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

Lidocaine is dealkylated in the liver by CYPs to monoethylglycine
xylidide and glycine xylidide, which can be metabolized further
to monoethylglycine and xylidide. Both monoethylglycine
xylidide and glycine xylidide retain local anesthetic activity. In
humans, ~75% of the xylidide is excreted in the urine as the further
metabolite 4-hydroxy-2, 6-dimethylaniline (Arthur, 1987).
Toxicity. The side effects of lidocaine seen with increasing dose
include drowsiness, tinnitus, dysgeusia, dizziness, and twitching. As
the dose increases, seizures, coma, and respiratory depression and
arrest will occur. Clinically significant cardiovascular depression
usually occurs at serum lidocaine levels that produce marked CNS
effects. The metabolites monoethylglycine xylidide and glycine xylidide
may contribute to some of these side effects.
Clinical Uses. Lidocaine has a wide range of clinical uses as a local
anesthetic; it has utility in almost any application where a local anesthetic
of intermediate duration is needed. Lidocaine also is used as
an antiarrhythmic agent (Chapter 29).
BUPIVACAINE
Pharmacological Actions. Bupivacaine (MARCAINE, SENSORCAINE,
others), is a widely used amide local anesthetic; its structure is similar
to that of lidocaine except that the amine-containing group is a
butyl piperidine (Figure 20–1). Bupivacaine is a potent agent capable
of producing prolonged anesthesia. Its long duration of action
plus its tendency to provide more sensory than motor block has made
it a popular drug for providing prolonged analgesia during labor or
the postoperative period. By taking advantage of indwelling
catheters and continuous infusions, bupivacaine can be used to provide
several days of effective analgesia.
Toxicity. Bupivacaine is more cardiotoxic than equi-effective doses
of lidocaine. Clinically, this is manifested by severe ventricular
arrhythmias and myocardial depression after inadvertent intravascular
administration. Although lidocaine and bupivacaine both rapidly
block cardiac Na + channels during systole, bupivacaine dissociates
much more slowly than does lidocaine during diastole, so a significant
fraction of Na + channels at physiological heart rates remains
blocked with bupivacaine at the end of diastole (Clarkson and
Hondeghem, 1985). Thus, the block by bupivacaine is cumulative
and substantially more than would be predicted by its local anesthetic
potency. At least a portion of the cardiac toxicity of bupivacaine
may be mediated centrally, as direct injection of small
quantities of bupivacaine into the medulla can produce malignant
ventricular arrhythmias (Thomas et al., 1986). Bupivacaine-induced
cardiac toxicity can be very difficult to treat, and its severity is
enhanced by coexisting acidosis, hypercarbia, and hypoxemia.
OTHER SYNTHETIC LOCAL ANESTHETICS
The number of synthetic local anesthetics is so large
that it is impractical to consider them all here. Some
local anesthetic agents are too toxic to be given by
injection. Their use is restricted to topical application to
the eye (Chapter 64), the mucous membranes, or the
skin (Chapter 65). Many local anesthetics are suitable,
however, for infiltration or injection to produce nerve
block; some of these also are useful for topical application.
The main categories of local anesthetics are given
in the following discussion; agents are listed alphabetically.
See Figure 20–1 for their structures.
Local Anesthetics Suitable for Injection
Articaine. Articaine (SEPTOCAINE) is approved in the U.S. for dental
and periodontal procedures. Although it is an amide local anesthetic,
it also contains an ester, whose hydrolysis terminates its action. Thus,
articaine exhibits a rapid onset (1-6 minutes) and duration of action
of ~1 hour.
Chloroprocaine. Chloroprocaine (NESACAINE, others) is a chlorinated
derivative of procaine. Its major assets are its rapid onset and short
duration of action and its reduced acute toxicity due to its rapid
metabolism (plasma t 1/2
~25 seconds). Enthusiasm for its use has been
tempered by reports of prolonged sensory and motor block after
epidural or subarachnoid administration of large doses. This toxicity
appears to have been a consequence of low pH and the use of sodium
metabisulfite as a preservative in earlier formulations. There are no
reports of neurotoxicity with newer preparations of chloroprocaine,
which contain calcium EDTA as the preservative, although these
preparations also are not recommended for intrathecal administration.
A higher than expected incidence of muscular back pain following
epidural anesthesia with 2-chloroprocaine has also been reported
(Stevens et al., 1993). This back pain is thought to be due to tetany in
the paraspinus muscles, which may be a consequence of Ca 2+ binding
by the EDTA included as a preservative; the incidence of back pain
appears to be related to the volume of drug injected and its use for
skin infiltration.
Mepivacaine. Mepivacaine (CARBOCAINE, POLOCAINE, others) is an
intermediate-acting amino amide. Its pharmacological properties are
similar to those of lidocaine. Mepivacaine, however, is more toxic to
the neonate and thus is not used in obstetrical anesthesia. The
increased toxicity of mepivacaine in the neonate is related to ion
trapping of this agent because of the lower pH of neonatal blood and
the pK a
of mepivacaine rather than to its slower metabolism in the
neonate. It appears to have a slightly higher therapeutic index in
adults than does lidocaine. Its onset of action is similar to that of
lidocaine and its duration slightly longer (~20%) than that of lidocaine
in the absence of a co-administered vasoconstrictor.
Mepivacaine is not effective as a topical anesthetic.
Prilocaine. Prilocaine (CITANEST) is an intermediate-acting amino
amide. It has a pharmacological profile similar to that of lidocaine.
The primary differences are that it causes little vasodilation and thus
can be used without a vasoconstrictor, and its increased volume of
distribution reduces its CNS toxicity, making it suitable for intravenous
regional blocks (described later). The use of prilocaine is
largely limited to dentistry because the drug is unique among the
local anesthetics in its propensity to cause methemoglobinemia. This
effect is a consequence of the metabolism of the aromatic ring to o-
toluidine. Development of methemoglobinemia is dependent on the
total dose administered, usually appearing after a dose of 8 mg/kg.
If necessary, it can be treated by the intravenous administration of
methylene blue (1-2 mg/kg). Methemoglobinemia following
prilocaine has limited its use in obstetrical anesthesia, because it
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CHAPTER 20
LOCAL ANESTHETICS