Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

INHALATION ANESTHETIC AGENTS
relatively insoluble in blood. This factor, coupled with
a low solubility in tissues, accounts for the more rapid
rate of onset, recovery and change of anesthetic depth
associated with this agent.
However, the oil:gas partition coefficient is low, hence
the low potency and high MAC of desflurane (7.2% in
the dog).
Metabolism and elimination
A further desirable feature of desflurane is its low rate
of biotransformation. In people, as little as 0.02% of
the inhaled dose of desflurane undergoes metabolism.
Adverse effects
Central nervous system effects
Desflurane is typical of the inhalation anesthetics, reducing
cerebral metabolic rate while increasing cerebral
blood flow and thereby intracranial pressure. As for
isoflurane and sevoflurane, the responsiveness of the
cerebral vasculature to carbon dioxide is maintained. In
addition, desflurane may have an unfavorable effect on
CSF pressure, which tends to increase.
Cardiovascular effects
Cardiac output is frequently maintained at clinically
useful concentrations, as it is for isoflurane and sevoflurane.
Rapid increases in the inspired concentration of
desflurane may elevate plasma levels of catecholamines
leading to increases in heart rate and arterial blood
pressure. Despite this, desflurane does not appear to
sensitize the myocardium to adrenaline (epinephrine)-
induced arrhythmias.
Respiratory effects
Desflurane produces dose-dependent depression of
respiratory function. High inspired concentrations cause
airway irritation, coughing, breath holding and laryngospasm
in people and so this agent is not suitable for
mask induction.
Hepatic and renal effects
Although desflurane undergoes limited biotransformation,
trifluoroacetic acid is a potential metabolite. Cases
of desflurane-induced hepatitis have been reported
although the incidence is extremely low. Desflurane
causes minimal depression of renal blood flow and there
is no evidence of nephrotoxicity.
Methoxyflurane
Methoxyflurane was once a popular inhalation agent,
used primarily in small animal anesthesia. However,
it has been largely superseded by newer, safer agents.
Today it is mainly of interest as an example of a less
than ideal volatile anesthetic.
Pharmacokinetics
Chemical and physical properties
Methoxyflurane is a halogenated ether (see Fig. 5.1). It
is nonflammable but unstable and so an antioxidant
preservative must be included. It has an unusually low
vapor pressure (see Table 5.2) so does not readily evaporate.
This feature may limit the usefulness of an inhalation
anesthetic, i.e. if a therapeutic vapor concentration
cannot be achieved. In this case the impact of low vapor
pressure is largely offset by the high potency of
methoxyflurane.
Solubility
The blood:gas partition coefficient for methoxyflurane
is high, so induction, recovery and rate of change of
anesthetic depth are slowed. This is compounded by a
high solubility in the tissues, particularly fat.
Furthermore, methoxyflurane has a high solubility in
rubber and will dissolve in components of the breathing
system.
Methoxyflurane is an extremely potent inhalation
anesthetic as indicated by its very high oil:gas partition
coefficient and extremely low MAC value – 0.29% in
the dog.
Metabolism and elimination
Methoxyflurane undergoes extensive hepatic biotransformation
and as much as 50% of the inhaled agent is
metabolized in people. The main metabolites are fluoride,
dichloroacetic acid and oxalic acid. Recent studies
have shown that methoxyflurane also undergoes significant
metabolism to fluoride within the kidney itself.
Adverse effects
The side effects of methoxyflurane are typical of the
older inhalation agents such as halothane.
Central nervous system effects
Methoxyflurane is an extremely potent anesthetic. Some
authors suggest that it also possesses analgesic properties
that extend into the recovery period, but it is unclear
if this simply reflects the delayed recovery from this
agent.
Cardiovascular effects
Like halothane, methoxyflurane depresses myocardial
contractility, reducing cardiac output and arterial blood
pressure. It is also capable of sensitizing the heart to
adrenaline (epinephrine)-induced arrhythmias, but this
effect is much less common than with halothane.
Renal effects
Free fluoride, the main metabolite of methoxyflurane,
is potentially nephrotoxic. Traditionally the risk of
nephrotoxicity has been correlated to plasma fluoride
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