A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Tracrium Pharmacology, Pharmacokinetics, Studies, Metabolism - Atracurium Besylate
Tracrium Pharmacology, Pharmacokinetics, Studies, Metabolism - Atracurium Besylate
CLINICAL PHARMACOLOGY
TRACRIUM 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.
TRACRIUM 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 TRACRIUM
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 doses of TRACRIUM.
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
dose of TRACRIUM 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 TRACRIUM is enhanced in the presence of potent
inhalation anesthetics.
Isoflurane and enflurane increase the potency
of TRACRIUM 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 TRACRIUM 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
the neuromuscular
blocking effects of
TRACRIUM begins, it proceeds more rapidly than recovery
from d-tubocurarine, metocurine, and pancuronium. Regardless of
the dose of TRACRIUM ,
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 TRACRIUM
can be achieved with an anticholinesterase
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
dose of TRACRIUM 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 neuromuscular
block induced
by TRACRIUM. 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 TRACRIUM 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 TRACRIUM
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 TRACRIUM
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 TRACRIUM undergoes extensive
degradation in cats, and that neither kidney
nor liver plays a major
role in its 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 TRACRIUM 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 TRACRIUM.
TRACRIUM is a less potent
histamine releaser
than d-tubocurarine or metocurine. Histamine release
is minimal with initial
doses of TRACRIUM 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 TRACRIUM.
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
TRACRIUM. The prior use of succinylcholine decreases by approximately
2 to 3 minutes the time
to maximum block induced
by TRACRIUM, and may increase the depth
of block. TRACRIUM should be administered only after a patient
recovers from succinylcholine-induced neuromuscular block.
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