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

SECTION II
NEUROPHARMACOLOGY
538 Etomidate
Etomidate is a substituted imidazole that is supplied as
the active d-isomer (Figure 19–1). Etomidate is poorly
soluble in water and is formulated as a 2 mg/mL solution
in 35% propylene glycol. An aqueous solution of
etomidate using sulfobutyl ether-7β-cyclodextrin as a
solubilizing agent has been developed; this formulation
is not currently available for clinical use in the
U.S.. Unlike thiopental, etomidate does not induce precipitation
of neuromuscular blockers or other drugs
frequently given during anesthetic induction.
Etomidate’s clinical pharmacological properties are
listed in Table 19–2.
Dosage and Clinical Use. Etomidate (AMIDATE, others) is primarily
used for anesthetic induction of patients at risk for hypotension.
Induction doses of etomidate (0.2-0.6 mg/kg) have a rapid
onset and short duration of action (Table 19–2) and are accompanied
by a high incidence of pain on injection and myoclonic movements.
Lidocaine effectively reduces the pain of injection, while
myoclonic movements can be reduced by premedication with either
benzodiazepines or opiates. These myoclonic movements, which are
similar to seizures, are not associated with convulsive activity on the
EEG. Etomidate is pharmacokinetically suitable for off-label infusion
for anesthetic maintenance (10 μg/kg per minute) or sedation
(5 μg/kg per minute); however, long-term infusions are not
recommended (see below, under “Respiratory and Other Side
Effects”). Etomidate also may be given rectally (6.5 mg/kg) with
an onset of ~5 minutes.
Pharmacokinetics and Metabolism. An induction dose of etomidate
has a rapid onset; redistribution limits the duration of action
(Table 19–2). Metabolism occurs in the liver, primarily to inactive
compounds. Elimination is both renal (78%) and biliary (22%).
Compared to thiopental, the duration of action of etomidate increases
less with repeated doses (Figure 19–3). The plasma protein binding
of etomidate is high but less than that of barbiturates and propofol
(Table 19–2).
Side Effects
Nervous System. Etomidate produces hypnosis and has no analgesic
effects. The effects of etomidate on cerebral blood flow, metabolism,
and intracranial and intraocular pressures are similar to those of
thiopental (without dropping mean arterial blood pressure) (Modica
and Tempelhoff, 1992). Etomidate has been used as a protectant
against cerebral ischemia; however, animal studies have failed to
show a consistent beneficial effect (Drummond et al., 1995), and no
controlled human trials have been performed. Etomidate produces
increased EEG activity in epileptogenic foci and has been associated
with seizures (Ebrahim et al., 1986).
Cardiovascular System. Cardiovascular stability after induction is a
major advantage of etomidate over either barbiturates or propofol.
Induction doses of etomidate typically produce a small increase in
heart rate and little or no decrease in blood pressure or cardiac output
Etomidate has little effect on coronary perfusion pressure while
reducing myocardial O 2
consumption (Kettler et al., 1974). Thus, of
all induction agents, etomidate is best suited to maintain cardiovascular
stability in patients with coronary artery disease, cardiomyopathy,
cerebral vascular disease, or hypovolemia.
Respiratory and Other Side Effects. The degree of respiratory depression
due to etomidate appears to be less than that due to thiopental.
Like methohexital, etomidate may induce hiccups but does not significantly
stimulate histamine release. Despite minimal cardiac and
respiratory effects, etomidate does have two major drawbacks.
Etomidate has been associated with nausea and vomiting. The drug
also inhibits adrenal biosynthetic enzymes required for the production
of cortisol and some other steroids. Single induction doses of
etomidate may mildly and transiently reduce cortisol levels but no
significant differences in outcome after short-term administration
have been found, even for variables specifically known to be associated
with adrenocortical suppression (Wagner et al., 1984). Thus,
while etomidate is not recommended for long-term infusion, it
appears safe for anesthetic induction and has some unique advantages
in patients prone to hemodynamic instability. A rapidly metabolized
and ultra-short-acting analog, methoxycarbonyl-etomidate,
has been developed that retains the favorable pharmacological properties
of etomidate but does not produce adrenocortical suppression
after bolus dosing (Cotton and Claing, 2009).
Ketamine
Ketamine is an arylcyclohexylamine, a congener of
phencyclidine (Figure 19–1). Clinical pharmacokinetic
data for ketamine appear in Table 19–2.
Ketamine is supplied as a mixture of the R+ and S- isomers
even though the S- isomer is more potent with fewer side effects.
Although more lipophilic than thiopental, ketamine is water soluble
and available as 10-, 50-, and 100-mg/mL solutions in sodium chloride
plus the preservative benzethonium chloride.
Dosage and Clinical Use. Ketamine (KETALAR, others) has unique
properties that make it useful for anesthetizing patients at risk for
hypotension and bronchospasm and for certain pediatric procedures.
However, significant side effects limit its routine use. Ketamine rapidly
produces a hypnotic state quite distinct from that of other anesthetics.
Patients have profound analgesia, unresponsiveness to
commands, and amnesia, but may have their eyes open, move their
limbs involuntarily, and breathe spontaneously. This cataleptic state
has been termed dissociative anesthesia. The administration of ketamine
has been shown to reduce the development of tolerance to
long-term opioid use. Low-dose ketamine infusion for this purpose
has been advocated in patients who have developed significant tolerance
to opioids (Himmelseher and Durieux, 2005).
Ketamine typically is administered intravenously but also is
effective by intramuscular, oral, and rectal routes. The induction
doses are 0.5-1.5 mg/kg IV, 4-6 mg/kg IM, and 8-10 mg/kg PR.
Onset of action after an intravenous dose is similar to that of the
other parenteral anesthetics, but the duration of anesthesia of a single
dose is longer (Table 19–2). For anesthetic maintenance, ketamine
occasionally is continued as an infusion (25-100 μg/kg per
minute). Ketamine does not elicit pain on injection or true excitatory
behavior as described for methohexital, although involuntary
movements produced by ketamine can be mistaken for anesthetic
excitement.