Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 6 SEDATIVES
respectively. Higher doses have more prolonged effects
and for all α 2 -agonists, complete recovery may take
several hours.
α 2 -Agonists undergo extensive first-pass metabolism
and so activity is poor following oral administration.
These drugs may, however, be absorbed through the
oral and pharyngeal mucosa and sedation has been
reported after squirting α 2 -agonists into the mouths of
fractious patients.
These agents have also been administered into the
epidural space to achieve analgesia. This results primarily
from inhibition of nociceptive transmission at the
level of the dorsal horn cells in the spinal cord, although
local anesthetic-like effects have also been described
following epidural administration of xylazine. Systemic
side effects are generally less evident if this route is used
but they do still occur. Duration of action is extended.
In a study conducted in dogs, epidural administration
of 15 µg/kg medetomidine produced analgesia for
4–8 h.
α 2 -Agonists are lipid-soluble drugs that are therefore
widely distributed. Medetomidine is very lipophilic and
has a high volume of distribution, 2.8 L/kg in the dog
and 3.5 L/kg in the cat. The volume of distribution of
xylazine is slightly less, ranging from 1.9 to 2.7 L/kg.
α 2 -Agonists are not extensively bound to plasma
proteins.
Xylazine is metabolized by hepatic mono-oxygenases.
Hydroxylated metabolites undergo glucuronide conjugation
(except in cats), prior to excretion in the urine.
The elimination half-lives for xylazine and medetomidine
in the dog are respectively 30 min and 1–1.6 h.
Adverse effects
Central nervous system effects
● α 2 -Agonists appear to have both anti- and proconvulsant
effects. This may be related, at least in part,
to dose. Low doses of dexmedetomidine have been
shown to raise the seizure threshold, whereas high
doses tend to lower it. In addition, low doses may
have neuroprotective properties. Convulsions have
been reported following inadvertent intracarotid
injection of xylazine and this may reflect high plasma
concentrations in blood reaching the brain.
● Alterations in body temperature, both increased and
decreased, have been reported in animals sedated
with α 2 -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 this species indicate that α 2 -agonists may induce a
degree of cutaneous hypersensitivity.
Cardiovascular effects
● The α 2 -agonists exert profound effects on the cardiovascular
system, even when low doses are used.
Indeed, the hemodynamic effects of IV medetomidine
have been shown to be almost maximal at doses of
5 µg/kg in the dog. Similarly for romifidine, increasing
the dose beyond 25 µg/kg IV appears to produce
little additional alteration in cardiovascular
function.
● 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.
● Effects on vascular tone and thereby arterial blood
pressure are complex. Activation of peripheral postsynaptic
α 2 - and α 1 -receptors (NB: α 2 -agonists are
not specific) leads to vasoconstriction. In contrast,
activation of central and peripheral presynaptic α 2 -
receptors tends to cause vasodilation through reductions
in noradrenaline (norepinephrine) release and
sympathetic outflow.
● The balance of these effects influences blood
pressure. Theoretically, 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. Studies conducted in experimental
dogs have confirmed the biphasic nature of the blood
pressure response to intravenous medetomidine or
romifidine. The extent of the hypertensive phase is
variable, being influenced by the dose and the route
of administration. It is more evident if the α 2 -agonist
is administered intravenously and if high doses are
used. These studies have also confirmed that arterial
blood pressure subsequently falls below baseline
values, although hypotension (i.e. mean arterial
blood pressure less than 80 mmHg) was not seen at
the doses used.
● Despite causing relatively little direct myocardial
depression, α 2 -agonists cause a marked reduction in
cardiac output, primarily as a consequence of bradycardia,
although increased afterload may contribute.
Central venous pressure tends to increase as a result.
Anticholinergics, such as atropine and glycopyrrolate,
have been recommended to both prevent and
treat α 2 -agonist induced bradycardias. However,
their use is questionable since they tend to cause
tachycardia and extend the hypertensive phase,
thereby producing further reductions in cardiac
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