Interactions among Nondepolarizing Neuromuscular Blockers
Mixtures of two nondepolarizing neuromuscular blockers are considered
to be either (1) additive when the effect is
the sum of equipotent doses of either drug given alone or (2) synergistic when the
effect of the mixture is greater than the equipotent dose of either drug. Antagonistic
interactions have not been reported in this class of drugs.
Additive interactions have been demonstrated after the administration
of chemically related agents such as atracurium-mivacurium,[424]
atracurium-cisatracurium,[425]
or various pairs
of steroidal neuromuscular blockers.[179]
[426]
[427]
[428]
On
the
other hand, combinations of structurally dissimilar (a steroidal with a benzylisoquinolinium)
neuromuscular blockers, for example, pancuronium-dTc,[429]
pancuronium-metocurine,[429]
rocuronium-mivacurium,
[251]
rocuronium-cisatracurium,[212]
and pancuronium-mivacurium,[430]
produce a synergistic
(potentiating) response.
The administration of two neuromuscular blockers in combination
was first introduced by Lebowitz and colleagues[429]
in an attempt to reduce the cardiovascular side effects of neuromuscular blockers
by giving smaller doses of each drug as a combination.[429]
Additional advantage (rapid onset and short duration) is noted for mivacurium-rocuronium
combinations.[251]
Although the precise mechanisms
underlying a synergistic interaction are not known, hypotheses that have been put
forward include (1) the existence of multiple binding sites at the neuromuscular
junction (presynaptic and postsynaptic receptors)[431]
and (2) nonequivalence of binding affinities of the two α-subunits (αH
and αL
) (see the section "Principles of Action of Neuromuscular
Blockers at the Neuromuscular Junction"). Furthermore, inhibition of butyrylcholinesterase
by pancuronium results in decreases plasma clearance of mivacurium and marked potentiation
of neuromuscular blockade.[432]
It should be noted that the pharmacodynamic response after the
use of two different nondepolarizing blockers in the course of anesthesia depends
not only on the specific drugs used but also on the sequence of their administration.
It has been shown that the effect of a maintenance dose of vecuronium given during
recovery from an initial dose of either pipecuronium[433]
or pancuronium[434]
[435]
is dependent on the neuromuscular blocker that was used initially. Approximately
three half-lives will be required for a clinical changeover (so that 95% of the first
drug has been cleared) and for the duration of block to begin to take on the characteristics
of the second drug. Smith and White[433]
noted
that the mean duration of a maintenance dose of vecuronium was significantly longer
after pipecuronium (40 minutes) than after vecuronium (29 minutes) and was similar
to that of pipecuronium after pipecuronium (49 minutes). After pipecuronium, they
detected clinically significant prolongation after four maintenance doses of vecuronium.
[433]
After pancuronium, it has been reported that
recovery from the first two maintenance doses of vecuronium is prolonged; however,
this effect becomes negligible by the third dose.[434]
Similarly, Naguib and coworkers[424]
noted that
the mean duration of the first maintenance dose of mivacurium to 10% recovery of
the first twitch was significantly greater after atracurium (25 minutes) than after
mivacurium (14.2 minutes). However, the duration of the second maintenance dose
of mivacurium after atracurium (18.3 minutes) was similar to that of mivacurium after
mivacurium (14.6 minutes).
The apparent prolongation of action of the first maintenance dose
of mivacurium administered after atracurium[424]
and those reported with vecuronium after pancuronium[434]
[435]
or pipecuronium[433]
is not related to synergism. Combinations of atracurium and mivacurium[424]
and combinations of vecuronium and pancuronium or pipecuronium[179]
[426]
are simply additive. However, this prolongation
in duration of action could be attributed to the relative concentrations of these
drugs at the receptor site. Because most receptors remain occupied by the drug administered
initially, the clinical profile depends on the kinetics/dynamics of the drug administered
first rather than on that of the second (maintenance) drug. However, with further
incremental doses of the second drug, a progressively larger proportion of the receptors
are occupied by the second drug, and the clinical profile of that drug becomes evident.
