function

- mammry hyperplasia

- adencarcinoma (mammary)

- endometrial hyperplasia

- pyometra

- aspermatogensis

- adrenocroticol supression

- bone marrow suppression

-retinal detachment

Are progestagens licensed?

Yes unfortunately

dogs

also advocated for use in cats

sometimes used to test for effect of castration

beware secondary sedative effect which may mean castration doesnt have same impact

testosterone driven tumours may shrink with progestagen use - if this proves true then castration will hope treat tumour

Give 4 treatments of age related changes

selegeline

A antag

Xanthine derivative

Dietary intervention

Give a common drug combination

Benzodiazepenes and TCAs to manage acute episodes in dogs

What does polypharmacy increase the risk of?

Side effects and problems with long term use

What should be carried out throughout pharmacological treatment?

Blood monitoring (prior to starting medication swell to check for normal levels)

Can off label drugs be used?

Yes providing informed consent is given