Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 5 ANESTHETIC AGENTS
concentrations, which reflect hepatic metabolism.
However, methoxyflurane also undergoes metabolism
to fluoride within the kidney and this intrarenal production
of fluoride appears to be a key factor in the development
of nephrotoxicity (compare sevoflurane).
High-output renal failure has been recorded in people
anesthetized with methoxyflurane. In dogs anesthetized
with this agent increased serum concentrations of fluoride
have been documented; however, reports of renal
damage are limited to dogs given additional nephrotoxic
drugs, such as nonsteroidal anti-inflammatories.
Known drug interactions
As for halothane, metabolism of methoxyflurane may
be enhanced by microsomal enzyme inducers such as
phenobarbital.
Nitrous oxide
Clinical applications
Nitrous oxide is used primarily as an adjunct to anesthesia
induced and maintained by other agents. It is not
sufficiently potent to be used alone; however, its use at
relatively high inspired concentrations may be advantageous
in selected patients. Nitrous oxide is unusual in
having analgesic properties, but inspired concentrations
of 50% and greater are needed if it is to contribute significantly
to analgesia and anesthesia. This inevitably
reduces the inspired concentration of oxygen and an
upper limit of 66% inspired nitrous oxide (or minimum
33% inspired oxygen) should be observed to avoid
hypoxemia.
The main indication for using nitrous oxide is as part
of a balanced anesthetic technique, i.e. its use allows a
reduction in the inspired concentration of the more
potent volatile agent with an associated decrease in
adverse effects. Nitrous oxide may also be useful at
induction: its addition to the inspired gases speeds the
onset of anesthesia.
Pharmacokinetics
Chemical and physical properties
Nitrous oxide (N 2 O) is an example of an anesthetic gas.
It is nonirritant and nonflammable, although it can
support combustion. It is supplied in cylinders as a
liquid under increased pressure (approximately 50
atmospheres – 5000 kPa). Cylinders must be weighed to
determine the quantity of nitrous oxide remaining, since
a pressure gauge will not accurately reflect the contents
of the cylinder. Pressure gauges measure the pressure of
the gas overlying the liquid phase and this will not
change until all the liquid has evaporated, i.e. the pressure
gauge will indicate that the cylinder is full until it
is almost empty.
Solubility
If nitrous oxide is used in combination with a second
agent, such as halothane, the speed of anesthetic induction
is increased. Two factors contribute to this. Nitrous
oxide has a very low blood:gas partition coefficient (see
Table 5.2); therefore any contribution to anesthesia by
nitrous oxide is extremely rapid in onset. More importantly,
since nitrous oxide is used in high concentrations,
uptake from the alveoli of a relatively large
volume of nitrous oxide has a concentrating effect on
the second agent and the alveolar partial pressure of
that agent rises more rapidly as a result. This has been
termed the second gas effect.
The inclusion of nitrous oxide in the inspired gas
mixture may cause expansion of gas-filled spaces within
the body. This effect is rarely important in normal
animals, with the possible exception of adult ruminants.
However, it may be significant in situations where a
closed gas space contributes to cardiovascular or respiratory
compromise, e.g. pneumothorax or gastric dilation
and volvulus. The use of nitrous oxide in such
patients is contraindicated. Expansion of such air-filled
spaces arises because nitrous oxide diffuses in more
rapidly than nitrogen can diffuse out and this is primarily
a consequence of nitrogen’s extremely low solubility
in blood (blood:gas partition coefficient for nitrogen =
0.015).
This unequal exchange of nitrous oxide and nitrogen
may also lead to complications at the end of anesthesia
when the nitrous oxide is turned off and the patient is
breathing room air. Nitrous oxide diffuses out of the
blood and back into the alveoli more rapidly than nitrogen
can diffuse from the alveoli into the blood. This
tends to reduce the alveolar oxygen concentration,
leading to diffusion or dilutional hypoxia. To avoid this
complication patients should be maintained on oxygen
for approximately 10 min after the nitrous oxide has
been turned off.
The oil:gas partition coefficient of nitrous oxide is
very low and this is associated with its low potency and
high MAC value. In fact, the MAC is so high (>200%)
that it cannot be achieved, hence nitrous oxide is used
as an adjunct to anesthesia, not as the sole agent.
Metabolism and elimination
Nitrous oxide is extremely stable and undergoes virtually
no metabolism. Reduction to nitrogen, mediated
by anaerobic intestinal bacteria, occurs to a limited
extent.
Adverse effects
Central nervous system effects
Nitrous oxide has analgesic properties and has recently
been shown to be an N-methyl-D-aspartate (NMDA)
receptor antagonist. This receptor is crucial in the
94