Sedatives_hypnotics_tranquilizers

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SEDATIVES & HYPNOTICS

CONTENTS:
 DEFINITION OF SEDATIVES & HYPNOTICS
 COMPARISON OF SEDATIVES & HYPNOTICS
 ACTUAL PICTURE OF SEDATIVES & HYPNOTICS
 USES OF SEDATIVES AND HYPNOTICS
 CLASSIFICATION OF SEDATIVES & HYPNOTICS ALONG WITH
THEIR
DESCRIPTION
 PAST QUESTIONS RELATED TO SEDATIVES & HYPNOTICS

WHAT ARE SEDATIVES &
HYPNOTICS ????
Sedatives are CNS acting drugs which :
 Decrease activity
 Moderate excitement
 Produce drowsiness
 Calm the recipient
Hypnotics are the sedatives at higher dose which produce
deep sleep or anesthesia.

USES OF SEDATIVES & HYPNOTICS
1)TO REDUCE ANXIETY & PAIN .
2) TO PROVIDE CHEMICAL RESTRAINT.
3) TO FACILITATE THE HANDLING OF ANIMALS .
4) TO ALLOW THOROUGH EXAMINATION AND MEDICATION OF ANIMALS.
5)TO INDUCE SLEEP INCASE OF INSOMNIA IN HUMANS.
6) TO PREVENT AND CURE EPILEPSY.
7) TO TREAT NEONATAL JAUNDICE.

1)
• BENZODIAZEPINES (e.g. Diazepam ,Midazolam)
2)
• BARBITURATES (e.g. Barbital ,Phenobarbital)
3)
• ALPHA 2 –ADRENORECEPTOR AGONISTS (e.g. Xylazine
,Detomidine)
4)
• CHLORAL DERIVATIVES (e.g. Chloral hydrate)
5) • PARALDEHYDES (e.g. Aldehydes)
CLASSIFICATION OF SEDATIVES & HYPNOTICS:

1)BENZODIAZEPINES :
Benzodiazepines (BZD ,BDZ ,BZs) ,sometimes called ‘benzos’ are a class of
psychoactive drugs .Most widely prescribed drugs for anxiety & insomnia.
(Over 50 million prescriptions are written yearly in the US )
USED IN HUMANS & ANIMALS AS :
1)Hypnotic - sedative
2) Anxiolytics
3)Anticonvulsants
4)Muscle relaxant
5)Appetite stimulant
6) Amnesiacs
7) Anesthetics

BASIC STRUCTURE :
1)The core chemical structure of Benzodiazepines is the fusion of
Benzene ring (A) + 7 member diazepene ring (B) (2 nitrogen & 5 carbon).
2)All important benzodiazepine member contain a 5 aryl substituent
(Ring C)
Various modification in the ring
system (A ,B ,and /or C) can
affect the binding of molecule to
the GABA A receptor & modulate
the pharmacological properties .

MECHANISM OF ACTION OF
BENZODIAZEPINES :
1) Primarily increase the pharmacological effect of GABA A receptor
in CNS and decrease the excitability of neurons .
2)WHAT IS GABA A RECEPTOR ??
a) It is the receptor having ion channel that effluxes Chloride ion.
b)Receptor has separate binding site for neurotransmitter GABA &
BZD ,two binding sites (active sites ) for neurotransmitter GABA &
one binding site (allosteric site )for benzodiazepine.

Mechanism continued :
3)Empty GABA A receptor is inactive & coupled chloride channel is
closed.
4)Binding of GABA to GABA A receptor causes chloride channel to
open.
5)Binding of benzodiazepines to BZD receptor alone cannot open
Chloride channel.
6) Benzodiazepines potentiates the activity of GABA to cause wide
opening of chloride channel & greater entry of Chloride.

SEDATIVE ACTION OF BENZODIAZEPINES
Opening of chloride channel
Inhibitory effect of available
GABA is potentiated.
• SEDATORY & ANXIOLYTIC
EFFECTS
Hyperpolarisation of the membrane
of associated neurons

MOST COMMONLY USED
BENZODIAZEPINES :
1) DIAZEPAM
2) MIDAZOLAM
3) LORAZEPAM

Pharmac-
ological
Effects
Pharma-
cokinetics
Adverse
Effects
Antidote Contra-
indications
Dose
rate
•CNS ,
a)sedation,
b)Anxiety
reduction
c)Muscle relaxant
d)Anticonvulsant
Effect
•Respiratory
system: can cause
decreased
ventilation in high
dose
•Cardiovascular
system: Decrease
blood pressure
and increase
heart rate
•Digestive system :
decreases
nocturnal gastric
1)Well
absorbed from
the
gastrointestinal
tract
2)Peak plasma
levels usually
achieved in 1
hr
3)Lipid soluble
4)Penetrates
blood brain
barrier
5) Metabolized
by hepatic
microsomal
enzyme
1)In horses
,Muscle
fasciculation
,weakness
,ataxia
2)In cats :
Behavior
changes
(Irritability)
3)In Dogs :
Excitement
4)Confusion
5)Decreased
reflexes
6)Prolonged
sleep
7) Liver
Damage
Fumazenil 1)Hypersensitivity
2)Severe hepatic
Damage
3)Greyhound and
its related breed
shouldn’t use
these drugs
1)Dogs: 0.3-
0.5 mg /kg
,IM
2)Cats : 0.3
-1 mg/kg
,IM
ABOUT DIAZEPAM :

2) BARBITURATES
• Widely used as hypnotic –sedatives in the past ,but now better and
safer drugs have largely replaced them.

PROPERTIES OF BARBITURATES :
S
N
Mechanism of
action
•Pharm
acologi
cal
effect
Pharm
acokin
etics
Adverse
effects
Anti
dot
e
Contraindica
tions
Dose
rate
Therapeuti
c
use
1 Prolong the
opening of
chloride influx
through GABA
A receptor &
block the
sodium
channels
• CNS :
Depresse
d
cerebral
Blood
flow,
Depresse
d
Cerebral
Metabolis
m
Cardiova
scular
effects ;
Slight
myocardi
al
depressio
n
•Low
respiratio
n
Rapidity
of onset
&
shorter
duration
of
action
•Physical
&
psycholo
gical
addiction
•Overdos
e
potential
•Sluggish
ness
•In -
coordinat
ion
•Slowness
of
speech
•Faulty
judgemen
t
Met-
hyle-
thyl-
gluta
rimid
e
•High amount
of ammonium
in blood
•Porphyria
•Drug abuse
•depression
Barbita
l ;150
-1000
mg
(total
dose
in dog
)
Pheno
barbital
;2 mg
/kg
(Dogs
& cats
)
•Seizures
treatment
•Anxiolytics
•Anticonvulsa
nts
•Treatment of
acute
migraine

3 ) ALPHA 2 ADRENORECEPTOR AGONISTS
They are distinct class of sedatives with significant
analgesic action primarily used for :
1)Sedation 2)Chemical restraint 3)Muscle relaxant
4)Analgesia
MECHANISM OF ACTION :
1) Activates membrane associated inhibitory G proteins.
2)Opens potassium channels in the neuronal
membrane.
3) Hyperpolarizes the cells.
4) Stimulates the central alpha 2 adrenergic receptors.

COMMON ALPHA 2 ADRENORECEPTOR AGONISTS
1) Xylazine
2) Medetomidine
3) Romifidine
4) Detomidine

ABOUT XYLAZINE
Pharmacolo
gical
effects
Pharmacoki
netics
Side
effects
Treatment Dose
rate
Therapeutic
use
•CNS :
sedation
,analgesia,
muscle
relaxation
,anxiolytics
•Cardiovascular
system
;hypertension
•Respiratory
system
;decreased
respiration
•DigestIve
system
;Decrease
gastric
secretions
After IM
administration
,absorbed
rapidly but to
variable
extents.
•Bioavailability
:40 -48 %
(horses) , 52-
90% (dogs)
•Half life : 50
mins (horses ) ,
30 mins (dogs)
•Dog & cats :
Cardiac
arrhythmias
,vomiting
,bradycardia
,reduced
respiratory rate
•Selective
adrenoreceptor
antagonists like
Yohimbine
•Respiratory
stimulants
(Doxapram)
•Anticholinergic
drugs (eg .
Atropine)
•Dogs & cats
:
•1 mg /kg ,IV
,1-3 mg /kg ,IM
•Sedative
•General
anesthetic
agents
Emetic in
cats to
induce
vomiting ,
Analgesics

4 ) CHLORAL DERIVATIVES
1) I t is one of the oldest sedatives still used occasionally for sedation
in large animals.
2) It can ‘t be used in small animals due to its toxicity.
3) It depresses the cerebral cortex resulting in hyperoreflexia.
4) It is rapidly absorbed from the gastrointestinal tract following oral or
rectal administration.
5) Uses : Sedative or hypnotics
6) Side effects :Drowsiness ,nausea ,vomiting ,stomach pain ,diarrhoea
7) Antidote : no specific antidote but there has been a case report
reversal with Flumazenil.

5) PARALDEHYDE
1) It is the condensation product of 3 molecules of acetaldehyde
in the form of cyclic ether.
2)It is irritant and inflammable.
3)It is metabolized in liver to acetaldehyde and then to carbon dioxide.
4)It is a potent hypnotic –sedative with a short lasting action.
5) In normal doses , it is considered the safe because it depresses
only the cerebrum ,not the vital medullary centers.
6) Adverse effects ; Acidosis ,liver & kidney damage ,soreness of trachea

6)OTHER SEDATIVES & HYPNOTICS :
1) Inorganic salts like Sodium bromide ,Potassium bromide ,etc.
2) Alcohols
3) Opioids
4) Carbamates ,etc .

PAST QUESTIONS OF BVSc .& A.H. ,AFU RELATED TO
SEDATIVES & HYPNOTICS..
1) Write down the mechanism of action of Benzodiazepine. (2071 B.S.)
2) Write short notes on Hypnotic.(2071 B .S)
3) Define hypnotics & sedatives .How does Benzodiazepine work as
sedative? (2072 B.S. & 2074 B.S. ,Baishakh )
4) What is barbiturates & how does the structural modification affect
its activity?(2074 , Baishakh )
5) Structural modification of barbiturates affects its activity. Describe in
detail..(2074 ,Baishakh )
6)Describe the mechanism of action of and pharmacological effect of
Diazepam .(2074 ,Baishakh )

Psychotropics
&
Tranquillisers

Psychotropic Drugs
 Also called psychoactive drugs or
psychopharmaceuticals.
 Chemicals which act primarily upon the CNS where they
alter brain functions, resulting in changes in perception,
mood, consciousness, cognition and behavior.
 Used in animals for the treatment of behavior disorders.
 Includes:
1. Anxiolytics (hypnotic-sedative)
2. Neuroleptics (tranquillizer-sedative) and
3. Antidepressant agents

1. Anxiolytics
 Used to control the symptoms of anxiety in humans to
produce a restful state of mind without affecting the
normal or physical functions.
 In animals primary use is as hypnotic-sedative.
 Include:
i. Benzodiazepines
ii. Azapirones

i. Benzodiazepines
 Used in treatment of various forms of anxiety in humans.
 When used as antianxiety drugs, they are often
associated with some degree of psychomotor
impairment and also an impairment of memory
(particularly short-term) and consequently learning
ability in animals.

Mechanism of Anxiolytic action by
BZD
 Antagonism of serotonin
 Increased release and/or facilitation of GABA activity
 Diminished release or turnover of Ach in the CNS
 Hypnotic-sedative effect of it is exerted mainly via
increasing the opening frequency of chloride ion channel
of GABAA receptors

Clorazepate
 Long acting benzodiazepine
 Anxiolytic, anticonvulsant, sedative, hypnotic and
skeletal muscle relaxant properties
 Widely used in humans and veterinary practices
 May also be prescribed as a premedication,
anticonvulsant or muscle relaxant.

Pharmacological effects
 Anxiolytic and mild sedative effects on the CNS to
alleviate fear related behaviors in animals.
 May not have any anxiolytic or sedative effect in fear-
related aggression in certain animals, but instead may
cause a paradoxical increase in behaviors.
 Prodrug for an active metabolite nordiazepam or
desmethyldiazepam, which is responsible for most of the
therapeutic effect of clorazepate.

Pharmacokinetics
 Converted into active nordiazepam in the GI tract, which
is completely absorbed.
 Peak plasma levels seen between 30 minutes and 2
hours after oral administration.
 Widely distributed and highly bound to plasma proteins.
 Crosses readily over the CNS and placenta and
distributed into milk.
 Nordiazepam putatively has been suggested to be
responsible for most of the anxiolytic effects and side
effects of clorazepate in animals.

Side effects/adverse effects
 In dogs clorazepate may produce mild and transient
sedation and ataxia.
 Overdosage causes significant CNS depression.
 Interferance with learning and memory, and disinhibition.
 In cats, may affect depth perception and have
dibetogenic effect.
 Has been associated with liver failure after prolonged
use.
 Chronic administration may lead to dependence and a
withdrawal syndrome if abruptly discontinued.

Contraindications and precautions
 Should not be used in patient with hepatic or renal
impairment.
 May provoke dog showing fear induced aggression to
attack. In such cases, decreasing the fear that may be
inhibiting the dog from attacking nay actually increase the
probability that dog will attack.
 Gradual withdrawal.

Drug interaction
 No significant interactions are reported.
 May potentiate effects of other CNS depressants.

Clinical use
 Anxiety or phobia related behavior problem treatment.
 Must be given before beginning of fear eliciting stimulus.
 Effective in suppressing urine spraying behavior in
companion animals.
 Has also been used in dogs as adjunctive anticonvulsant
and may be useful in treating behaviors based on non-
convulsive seizures.

Dose
 For behavior modification
 Cats : 0.2 to 0.4 mg/kg PO, 1 to 2 times daily. Dosage
may be
increased up to 0.5 to 2 mg/kg, PO
 Dogs : 0.5 to 2 mg/kg PO, 2 times daily. Dosage
adjustment based on
dogs’ response may be necessary.

Diazepam
 Prototype BZD, good antianxiety effect.
 Effective in eliminating or markedly reducing urine
spraying behavior.
 Good pharmacological adjuvant to behavioral therapy
for fear induced problems like fear-biting, fear of
thunderstorm, strangers etc.
 Has been described in treatment of seizure related
aggression.
 Extremely short half life in dogs, so frequent
administration may seriously limit its usefulness.
 Contraindicated in aggressive animals.

Dose
 For behavior modification:
 Dogs: 0.5 to 2.2 mg/kg, PO, as required
 Cats: 0.2 to 0.4 mg/kg, PO, 1 to 2 times daily

Alprazolam
 Potent antianxiety benzodiazepine, in addition has some
mood elevating action in mild depression.
 Has also produced good response in panic disorders.
 Hydroxylated to α-hydroxyalprazolam, an active
metabolite, before glucurodination and excretion from
the body.
 Used in acute fears, refractory feline elimination
problems, feline anxiety related conditions, appetite
stimulation, etc.
 Side effects and contraindications similar to that of
clorazepate and diazepam.

Dose
 For behavior modification
 Dogs : 0.1 to 0.125 mg/kg, PO, 2 times daily.
 Cats : 0.1 mg/kg, PO, 3 times daily.

Oxazepam
 Used for the treatment of behavior problems and anxiety
disorders in animals.
 Also possesses sedative and appetite stimulant
property.
 Metabolite of diazepam and some other BZD.
 Does not undergo extensive hepatic metabolism but is
glucuronidated before excretion.
 Dogs: 0.2 to 1 mg/kg, PO, 1 to 2 times daily
 Cats : 0.2 to 0.5 mg/kg, PO, 1 to 2 times daily

ii. Azapirones
 Have specific antianxiety action and are reported to have
minimal side effects.
 Do not produce significant sedation, tolerance or
physical dependence and have no muscle relaxant or
anticonvulsant activity.
 Represented by only one drug in veterinary medicine,
Buspirone

Mechanism of Action
 Exact mechanism of action not clearly known.
 Action appears to be dependent on the selective partial
agonistic action on 5-HT receptors on both pre- and
postsynaptic sites.
 Reduce activity of dorsal raphe serotonergic neurons by
stimulating presynaptic receptors.
 The effect include decreased firing of dorsal raphe
serotonergic neurons and decreased synthesis and
release of 5-HT.
 Have tendency to increase turnover of both dopamine
and norepinephrine, possibly through action at
autoreceptors.

Buspirone
 Used clinically as an anxiolytic drug, specifically for
generalized anxiety disorders.
 Only used azapirone in veterinary medicine for behavior
disorders in animals.

Mechanism of Action
 Functions as serotonin 5-HT1A receptor partial agonist
to mediate its anxiolytic and antidepressant effects.
 Functions as a dopamine D2 as well as α1- and α2-
adrenergic receptor antagonist to a lesser degree,
though these properties are generally undesirable in an
anxiolytic and likely to contribute only to side effects.

Pharmacological effects
 Selective antianxiety action.
 Relieves mild to moderate anxieties, but is ineffective in
severe cases or in those showing panic reactions.
 Helpful in treatment of fearful situations.
 Shows no potential for addiction or dependence, and
the development of tolerance has not been observed.
 Therapeutic effect develops slowly as more than two
weeks of daily treatment may be needed before
therapeutic levels are reached in dogs.

Pharmacokinetics and Side effects
 High first-pass effect limits systemic bioavailability to 5%.
 Plasma protein binding is very high.
 Metabolized in liver and metabolite excreted primarily in
urine and also feces.
 Side effect may include mild disorientation and GI
symptoms.
 In cats increased aggressiveness towards other cats in
household, mild sedation increased affection, friendliness
and attention seeking behavior, and agitation over dosing.
 Oral overdoses may produce vomiting, dizziness,
drowsiness etc.

Contraindication and Precaution
 Contraindicated in severe renal or hepatic disease.
 Should be used with extreme caution in epileptics.
 Should be carefully used in fear related aggression as it
may cause paradoxical increase in aggression in
companion animals.
 Sharp rise in blood pressure when used with monoamine
oxidase
 Its use along with other serotonin antagonists and
selective serotonin re-uptake inhibitors is not
recommended.

Clinical use
 Treatment of anxiety related behavior problems,
especially against urine spraying in cats.
 Useful in the treatment of low grade anxieties and fears
(e.g. rains and social situations)
 But is ineffective when animal is exposed to intense fear
inducing stimuli.
 Useful in cases of aggression in dogs and cats, but may
increase aggression in some cats.

2. Tranquillizer
sedative/Neuroleptics
 Mainly foe calming effects in animals.
 Causes decrease in spontaneous activity that generally
results in decreased response to external or social
stimuli.
 Sometimes used to decrease anxiety, fear or phobias
accompanying sedative effect causing unsuitable for
behavior modification

i. Phenothiazines
 Used primarily for chemical restrain and sedation.
 Anxiolytic effect not well established.
 Non specific in action and can affect other aspects of
animal behavior.
 Decrease motor function and reduce awareness to external
stimuli.
 Profound sedative effect and moderate antimuscarinic and
extrapyramidal side effects, especially after long-term use.
 Doubtful antianxiety and marked sedative effects in dogs
and cats
 Can be used to treat dogs with loud-noise phobias or
separation anxiety.

Acepromazine
 Widely used as sedative and to immobilize animals.
 Inappropriate in treatment of aggression because it
blunts both normal and abnormal animal behavior rather
than treating the cause of aggression.
 Particularly, it must be used with extreme caution for
restrain of aggressive drugs because they are more
reactive to noises and are more likely to startle under its
influence.
 Cats : 0.5 to 2 mg/kg, PO, once daily

ii. Butyrophenones
 Highly potent neuroleptics, used mainly for sedation and
chemical restrain.
 Least sedative, hypotensive and antimuscarinic effects of
sedative-tranquillisers.
 Non specific in action and less used in behavior
modification.
 Can be used for compulsive and aggressive states in
animal.

Azaperone
 Used primarily in pigs
 Used in control of fighting, and to reduce stress and
excitement in pigs.
 Used in sows having weak mother instincts where it
successfully prevents maternal rejection of piglets.
 Pigs: 0.4 to 2 mg/kg, IM

3. Antidepressants
 Big family of pharmaceuticals used for the treatment of
depression and anxiety disorders in humans and animals.
 Three groups:
a. Neurotransmitter re-uptake inhibitors
b. Monoamine oxidase inhibitors
c. Atypical antidepressants

a. Neurotransmitter Reuptake
Inhibitors
 Inhibition of transporters involved in the re-uptake of
biogenic amine neurotransmitters into pre-synaptic
neurons.
 Depending on the biogenic amine neurotransmitter
involved, further division into:
i. Serotonin and Norepinephrine re-uptake inhibitors
ii. Selective serotonin re-uptake inhibitors
iii. Selective norepinephrine reuptake inhibitors

i. Serotonin and Norepinephrine
Re-uptake Inhibitors
1. Tricyclic antidepressant (TCAs)
 Oldest class of antidepressant drugs.
 Less common in humans nowadays due to more
selective and safer drugs.
 Clinical usage is still common in veterinary medicine foe
wide range of behavior disorders.
 Antianxiety properties noticeable

 Mechanism of action:
 Inhibit mainly the active reuptake of biogenic amines like
serotonin and norepinephrine into their respective presynaptic
nerve terminals, by blocking the transporter.
 No efficacy as dopamine reuptake inhibitors and thus have less
effect on dopamine re-uptake.
 Lead to increased concentration of serotonin or norepinephrine
in synaptic cleft, resulting in antidepressant action.

Imipramine
 Pharmacological effect
 Elevation of mood in depressed mood but in normal
causes sedation, confusion, motor incoordination etc.
 Alters avoidance behavior in animals.
 Affects ANS due to inhibition of norepinephrine transport
into adrenergic nerve terminals and from antagonism of
muscarinic-cholinergic and alpha1 -adrenergic receptors.
 Pain relieving property due to interaction with µ-opoid
receptors.

 Side effects/ Adverse effects
 Sedating and anticholinergic activities
 Dry mouth, constipation, mydriasis, tachycardia, arrhythmia,
urine retention and sedation.
 In dogs, GI distress is common side effect.
 Overdosage can be life threatening due to arrhythmias and
cardiovascular collapse.
 Cats are more sensitive than dogs.

 Contraindications and precautions
 Use of imipramine and other TCAs is contraindicated in animals
with the history of urinary retention or severe uncontrolled
cardiac arrhythmias.
 Should not be used if prior sensitivity has been noted with other
TCAs.
 Avoid use in pregnant

 Drug interactions
 TCAs potentiate action of direct acting sympathomimetic
amines and inhibit action of indirect sympathomimetic.
 Concomitant use with monoamine oxidase inhibitors may cause
dangerous hypertensive crisis with excitement and aggression,
so imipramine should not be used with MAO-inhibitors.
 Additive effect with anticholinergics and CNS depressants

 Clinical uses
 Used in behavior disorders in animals
 Treating mild attention deficit disorders in humans and may be
useful in dogs
 Used in dogs to treat cataplexy and urinary incontinence.
 Used in horses to treat narcolepsy and ejaculatory dysfunction.

 Dose
 For adjunctive therapy of separation anxiety or other behavior
disorders
 Dogs: 2 to 4 mg/kg , PO, 1-2 times daily
 For cataplexy
 For urethral incompetence
 Dogs: 5-15 mg, PO, 2 times daily
 Cats: 2.5-5 mg, PO, 2 times daily

Amitriptyline
 Most widely used TCA.
 Used for behavior disorders.
 Useful when anxiety and fearfulness are components of the
behavior.
 Pharmacological effects:
 Primarily as a serotonin-norepinephrine reuptake inhibitor,
with strong actions on the norepinephrine transporter and
moderate effect on the serotonin transporter.
 Negligible influence on the dopamine reuptake
 Act as Na, Ca and K blocker as well

 Pharmakokinetics
 Readily absorbed from both GI tract and parenteral site of
injection..
 Highly bound to plasma proteins.
 Metabolized in liver to several metabolites including active one.
 Side effects/Adverse effects
 Sedation, mydriasis, dry mucous membrane, constipation, urine
retention, cardiac arrhythmias and hepatotoxicity.
 Narrow therapeutic index with high risk of toxicity with
overdoses.
 Bitter taste so not easy to administer orally
 Extreme high doses are associated with convulsions, cardiac
abnormalities and hepatotoxicity.

 Can be used with care in patient with a history of cardiac or
hepatic disease, seizures, glaucoma and hyperthyroidism.
 ECG is recommended before treatment with it because of low
safety of margin.
 Drug interaction
 Concomitant use with MAO-inhibitors is contraindicated.
 It should be cautiously with other agents possessing Ach or CNS
depressant effects.
 When used with antithyroid agents may increase the potential
risk of agranulocytosis

 Clinical use
 Very successful in the treatment of separation anxiety and
generalized anxiety.
 Useful in the treatment of excessive grooming and urine marking
in cats.
 Used in pruritic conditions which may be involved in acral lick
dermatitis and some neuroleptic disorders.
 Not much effective in treating aggressive behavior in dogs,
compared to behavior modification alone.
 Dose
 Dogs: 1-2 mg/kg, PO, 1-2 times daily. Upto 4 mg/kg, 1-2 times
daily
 Cats: 0.5 -1 mg/kg, PO, once daily

2. Non Tricyclic Antidepressants
 Venlafaxine
 Duloxetine
 Amoxapine
 They cause less side effects than the TCAs

ii. Selective Serotonin Re-Uptake
Inhibitors
 Relatively selective effects on reuptake of serotonin with
limited direct action at other sites.
 Increasingly used in place of the older TCAs due to
better tolerability and safety
 Mechanism of Action
 Highly selective and powerful inhibitor of serotonin
transporter, present in the presynaptic serotonergic
nerve terminals.
 Enhanced effect of serotonin in CNS.

Fluoxetine
 Used in the treatment of various animal behavior
problems.
 It remains the representative drug of this class.
 Pharmacological effect:
 Reduces canine dominance related aggression in dogs.
 No anticholinergic, antihistaminic or antiadrenergic
activities, so less side effects.

 Pharmakokinetics
 Well absorbed
 Metabolized primarily in liver by isoenzymes of the cytochrome
P450 system to many metabolites including norfluoxetine, which
has pharmacological properties like that of parent drug.
 Extremely slow elimination of the drug and its metabolite.
 With time they inhibit their own metabolism and increase half
life.
 Irritability, transient anorexia, decreased sociability, decreased
responsiveness to environment and mild GI upset.
 Overdosage may produce ataxia, nystagmus, tremors and
seizures.

 Contraindicated in severe hepatic or renal impairment
 Should be used with caution in patients with diabetes mellitus as
it may alter blood glucose.
 Should be used with caution in patient with seizure disorders
 Dangerous TCA poisoning may occur if two type of
antidepressant are used.
 Also should not be used with MAO-inhibitors

 Clinical uses
 Treatment of depression, separation anxiety, panic, avoidance
disorders and obsessive-compulsive disorders in companion
animals
 Treatment of profound aggression, stereotypies, dominance
aggression and generalized and recurrent fears and anxieties.
 In cat for decreasing urine spraying.
 Doses
 Dogs: 1mg/kg, PO, 1-2 times daily
 Cats : 0.5 to 1 mg/kg, PO, once daily

 Others:
 Paroxetine
 Dogs and cats : 0.5 to 1 mg/kg, PO, once daily
 Sertraline
 Dogs :
1mg/kg, PO, 2 times daily for 1 week, then
1-2 mg/kg, PO, 2 times daily
 Fluvoxamine
 Dogs :
1 to 3 mg/kg, PO, 2 times daily
0.25 to 0.5 mg/kg, PO, once daily

iii. Selective Norepinephrine
Reuptake Inhibitor
 Reboxetine
 Viloxazine
 Both of them are used in human. No or very less use in
animals

b. Monoamine Oxidase Inhibitor
 Have potentially lethal dietary and drug interactions.
 Mechanism of Action:
 Irreversibly or reversibly inactivate the MOA causing
neurotransmitter to escape metabolism.
 It causes increased neurotransmitter and subsequent
activation of receptors.

Selegiline
 Selective MAO-B inhibitor binding to it covalently causing long
lasting and non-competitive inhibition.
 Recovery of MAO activity may take several days.
 Dopamine increases at receptor sites.
 Pharmacological effects:
 Improves synaptic transmission by increasing availability of certain
neurotransmitters, in particularly dopamine.
 Maintains dopamine and corticotropin releasing hormone in
balance
 Neuroprotective action via superoxide dismutase and catalase
activation

 Pharmacokinetics
 High first pass effect
 Excreted primarily in urine in conjugated and unconjugated
form.
 In dog, vomiting, siarrrhoea, lethargy, salivation, repetitive
movement, etc.
 Contraindication
 Contraindicated in hypersensitive patient.
 Safety in pregnant and lactating has not been established.

 Drug interactions
 Should not be used along with pethidine, fluoxetine,
phenothiaxine and alpha2-adrenoreceptor stimulants.
 Concurrent administration of MAO-inhibitors and tricyclic
antidepressants should be avoided and a drug free period of 2
weeks with either group is recommended.
 Serotonin syndrome is seen when they are used with biogenic
amine neurotransmitter inhibitor.
 Clinical uses
 Behavior problem of emotional origin in dog
 Age related problem like canine cognitive dysfunction where
decreased dopamine concentration is believed to be connected
with problems of memory loss and disorientation

 Dose
 Dogs: 0.5mg/kg, PO, once daily for 2 months. If no
improvement is seen, the dose may be increased to 1
mg/kg, once daily.
 Cats : 0.25-0.5 mg/kg, PO, 1 to 2 times daily.

c. Atypical Antidepressant
 This group includes antidepressant drugs not falling to
the other above mentioned groups.
 It consists of drugs having different mechanism of
action.
 i. Mirtazapine
 ii. Trazodone
 iii.Bupropion

TRANQUILLISERS
 CNS acting drugs which causes decreased activity,
calmness, block conditioned reflexes etc. and used to
reduce anxiety.
 In animals they are primarily used in chemical restrain for
various purpose.
 They only block conditional reflex.
 1) Phenothiazine derivatives
 2) Thioxanthenes
 3) Butyrophenone Derivatives

1. Phenothiazine Derivatives
 Used primarily for chemical restrain during examination or
transport and to prevent animals from chewing their bandages
and splints.
 They are not reliable to control a response to unconditioned
stimuli.
 Acepromazine is the most commonly used phenothiazine in
veterinary medicine.

Mechanism of Action
 Exact mechanism of action is not fully understood.
 Potent blocking action on dopamine receptor, especially
D2 -receptor family (D2,D3 and D4). They block
postsynaptic dopamine receptors in the CNS and may
also inhibit synthesis and/or release of dopamine
through D2 - receptors located presynaptically.
 They exert sedative action by depressing the brain stem
and the connection to the cerebral cortex.
 They have varying degree of serotonin receptor,
histamine receptor, alphaadrenoreceptor and muscarine
receptor blocking activity.

Chlorpromazine
 Has been suppressed as a tranquillizer-sedative by other
drugs but still considered the prototype phenothiazine
agent.
 Pharmacological effects
 Sedation
 Mild to moderate sedation
 Does not produce drowsiness
 Higher doses does not produce deeper sedation but
produce increased duration of action and side effects

 Behavioral effects:
 May decrease spontaneous motor activity in animals.
 At higher dosed, cataleptic effects may be produced so that the
animal remain immobile in fixed position for long period of time,
though may still respond to stimuli.
 Suppress conditioned avoidance response
 Animals may react to noises and get startled
 Antiemetic effect
 Effective in antagonizing apomorphine inducing emesis in dogs
but not in cats.
 Endocrine effect
 Block release of FSH and LH.
 Ovulation is blocked and oestrus cycle suppressed
 Release of prolactin, GH, MSH and ADH

 Body Temperature
 Produces hypothermia in treated animals.
 Other effects
 Blurring of eye
 Dry mouth and eye
 Arrhythmias
 Reduced hematocrit
 Hyperglycemia in several species
 No analgesic effect

 Rapidly absorbed but undergoes extensive first pass effect in
the liver
 Well absorbed after IM injection.
 Brain concentrations are higher than those in plasma.
 Metabolized mainly in kidney and liver by hydroxylation and
glucuronide conjugation.
 Has many active metabolites with greatly varying half-lives and
pharmacological profiles.
 Some active metabolites produced.
 Long half life due to lipophilicity.
 Stimulates hepatic microsomal enzymes in animal.

 Side effect/adverse effect
 Fall in blood pressure, hypothermia, protrusion of nictitating
membrane, thrombocytopenia, platelet dysfunction and ataxia.
 Extrapyramidal signs in cats in high doses characterized by
tremors, shivering, diarrhea and loss of righting reflex.
 Lethargy, diarrhora and loss of anal sphincter tone may also be
seen.
 Cardiovascular collapse, secondary to bradycardia and
hypotension, has all been in all major species.
 Occasionally, clinical doses may cause hyperaesthesia and
marked excitement in horses.
 Horses may stumble and fall, then stand and continue to move
forward and backwards. This violent reaction alternates with
periods of sedation. So rarely used in horses.

 Contraindication and Precaution
 Contraindicated in patients with hypovolemia or shock, and
should be used carefully in animals with hepatic dysfunction,
cardiac disease or general debilitation.
 Should not be used in patient with tetanus, epilepsy or
strychnine poisoning as it decreases seizures threshold.
 Generally not recommended in bleeding stallion.
 IV injection must be made slowly.
 Inadvertent intra-arterial injection in horses may cause severe
CNS excitation/depression, seizures and death.

 Additive CNS depression with CNS depressant drug.
 With Quinidine cause cardiac depression.
 Procaine activity may be enhanced by it.
 Blocks hypertensive effects of epinephrine and may cause
vasodilation and epinephrine reversal effect
 Clinical use
 As a neuroleptic and behavior-modifying drug
 Antiemetic effect in small animals

 Dose
 For sedation/restraining
 Dogs : 3mg/kg, PO, 2 times daily; 0.5mg/kg, IM or IV, 2 times
daily
 Cats : 3mg/kg, PO, once daily; 0.5 mg/kg, IM or IV, once daily
 Swine: 1mg/kg, IM
 Sheep and goat : 2.2 mg/kg, PO ; 1-4 mg/kg, IM ; 1-2.2 mg/kg,IV
 For pre-anaesthetic medication
 Dogs and cats : upto 1.1 mg/kg, IM (1 to 2.5 hrs prior to surgery)
 Cattle : 0.2 -1 mg/kg, IV ; 1 - 4.4 mg/kg, IM
 Swine : 1mg/kg, IM

Acepromazine
 Currently less in use in humans but extensively used in animals.
 Has been used as a tranquillizer for large animal immobilization
and has been greatly accepted as the first choice phenothiazine
for animals.
 10 to 20 times more potent than chlorpromazine.
 Produces mild to moderate sedation for shorter duration.
 Peak sedation generally seen within 5 minutes.
 Higher doses leads to increase in duration of sedation not
depth.
 Oral administration produces undesirable effects in some
animals.

 Onset of action is slowly produced and maximal effect is noticed
after about 1 hour.
 Absorption after SC injection is variable.
 It is administered by IV and IM routes.
 Highly protein bound and a fairly high volume of distribution in
horses.
 Metabolised in liver and both conjugated and unconjugated
metabolites removed in urine.
 Side effects/adverse effects
 Include hypotension, bradycardia, protrusion of nictitating
membranes, ataxia, muscle tremors, hypothermia etc.
 Protrusion of penis especially in Stallion and sometimes prolapse
persists
 Boxer has breed sensitivity to acepromazine.

 Contraindication and precautions
 Should be used at lower rates and penile prolapse must be
treated at once if seen in stallion.
 Caution should be observed when used in large dog breeds.
 Not recommended in pregnant, lactating or animals in shock.
 It lowers bold pressure so used in caution with animals
experiencing anaemia, dehydration or colic.
 Horse should not be ridden within 36 hrs of treatment.
 Drug Interactions
 Should not be used in horses dewormed with piperazine.
 Similar to that for chlorpromazine.

 Clinical uses
 Tranquilliser sedative for controlling intractable animals, to
alleviate itching as a result of skin irritation and to immobilize
large anmals.
 Decreases response to stimuli, fears and phobias and used
for behavior modification.
 Used as pre anaesthetic sedative
 As antiemetic to control vomiting associate dwit motion
sickness
 Drug withdrawl time in ruminants is 7 days for meat and 2 for
milk

 Dose
Dogs : 0.025-0.2 mg/kg, IV
0.1 – 0.25 mg/kg, IM
0.25 – 3 mg/kg, PO
Cats : 0.05 – 0.1 mg/kg, IM or IV
0.25 – 3 mg/kg, PO
Cattle : 0.01 – 0.02 mg/kg, IV
0.03 – 0.1 mg/kg, IM
Horse : 0.03 – 0.1 mg/kg, IM or slow IV
0.13 – 0.26 mg/kg, PO
Pigs : 0.2 – 0.3 mg/kg, IM
Sheep/Goat : 0.05 – 0.1 mg/kg, IM

2. Thioxanthenes
 Closely related chemically to phenothiazine
 Antagonism of D2 receptors in brain
 Limited importance in veterinary medicine
 Chlorprothixene
 Greater depressant and anticholinergic activity than
chlorpromazine.
 Antiemetic and antihistaminic activities
 Can be used in sheep, goats, swine and for control intractable
dogs.
 IV administration permits surgical procedures in conjunction with
local or regional anaesthesia.
 Side effects similar to those produced by phenothiazines.

 Dose
 Dogs : 2.2 – 4.4 mg/kg, IV or
IM
 Sheep and goat : 0.5 mg/kg, IV
 Swine : 0.3 – 1 mg/kg, IV

3. Butyrophenone Derivatives
 Organic compound with ketone functional group.
 Several of the derivatives are widely used as
antipsychotics or neuroleptic drugs in human medicine.
 Commonly used as tranquillizer-sedatives for sedation
and chemical restrain of animals.
 Some poses antiemetic effects.
 Probably act through central mechanism to the
phenothiazines and primarily antagonize dopamine D2
receptors.
 Fewer side effects at equi-effective dose rates than
phenothiazine

Azaperone
 Sedative and antiemetic effects, mainly used as a
tranquillizer sedative in veterinary medicine.
 Mainly used in pigs, for which it is the sedative of choice
 Antagonism of central dopamine D2 receptors.
 Mild to moderate sedative and less antimuscarine and
antiadrenergic effects.
 Quality of sedation in horses and pigs is however
unexpected to that expected of tranquillizer-sedative.
Produces marked drowsiness and suppression of arousal
in them causing hypnotic-like effect.

 IV injection causes violent excitement in pigs with good sedation
afterwards.
 IM produces deep sedation in horses but excitement is severe
and common.
 Violent reactions in horses limit usefulness of azaperone in this
species.
 Relatively short acting that is rapidly detoxified and eliminated.
 Following IM administration, it has fairly rapid onset of action in
pigs with a peak effect at approximately 30 minutes.
 Duration of action is 2 to 3 hrs in young pigs while 3 to 4 hrs in
older.
 Metabolized in liver about 13% excreted in the faeces.

 Transient salivation or panting, extrapyramidal effects,
hypotension and respiratory stimulation.
 Quite frequently evokes excitement or a panic reaction following
IV administration.
 Should not be administered by IV route as it produces a
significant excitatory phase in pigs.
 Caution to be taken while administering to anemic, hypovolemic
or debilitated animals.
 Pigs should be leht undisturbed after injection until the drug’s
full effect has been expressed, as disturbance during this period
results excitement.
 Should be used carefully in very cold condition.

 Clinical use:
 Clinically used as a general tranquillizer or sedative for swine in
aggressive sows to allow piglets to be accepted and prevention
and cure of fighting when pigs are mixed.
 Pre-anaesthetic agent prior to general anaesthesia or caesarean
section with local or regional anaesthesia.
 Occasionally used as a behavior modifying agent.
 Administered by IM routes or it will be ineffective.
 Dose
 For sedation, 1mg/kg, IM swine
 For reduction of aggressiveness/pre-anaesthetic medication,
2 to 4 mg/kg, IM swine
 For immobilization or knockdown, 5 to 10 mg/kg, IM swine

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