Download Anticonvulsants. Sedatives. Behaviour

Anticonvulsants, Sedatives and
Behavior-modifying drugs
Assoc. Prof. Ivan Lambev: www.medpharm-sofia.eu
I. Anticonvulsants
(Antiepileptic or Antiseizure Drugs)
EPILEPSY
is due to sudden, excessive depolarization of
some or all cerebral neurons. This may be:
●localized (focal or partial) seizure
●spread to cause a secondary generalized seizure
●affect all cortical neurons simultaneously
(primary generalized seizure).
Estimates of lifetime seizure frequency vary
from 0.5% to 5.7% in dogs and 0.5% to 1.0%
in cats.
Although many different types of seizures occur
in dogs and cats, a universally accepted
classification system has not been established.
The most frequently recognized seizure type
is the generalized seizure.
Anticonvulsant drugs are evaluated primarily
on their efficacy in the control of such seizures.
Generalized seizure
Partial seizures are also called focal seizures
(the electrical storm is affecting only a part of the brain).
A partial seizure may stay localized or it may expand
to the whole brain and cause a tonic-clonic seizure.
Because the seizure starts in only a part of the brain,
an underlying disease or injury is highly suspected.
Cluster seizures are more than one
seizure within a 24-h period.
Status epilepticus is a continuous seizure,
or two or more discrete seizures between
which there is incomplete recovery of
consciousness, lasting at least 5 min.
True epilepsy originates from a
nonprogressive intracranial disorder.
Symptomatic epilepsy is caused by
progressive intracranial disease.
Disorders that induce seizures may arise either outside
the nervous system (extracranial) or within the nervous
system (intracranial). Extracranial causes may be
subdivided into those that originate outside the body
(e.g. toxic agents – lead, organophosphates) and
those that originate within the body but outside the
nervous system (e.g. hypoglycemia, liver disease).
Intracranial causes of seizures are divided into
progressive and nonprogressive diseases.
Progressive diseases include inflammation (e.g.
granulomatous meningoencephalitis), neoplasia, nutritional problems, (e.g. thiamine deficiency), infection
(e.g. feline infectious peritonitis, cryptococcosis,
distemper), anomalous disorders (e.g. hydrocephalus,
intra-arachnoid cyst), trauma and vascular diseases.
Nonprogressive diseases include true epilepsy, such
as inherited, acquired or idiopathic epilepsy.
Inherited epilepsy is caused by a genetically
determined intracranial disorder.
Acquired epilepsy is caused by a previously active
intracranial disorder, which is no longer active.
Idiopathic epilepsy is where the cause and
mechanism for the seizures are unknown.
Therapy for symptomatic epilepsy
requires not only control of seizures but also
specific therapy for the underlying disease.
Therapy is most effective when the underlying
disease is diagnosed in a timely manner, before
anticonvulsant therapy is initiated. ADRs may
limit the usefulness of an anticonvulsants;
therefore, it is essential to study the mechanisms
of action and drug interactions in the species in
which the drug is to be used.
Immediate, short-term (acute) anticonvulsant
therapy is required to treat status epilepticus,
cluster seizures and seizures resulting from
some toxicities.
Chronic anticonvulsant therapy is used in the
management of epilepsy, where seizures are
longer than 3 minutes’ duration, are cluster
seizures or occur more frequently than once
every 4–6 weeks. Anticonvulsants are most
effective when started early in the course of
a seizure disorder.
Anticonvulsant drugs are contraindicated in
animals with extracranial causes of seizures,
except these with portosystemic shunts and in
animals with toxicities. Animals with seizures from
a progressive intracranial disease may require
additional therapy to treat the underlying disease
(e.g. neoplasia or inflammation).
Successful anticonvulsant therapy depends on the
maintenance of plasma concentrations of drugs
within a therapeutic range. The elimination half-life
of drugs varies considerably between species.
MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS
Antiepileptics inhibit the neuronal discharge or
its spread in one or more of the following ways:
(1) Enhancing GABA synaptic transmission
(2) Reducing cell membrane permeability to
voltage-dependent sodium channels
(3) Reducing cell membrane permeability
to calcium T-channels
GABA
•Barbiturates
•Bromides
•Benzodiazepines
•Valproates
(Depakine Chrono®)
•Gabapentin
•Levetiracetam
•Topiramate
Na+
•Carboxamides
(Carbamazepine)
•Valproates
•Hydantoins
(Phenytoin)
•Lamotrigine
•Topiramate
Antiseizure drugs, induced reduction of
current through T-type Ca2+ channels.
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
Few of the antiseisure drugs, used for the
treatment of epilepsy in people, are suitable
for use in animals. This is due to differences
in the pharmacokinetics of drugs in animals.
Phenobarbital and bromide are
appropriate for
management of chronic
seizure disorders
of cats and dogs.
Few of the antiseisure drugs, used for the treatment
of epilepsy in people, are suitable for use in dogs
and cats. This is largely due to differences in the
pharmacokinetics of drugs in animals. Pharmacokinetic data for, and/or clinical experience with,
many anticonvulsant drugs are lacking in cats.
Phenobarbital and bromide are considered
the anticonvulsant drugs most appropriate
for management of chronic seizure disorders
of cats and dogs.
BARBITURATES (enzyme inducers)
Phenobarbital (phenobarbitone),
methylphenobarbital and primidone (it is
metabolized to phenobarbital) are still used
for generalized seizures but sedation is usual.
Primidone and its
active metabolites
Basic & Clinical
Pharmacology –
10th Ed. (2007)
Cl−
Hyperpolarization
Phenobarbital is available as oral (tablets
or elixir) or injectable preparation (i.v./i.m.).
• For the chronic treatment of seizures in
dogs dosing should begin at
2–5 mg/kg/12 h orally.
Cats: 1.5–2.5 mg/kg/12 h orally.
In some dogs or cats, the starting dosage
may result in ADRs. Should these adverse effects
not resolve after 2 weeks of therapy, a reduction in
dose may be indicated.
Steady-state serum phenobarbital concentrations
should be determined after 3 weeks of therapy. If a
patient’s seizures are adequately controlled, then
serum concentrations may be determined again
after 3–6 months. If a patient’s seizures are not
adequately controlled after 3 weeks of therapy, the
dose of phenobarbital may be increased by 25%
and serum concentrations should be determined
again after 3 weeks of therapy at this higher dose.
Dogs are refractory to phenobarbital therapy when
seizure activity or unacceptable effects persist
when plasma concentrations reach 35 µg/mL.
In dogs, phenobarbital elimination half-life
decreases when administered chronically
(47.3 h when administered for 90 days versus
88.7 h). It increases its own rate metabolism
(autoinduction). Therefore the drug concentration
of phenobarbital is expected to decrease in
animals receiving chronic therapy after 3–6
months of therapy. In contrast, in cats,
repeated phenobarbital administration does not
alter serum steady-state concenation.
• Reductions in dosage should be made gradually
as physical dependence may develop and
withdrawal seizures may occur as serum levels
decline. Therapy should not be discontinued
abruptly, except in animals that develop fulminant
liver dysfunction. Phenobarbital should be avoided
in animals with hepatic dysfunction.
• Phenobarbital may be administered IV for the
treatment of toxic seizures or status epilepticus;
however, a lag time of 20 min may be observed
prior to maximal effect.
Bromides have been used as a sole therapy,
particularly in dogs with hepatic dysfunction
or in patients with mild seizures. Bromides is
best suited for noncompliant owners because of
its long half-life (> 2 weeks).
Bromides is not recommended in cats.
The elimination of bromide in cats is
faster than in dogs.
Bromide does not affect hepatic enzymes.
Bromide toxicity appear to be dose
dependent and include polyphagia, vomiting,
anorexia, constipation, pruritus, muscle pain,
sedation and pelvic limb weakness.
● Asthma (may be fatal) is associated with bromide
administration in cats.
● Ataxia and sedation are the major dose-limiting
adverse effects in dogs.
● High-dose bromide therapy has been associated
with thyroid dysfunction in humans and rats.
Hydantoins: Phenytoin is approved for
control of epileptiform convulsions in dogs.
IV injection of the drug causes a drop
in arterial pressure and is not advised.
Phenytoin is a potent inducer of hepatic
metabolizing enzymes affecting itself and
carbamazepine, warfarin, adrenal and gonadal
steroids, thyroxine, tricyclic antidepressants,
doxycycline, vitamin D, folate. Drugs that inhibit
its metabolism are: valproates, co-trimoxazole,
chloramphenicol, NSAIDs.
Benzodiazepines:
In dogs, the use of diazepam is limited
to treatment of status epilepticus,
because of the rapid
development of
tolerance.
In cats, diazepam is effective
as an acute and chronic anticonvulsant.
Status epilepticus
•An IV bolus of diazepam should initially be given
at a dosage of 0.5–1 mg/kg. Onset of its activity
occurs about 2–3 min after administration. This
dosage may be repeated 2–3 times.
Midazolam. Since it is water soluble,
it is much less
irritating with IV or
IM administration.
Others: Clorazepate and Lorazepam.
Carboxamides (enzyme inducers):
Carbamazepine
Although there are isolated reports of the use of
carbamazepine as an anticonvulsant in dogs,
appropriate studies of its clinical efficacy
in canine or feline seizure control are lacking.
The rapid metabolism in dogs makes it
unsuitable as an anticonvulsant.
Valproates (enzyme inhibitors):
Valproic acid (Depakine Chrono®)
Since it is not possible to attain therapeutic blood
levels even with high-dose therapy or sustainedrelease formulations, valproic acid is of limited
usefulness in dogs. Reports of the clinical use
of valproic acid in cats are lacking. Additional
studies are necessary to evaluate the efficacy
of this drug.
Dicarbamates:
They have dual mechanism of action as a:
• positve modulatar of GABAA receptors
• blocker of NMDA receptors
Felbamate does not cause sedation and
may be added to phenobarbital and/or
bromide without potentiation of the
sedative effect of these drugs.
Analogs of GABA
Gabapentin has the advantage of not undergoing
hepatic metabolism. Although there are anecdotal
reports of gabapentin as an anticonvulsant in
dogs, studies of its clinical efficacy in dogs and
cats are lacking.
Pyrrolidone derivatives
Levetiracetam is used primarily in dogs as an
anticonvulsant. There are no reports on its use
clinically in dogs although there is a clinical trial
underway at North Carolina State University.
II. Sedative drugs in VM
• Typical Neuroleptics
• Benzodiazepines
• α2-adrenergic agonists
• Herbal sedatives
All sedatives depress CNS.
CLINICAL APPLICATIONS
Sedatives may be used to relieve anxiety or to provide
chemical restraint. They facilitate the handling of
patients, allowing thorough examination or positioning
radiography. Sedatives are also used for
preanesthetic medication. Their use renders the
patient more tractable, improves staff safety and helps
the placement of i.v. catheters. There are benefits
for the patient too: By reducing fear and anxiety prior
to induction of anesthesia, the potential for
catecholamine-induced arrhythmias is reduced.
Many sedatives do not possess analgesic activity
and in these cases they should be combined with an
opioids. The sedative and opioid act synergistically to
enhance sedation; thus lower doses are required and
the risk of ADRs is reduced. In addition, the sedative
may counteract some of the undesirable effects of
the opioid, such as vomiting or excitement. Where
high doses of a very potent opioid are combined with
a sedative the degree of CNS depression may be
sufficient to permit minimally invasive surgery.
Such combination is termed neuroleptanesthetics.
NEUROLEPTICS
(Antipsychotics,
(Antischizophrenic
drugs in humans)
 Typical Neuroleptics
(with extrapyramidal motor symptoms as ADRs)
- Phenothiazines
- Butyrophenones
- Thioxanthenes, etc.
Used in VM
 Atypical antipsychotics
(lack of extrapyramidal motor symptoms in rats)
Schizophrenia:
>> DA and >> 5-HT in human brain
•Anxiety
Mood
•Impulse
Cognitive function
•Irritability
Appetite
•Obsessions &
Sex
Compulsions
Aggression
•Memory
Dopamine
Serotonin
(DA)
(5-HT)
•Attention
•Plesure
•Reward
•Motivation
•Motor control
•
•
•
•
•
The effects of DA and 5-HT on the brain functions
Neuroleptics – mechanism of action
The therapeutic potency of the most
neuroleptic drugs (especially
Typical Neuroleptics)
correlates strongly
with their
D2-receptor blocking
activity in CNS.
D1-receptor family:
D2-receptor family:
Distribution and characteristics of DA
receptors in the central nervous system
Goodman & Gilman's The Pharmacologic Basis of Therapeutics – 11th Ed. (2006)
Main effects in humans
(1) CNS. In normal individuals antipsychotics produce
neuroleptic syndrome – indifference to surroundings,
paucity of thought, psychomotor slowing, emotional
quietening, reduction in initiative.
In psychotic patients neuroleptics reduce
irrational behaviour, agitation and aggresiveness.
Hyperactivity, hallucinations, and delusions are
suppressed.
The sedative effect is produced immediately while the
antipsychotic (neuroleptic) effect develops after weeks.
Tolerance develops only to the sedative effect.
The thermoregulatory centre is turned off,
rendering the patient poikilothermic
– cold-blooded
(body temperature falls
if surroundings are cold
and the contrary).
The medullary, respiratory and other vital centres
are not affected, except of very high doses. It is very
difficult to produce coma with neuroleptics.
Antiemetic effect is exerted through the CTZ.
Neuroleptics, except thioridazine, have this effect.
(2) ANS. Neuroleptics have varying degrees of alphaadrenergic blocking activity and produce
hypotension (primarily postural) especially
after parenteral administration.
Anticholinergic property of neuroleptics is weak.
The phenothiazines have weak H1-antihistaminic and
anti-5-HT actions but Promethazine has strong
sedative and H1-antihistaminic action.
(3) Endocrine system. Neuroleptics consistently
increase prolactin release by blocking the inhibitory
action of DA on pituitary gland. This may result
in galactorrhea and gynecomastia. They reduce
gonadotropins, ACTH, GH and ADH secretion.
Typical Neuroleptics
(D2-blockers)
Phenothiazines, used in VM
as sedative drugs
•Acetylpromazine (Acepromazine)
•Chlorpromazine
•Prochlorperazine
(10)
•Promazine
•Promethazine
(2)
Phenothiazines
Type 1 (aliphatic side chain)
Chlorpromazine, Promazine,
Promethazine
Type 2 (piperidine side chain):
Acepromazine
Thioridazine
Type 3 (piperazine side chain)
Prochlorperazine
Trifluoperazine
Clinical applications
Acepromazine is used to facilitate the handling or
restraint of patients and is often employed
as a premedicant prior to general anesthesia.
In low doses it has a general calming effect.
Increasing the dose induces a degree of
sedation, which is more apparent in dogs than cats.
Phenothiazines do not possess analgesic activity and
must be combined with an opioid. The antiemetic
effects of phenothiazines are of benefit in such
combinations. Phenothiazines also can protect the
myocardium against adrenaline-induced fibrillation.
Some phenothiazines, such
as prochlorperazine,
are used principally for their
antiemetic properties.
Others, such as promethazine, are used
primarily for their potent antihistamine
H1-blocking activity.
Phenotiazines are ineffective
in motor sickness as antiemetics.
Dogs and Cats
Chlorpromazine
• Largactil® in France (1952)
• 50–1000 mcg/kg i.v., i.m., s.c.
• 3 mg/kg p.o.
Metabolism
Phenothiazines are metabolized by hepatic
microsomal enzymes. Prolonged duration of action
may be observed in patients with impaired liver
function. Metabolites are excreted primarily in urine.
Adverse Drug Reactions (ADRs)
● Extrapyramidal signs (restlessness, rigidity,
tremor, catalepsy).
● Diminish the seizure threshold.
● Modification of thermoregulatory mechanisms
at the level of the hypothalamus, which may
lead to hypothermia. This effect is compounded
by peripheral vasodilation and is significant in
small patients with large surface area.
Catalepsy
(to take
(strange posture)
● The main cardiovascular adverce effect
of phenothiazines is peripheral vasodilation
and a consequent fall in blood pressure, which
is mediated mainly through α1-adrenergic blockade.
The hypotension is generally well tolerated in
healthy animals. Marked hypotension has also
been described in excessively fearful dogs given
acepromazine.
● Phenothiazines have a spasmolytic (M-cholinolytic) action and will reduce GI motility in the dogs.
Contraindications and precautions
● Hypovolemia, shock and patient with history of
seizures.
Known drug interactions
● The CNS-depressant effects of phenothiazines will
potentiate the CNS-depressant effects of concomitantly
administered drugs (e.g. opioid analgesic).
Phenothiazines are mild cholinesterase inhibitors and
may therefore enhance the action of suxamethonium.
They may potentiate the toxicity of organophosphates.
Butyrophenones in VM
• Fluanisone (with Fentanyl = Hypnorm®)
• Droperidol (with Fentanyl = Innovar-Vet®)
• Azaperone (Stresnil®)
•Haloperidol
The butyrophenones are structurally similar
to GABA. They offer greater potency and
fewer autonomic ADRs in comparison
with phenothizines.
Fluanisone
Droperidol
Clinical applications
Azaperone is used
exclusively in pigs as a
sedative/premedicant
or to reduce fear and
aggression in recently
mixed groups of pigs. It is not recommended for use in
small animals. Fluanisone and droperidol are marketed
in combination with fentanyl. The butyrophenones
are potent antiemetic agents and are particularly
effective in inhibiting opioid-induced vomiting. Similarly
to phenothiazines, butyrophenones provide protection
against adrenaline-induced arrhythmias.
Azaperone
®
(Stresnil )
2 mg/kg IM
Effect lasts 6 h.
4000 mg/100 ml
ADRs of butyrophenones
●Muscle tremors and rigidity (in high doses).
●Excitement reactions after i.v. administration.
●Butyrophenone and fentanyl combinations may cause
salivation and defecation. These effects can be
reduced by anticholinergic premedication.
Contraindications and precautions
●Shock and hypovolemia
●Patients with a history of seizures
●Butyrophenone–fentanyl combinations should also
be avoided in patients with respiratory disease and
renal or hepatic dysfunction.
Known drug interactions
●Butyrophenones potentiate the action of other
CNS-depressant drugs such as general
anesthetics and analgesics.
●Concomitant use of
adrenaline (epinephrine)
is contraindicated.
Benzodiazepines
They are classed primarily as anxiolytic drugs although
high doses may cause sedation and sleep. A wide range
of benzodiazepines are available for use in people.
Benzodiazepines do not induce reliable sedation in
normal healthy animals. Their anxiolytic action may
increase excitement and render patients more difficult to
handle. However, in very young, very old and critically
ill patients benzodiazepines may produce effective
sedation and their relative lack of ADRs is an advantage
in such “high-risk” groups.
Benzodiazepines have also been used to calm
distressed or restless patients in the postoperative
period. Benzodiazepines do not have analgesic activity
and should not be used to compensate for pain control.
Benzodiazepines may be used to induce general
anesthesia in combination with other drugs, typically the
dissociative anesthetics. The anticonvulsant and musclerelaxant properties of the benzodiazepines counteract
some of the less desirable effects of the dissociative
drugs, reducing muscle tone and decreasing the
incidence of seizures.
Benzodiazepines may be used specifically for their
anticonvulsant action and diazepam is a drug of
choice in the treatment of status epilepticus.
The ability to relax skeletal muscles may also have
specific indications such as the treatment of tetanus
and relief of urethral spasm. Benzodiazepines will
stimulate appetite in anorexic cats.
All actions of the benzodiazepines
can be reversed by the specific
benzodiazepine antagonist flumazenil.
Most drugs used in insomnia act as agonists
at the GABAA-receptor and have effects other
than their direct sedating action, incl. muscle
relaxation, memory impairment, and ataxia,
which can impair performance of skills such
as driving. Clearly those drugs with onset
and duration of action confined to the night
period will be most effective in insomnia and
less prone to unwanted effects during the day.
Transmitters: waking state and sleep.
During the sleep dominates GABA.
Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
In animal dominates REM phase of sleep!
In high doses benzodiazepines may cause sedation and sleep.
In contrast to barbiturates which prolong phase NREM-sleep,
benzodiazepines restore normal age ratio between the phases
of sleep, facilitate and shorten the sleep time. Benzodiazepines
have a euhypnotic effect (eu = good).
The most used
BENZODIAZEPINES
in VM
as Sedatives,
and Euhypnotics:
• Bromazepam
• Diazepam
• Midazolam
(t1/2 2 h)
• Triazolam
(t1/2 3 h)
Benzodiazepines in clinical use
enhance the effectiveness of
GABA by increasing the
frequency of the opening of
the chloride ions. They cause
hypopolarization.
A model of the GABAA
receptor-chloride ion
channel macromolecular complex
Basic & Clinical
Pharmacology –
10th Ed. (2007)
Benzodiazepines (BDZs)
Zolpidem, Zopiclone
+
GABAAsite
+
+
Cl+ Barbitu-
rate sate
Ethanol
Adapted from Bennett and Brown,
Clinical Pharmacology – 9th Ed. (2003)
Barbiturates
Clorazepate
Biotransformation of benzodiazepines
Lüllmann, Color Atlas of Pharmacology – 2nd Ed. (2000)
Adverse effects
●Therapeutically doses of benzodiazepines have a
minimal effect on RS and CVS. However, high
doses cause slight reductions in blood pressure.
●Benzodiazepines enhance the depressant effects
of the opioids.
●Fulminant hepatic failure has been reported in cats
treated with repeated oral doses of diazepam.
●Flumazenil (i.v.) is the treatment of choice if
overdose happened.
●Adverse CV, such as arrhythmias, have been
reported following the rapid i.v. injection of diazepam.
●Congenital abnormalities have been reported
in babies born to women given diazepam during
the first trimester of pregnancy (PRC D).
●Dependence and tolerance are features of
long-term benzodiazepine use in people. Physical
signs of withdrawal (nervousness, loss of appetite
and tremor), have also been documented in animals.
Green
Reception
Form
for
Prescribing
of
Benzodiazepines.
Durability: 7 days.
The recipe is stored
in licensed pharmacies
10 years!
Contraindications and precautions
Benzodiazepines should be used with caution in:
● Patients with hepatic encephalopathy, especially
those with portosystemic shunts.
● Patients during early pregnancy
Known drug interactions
● Benzodiazepines potentiate the CNS-depressant
effects of propofol and barbiturates.
Melatonin is the hormone
produced by the pineal gland
during darkness. It is released
mainly at night. The impressive
nature of the diurnal rhythm in
melatonin secretion has stimulated interest in its
use to reset circadian rhythm to prevent jet-lag
on long-haul flights and for blind or partially
sighted people who cannot use daylight to
synchronize their natural rhythm.
Ramelteon (in humans) – analogue of melatonin
Alpha-2-Adrenoceptor agonists as Sedatives
• Xylazine: 3 mg/kg i.m. in dogs and cats
• Detomidine
• Romifidine
• Medetomidine, Dexmedetomidine
Clinical applications
α2-Adrenoceptor agonists may be classed as sedative-hypnotics
with additional muscle-relaxant and analgesic properties.
They are widely used for chemical restraint and premedication
in small and large animals. The level of sedation induced by
α2-agonists is more predictable than that achieved with
phenothiazines or benzodiazepines.
In most countries detomidine is only licensed
for use in the horse. Xylazine, medetomidine and
romifidine are generally licensed for use in cats
and dogs.
Xylazine, medetomidine
and romifidine
Detomidine
The sedative, analgesic and musclerelaxant effects of the α2-agonists
are mediated at central α2-receptors
(prejunctional inhibitory receptors!),
which inhibit noradrenaline exocytosis.
(+)
Detomidine
α2-Adrenoceptors are G protein-coupled receptors
linked to the cAMP second messenger system.
Their activation inhibits adenylate cyclase
and reduces cAMP, opens K+ channels and
reduced Ca2+ .Three different α2-adrenoceptor
subtypes have been identified: α2a, α2b and α2c:
α2a-adrenoceptors mediate sedation,
analgesia and hypotension while the
α2b-adrenoceptors mediate vasoconstriction
and hypertension (i.e. postsynaptic
α2-adrenoceptors are probably of the α2b subtype).
α2-Agonists undergo extensive first-pass
metabolism after oral administration. These agents
have also been administered into the epidural
space to achieve analgesia. In a study conducted
in dogs, epidural administration of 15 µg/kg
Medetomidine produced analgesia for 4–8 h.
α2-Agonists are lipid-soluble drugs that are
therefore widely distributed. Medetomidine is
very lipophilic.
Adverse effects
● Alterations in body temperature, both increased and
decreased, have been reported in animals sedated with
α2-agonists. In small animal patients, centrally
mediated hypothermia appears to be the
predominant finding.
● There are anecdotal reports of dogs responding
unexpectedly, and in some cases aggressively,
to touch, despite appearing heavily sedated.
A similar phenomenon is recognized in the
horse and studies in indicate that α2-agonists
may induce cutaneous hypersensitivity.
● Bradycardia is common and heart rates frequently
fall by 50% or more following administration of
sedative doses. This effect has been attributed to a
central decrease in sympathetic drive and thereby a
predominance of vagal tone, although a baroreceptor
response to hypertension may also contribute.
Bradycardia may also be accompanied by alterations
in rhythm. Sinus arrhythmia, sinoatrial block and
first-, second- and third-degree atrioventricular
blocks occur not infrequently.
● Activation of peripheral postsynaptic α2- and
α1-receptors (α2-agonists are not specific) leads to
vasoconstriction. In contrast, activation of central
and peripheral presynaptic α2-receptors causes
vasodilation through reductions in NA release
and sympathetic outflow. The balance of these
effects influences blood pressure. The vasoconstrictive effects predominate initially, resulting
in a period of hypertension. This is followed by
a more sustained fall in arterial blood pressure
as the central effects become more important.
● Vomiting is a frequent occurrence following i.m.
administration of α2-agonists. It is most
common with xylazine, especially in cats, in which
the incidence may approach 50%. It is mediated
centrally through direct activation of receptors in the
chemoreceptor trigger zone (CTZ).
● Overall, α2-agonists depress gastrointestinal motility
and prolong gut transit times. This parasympatholytic effect has been attributed to reduced release of
ACh from cholinergic nerve terminals innervating the
GI. Reductions in salivary and gastric secretions
may also occur.
Known drug interactions
●α2-Agonists act synergistically with opioids
and inhalation anesthetics.
●Fatalities have been documented in horses
sedated with detomidine that concurrently
received
i.v.
Sulfonamides.
Herbal sedatives
Randomized clinical trials have shown some
effect of valerian in mild to moderate insomnia,
and hops, lavender and some other plants too.
The valerian extract contains valeopotriates,
which possess GABA-mimetic action.
Combined phytoprepartions for oral
applications are:
Benosen®, Dormiplant®, ReDormin®
•Valerian
•Extracts contain
valeoptriates
(GABAA-mimetics)
Genetics…
Humulus lupulus (Hop)
- Strobuli Lupuli
The species is
a main ingredient
of many beers.
Extracts contain
phytoestrogens,
humuleine,
linalool,
tannins.
Leonurus cardiaca (Throw-wort)
- Folia Leonuri
Melissa officinalis (Lemon balm)
- Herba et foliae
Lavandula angustifolia (Lavender)
Avena sativa
(Oat)
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III. Behavior-Modifying
Drugs (BMDs)
Most information on BMDs is derived from
human literature and thus cannot necessarily
be extrapolated directly to other animal species.
Establishing a diagnosis
Before prescribing any drug to modify an
animal’s behavior, it is important that the
veterinarian has made a diagnosis based
on a thorough physical examination and
behavioral history.
Client consent and compliance
As most medications used in veterinary behavioral
therapy are not registered for use in animals, it is
even more important that the rationale for drug use
and potential side effects should be clearly explained
and the owner should give informed consent to the
use of the drug on their pet. A signed consent form
is recommended to ensure that a client has
understood the implications of the treatment program,
possible side effects and likely length of treatment
required (> 2 months).
Pretreatment screening
Blood tests prior to prescribing medication are strongly
recommended. A minimum database should include
a complete blood count, biochemistry and urinalysis.
As most behavior-modifying drugs are metabolized by
the liver and renally excreted. It is important to assess
liver enzymes and renal function prior to starting treatment.
It may be useful in some cases to reassess liver and renal
function approximately 4–6 weeks after starting treatment.
All animals on long-term behavior-modifying medication
should be retested at least every 6–12 months.
Clinical applications of BMDs:
• anxiety-related problems
(incl. fears and phobias)
• obsessive-compulsive behaviors
• some types of aggression
• abnormal sexual behavior
• geriatric behavior problems
(1) H1-blockers from
1st generation
(with sedative and
M-cholinolytic effects)
•Dimetindene
•Diphenhydramine
•Chloropyramine
•Doxepin (TCA)
•Hydroxyzine
(anxiolytic!)
•Promethazine (with
sedative & antiemetic
activity)
•Cyproheptadine
(H1&5-HT2)
In VM H1-blockers
have proved useful for treating
inappropriate urination associated with
anxiety, to reduce anxiety and motion
sickness associated with car travel and
to reduce excessive unexplained nocturnal
activity of cats such as pacing and
vocalization while the owners are at home.
Antihistamines act by competitive inhibition of H1-receptors.
They have mild hypnotic and sedative effects.
Antihistamines may be effective in the management
of pruritus associated with anxiety, but relatively
high doses are necessary. Doxepin, a tricyclic
antidepressant (TCA), has proved more useful than
antihistamines for the treatment of anxiety-related
pruritus and self-mutilation.
Cyproheptadine is used to treat urine spraying and
masturbation in a neutered (castrated) male cats.
The use of cyproheptadine as an appetite stimulant
in dogs and cats may result from 5-HT antagonism.
H1-blockers from 1st generation
Cats
Dogs
Cyproheptadine
Cyproheptadine
0.4–0.5 mg/kg/12 h p.o. 0.3–2 mg/kg/12 h p.o.
Diphenhydramine
2–4 mg/kg/12 h p.o.
Hydroxyzine
2.2 mg/12 h p.o.
Diphenhydramine
2–4 mg/kg/12 h p.o.
Hydroxyzine
0.5–2.2 mg/12 h p.o.
Adverse effects
● Mild CNS depression or sleepiness
● Anticholinergic effects
●Contraindications
● Urinary retention
● Glaucoma
● Hyperthyroidism
Known drug interactions
● Comedications with of other drugs that cause
CNS depression can produce additive effects.
● MAOIs may intensify the M-cholinolytic
effects of H1-histamine antagonists.
(2) Neuroleptics as BMDs
Typical neuroleptics (D2-blockers)
•phenothiazines
•butyrophenones and others
Atypical neuroleptics (5-HT2- & D4-blockers)
Phenothiazines as BMDs
They are commonly used in VM as tranquilizers
for restraint and sedation or for brief treatment
of agitation, alertness to excitement or
hypersensitivity, often associated with fear- or
anxiety-provoking circumstances or excitement
from anticipation. However, they are seldom
used in long-term behavioral therapy because
of potential extrapyramidal effects.
•Acepromazine is used for motion sickness
and anxiety associated with car travel.
•Acepromazine and chlorpromazine have
also been used in the treatment of
aggression, to reduce excitement.
•Thioridazine was used
to control aberrant
motor activity
in a dog.
Butyrophenones as BMDs
Haloperidol assists in the control of stress
and therefore to prevent injuries when several
species of wild African herbivore are handled at
game parks. Haloperidol has a slight effect in
dogs with obsessive-compulsive disorders
and certain types of aggression.
It is used long term (up to
9 years) in the management
of self-mutilation and
feather-plucking in birds.
Atypical neuroleptics as BMDs
Clozapine is effective in treating aggression in animal
models of self-abuse. However, its use in treating
aggressive dogs has been disappointing.
(3) Anticonvulsants as BMDs
Carbamazepine may control some
forms of fear aggression in cats and
can use to control motor activity
in dogs, associated with seizures.
(4) Benzodiazepines as BMDs
•Alprazolam
(Xanax®)
•Clonazepam
(Rivotril®)
•Diazepam (Valium®)
•Flunitrazepam
•Oxazepam
•Lorazepam
•Midazolam
•Triazolam
In cats benzodiazepines are used to treat inappropriate
elimination associated with anxiety, urine marking or
spraying and fear aggression, as well as to
stimulate appetite. They have been used in dogs
in the treatment of noise phobias, panic attacks and
sleep disorders such as night-time waking.
Clorazepate (active metabolite is nordiazepam)
because of its longer half-life, may be more
suitable for dogs
(0.5 – 1 mg/kg/8 h or 2 mg/kg/12 h p.o.).
•Alprazolam is used in dogs in the anticipatory
phase of thunderstorm phobias and separation
anxiety.
•Flurazepam is used to treat night-time
waking or changed sleep patterns that may
be associated with anxiety in companion animals.
•Triazolam has also been used to treat some
cases of aggression in cats.
(5) Azapirones as BMDs
Buspirone is a selective partial agonsist of
presynaptic 5-HT1A-receptors. It does
not produce dependence.
It is used in anxiety related problems in cats,
including urine marking/spraying and
grooming.
It is used successfully for travel sickness too.
Advantages of buspirone in comparison to
benzodiazepines include lack of sedation and
a high safety margin.
(5) Antidepressants as BMDs
In depression
there is
deficiency
of NA and
5-HT
in the brain.
The effects of DA, 5-HT and NE on the brain functions
Monoamine Reuptake Inhibitors
α2-adrenergic
blockers
MAO
inhibitors
(1) Tricyclic antidepressants
(non-selective inhibitors)
(1a) Drugs
Desipramine
Nortriptyline
(2) Selective NARIs
Reboxetine
(1b) Prodrugs
Amitriptyline
Clomipramine
Doxepin
Imipramine
(3) Selective SSRIs
Citalopram, Fluoxetine
Escitalopram, Fluvoxamine
Paroxetine, Sertraline
Mirtazapine
Trazodone
Selegiline
(MAO-B)
Moclobemide
(MAO-A)
The structures of TCAs
are similar to phenothiazines.
A. The Tricyclic antidepressants (TCAs):
● Block reuptake of NA and 5-HT
● Have antimuscarinic (atropine-like) effects
● Have α1-adrenolytic effects
● Have H1-blocking effects to varying degrees
● Produce sedation in animals
In cats TCAs have been recommended as part of the treatment
of anxiety-related disorders: inter-cat aggression,
fear aggression, excessive licking in obsessivecompulsive disorder, excessive vocalization due to anxiety,
urine spraying (with amitriptyline or clomipramine).
TCAs with strong antimuscarinic activity have also been used
to reduce predation in cats, as ACh is the principal
neurotransmitter involved in predatory aggression.
In dogs, TCAs have been used as part of the treatment
of dominance aggression, fear aggression,
separation anxiety, obsessive-compulsive
disorders, including acral lick granulomas, fears and
phobias (thunderstorm phobia, enuresis, narcolepsy).
Amitriptyline has been used in the management of
cats with lower urinary tract disease. Imipramine has
been used in the treatment of urethral incompetence
because of its M-cholinolytic effect.
Doxepin and amitriptyline have considerable
antihistaminergic (H1-blocking) effects. They are
useful in cases where antipruritic or sedating
effects are also needed.
Amitriptyline
Tricyclic
Antidepressants
1 – 4 mg/kg p.o.
q. 12 – 24 h
0.5 – 1 mg/kg
p.o. q. 24 h
Doxepin
3 – 5 mg/kg p.o.
q. 8 – 12 h
in acral lick
dermatitis
0.5 – 1 mg/kg p.o.
q. 12 – 24 h
Adverse effects of TCAs
● Short-term lethargy
● Mild intermittent vomiting
● Increases or decreases in appetite
● Sedation (antihistaminic effect)
● Ataxia
● Atropine-like side effects:
– Dry mouth
– Constipation (antimuscarinic effect)
– Urinary retention
– Tachycardia
– Cardiac arrhythmias
– Decreased tear production
– Mydriasis
– Disturbances of accommodation
Known drug interactions
●Concurrent MAOI administration should be
avoided as it may lead to a serotonin syndrome.
●TCAs used with antithyroid medications may
increase the potential risk of agranulocytosis.
●As TCAs are strongly bound to plasma protein,
their effects may be enhanced by drugs that
compete for protein-binding sites (e.g. Aspirin).
Contraindications
●Urinary retention
●Concurrent use of hypertensive drugs
●Narrow angle glaucoma
●Seizures
●Cardiac dysrhythmias
B. Selective
Serotonin
Reuptake
Inhibitors
(SSRIs)
Clinical applications
Apart from the treatment of depression,
SSRIs have been used in panic disorder,
obsessive-compulsive disorder, post-traumatic
stress disorder, chronic pain,
social phobias, enuresis and
eating disorders
(including
bulemia neurosa)
in humans.
In cats, fluoxetine and paroxetine have been
used to treat urine spraying, aggression and
obsessive-compulsive disorders.
In dogs, fluoxetine and sertraline have been
used in the treatment of acral lick granulomas.
Fluoxetine has also been used to treat
obsessive-compulsive disorders,
separation anxiety, generalized anxiety or
global fear and dominance aggression.
Paroxetine has also been used to treat
generalized anxiety disorder.
Citalopram
has been
used to treat
acral lick
dermatitis
with a
satisfactory
result being
seen in about
2 weeks.
SSRIs
Fluoxetine
Paroxetine
1 – 2 mg/kg p.o.
q. 24 h
1 mg/kg p.o.
q. 24 h
0.5 – 1 mg/kg p.o.
q. 24 h
0.5 – 1 mg/kg p.o.
q. 24 h
ADRs of SSRIs
●Mild sedation
●Transient decreased appetite
●Increased anxiety
●Decreased sexual motivation in animals and humans
●Nausea, vomiting, diarrhea, lethargy, weight loss,
tremors and agitation in humans.
●The serotonin syndrome is a rare but dangerous
complication with features restlessness, tremor,
hуperthermia, convulsions, coma and death
in humans. Risk is increased by co-administration
with MAOIs.
C. Monoamine oxidase inhibitors (MAOIs)
● Selegiline (Selective MAO-B irreversible inhibitor)
In humans, selegiline has been used in
Parkinson’s disease. In VM it has been used
in older cats with anxiety, disturbed sleep/wake
cycles and excessive vocalization associated
with aging. It has also been used to treat
generalized anxiety, compulsive licking and
several types of aggression, but higher doses
are required for cats than dogs.
Adverse effects of MAOIs
●Stereotypic behaviors with overdosage
●Vomiting and/or diarrhea
●Hyperactivity or restlessness
●Pruritus, hypersalivation, anorexia, diminished
hearing and listlessness in dogs
Known drug interactions
●Comedication with ephedrine or opioids is
not recommeded. The mechanism is not
understood but this interaction can be fatal.
(6) LITHIUM
Lithium is a monovalent cation that is used in
acute mania in humans. It has been used to
treat some cases of unpredictable, severe
aggression in dogs. It has a narrow
therapeutic window.
Regular monitoring of
its plasma concentration
is required.
Lithium inhibits
hydrolysis of inositol phosphate, so
reducing the recycling of free inositol for
synthesis of phosphatidylinositides. These
intracellular molecules are part of the
transmembrane signaling system
that is important in regulating
intracellullar Ca2+ concentration.
ADRs of lithium
●Acute overdose of lithium causes confusion,
convulsions, cardiac arrhythmias and death.
Known drug interactions
●Diuretics enhance lithium’s action and
increase the likelihood of toxicity.
(7) Antiadrenergic drugs as BMDs
A. Postsynaptic
α-blockers
Nicergoline has been recommended in dogs with
canine cognitive dysfunction syndrome (CCDS) and
cerebral insufficiency of vascular origin. These include
alteration in sleep/wake cycles and loss of learned
behaviors such as house training. It also used
in the treatment of aggression associated with aging.
Nicergoline has been reported to be beneficial
for cats with behavioral problems associated
with aging, such as excessive vocalization and
restlessness, especially at night.
Known drug interactions
●Nicergoline can be expected to have an additive
effect if used concurrently with other vasodilators.
●Treatment should be stopped 24 h before
induction of anesthesia with xylazine. Because it
is an α-antagonist, nicergoline may interfere with
the activity of xylazine, reducing or negating its
sedative effects. Alternatively, xylazine may
reduce the effectiveness of nicergoline.
B. Non-selective Beta-blockers
NA is released in fear- or anxiety-provoking
situations. Blocking some of the effects of NA
reduces the physical manifestations of fear
and anxiety (muscle tremors, trembling,
tachycardia and altered GI motility).
β-blockers can have a calming effect on
anxious animals. Propranolol have been
used to treat some forms of anxiety such as
noise phobias in animals.
Non-selective Beta-blockers as
Sedative, resp. as BMDs
Propranolol p.o. Pindolol p.o.
0.5–3 mg/kg/12 h
0.2–1 mg/kg/8 h
0.125–0.25
mg/kg/12 h
–
(8) Opioid agonists/antagonists as BMDs
Agonist: Hydrocodone
Antagionists: Naloxone, Naltrexone
•Naloxone has a briefly effect. It is used as
a diagnostic aid for compulsive disorders.
•Naltrexone is longer acting and used therapeutically.
•The opioid agonist Hydrocodone is used in some
cases of self-mutilation in cats and chronic
management of canine acral lick dermatitis.
(9) Progestins
Synthetic progestins (medrogyprogesterone
and megestrol) have been used traditionally
in VM in the treatment of problems ranging
from roaming, sexual perversion, raucous
behavior, obsessive barking, destructiveness,
hole digging, car chasing, excessive timidity
and poultry killing to urine spraying and
aggression.
Progesterone and its metabolites act as nonspecific
sedatives and have barbiturate-like activity. They are
antiandrogenic and act mainly in the medial preoptic
area (part of anterior hypothalamus). This area control
male sexual behavior and urine marking. Progesterone
also interferes with synthesis of estrogen receptors
and suppresses the production of testosterone in
the reproductive tract of intact animals. However,
progestins also suppress male-like behavior
in castrated cats. The behavioral and physiological
effects of progestins due to inhibition
of 5α-steroid reductase.
(−)
Progestins
(10) Pheromones
are volatile chemical messengers that are
produced in exocrine glands. They are
released into the environment by animals to
communicate with and alter the behavior of
other members of usually the same species.
Cats are believed to use facial
pheromones to familiarize themselves
with their environment.
Other uses include calming cats prior to travel by
spraying the cat-carrier prior to placing the cat
inside, helping cats to become familiar with a
new house and in the introduction of a new cat
to the household. Additionally, it appears to be
useful in stimulating appetite in hospitalized cats.
It helps to control undesirable
scratching behavior.
To date, five functional fractions (Fs) of facial
secretions of cats have been identified. The F3
fraction of facial pheromone is thought to inhibit
urine marking, enhances feeding in an unknown
situation and enhances exploratory behavior in
unfamiliar surroundings. The F4 fraction
familiarizes and calms the cats. Feliway® contains
a synthetic analog of the F3 fraction of feline
facial pheromone, along with a cat attractant
(the alcoholic extract of the plant Valerian).
Feliway® has been advocated for use in cases
of urine spraying or anxiety in domestic cats
and cheetahs. It has been reported to be help
decrease intercat aggression in multi cat households
(one of the major causes of urine spraying).
Feliway® is also
recommended
to help cats tolerate
clinical examinations
during a veterinary
consultation.
Feliway®
Spray (75 ml): for scratching/urine marking, spray daily at a height
of 20 cm (cat nose level) in 6–8 prominent locations per room, incl.
areas that have been marked with urine. Needs to be used continuously for 21 d for scratching, 30 d for urine marking, 45 d for older
cats; for travel: spray cat carrier 15 min prior to introducing the cat.
Diffuser: needs to be plugged in the room where the cat spends
most of its time. One diffuser covers around 50 m2 (sq m) and lasts
approximately 1 month. In multistory houses diffusers need to be
placed on each level. The product should be used continuously for
1 to 3 months initially depending on the problem.
DAP® (Dog Appeasement Pheromone) is a synthetic
analog of the appeasing pheromone that the bitch
secretes in the first few days after birth which helps
the attachment process of mother to pups.
I only cuddle pups
but don’t kiss them!
DAP® (Dog Appeasement Pheromone) has been used
in dogs in the treatment of noise phobias (fireworks,
thunderstorms), separation anxiety, motion sickness
and helping puppies settle in to their new home.
It has also been used successfully in boarding establishments and veterinary hospitals to help decrease
anxiety, facilitate handling of dogs and assist dogs to
familiarize themselves with the new environment.
DAP®: Spray, diffuser and collar are now available.
Spray (e.g. for car travel): spray 8–10 pumps of DAP 15 min
before effect is required and before introducing the dog into the car
or crate. It can also be sprayed onto a bandana and tied around the
dog’s neck if the DAP collar is not available.
Diffuser: should be placed in the room where the dog spends most
of its time. It should not be placed behind furniture or areas that the
dog cannot access as many dogs prefer to lie close to the diffuser.
It should not be placed under tables as this will prevent circulation
through the room. One diffuser covers approximately 50–70 m2
and lasts around 30 days. In multistory houses a diffuser should
be placed on each level. The diffuser should be plugged in
continuously for at least 30 days.
Collar: the collar should be fitted firmly on the dog’s neck (one
finger between collar and neck!). Each collars lasts about 1 month.
Adverse effects of Phermone-containing preparations:
●None have been reported, although some clients
claim that the alcohol vehicle is irritating.
●Caution should be exercised if there are birds in
the environment as they are likely to investigate
anything new in the environment by sniffing.