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

544 response to reduced blood pressure; however, rapid changes in
isoflurane concentration can produce both transient tachycardia and
hypertension due to isoflurane-induced sympathetic stimulation.
Respiratory System. Isoflurane produces concentration-dependent
depression of ventilation. Patients spontaneously breathing isoflurane
have a normal respiration rate but a reduced tidal volume, resulting
in a marked reduction in alveolar ventilation and an increase in
arterial CO 2
tension (Figure 19–7). Isoflurane is particularly effective
at depressing the ventilatory response to hypercapnia and
hypoxia (Hirshman et al., 1977). While isoflurane is an effective
bronchodilator, it also is an airway irritant and can stimulate airway
reflexes during induction of anesthesia, producing coughing and
laryngospasm.
Nervous System. Isoflurane dilates the cerebral vasculature, producing
increased cerebral blood flow; this vasodilating activity is less
than that of either halothane or enflurane (Drummond et al., 1983).
There is a modest risk of an increase in intracranial pressure in
patients with preexisting intracranial hypertension. Isoflurane
reduces cerebral metabolic O 2
consumption in a dose dependent
manner. At 1.5-2.0 MAC, isoflurane produces burst suppression of
the EEG and reduces cerebral metabolic rate by ~50%. The modest
effects of isoflurane on cerebral blood flow can be reversed readily
by hyperventilation (McPherson et al., 1989).
SECTION II
NEUROPHARMACOLOGY
Muscle. Isoflurane produces some relaxation of skeletal muscle by its
central effects. It also enhances the effects of both depolarizing and
non-depolarizing muscle relaxants. Isoflurane is more potent than
halothane in its potentiation of neuromuscular blocking agents. Like
other halogenated inhalational anesthetics, isoflurane relaxes uterine
smooth muscle and is not recommended for analgesia or anesthesia
for labor and vaginal delivery.
Kidney. Isoflurane reduces renal blood flow and glomerular filtration
rate, resulting in a small volume of concentrated urine. Changes
in renal function observed during isoflurane anesthesia are rapidly
reversed, with no long-term renal sequelae or toxicities.
Liver and Gastrointestinal Tract. Splanchnic and hepatic blood flows
are reduced with increasing doses of isoflurane as systemic arterial
pressure decreases. Liver function tests are minimally affected by
isoflurane, with no reported incidence of hepatic toxicity.
Enflurane
Enflurane (ETHRANE, others) is 2-chloro-1,1,2-trifluoroethyl
difluoromethyl ether (Figure 19–4).
It is a clear, colorless liquid at room temperature with a mild,
sweet odor. Like other inhalational anesthetics, it is volatile and must
be stored in a sealed bottle. It is nonflammable and non-explosive in
mixtures of air or oxygen.
Pharmacokinetics. Because of its relatively high
blood:gas partition coefficient, induction of anesthesia
and recovery from enflurane are relatively slow
(Table 19–1).
Enflurane is metabolized to a modest extent, with 2-8% of
absorbed enflurane undergoing oxidative metabolism in the liver by
CYP2E1. Fluoride ions are a by-product of enflurane metabolism,
but plasma fluoride levels are low and nontoxic. Patients taking isoniazid
exhibit enhanced metabolism of enflurane with significantly
elevated serum fluoride concentrations (Mazze et al., 1982).
Clinical Use. As with isoflurane, enflurane is primarily
utilized for maintenance rather than induction of
anesthesia.
Surgical anesthesia can be induced with enflurane in < 10
minutes with an inhaled concentration of 4% in oxygen.
Anesthesia can be maintained with concentrations from 1.5-3%.
As with other anesthetics, the enflurane concentrations required to
produce anesthesia are reduced when it is co-administered with
nitrous oxide or opioids. With the advent of new inhalational
agents, enflurane is rarely used for clinical anesthesia in developed
countries.
Side Effects
Cardiovascular System. Enflurane causes a concentration-dependent
decrease in arterial blood pressure. Hypotension is due in part to
depression of myocardial contractility, with some contribution from
peripheral vasodilation (Figure 19–6). Enflurane has minimal effects
on heart rate and produces neither the bradycardia seen with
halothane nor the tachycardia seen with isoflurane.
Respiratory System. The respiratory effects of enflurane are similar to
those of halothane. Spontaneous ventilation with enflurane produces
a pattern of rapid, shallow breathing. Minute ventilation is
markedly decreased, and a Pa CO2
of 60 mm Hg can be seen with 1 MAC
of enflurane (Figure 19–7). Enflurane produces a greater depression of
the ventilatory responses to hypoxia and hypercarbia than do either
halothane or isoflurane (Hirshman et al., 1977). Enflurane, like other
inhalational anesthetics, is an effective bronchodilator.
Nervous System. Enflurane is a cerebral vasodilator and thus can
increase intracranial pressure in some patients. Like other inhalational
anesthetics, enflurane reduces cerebral metabolic O 2
consumption.
Enflurane has an unusual property of producing electrical
seizure activity. High concentrations of enflurane or profound
hypocarbia during enflurane anesthesia result in a characteristic
high-voltage, high-frequency electroencephalographic (EEG) pattern
that progresses to spike-and-dome complexes. The spike-anddome
pattern can be punctuated by frank seizure activity that may or
may not be accompanied by peripheral motor manifestations of
seizure activity. The seizures are self-limited and are not thought to
produce permanent damage. Epileptic patients are not particularly
susceptible to enflurane-induced seizures. Nonetheless, enflurane
generally is not used in patients with seizure disorders.
Muscle. Enflurane produces significant skeletal muscle relaxation in
the absence of muscle relaxants. It also significantly enhances the
effects of non-depolarizing muscle relaxants. As with other inhalational
agents, enflurane relaxes uterine smooth muscle. It is not
widely used for obstetric anesthesia.
Kidney. Like other inhalational anesthetics, enflurane reduces renal
blood flow, glomerular filtration rate, and urinary output. These effects
are rapidly reversed upon drug discontinuation. Enflurane metabolism
produces significant plasma levels of fluoride ions (20-40 μmol) and
can produce transient urinary-concentrating defects following prolonged
administration (Mazze et al., 1977). There is scant evidence of