CLINICAL PHARMACOLOGY
Atracurium besylate is a
nondepolarizing skeletal muscle relaxant.
Nondepolarizing agents antagonize the
neurotransmitter action of acetylcholine by
binding competitively with cholinergic receptor
sites on the motor end-plate. This antagonism is
inhibited, and neuromuscular block reversed, by
acetylcholinesterase inhibitors such as
neostigmine, edrophonium, and
pyridostigmine.
Atracurium can be used most
advantageously if muscle twitch response to
peripheral nerve stimulation is monitored to
assess degree of muscle relaxation.
The duration of neuromuscular block
produced by atracurium is approximately one-third
to one-half the duration of
block by d-tubocurarine, metocurine, and
pancuronium at initially equipotent doses. As with
other nondepolarizing neuromuscular blockers, the
time to onset of paralysis decreases and the
duration of maximum effect increases with
increasing atracurium doses.
The ED95 (dose required to
produce 95% suppression of the muscle twitch
response with balanced anesthesia) has averaged
0.23 mg/kg (0.11 to 0.26 mg/kg in various
studies). An initial atracurium dose of 0.4 to 0.5
mg/kg generally produces maximum neuromuscular
block within 3 to 5 minutes of injection,
with good or excellent intubation conditions
within 2 to 2.5 minutes in most patients. Recovery
from neuromuscular block (under balanced
anesthesia) can be expected to begin approximately
20 to 35 minutes after injection. Under balanced
anesthesia, recovery to 25% of control is
achieved approximately 35 to 45 minutes after
injection, and recovery is usually 95%
complete approximately 60 to 70 minutes after
injection. The neuromuscular blocking action of
atracurium is enhanced in the presence of potent
inhalation anesthetics. Isoflurane and enflurane
increase the potency of atracurium and prolong
neuromuscular block by approximately 35%;
however, halothane’s potentiating effect
(approximately 20%) is marginal (see
DOSAGE AND
ADMINISTRATION
).
Repeated administration of maintenance
doses of atracurium has no cumulative effect on
the duration of neuromuscular block if recovery is
allowed to begin prior to repeat dosing. Moreover,
the time needed to recover from repeat doses does
not change with additional doses. Repeat doses can
therefore be administered at relatively regular
intervals with predictable results. After an
initial dose of 0.4 to 0.5 mg/kg under balanced
anesthesia, the first maintenance dose (suggested
maintenance dose is 0.08 to 0.10 mg/kg) is
generally required within 20 to 45 minutes, and
subsequent maintenance doses are usually required
at approximately 15 to 25 minute
intervals.
Once recovery from atracurium’s
neuromuscular blocking effects begins, it proceeds
more rapidly than recovery from d-tubocurarine,
metocurine, and pancuronium. Regardless of the
atracurium dose, the time from start of recovery
(from complete block) to complete (95%)
recovery is approximately 30 minutes under
balanced anesthesia, and approximately 40 minutes
under halothane, enflurane or isoflurane. Repeated
doses have no cumulative effect on recovery
rate.
Reversal of neuromuscular block
produced by atracurium can be achieved with an
anti-cholinesterase agent such as neostigmine,
edrophonium, or pyridostigmine, in conjunction
with an anticholinergic agent such as atropine or
glycopyrrolate. Under balanced anesthesia,
reversal can usually be attempted approximately 20
to 35 minutes after an initial atracurium besylate
dose of 0.4 to 0.5 mg/kg, or approximately 10 to
30 minutes after a 0.08 to 0.10 mg/kg maintenance
dose, when recovery of muscle twitch has started.
Complete reversal is usually attained within 8 to
10 minutes of the administration of reversing
agents. Rare instances of breathing difficulties,
possibly related to incomplete reversal, have been
reported following attempted pharmacologic
antagonism of atracurium-induced neuromuscular
block. As with other agents in this class, the
tendency for residual neuromuscular block is
increased if reversal is attempted at deep levels
of block or if inadequate doses of reversal agents
are employed.
The pharmacokinetics of atracurium in
humans are essentially linear within the 0.3 to
0.6 mg/kg dose range. The elimination half-life is
approximately 20 minutes. THE DURATION OF
NEUROMUSCULAR BLOCK PRODUCED BY ATRACURIUM
BESYLATE DOES NOT CORRELATE WITH PLASMA
PSEUDOCHOLINESTERASE LEVELS AND IS NOT ALTERED BY
THE ABSENCE OF RENAL FUNCTION. This is consistent
with the results of
in
vitro
studies which have shown
that atracurium is inactivated in plasma via two
nonoxidative pathways: ester hydrolysis, catalyzed
by nonspecific esterases; and Hofmann elimination,
a nonenzymatic chemical process which occurs at
physiological pH. Some placental transfer occurs
in humans.
Radiolabel studies demonstrated that
atracurium undergoes extensive degradation in
cats, and that neither kidney nor liver plays a
major role in this elimination. Biliary and
urinary excretion were the major routes of
excretion of radioactivity (totaling >90%
of the labeled dose within 7 hours of dosing), of
which atracurium represented only a minor
fraction. The metabolites in bile and urine were
similar, including products of Hofmann elimination
and ester hydrolysis.
Elderly patients may have slightly
altered pharmacokinetic parameters compared to
younger patients, with a slightly decreased total
plasma clearance which is offset by a
corresponding increase in volume of distribution.
The net effect is that there has been no
significant difference in clinical duration and
recovery from neuromuscular block observed between
elderly and younger patients receiving atracurium
besylate.
Atracurium is a less potent histamine
releaser than d-tubocurarine or metocurine.
Histamine release is minimal with initial
atracurium besylate doses up to 0.5 mg/kg, and
hemodynamic changes are minimal within the
recommended dose range. A moderate histamine
release and significant falls in blood pressure
have been seen following 0.6 mg/kg of atracurium
besylate. The histamine and hemodynamic responses
were poorly correlated. The effects were generally
short-lived and manageable, but the possibility of
substantial histamine release in sensitive
individuals or in patients in whom substantial
histamine release would be especially hazardous
(e.g., patients with significant cardiovascular
disease) must be considered.
It is not known whether the prior use
of other nondepolarizing neuromuscular blocking
agents has any effect on the activity of
atracurium. The prior use of succinylcholine
decreases by approximately 2 to 3 minutes the time
to maximum block induced by atracurium besylate,
and may increase the depth of block. Atracurium
should be administered only after a patient
recovers from succinylcholine-induced
neuromuscular block.
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