Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 5 ANESTHETIC AGENTS
X
R 3
C
(1) (6)
C (2)N
(5) C
H
(3) (4)
N C
Chemical structure
The injectable anesthetic agents are a diverse group of
unrelated chemicals. Thiopental and pentobarbital
belong to the barbituric acid group, which are classified
according to either duration of action or chemical substitutions
on the parent molecule. Thiopental is an ultrashort-acting
agent providing less than 15–20 min of
anesthesia after a single dose. Pentobarbital is classified
as a short-acting barbiturate, although it provides anesthesia
for 30–90 min after a single dose.
The barbiturates are derived from barbituric acid and
share a common basic structure (Fig. 5.4). Pentobarbital
is an oxybarbiturate having an oxygen atom at the
carbon 2 position (i.e. X=O). If this oxygen atom is
replaced by sulfur (X=S), a thiobarbiturate such as thiopental
is produced. This modification reduces the time
to onset and duration of action of the drug. Methohexital
is a third barbiturate anesthetic that is no longer
widely used. It is an oxybarbiturate with a methylated
nitrogen in position 1 (i.e. X=O, R 3 =CH 3 ). This methylation
also produces a drug with a more rapid onset
and shorter duration but unfortunately also confers
unwanted excitatory side effects.
Ketamine and tiletamine are dissociative anesthetic
agents, so-called because in humans they produce a
sense of dissociation from the body and the environment.
The remaining injectable anesthetics are an unrelated
group. Alphaxalone is a steroidal anesthetic,
propofol an alkylphenol and etomidate an imidazole
anesthetic agent.
General physical properties
O
O
Fig. 5.4 Basic structure of the barbiturates.
R 2
R 1
The barbiturates, ketamine, tiletamine and etomidate
have asymmetrical carbon atoms resulting in isomers
with varying potency. Other than etomidate, which is
available as a single active dextrorotatory isomer, all
other isomeric anesthetic agents are manufactured as
racemic mixtures. Potency is dependent upon the concentration
of active isomer, whereas side effects may be
produced by either form of the molecule.
General pharmacokinetics
Intravenously administered injectable anesthetics produce
a rapid smooth transition to unconsciousness
because, provided an adequate dose is given, the animal
passes through the first excitatory phases of anesthesia
within a matter of seconds. There are several factors that
determine the plasma (brain) concentration required to
produce anesthesia, the speed of onset and the duration
of anesthetic effect. The dose of drug administered has an
effect, as does the route of administration and, for some
intravenously administered drugs, the speed of injection.
After intravenous administration the injectable agents
are rapidly delivered to the brain and other organs with
high perfusion. There is simultaneous uptake by other
tissues, which is slower and of longer duration.
For agents that rely on redistribution for recovery
(thiopental), peak muscle uptake corresponds to a lightening
of anesthesia that occurs about 10–15 min after
administration. Recovery from agents with a shorter
duration of action (alphaxalone, propofol, etomidate)
is due to a combination of redistribution and rapid
metabolism. The injectable anesthetics are ultimately
biotransformed in the liver and other tissues and eliminated
in the urine and/or bile. The rate of transformation
varies with species, age, the physical condition of
the animal and the presence or absence of concurrently
administered drugs.
Mechanism of action
Studies have demonstrated that most injectable
anesthetic agents produce anesthesia by enhancing γ-
aminobutyric acid (GABA)-mediated neuronal transmission,
primarily at GABA A receptors. GABA is an
inhibitory neurotransmitter found throughout the CNS.
On binding to postsynaptic GABA A receptors, it causes
an increase in chloride conductance that results in cellular
hyperpolarization. Hyperpolarization inhibits or
depresses neuronal function. These receptors, in addition
to binding GABA, also bind benzodiazepines (diazepam,
midazolam), barbiturates, etomidate, propofol
and probably alphaxalone.
The dissociative anesthetic agents (ketamine and tiletamine)
do not produce a ‘true’ anesthetic state and they
do not appear to have an affect at the GABA receptor.
They induce a dissociative state and analgesia by acting
as antagonists of the excitatory amino acid glutamate
at NMDA receptors. The NMDA receptor is linked to
a calcium ion channel and by regulating calcium entry
is able to amplify excitatory signals. Ketamine (and
probably tiletamine) can block the channel, thus preventing
ion movement. Ketamine and tiletamine are not
generally administered as sole agents but are combined
with CNS depressants such as α 2 -agonists (xylazine,
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