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

546 nonflammable and non-explosive in mixtures of air or
oxygen. However, sevoflurane can undergo an exothermic
reaction with desiccated CO 2
absorbent (BARA-
LYME) to produce airway burns (Fatheree and Leighton,
2004) or spontaneous ignition, explosion, and fire
(Wu et al., 2004a).
Care must be taken to ensure that sevoflurane is
not used with an anesthesia machine in which the CO 2
absorbent has been dried by prolonged gas flow
through the absorbent. The reaction of sevoflurane with
desiccated CO 2
absorbent also can produce CO, which
can result in serious patient injury; this effect is less
than that with desflurane.
SECTION II
NEUROPHARMACOLOGY
Pharmacokinetics. The low solubility of sevoflurane in
blood and other tissues provides for rapid induction of
anesthesia, rapid changes in anesthetic depth following
changes in delivered concentration, and rapid emergence
following discontinuation of administration (Table 19–1).
Approximately 3% of absorbed sevoflurane is biotransformed.
Sevoflurane is metabolized in the liver by CYP2E1, with
the predominant product being hexafluoroisopropanol (Kharasch
et al., 1995). Hepatic metabolism of sevoflurane also produces
inorganic fluoride. Serum fluoride concentrations peak shortly
after surgery and decline rapidly. Interaction of sevoflurane with
soda lime also produces decomposition products. The major product
of interest is referred to as compound A, pentafluoroisopropenyl
fluoromethyl ether (see “Kidney” under “Side Effects”)
(Hanaki et al., 1987).
Clinical Use. Sevoflurane is widely used, particularly for outpatient
anesthesia, because of its rapid recovery profile. It is well-suited for
inhalation induction of anesthesia (particularly in children) because
it is not irritating to the airway. Induction of anesthesia is rapidly
achieved using inhaled concentrations of 2-4% sevoflurane.
Side Effects
Cardiovascular System. Sevoflurane, like all other halogenated
inhalational anesthetics, produces a concentration-dependent
decrease in arterial blood pressure. This hypotensive effect primarily
is due to systemic vasodilation, although sevoflurane also produces
a concentration-dependent decrease in cardiac output (Figure 19–6).
Unlike isoflurane or desflurane, sevoflurane does not produce tachycardia
and thus may be a preferable agent in patients prone to
myocardial ischemia.
Respiratory System. Sevoflurane produces a concentration-dependent
reduction in tidal volume and increase in respiratory rate in spontaneously
breathing patients. The increased respiratory frequency does
not compensate for reduced tidal volume, with the net effect being
a reduction in minute ventilation and an increase in Pa CO2
(Doi and
Ikeda, 1987) (Figure 19–7). Sevoflurane is not irritating to the airway
and is a potent bronchodilator. Because of this combination of properties,
sevoflurane is the most effective clinical bronchodilator of the
inhalational anesthetics (Rooke et al., 1997).
Nervous System. Sevoflurane produces effects on cerebral vascular
resistance, cerebral metabolic O 2
consumption, and cerebral blood
flow that are very similar to those produced by isoflurane and desflurane.
Its cerebral vasodilating capacity is less than that of isoflurane,
and particularly desflurane. At ~2 MAC anesthesia, sevoflurane
produces burst suppression of the EEG, and at this level, CMRO 2
is
reduced by ~50%. While sevoflurane can increase intracranial pressure
in patients with poor intracranial compliance, the response to
hypocapnia is preserved during sevoflurane anesthesia, and increases
in intracranial pressure can be prevented by hyperventilation. In children,
sevoflurane is associated with delirium upon emergence from
anesthesia. This delirium, the causes of which are not clear, is short
lived and without any reported adverse long-term sequelae.
Muscle. Sevoflurane produces skeletal muscle relaxation and
enhances the effects of non-depolarizing and depolarizing neuromuscular
blocking agents. Its effects are similar to those of other
halogenated inhalational anesthetics.
Kidney. Controversy has surrounded the potential nephrotoxicity of
compound A, the degradation product produced by interaction of
sevoflurane with the CO 2
absorbent soda lime. Biochemical evidence
of transient renal injury has been reported in human volunteers (Eger
et al., 1997). Large clinical studies have shown no evidence of
increased serum creatinine, blood urea nitrogen, or any other evidence
of renal impairment following sevoflurane administration
(Mazze et al., 2000). The FDA recommends that sevoflurane be
administered with fresh gas flows of at least 2 L/min to minimize
accumulation of compound A.
Liver and GI Tract. Sevoflurane is not known to cause hepatotoxicity
or alterations of hepatic function tests.
Nitrous Oxide
Nitrous oxide (dinitrogen monoxide; N 2
O) is a colorless,
odorless gas at room temperature (Figure 19–4).
N 2
O is sold in steel cylinders and must be delivered through
calibrated flow meters provided on all anesthesia machines. Nitrous
oxide is neither flammable nor explosive, but it does support combustion
as actively as oxygen does when it is present in proper concentration
with a flammable anesthetic or material.
Pharmacokinetics. Nitrous oxide is very insoluble in
blood and other tissues (Table 19–1). This results in
rapid equilibration between delivered and alveolar
anesthetic concentrations and provides for rapid induction
of anesthesia and rapid emergence following discontinuation
of administration.
The rapid uptake of N 2
O from alveolar gas serves to concentrate
co-administered halogenated anesthetics; this effect (the “second
gas effect”) speeds induction of anesthesia. On discontinuation
of N 2
O administration, nitrous oxide gas can diffuse from blood to
the alveoli, diluting O 2
in the lung. This can produce an effect called
diffusional hypoxia. To avoid hypoxia, 100% O 2
rather than air
should be administered when N 2
O is discontinued.
Nitrous oxide is almost completely eliminated by the lungs,
with some minimal diffusion through the skin. Nitrous oxide is not
biotransformed by enzymatic action in human tissue, and 99.9% of
absorbed nitrous oxide is eliminated unchanged. N 2
O can oxidize