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

Pharmacokinetics and Metabolism. The onset and duration of an
induction dose of ketamine are determined by the same
distribution/redistribution mechanisms operant for all the other parenteral
anesthetics.
Ketamine is hepatically metabolized to norketamine, which
has reduced CNS activity; norketamine is further metabolized and
excreted in urine and bile. Ketamine has a large volume of distribution
and rapid clearance that make it suitable for continuous infusion
without the lengthening in duration of action seen with
thiopental (Table 19–2 and Figure 19–3). Protein binding is much
lower with ketamine than with the other parenteral anesthetics
(Table 19–2).
Side Effects
Nervous System. Ketamine has indirect sympathomimetic activity
and can support blood pressure on anesthetic induction in patients
who are at risk of developing significant hypotension. Ketamine’s
behavioral effects are distinct from those of other anesthetics. The
ketamine-induced cataleptic state is accompanied by nystagmus with
pupillary dilation, salivation, lacrimation, and spontaneous limb
movements with increased overall muscle tone. Although ketamine
does not produce the classic anesthetic state, patients are amnestic
and unresponsive to painful stimuli. Ketamine produces profound
analgesia, a distinct advantage over other parenteral anesthetics.
Unlike other parenteral anesthetics, ketamine increases
cerebral blood flow and intracranial pressure (ICP) with minimal
alteration of cerebral metabolism. The racemic mixture of ketamine
can increase cerebral metabolic rate (CMR) and cerebral blood flow
(CBF), particularly in the anterior cingulate and frontal cortex, thalamus,
and putamen (Langsjo et al., 2004). S ketamine produces similar
changes in CBF and CMR whereas R+ ketamine reduces both
CMR and CBF (Vollenweider et al., 1997). These properties of ketamine
have raised a concern that ICP can increase in patients with
compromised intracranial compliance. However, ketamine does not
increase ICP in patients with intracranial hypertension (Bourgoin et
al., 2005). Moreover, the effects of ketamine on CBF can be readily
attenuated by the simultaneous administration of sedative hyponotics
(propofol, midazolam, barbiturates). In aggregate, the available data
suggest that the contraindication of ketamine in patients with
intracranial pathology or cerebral ischemia needs re-evaluation
(Himmelseher et al., 2005).
In some studies, ketamine increased intraocular pressure, and
its use for induction of patients with open eye injuries is controversial
(Whitacre and Ellis, 1984). The effects of ketamine on seizure
activity appear mixed, without either strong pro- or anticonvulsant
activity. Emergence delirium, characterized by hallucinations, vivid
dreams, and delusions, is a frequent complication of ketamine that
can result in serious patient dissatisfaction and can complicate postoperative
management. Delirium symptoms are most frequent in the
first hour after emergence and appear to occur less frequently in children.
Benzodiazepines reduce the incidence of emergence delirium
(Dundee and Lilburn, 1978).
Cardiovascular System. Unlike other anesthetics, induction doses of
ketamine typically increase blood pressure, heart rate, and cardiac
output. The cardiovascular effects are indirect and are most likely
mediated by inhibition of both central and peripheral catecholamine
reuptake. Ketamine has direct negative inotropic and vasodilating
activity, but these effects usually are overwhelmed by the indirect
sympathomimetic action (Pagel et al., 1992). Thus, ketamine is a
useful drug, along with etomidate, for patients at risk for hypotension
during anesthesia. While not arrhythmogenic, ketamine increases
myocardial O 2
consumption and is not an ideal drug for patients at
risk for myocardial ischemia.
Respiratory System. The respiratory effects of ketamine are perhaps
the best indication for its use. Induction doses of ketamine produce
small and transient decreases in minute ventilation, but respiratory
depression is less severe than with other general anesthetics.
Ketamine is a potent bronchodilator due to its indirect sympathomimetic
activity and perhaps some direct bronchodilating activity.
Thus, ketamine is particularly well-suited for anesthetizing patients
at high risk for bronchospasm. Increased salivation that attends ketamine
administration can be effectively prevented by anticholinergic
agents such as glycopyrrolate.
Summary of Parenteral Anesthetics
Parenteral anesthetics are the most common drugs used
for anesthetic induction of adults. Their lipophilicity,
coupled with the relatively high perfusion of the brain
and spinal cord, results in rapid onset and short duration
after a single bolus dose. However, these drugs ultimately
accumulate in fatty tissue, prolonging recovery
if multiple doses are given, particularly for drugs with
lower rates of clearance. Each anesthetic has its own
unique set of properties and side effects (Table 19–3).
Propofol and thiopental are the two most commonly
used parenteral agents. Propofol is advantageous for
procedures where rapid return to a preoperative mental
status is desirable. Thiopental has a long-established
track record of safety. Etomidate usually is reserved for
patients at risk for hypotension and/or myocardial
ischemia. Ketamine is best suited for patients with asthma
or for children undergoing short, painful procedures.
INHALATIONAL ANESTHETICS
Introduction
A wide variety of gases and volatile liquids can produce
anesthesia. The structures of the currently used
inhalational anesthetics are shown in Figure 19–4. One
of the troublesome properties of the inhalational anesthetics
is their low safety margin. The inhalational anesthetics
have therapeutic indices (LD 50
/ED 50
) that range
from 2 to 4, making these among the most dangerous
drugs in clinical use.
The toxicity of these drugs is largely a function
of their side effects, and each of the inhalational anesthetics
has a unique side-effect profile. Hence, the
selection of an inhalational anesthetic often is based on
matching a patient’s pathophysiology with drug sideeffect
profiles. The specific adverse effects of each of
539
CHAPTER 19
GENERAL ANESTHETICS AND THERAPEUTIC GASES