Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 6 SEDATIVES
● noradrenaline (norepinephrine)
● dopamine
● 5-hydroxytryptamine
● acetylcholine
● histamine.
Glutamate, GABA and glycine
Glutamate, GABA and glycine are amino acid transmitters.
Glutamate is the principal excitatory amino acid
transmitter in the CNS. It acts at four main types of
receptor: NMDA, AMPA, kainate and metabotropic
receptors. NMDA and metabotropic receptors are
involved in the development of adaptive responses that
modulate synaptic transmission, known collectively as
synaptic plasticity. These responses have a role in both
physiological (e.g. learning) and pathological processes
(e.g. facilitation of central nociceptive transmission in
chronic pain states). The dissociative anesthetic ketamine
blocks the channel associated with the NMDA
receptor (see p. 104).
The principal inhibitory neurotransmitter in the CNS
is GABA. There are two types of GABA receptor:
GABA A and GABA B . The benzodiazepines owe their
sedative action to facilitation of this inhibitory neurotransmitter,
binding to a discrete site on the GABA A
receptor.
Glycine is primarily an inhibitory transmitter found
in the gray matter of the spinal cord. However, it is also
a coagonist for NMDA receptors and in this context
may be considered excitatory.
Noradrenaline (norepinephrine)
Noradrenergic transmission in the CNS appears to be
important in control of alertness and mood and in
the regulation of blood pressure. As in the periphery,
adrenoceptors are recognized and further divided into
subtypes, i.e. α 1 , α 2 , β 1 , β 2 and β 3 . While noradrenaline
(norepinephrine) appears to have an inhibitory effect
on individual brain cells, mediated primarily via β-
receptors, excitatory effects may also be observed at
both α- and β-receptors. The α 2 -adrenoceptor agonists
owe their sedative action to effects on central noradrenergic
transmission.
Dopamine
Dopamine, a precursor of noradrenaline (norepinephrine),
has a role in the control of movement and in
aspects of behavior. There are two families of dopamine
receptor: D 1 and D 2 . The D 2 group appears more important
in the CNS and comprises D 2 , D 3 and D 4 receptors.
The D 1 group is subdivided into D 1 and D 5 receptors.
The sedative action of the phenothiazines and the butyrophenones
has been ascribed to dopamine antagonism,
primarily at the D 2 family of receptors. Since dopaminergic
neurones are also involved in the production of
nausea and vomiting, these drugs have additional antiemetic
activity.
5-Hydroxytryptamine
Various functions have been attributed to 5-hydroxytryptamine
(5-HT). These include the regulation of
sensory pathways and the control of mood, wakefulness,
feeding behavior and vomiting. An equally large
number of receptor types and subtypes have been identified,
although receptors belonging to the 5-HT 1 , 5-HT 2
and 5-HT 3 groups are probably the most important in
the CNS. While none of the veterinary sedatives act
principally on 5-HT pathways, the phenothiazines and
butyrophenones have mild 5-HT 2 blocking effects.
Acetylcholine
Functions associated with acetylcholine in the CNS
include arousal, learning, memory and motor control.
Muscarinic receptors appear to be more important,
although nicotinic receptors are also present. The effects
of acetylcholine are mostly excitatory, although inhibition
may be seen at some central muscarinic receptors.
Histamine
Histaminergic pathways have been described in the
brain, and H 1 , H 2 and H 3 receptors have been identified.
The central functions of histamine are poorly understood,
although involvement in the control of wakefulness
seems likely, since H 1 -receptor antagonists induce
sedation as a side effect. The phenothiazines have variable
H 1 -receptor blocking activity.
CLASSES OF SEDATIVE/TRANQUILIZER
Phenothiazines
EXAMPLES
Acepromazine, chlorpromazine, promethazine, promazine,
prochlorperazine.
Clinical applications
Phenothiazines may be classed as tranquilizers, neuroleptics
or antipsychotics. Acepromazine is the drug most
commonly used and is licensed for use in the dog and
cat in most countries. It is used to facilitate the handling
or restraint of patients and is often employed as a premedicant
prior to general anesthesia.
Low doses of acepromazine have a general calming
effect. Increasing the dose will induce a degree of seda-
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