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

F A /F I
1
0.5
Nitrous
Oxide
Desflurane
Sevoflurane
Isoflurane
Halothane
0
0
0 10 20 30
Minutes
Figure 19–5. Uptake of inhalational general anesthetics. The
rise in end-tidal alveolar (F A
) anesthetic concentration toward
the inspired (F I
) concentration is most rapid with the least soluble
anesthetics, nitrous oxide and desflurane, and slowest with
the most soluble anesthetic, halothane. All data are from human
studies. (Reproduced with permission from Eger EI, II: Inhaled
anesthetics: Uptake and distribution, in Miller RD et al, (eds):
Miller’s Anesthesia, 7th ed. Philadelphia: Churchill Livingstone,
2010, p 540. Copyright © Elsevier.)
because fat represents a huge anesthetic reservoir that
will be filled only slowly because of the modest blood
flow to fat. This is illustrated by the slow approach of
halothane alveolar partial pressure to inspired partial
pressure of halothane in Figure 19–5.
In considering the pharmacokinetics of anesthetics,
one important parameter is the speed of anesthetic
induction. Anesthesia is produced when anesthetic partial
pressure in brain is equal to or greater than MAC.
Because the brain is well perfused, anesthetic partial
pressure in brain becomes equal to the partial pressure
in alveolar gas (and in blood) over the course of several
minutes. Therefore, anesthesia is achieved shortly
after alveolar partial pressure reaches MAC. While the
rate of rise of alveolar partial pressure will be slower
for anesthetics that are highly soluble in blood and other
tissues, this limitation on speed of induction can be
overcome largely by delivering higher inspired partial
pressures of the anesthetic.
Elimination of inhalational anesthetics is largely
the reverse process of uptake. For agents with low
blood and tissue solubility, recovery from anesthesia
should mirror anesthetic induction, regardless of the
duration of anesthetic administration. For inhalational
agents with high blood and tissue solubility, recovery
will be a function of the duration of anesthetic administration.
This occurs because the accumulated amounts
1
0.5
of anesthetic in the fat reservoir will prevent blood (and
therefore alveolar) partial pressures from falling rapidly.
Patients will be arousable when alveolar partial
pressure reaches MAC awake
, a partial pressure somewhat
lower than MAC (Table 19–1).
Halothane
Halothane is 2-bromo-2-chloro-1,1,1-trifluoroethane
(Figure 19–4). Halothane is a volatile liquid at room
temperature and must be stored in a sealed container.
Because halothane is a light-sensitive compound that
also is subject to spontaneous breakdown, it is marketed
in amber bottles with thymol added as a preservative.
Mixtures of halothane with O 2
or air are neither flammable
nor explosive.
Pharmacokinetics. Halothane has a relatively high
blood:gas partition coefficient and high fat:blood partition
coefficient (Table 19–1). Induction with halothane
therefore is relatively slow, and the alveolar halothane
concentration remains substantially lower than the
inspired halothane concentration for many hours of
administration. Because halothane is soluble in fat and
other body tissues, it will accumulate during prolonged
administration. Therefore, the speed of recovery from
halothane is lengthened as a function of duration of
administration.
Approximately 60-80% of halothane taken up by the body is
eliminated unchanged by the lungs in the first 24 hours after its
administration. A substantial amount of the halothane not eliminated
in exhaled gas is biotransformed by hepatic CYPs. The major
metabolite of halothane is trifluoroacetic acid, which is formed by
removal of bromine and chlorine ions. Trifluoroacetic acid, bromine,
and chlorine all can be detected in the urine. Trifluoroacetylchloride,
an intermediate in oxidative metabolism of halothane, can trifluoroacetylate
several proteins in the liver. An immune reaction to these
altered proteins may be responsible for the rare cases of fulminant
halothane-induced hepatic necrosis. A minor reductive pathway
accounts for ~1% of halothane metabolism that generally is observed
only under hypoxic conditions.
Clinical Use. Halothane, introduced in 1956, was the
first modern, halogenated inhalational anesthetic used
in clinical practice. It is a potent agent that usually is
used for maintenance of anesthesia. It is not pungent
and is therefore well tolerated for inhalation induction
of anesthesia. This is most commonly done in children,
in whom preoperative placement of an intravenous
catheter can be difficult. Anesthesia is produced by
halothane at end-tidal concentrations of 0.7-1%. The
use of halothane in the U.S. has diminished substantially
in the past decade because of the introduction of
newer inhalational agents with better pharmacokinetic
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CHAPTER 19
GENERAL ANESTHETICS AND THERAPEUTIC GASES