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

Minute volume (liters/min) Pa CO2 (mm Hg)
90
80
70
60
50
40
30
10
9
8
7
6
5
4
3
2
Desflurane
Sevoflurane
Enflurane
Halothane
Isoflurane
0
0 1
2
[Anesthetic] (MAC units)
Figure 19–7. Respiratory effects of inhalational anesthetics.
Spontaneous ventilation with all of the halogenated inhalational
anesthetics reduces minute volume of ventilation in a dose-dependent
manner (lower panel). This results in an increased arterial carbon
dioxide tension (top panel). Differences among agents are
modest. (Data from Calverley et al., 1978; Doi and Ikeda, 1987;
Fourcade et al., 1971; Lockhart et al., 1991; Munson et al., 1966.)
severe muscle contraction, rapid development of hyperthermia, and
a massive increase in metabolic rate in genetically susceptible
patients. This syndrome frequently is fatal and is treated by immediate
discontinuation of the anesthetic and administration of dantrolene.
Uterine smooth muscle is relaxed by halothane. This is a useful
property for manipulation of the fetus (version) in the prenatal
period and for delivery of retained placenta postnatally. However,
halothane inhibits uterine contractions during parturition, prolonging
labor and increasing blood loss, and therefore is not used as an analgesic
or anesthetic for labor and vaginal delivery.
Kidney. Patients anesthetized with halothane usually produce a small
volume of concentrated urine. This is the consequence of halothaneinduced
reduction of renal blood flow and glomerular filtration rate,
which may be reduced by 40-50% at 1 MAC. Halothane-induced
changes in renal function are fully reversible and are not associated
with long-term nephrotoxicity.
Liver and GI Tract. Halothane reduces splanchnic and hepatic blood
flow as a consequence of reduced perfusion pressure, as discussed
above. This reduced blood flow has not been shown to produce detrimental
effects on hepatic or GI function.
Halothane can produce fulminant hepatic necrosis in a small
number of patients. This syndrome generally is characterized by
fever, anorexia, nausea, and vomiting, developing several days after
anesthesia and can be accompanied by a rash and peripheral
eosinophilia. There is a rapid progression to hepatic failure, with a
fatality rate of ~50%. This syndrome occurs in ~1 in 10,000 patients
receiving halothane and is referred to as halothane hepatitis (Study,
1966). Current thinking is that halothane hepatitis is the result of an
immune response to hepatic proteins that become trifluoroacetylated
as a consequence of halothane metabolism (see the
“Pharmacokinetics” section for halothane earlier in the chapter).
Isoflurane
Isoflurane (FORANE, others) is 1-chloro-2,2,2-trifluoroethyl
difluoromethyl ether (Figure 19–4). It is a
volatile liquid at room temperature and is neither flammable
nor explosive in mixtures of air or oxygen.
Pharmacokinetics. Isoflurane has a blood:gas partition
coefficient substantially lower than that of halothane or
enflurane (Table 19–1). Consequently, induction with
isoflurane and recovery from isoflurane are faster than
with halothane. Changes in anesthetic depth also can
be achieved more rapidly with isoflurane than with
halothane or enflurane.
More than 99% of inhaled isoflurane is excreted unchanged
by the lungs. Approximately 0.2% of absorbed isoflurane is metabolized
by CYP2E1. This small amount of isoflurane degradation
products produced is insufficient to produce any renal, hepatic, or
other organ toxicity. Isoflurane does not appear to be a mutagen, teratogen,
or carcinogen.
Clinical Use. Isoflurane is a commonly used inhalational
anesthetic worldwide.
It is typically used for maintenance of anesthesia after induction
with other agents because of its pungent odor, but induction of
anesthesia can be achieved in < 10 minutes with an inhaled concentration
of 3% isoflurane in O 2
; this concentration is reduced to 1-2%
(~1-2 MAC) for maintenance of anesthesia. The use of other drugs
such as opioids or nitrous oxide reduces the concentration of isoflurane
required for surgical anesthesia.
Side Effects
Cardiovascular System. Isoflurane produces a concentration-dependent
decrease in arterial blood pressure. Unlike halothane, cardiac output
is well maintained with isoflurane, and hypotension is the result
of decreased systemic vascular resistance (Figure 19–6). Isoflurane
produces vasodilation in most vascular beds, with particularly pronounced
effects in skin and muscle. Isoflurane is a potent coronary
vasodilator, simultaneously producing increased coronary blood
flow and decreased myocardial O 2
consumption. In theory, this
makes isoflurane a particularly safe anesthetic to use for patients
with ischemic heart disease. Concern that isoflurane might produce
myocardial ischemia by inducing “coronary steal” has not been substantiated
in animal and human studies. Isoflurane significantly
attenuates baroreceptor function. Patients anesthetized with isoflurane
generally have mildly elevated heart rates as a compensatory
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CHAPTER 19
GENERAL ANESTHETICS AND THERAPEUTIC GASES