Sedatives

Question 1

What are sedatives and what are they used for?

Answer 1

• A sedative is a substance that induces sedation by reducing irritability or excitement; some provide analgesia
• used to relax/calm an animal (e.g.,trimming nails, taking X-rays, or drawing blood)
• commonly used in combinations as preanesthetics before general anesthesia to relax and sedate the animal

Question 2

Name the types of sedatives

Answer 2

• Tranquilizers
– Phenothiazines
– Butyrophenones
– Benzodiazepines
-Alpha-2 agonists

Question 3

What are hypnotics?

Answer 3

• Hypnotics – drugs inducing sleep.

Question 4

What are tranquilizers? Define major and minor tranquilizers

Answer 4

• Tranquilizer – a drug that induces tranquility (a state of calmness) in an individual; used to reduce stress or tension without reducing mental clarity.

• Major tranquilizers: antipsychotics-neuroleptics; psychoactive drugs commonly, but not exclusively used to treat psychosis (schizophrenia) (phenothiazines, butyrophenones)
• Minor tranquilizers: anxiolytic or anti anxiety agents for treatment of symptoms of anxiety (benzodiazepines); ataractics

Question 5

What are phenothiazine derivatives and what are they used for?

Answer 5

• used in vet. med. as tranquilizers

-Phenothiazine is the parent compound for all the derivatives in this group.

Question 6

Effects of phenothiazine derivatives and structures that they depress

Answer 6

• the effects of phenothiazines on the CNS were described firstly as “neuroleptic” but “major tranquilizer” is used now
• animals are usually calm and easy to handle, but they may be aroused by and respond to stimuli in a normal fashion (e.g., biting, scratching, kicking)
- ALL exert a sedative action by depressing the brain stem and connections to the
cerebral cortex

Question 7

Name the phenothiazine derivatives

Answer 7

• acepromazine (ACP);
• promazine, and
• chlorpromazine

Question 8

What are phenothiazine derivatives classified as?

Answer 8

Sedatives/Hypnotics/Anxiolytics, alpha-adrenergic antagonists

Question 9

Phenothiazine derivatives mechanism of action

Answer 9

• The principal central activity is blockade of the effects of dopamine which is in charge of fine control of movement
• Phenothiazines inhibit central dopaminergic receptors (D2) - sedation and
tranquilization
- peripherally blocks norepinephrine at alpha1-adrenergic receptors to cause vasodilation and hypotension
• decrease spontaneous motor activity in animals

Question 10

Effect of high doses of phenothiazine derivatives

Answer 10

– cataleptic effects - animals will remain immobile in a fixed position for long
periods;
– extrapyramidal symptoms (rigidity, tremor, akinesia)

Question 11

Effects of phenothiazine derivatives on the musculoskeletal and analgesia???

Answer 11

MUSCULOSKELETAL
• provide good muscle relaxation
ANALGESIA
• little or no analgesic activity

Question 12

Indications for using phenothiazine derivatives

Answer 12

• for general sedation, pre-anesthetically
• commonly administered with opioids (e.g., morphine) to produce neuroleptic analgesia (neuroleptanalgesia); the combination produces synergic effects of each class
• to prevent nausea and vomiting and some have antihistamine properties

Question 13

Contraindications of using phenothiazine derivatives

Answer 13

• should be used cautiously in boxer dogs, brachiocephalic dogs, breeding stallions, and debilitated animals

Question 14

Species differences to phenothiazine derivatives

Answer 14

Horse
• Chlorpromazine - not recommended - extreme ataxia and altered mentation.
Dog
• familial line of boxer dogs have an exaggerated reaction to acepromazine -
sedation and hypotension are greater than expected
Pig
• Acepromazine prevents
occurrence of halothane-induced malignant hyperthermia.

Question 15

Describe acepromazine maleate

Answer 15

• Acepromazine is the most commonly used phenothiazine in vet. medicine.
• The primary use - as a preanesthetic agent in the dog, cat, and horse.
– It markedly potentiates barbiturates and facilitates handling and restraint of
animals.

Question 16

Describe promazine hydrochloride use

Answer 16

• Major use: preanesthetic agent to facilitate handling through its sedative action - permits smoother induction of anesthesia and reduces the amount of anesthetic required by 30-50%.
• Indicated in animals manifesting nervous behavior and excitability.
• It has value in alleviation of self-inflicted mutilation associated with otitis, pruritus, and eczemic conditions.
• The drug assists in handling of animals for radiographic diagnosis or therapy and in other procedures where restraint is required

Question 17

Describe chlorpromazine hydrochloride use

Answer 17

• primarily used as an antiemetic in dogs and cats, occasionally used as a preanesthetic sedative
• It is generally contraindicated for use with horses, due to a high incidence of ataxia and altered mentation.
• slight antihistaminic activity
• has been used in capture of African lions; for induction of neuroleptanalgesia in bears in combination with analgesic preparations.

Question 18

Effects of alpha-2 adrenergic agonists and name the active substances.

Answer 18

• produce profound sedation (the best sedatives one can use), provide chemical restraint, and produce analgesia (the only sedatives which are able to provide analgesia)
• Furthermore, make drug tolerance of opioids better and act synergistically with opioids.
• Commonly used alpha-2 agonists in vet. medicine:
– xylazine,
– detomidine,
– medetomidine and dexmedetomidine.

• detomidine is like a xylazine for larger
  animals. Produces less side effects
• the last two are for small animals

Question 19

Classification of alpha-2 adrenergic agonists

Answer 19

Sedatives/major tranquilizers that also possess significant analgesic properties and suppress the neuroendocrine stress response

Question 20

Describe in detail the mechanism of action of alpha-2 adrenergic agonists

Answer 20

• Alpha-2-adrenergic agonists exert their mechanism of action on the α2-
adrenergic and/or imidazoline receptors.
• The α2-adrenergic rec. - subtypes A, B and C.
• The major sedative and analgesic effects are mediated via the activation of the
α2A- adrenergic receptor subtype
• Activation of the α2- adrenergic receptor will inhibit the positive feedback mechanism for the release of norepinephrine from the presynaptic nerve endings
- the attenuation of norepinephrine decreases arousal (causes sedation) and inhibits the afferent pain pathway.
• also have some agonistic activity on the α1-adrenergic receptor
• Imidazoline receptors – mediate central hypotension, antiarrhythmogenesis. Xylazine is not considered an imidazoline receptor agonist.

Question 21

Effects of alpha-2 adrenergic agonists on the CNS

Answer 21

CNS
– Different species react differently to alpha-2 agonists (due to different receptor
subtypes - Ruminants have α2D-adrenergic receptors which makes them the most sensitive species to alpha-2 agonists!!!!!!!!!}
• Activation of α1-adrenergic receptors in the CNS will cause arousal, agitation,
increased locomotor activity, and vigilance - paradoxical excitement or movement.
• α2 -adrenergic agonists show profound anesthetic sparing effects with both
induction agents and inhalant agents (MAC=minimum alveolar concentration needed to induce general anesthesia-sparing of up to 90%).

Question 22

Effects of alpha-2 adrenergic agonists on the GIT and endocrine system

Answer 22

GIT
• xylazine may cause vomiting in up to 90% in cats and 30% in dogs - acts on
the area postrema (chemotactic trigger zone) in the cat to cause emesis.
ENDOCRINE STRESS RESPONSE
• The suppression of the stress response - a reduction in catecholamine levels via
their actions on both α2-adrenergic and imidazoline receptors.

Question 23

Indications of alpha-2 adrenergic agonists

Answer 23

• The α2-adrenergic agonists are major tranquilizers that are used in veterinary
patients for sedation, chemical restraint, and analgesia.
• Xylazine is also used as an emetic in feline patients.

Question 24

Alpha-2 adrenergic agonists drug interactions

Answer 24

• α2-adrenergic agonists potentiate the effects of other sedative agents,
barbiturates, propofol, ketamine, etomidate, and inhalational agents. – The dosage of induction agents is greatly reduced and there is a profound MAC-sparing effect.

Question 25

Species differences regarding alpha-2 adrenergic agonists

Answer 25

Ruminants are the most sensitive and small laboratory animals the least sensitive to alpha-2 adrenergic agonists. Cattle need 1/10 of the dose of xylazine compared with dogs

Question 26

Describe xylazine hydrochloride

Answer 26

• Xylazine is the α2-agonist most likely to cause vomiting in the dog, whereas almost all α2- agonists cause vomiting in cats.
-CATTLE: particularly sensitive - require ~ 1/10 the dose compared with other species.

Question 27

Describe Detomidine hydrochloride

Answer 27

• a sedative-anagesic used in the horse, bovines
• detomidine is the analgesic of choice for relieving equine colic pain
• Detomidine is an effective preanesthetic for horses and cattle.

Question 28

Describe medetomidine hydrochloride

Answer 28

• approved for use in dogs and cats

Question 29

Describe dexmedetomidine hydrochloride

Answer 29

• approved for use in the dog and cat.

* sedation and analgesia similar to medetomidine;

Question 30

Describe romifidine

Answer 30

• a more selective α2 -agonist than xylazine

Question 31

What are alpha2- adrenergic receptor antagonists

Answer 31

• Alpha-2-adrenergic receptor antagonists are used primarily to reverse the
effects of the α2-adrenergic agonists (CNS depression).
• The ability to reverse the α2- adrenergic agonists increases their appeal for use,
especially for the chemical restraint of exotic wildlife.
-alpha2- agonists and antagonists are extraordinarily similar compounds

Question 32

Name the alpha2-adrenergic receptor antagonists

Answer 32

• yohimbine,
• atipamezol (only one licensed for use in vet med.)
• tolazoline

Question 33

Describe atipamezole

Answer 33

-a highly specific α2 -receptor antagonist that was designed to reverse the effects
of medetomidine in dogs, cats, and exotic species.
-Contains 5x the amount of sedative so need to apply the same quantity as used when giving the sedative because will competitively compete for binding sites

Question 34

Mechanism of action of alpha2-receptor antagonists

Answer 34

• Drugs in this class are all alpha2-receptor ligands that are competitive antagonists at the receptor site.
• blocks the negative feedback loop on the regulation of the norepinephrine release from the presynaptic nerve endings of the sympathetic nervous system.

Question 35

What are benzodiazepine derivatives?

Answer 35

Benzodiazepines are sedative-hypnotics due to their propensity to cause:
– anxiolysis,
– sedation, and
– sleep.
• minor tranquilizers, or ataractics
• belong to controlled drugs
• Many benzodiazepines are used in people and animals for behavioral modification; as sedatives and adjuncts to anesthesia:

Question 36

Name the benzodiazepine derivatives

Answer 36

• diazepam,
• midazolam,
• lorazepam, and
• zolazepam.

Question 37

Mechanism of action of benzodiazepines.

Answer 37

-Benzodiazepines bind to and activate the benzodiazepine receptor binding site
(BZ receptor), which is located on the γ subunit of GABA .
• Agonism of the BZ binding site on GABA rec. increases the frequency of the
opening of the Cl ion channels -> hyperpolarization of the postsynaptic neuron -> decreased neuronalt ransmission-> hypnotic,sedative,anxiolytic, anticonvulsant, and skeletal muscle-relaxant effects.
-highest concentration of GABA receptors is in the cerebral cortex with very few outside the CNS hence the minimal cardiovascular effects of benzodiazepines.

Question 38

Effect of benzodiazepines on the CNS and cardiovascular system

Answer 38

CNS

• very important ANTICONVULSANT effect!!!
• Clinical doses - minimal cardiovascular depression

Question 39

Effect of benzodiazepines on the muscles. Analgesia?

Answer 39

• reliable muscle relaxation

- do not produce analgesia

Question 40

Indications of benzodiazepine derivatives

Answer 40

• anticonvulsants, premedicants, adjuncts to anesthetic induction agents, skeletal muscle relaxants and for behavioral modification.

Question 41

Describe diazepam hydrochloride and it’s use

Answer 41

-The anticonvulsant properties are useful in treatment of:
– status epilepticus,
– tetanus,
– convulsions caused by metaldehyde toxicity, by overdoses of local anesthetics…
– Generally, diazepam and related benzodiazepines have been recommended as 1st agents in treatment of convulsions of different origin.
• Diazepam can be used in:
– dogs, cats, horses (in combination with ketamine and xylazine – smooth induction
of and recovery from anesthesia - also in other species),
– swine, mink (to prevent aggressivenes),
– goats, cattle, lab. animals and exotic species (for immobilization).
• diazepam and related drugs should not be used in breeding animals (possible teratogenic effect)
-Appetite stimulant in cats and goats

Question 42

Describe midazolam maleate

Answer 42

midazolam is classified as short lasting, whereas diazepam as long lasting.

Question 43

Describe lorazepam

Answer 43

-used for long-term treatment of epilepsy

Question 44

What is flumazenil used for and how does it work?

Answer 44

• is a specific and exclusive benzodiazepine (BZ) competitive antagonist with a high affinity for the benzodiazepine receptor sites on GABA receptor, thus preventing hyperpolarization of the postsynaptic membrane