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

intubated and mechanically ventilated. The sedation produced by
dexmedetomidine has been noted to be more akin to natural sleep,
with patients relatively easy to arouse (Hall et al., 2000). However,
dexmedetomidine does not appear to provide reliable amnesia and
additional agents may need to be employed if lack of recall is
desirable.
Dexmedetomidine is supplied as an aqueous solution of the
hydrochloride salt and should be diluted in normal saline to a final
concentration of 4 μg/mL for intravenous delivery, the only approved
route of administration. The recommended loading dose is 1 μg/kg
given over 10 minutes, followed by infusion at a rate of 0.2-0.7 μg/kg
per hour. Reduced doses should be considered in patients with risk
factors for severe hypotension. The distribution and terminal half-lives
are 6 minutes and 2 hours, respectively. Dexmedetomidine is highly
protein bound and is primarily hepatically metabolized; the glucuronide
and methyl conjugates are excreted in the urine.
Analgesics
With the exception of ketamine, neither parenteral nor
currently available inhalational anesthetics are effective
analgesics. Thus, analgesics typically are administered
with general anesthetics to reduce anesthetic
requirement and minimize hemodynamic changes
produced by painful stimuli. Nonsteroidal antiinflammatory
drugs, COX-2 inhibitors, and acetaminophen
(Chapter 34) sometimes provide adequate
analgesia for minor surgical procedures. However, opioids
are the primary analgesics used during the perioperative
period because of the rapid and profound
analgesia they produce.
Fentanyl (SUBLIMAZE, others), sufentanil
(SUFENTA, others), alfentanil (ALFENTA, others), remifentanil
(ULTIVA), meperidine (DEMEROL, others), and morphine
are the major parenteral opioids used in the
perioperative period. The primary analgesic activity of
each of these drugs is produced by agonist activity at
μ-opioid receptors. Their order of potency (relative to
morphine) is: sufentanil (1000 ×), remifentanil (300 ×),
fentanyl (100 ×), alfentanil (15 ×), morphine (1 ×), and
meperidine (0.1 ×). These agents are discussed in more
detail in Chapter 18.
The choice of a perioperative opioid is based primarily on
duration of action, since, at appropriate doses, all produce similar
analgesia and side effects. Remifentanil has an ultrashort duration of
action (~10 minutes) and accumulates minimally with repeated
doses or infusion; it is particularly well suited for procedures that
are briefly painful, but for which little analgesia is required postoperatively.
Single doses of fentanyl, alfentanil, and sufentanil all have
similar intermediate durations of action (30, 20, and 15 minutes,
respectively), but recovery after prolonged administration varies considerably.
Fentanyl’s duration of action lengthens the most with infusion,
sufentanil’s much less so, and alfentanil’s the least. Except for
remifentanil, all of the above-mentioned opioids are metabolized in
the liver, followed by renal and biliary excretion of the metabolites.
Remifentanil is hydrolyzed by tissue and plasma esterases. Given its
rapid elimination, termination of the effects of remifentanil can result
in significant pain in the surgical patient. Consequently, longer-acting
opiates are often given prior to discontinuation of remifentanil.
During the perioperative period, opioids often are given at
induction to preempt responses to predictable painful stimuli (e.g.,
endotracheal intubation and surgical incision). Subsequent doses
either by bolus or infusion are titrated to the surgical stimulus and the
patient’s hemodynamic response. Marked decreases in respiratory
rate and heart rate with much smaller reductions in blood pressure
are seen to varying degrees with all opioids. Muscle rigidity that can
impair ventilation sometimes accompanies larger doses of opioids.
The incidence of sphincter of Oddi spasm is increased with all opioids,
although morphine appears to be more potent in this regard
(Hahn et al., 1988). The frequency and severity of nausea, vomiting,
and pruritus after emergence from anesthesia are increased by all
opioids to about the same degree. A useful side effect of meperidine
is its capacity to reduce shivering, a common problem during emergence
from anesthesia (Pauca et al., 1984); other opioids are not as
efficacious against shivering, perhaps due to less κ receptor agonism.
Finally, opioids often are administered intrathecally and epidurally
for management of acute and chronic pain (Chapter 18). Neuraxial
opioids with or without local anesthetics can provide profound analgesia
for many surgical procedures; however, respiratory depression
and pruritus usually limit their use to major operations.
Neuromuscular Blocking Agents
The practical aspects of the use of neuromuscular
blockers as anesthetic adjuncts are briefly described
here. The detailed pharmacology of this drug class is
presented in Chapter 11.
Depolarizing (e.g., succinylcholine) and nondepolarizing
muscle relaxants (e.g., vecuronium) often
are administered during the induction of anesthesia to
relax muscles of the jaw, neck, and airway and thereby
facilitate laryngoscopy and endotracheal intubation.
Barbiturates will precipitate when mixed with muscle
relaxants and should be allowed to clear from the intravenous
line prior to injection of a muscle relaxant.
Following induction, continued muscle relaxation is
desirable for many procedures to aid surgical exposure
and to provide additional insurance of immobility. Of
course, muscle relaxants are not by themselves anesthetics
and should not be used in lieu of adequate anesthetic
depth. The action of non-depolarizing muscle
relaxants usually is antagonized, once muscle paralysis
is no longer desired, with an acetylcholinesterase
inhibitor such as neostigmine or edrophonium (Chapter 10)
combined with a muscarinic receptor antagonist (e.g.,
glycopyrrolate or atropine; Chapter 9) to offset the muscarinic
activation resulting from esterase inhibition.
Other than histamine release by some agents, nondepolarizing
muscle relaxants used in this manner have
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CHAPTER 19
GENERAL ANESTHETICS AND THERAPEUTIC GASES