DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

the cobalt I (Co + ) form of vitamin B 12
to Co 3+ (Sanders et al., 2007),
thereby preventing vitamin B 12
from acting as a co-factor for methionine
synthetase. The latter is important in the synthesis of a number
of products including DNA, RNA, and myelin. Indeed, methionine
synthetase activity is dramatically reduced after 3-4 hours of N 2
O
exposure; activity of the enzyme is restored in 3-4 days. Inactivation
of methionine synthetase can produce signs of vitamin B 12
deficiency,
including megaloblastic anemia and peripheral neuropathy.
This is of particular concern in patients with malnutrition, vitamin
B 12
deficiency, or alcoholism. For this reason, N 2
O is not used as a
chronic analgesic or as a sedative in critical care settings.
Clinical Use. N 2
O is a weak anesthetic agent that has
significant analgesic effects. Noncompetitive antagonist
activity at the NMDA receptor contributes to its
anesthetic mechanism. However, surgical anesthetic
depth is only achieved under hyperbaric conditions. By
contrast, analgesia is produced at concentrations as low
as 20%.
The analgesic property of N 2
O is a function of the activation
of opioidergic neurons in the periacqueductal gray matter (Fang et al.,
1997) and the adrenergic neurons in the locus ceruleus (Sawamura
et al., 2000). At least part of the activation of the locus ceruleus is due
to release of corticotrophin-releasing factor from the hypothalamus
as a result of antagonism of the NMDA receptor.
In doses approaching 70-80%, significant sedation is produced.
Therefore, N 2
O is frequently used in concentrations of ~50%
to provide analgesia and mild sedation in outpatient dentistry.
Nitrous oxide cannot be used at concentrations > 80% because this
limits the delivery of adequate O 2
. Because of this limitation, nitrous
oxide is used primarily as an adjunct to other inhalational or intravenous
anesthetics. Nitrous oxide substantially reduces the requirement
for inhalational anesthetics. For example, at 70% nitrous oxide,
the MAC for other inhalational agents is reduced by ~60%, allowing
for lower concentrations of halogenated anesthetics and a lesser
degree of side effects.
One major problem with N 2
O is that it will exchange with N 2
in any air-containing cavity in the body. Moreover, because of their
differential blood:gas partition coefficients, nitrous oxide will enter
the cavity faster than nitrogen escapes, thereby increasing the volume
and/or pressure in this cavity. Examples of air collections that
can be expanded by nitrous oxide include a pneumothorax, an
obstructed middle ear, an air embolus, an obstructed loop of bowel,
an intraocular air bubble, a pulmonary bulla, and intracranial air.
Nitrous oxide should be avoided in these clinical settings.
Side Effects
Cardiovascular System. Although N 2
O produces a negative inotropic
effect on heart muscle in vitro, depressant effects on cardiac function
generally are not observed in patients because of the stimulatory
effects of nitrous oxide on the sympathetic nervous system. The cardiovascular
effects of nitrous oxide also are heavily influenced by the
concomitant administration of other anesthetic agents. When nitrous
oxide is co-administered with halogenated inhalational anesthetics,
it generally produces an increase in heart rate, arterial blood pressure,
and cardiac output. In contrast, when nitrous oxide is co-administered
with an opioid, it generally decreases arterial blood pressure and
cardiac output. Nitrous oxide also increases venous tone in both the
peripheral and pulmonary vasculature. The effects of N 2
O on pulmonary
vascular resistance can be exaggerated in patients with preexisting
pulmonary hypertension; thus, the drug generally is not used
in these patients.
Respiratory System. N 2
O causes modest increases in respiratory rate
and decreases in tidal volume in spontaneously breathing patients.
The net effect is that minute ventilation is not significantly changed
and PaCO 2
remains normal. However, even modest concentrations of
nitrous oxide markedly depress the ventilatory response to hypoxia.
Thus, it is prudent to monitor arterial O 2
saturation directly in
patients receiving or recovering from nitrous oxide.
Nervous System. When administered alone, nitrous oxide can significantly
increase cerebral blood flow and intracranial pressure. This
cerebral vasodilatory capacity of N 2
O is significantly attenuated by
the simultaneous administration of intravenous agents such as opiates
and propofol. By contrast, the combination of N 2
O and inhaled
agents results in greater vasodilation than the administration of the
inhaled agent alone at equivalent anesthetic depth.
Muscle. Nitrous oxide does not relax skeletal muscle and does not
enhance the effects of neuromuscular blocking drugs. Unlike the
halogenated anesthetics, nitrous oxide does not trigger malignant
hyperthermia.
Kidney, Liver, and GI Tract. Nitrous oxide is not known to produce
any changes in renal or hepatic function and is neither nephrotoxic
nor hepatotoxic.
Xenon
Xenon is an inert gas that first was identified as an anesthetic
agent in 1951. It is not approved for use in the
U.S. and is unlikely to enjoy widespread use because it
is a rare gas that cannot be manufactured and must be
extracted from air. This limits the quantities of available
xenon gas and renders xenon very expensive.
Recent advances in the manufacturing technology, coupled
with development of low-flow circuit systems that
permit recycling of xenon, have led to a resurgence in
the interest in xenon as an anesthetic agent. Much of
this enthusiasm is based on the observation that xenon,
unlike other anesthetic agents, has minimal cardiorespiratory
side effects (Lynch et al., 2000).
Xenon exerts its analgesic and anesthetic effects at
a number of receptor systems in the CNS. Of these, noncompetitive
antagonism of the NMDA receptor and agonism
at the TREK channel (a member of the two-pore
K+ channel family) are thought to be the central mechanisms
of xenon action (Franks and Honore, 2004).
Xenon is extremely insoluble in blood and other
tissues, providing for rapid induction and emergence
from anesthesia (Table 19–1). It is sufficiently potent to
produce surgical anesthesia when administered with 30%
oxygen. However, supplementation with an intravenous
agent such as propofol appears to be required for clinical
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CHAPTER 19
GENERAL ANESTHETICS AND THERAPEUTIC GASES