Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CLASSES OF SEDATIVE/TRANQUILIZER
Noradrenergic
nerve terminal
Presynaptic
membrane
Postsynaptic
membrane
Noradrenaline
α 1
Inhibition
Fig. 6.1 a 2 -Receptors are located on both the pre- and
postsynaptic membranes. Activation of postsynaptic a 2 -
receptor initiates a response similar to that following
a 1 -receptor stimulation, while activation of presynaptic
a 2 -receptors serves to reduce further noradrenaline
(norepinephrine) release.
inhibition of impulse transmission. Sedation has been
attributed to depression of neurones in the locus ceruleus,
a region of the lower brainstem through which
impulses are transmitted to the forebrain and limbic
system.
α 2 -Adrenoceptors are G protein-coupled receptors
linked to the cAMP second messenger system. Activation
of the α 2 -receptor inhibits adenylate cyclase and
thereby reduces cAMP. Other effector mechanisms
include opening of potassium channels and reduced
calcium entry. Three different α 2 -adrenoceptor subtypes
have been identified: α 2a , α 2b and α 2c . Recent studies
have clarified the role of individual subtypes; for
example, α 2a -adrenoceptors appear to mediate sedation,
analgesia and hypotension while the α 2b -adrenoceptor
mediates vasoconstriction and hypertension (i.e. postsynaptic
α 2 -adrenoceptors are probably of the α 2b
subtype).
The α 2 -agonists in veterinary use are not truly specific
to α 2 -receptors and most exert some α 1 effects in addition.
Medetomidine is the most selective, having an
α 2 :α 1 selectivity ratio of 1620:1. Romifidine, detomidine
and xylazine are much less selective, having α 2 :α 1 ratios
of 340:1, 260:1 and 160:1 respectively. In addition,
α 2
α 2
some α 2 -agonists (detomidine and the dextrorotatory
isomer of medetomidine) also activate imidazoline
receptors.
Formulations and dose rates
Xylazine
Dogs
• 1–3 mg/kg IV, IM (preferred) or SC
Cats
• 3 mg/kg IM
Medetomidine
Dogs
• 10–40 µg/kg in dogs IV, IM or SC
Cats
• 40–80 µg/kg in cats IM or SC
Lower doses, 2–10 µg/kg IM, will produce suffi cient sedation for
premedication when combined with an opioid. Lower doses should
also be used if the drug is to be administered intravenously.
Romifidine
Dogs
• 40–120 µg/kg IM, IV or SC
Cats
• 200–400 µg/kg IM or IV
As for medetomidine, lower doses may be effective if combined with
an opioid.
Pharmacokinetics
The chemical structures of the α 2 -agonists are as
follows.
● Xylazine: 2-(2,6-dimethyl phenylamino)-4H-5,6-
dihydro-1,3-thiazine
● Medetomidine: 4-(2,3-dimethylphenyl)ethyl-1
H-imidazole
Medetomidine is a racemic mixture of two optical
isomers: dexmedetomidine and levomedetomidine. Dexmedetomidine
is the active enantiomer and has a potency
approximately twice that of the racemic mixture (i.e.
approximately half the dose is required). Dexmedetomidine
is likely to be available separately in the near
future.
For optimum activity, α 2 -agonists should be administered
by intravenous or intramuscular injection. They
are generally active within 3–5 min following intravenous
administration but may take 10–20 min to reach
full effect if the intramuscular route is used. Bioavailability
of xylazine following intramuscular injection
ranges from 52% to 90% in the dog. Absorption
from subcutaneous sites is very variable and this route
is not recommended. The duration of effect varies
according to the drug used and also the dose. A single
standard dose of xylazine will produce sedation of 30–
40 min duration, while medetomidine and romifidine
have a longer action, lasting for 60–90 or 60–120 min
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