Section 3
Chapter
Essential drugs in anesthetic practice
Neuromuscular blocking drugs
38 Heidrun Fink, Manfred Blobner, and J. A. Jeevendra Martyn
Introduction: a short
history from arrow poison
to muscle relaxants
The French physiologist Claude Bernard (1811–78) discovered
that curare, the arrow poison that the Amazon Indians ex-
tracted from the plant Chondrodendron tomentosum, induces
paralysis without interrupting nerve conductivity, leaving the
muscle susceptible to contraction by direct stimulation [1,2].
This finding was a milestone in the discovery of the neuro-
muscular junction – the interface between muscle and nerve.
In 1935, Harold King identified the chemical structure of
curare. In 1942, Harold Griffith and Enid Johnson used a
purified extract of curare as a paralytic agent in a patient
undergoing general anesthesia [3]. Although synthesized in
1906, succinylcholine was not introduced into clinical practice
until 1951 [4,5]. Daniel Bovet recognized that succinylcholine
and curare had different mechanisms of action at the neuro-
muscular junction, and this led to the classification of depolar-
izing and nondepolarizing muscle relaxants [6]. The second
nondepolarizing muscle relaxant, pancuronium, a derivative
of the Central African plant Malouetia bequaertiana, was intro-
duced in 1967 [7]. Currently, muscle relaxants are used in
the anesthetized patient to provide temporary paralysis of the
muscles to facilitate endotracheal intubation, and to improve
operative conditions. Less commonly, muscle relaxants are used
in the critically ill patient in the intensive care unit (ICU) to
facilitate mechanical ventilation, decrease oxygen consumption,
and attenuate rises in intracranial or intrathoracic pressures
that result from suctioning or coughing [8]. Another short-term
indication for muscle relaxants is to prevent motion during
therapeutic or diagnostic maneuvers, to prevent self-injury
(e.g., seizure) or to prevent dislodgement of devices (endotra-
cheal tube) [8]. Naturally, in the above situations, appropriate
sedative-hypnotics and analgesics should be used together with
the relaxants.
Anesthetic Pharmacology, 2nd edition, ed. Alex S. Evers, Mervyn Maze, Evan D. Kharasch. Published by Cambridge University Press. # Cambridge University Press 2011.
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Neuromuscular transmission
The physiologic and biochemical basis of neuromuscular
transmission is discussed in detail in Chapter 18. This chapter
highlights several specific aspects of neuromuscular transmis-
sion that are germane to the pharmacology of neuromuscular
paralysis.
Presynaptic physiology and pharmacology
The presynaptic release of acetylcholine (ACh) is triggered by
the influx of calcium through voltage-dependent calcium ion
channels. Certain drugs inhibit the influx of calcium into the
nerve terminal and the consequent release of acetylcholine.
These drugs impair neuromuscular transmission and poten-
tiate the effect of muscle relaxants. Magnesium (e.g., admin-
istered prophylactically for pre-eclampsia) competitively
inhibits the influx of calcium into the nerve terminals, whereas
calcium channel antagonists and aminoglycoside antibiotics
block the channel. As a corollary, the toxic effects of magne-
sium, calcium channel antagonists, and aminoglycosides can
be partially and temporarily reversed by exogenous calcium.
Notably, some acetylcholine receptors (AChRs) are located
on the presynaptic terminal of the neuromuscular junction.
Their subunit composition (a3b2) differs from the postsynap-
tic receptors. The function of these presynaptic acetylcholine
receptors is to facilitate the release of acetylcholine from the
nerve terminal through a positive feedback mechanism. This
mechanism prevents the fade (decrease) of transmitter release
during the increasing impulse rate of motor nerve stimulation.
Nondepolarizing neuromuscular blocking drugs not only bind
to the postsynaptic receptor, but also block presynaptic a3b2
acetylcholine receptors. Thus, the facilitated acetylcholine
release associated with this positive feedback mechanism is
impaired by the presence of nondepolarizing neuromuscular
blocking drugs. Clinically, the inhibition of the facilitation of
the presynaptic release of acetylcholine is detected as a “fade”
during repetitive nerve stimulation at frequencies of 2 Hz or
greater.

Postsynaptic physiology and pharmacology
In the healthy innervated muscle, the acetylcholine receptors
(also termed mature acetylcholine receptors) are highly local-
ized to the neuromuscular endplate region. The postsynaptic
receptor consists of two subunits of a1 and one each of b, d,
and e (2a1b1de). However, when there is deprivation of neural
influence or activity, as in the fetus or after denervation, the
muscle expresses immature or fetal acetylcholine receptors, in
which the e subunit is replaced by a g subunit [8]. Thus, the
subunit composition of the fetal receptor is 2a1b1dg. These
immature receptors are no longer localized to the endplate
region but are inserted throughout the muscle membrane into
the junctional, as well as extrajunctional, area, and they are
therefore also referred to as extrajunctional receptors. This
e-to-g switch of the acetylcholine receptor subunit has some
important physiologic and metabolic consequences for the
receptor itself [9–11]. The mature acetylcholine receptor is
more stable metabolically, with a half-life approximating 2
weeks, whereas immature acetylcholine receptors have a meta-
bolic half-life of around 24 hours. Immature receptors have
a smaller single-channel conductance, but a 2- to 10-fold
longer mean channel open time. In addition, the sensitivity
and affinity to ligands differ. Agonists such as acetylcholine
and succinylcholine, or its metabolite succinylmonocholine,
depolarize immature receptors more easily; one-tenth to one-
hundredth of normal doses of these agonists can effect
depolarization [9,10]. Apart from the above-described adult
and fetal acetylcholine receptors, acetylcholine receptors that
contain a combination of other a subunits (a2 to a9) or b
subunits (b2 to b4) have also been described [11]. These recep-
tors are almost exclusively located in the central nervous
system. Most recently, however, a homomeric receptor con-
sisting of five a7 subunits, previously described only in the
central nervous system, has been described in muscle denerva-
tion states [11]. The clinical pharmacology of the latter recep-
tor has not been well studied. In all of these muscle receptors,
depolarization of the endplate and opening of the receptor
channel occurs only when a molecule of acetylcholine binds
to each of the two a1 subunits on the receptor [8–11].
Margin of safety of neurotransmission
Approximately 10% of the total number of acetylcholine recep-
tors at the endplate must be open for the flow of ions to
increase the endplate potential from –70 mV to the threshold
of –50 mV, at which a muscle action potential is initiated. The
muscle action potential then runs across the muscle membrane
resulting in the activation and contraction of muscle fibers.
The action-potential signal is initiated by more transmitter
molecules than necessary, and these molecules evoke an
action-potential response greater than required. At the same
time, only a small fraction of the available vesicles and recep-
tors is used to initiate each action-potential signal. Conse-
quently, neuromuscular transmission is said to have a
substantial margin of safety or substantial reserve capacity
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Chapter 38: Neuromuscular blocking drugs
[12]. During the clinical administration of a neuromuscular
blocker, 75% of the acetylcholine receptors must be occupied
by an antagonist (neuromuscular blocker) before any effect
(decrease of twitch height) is seen. After blocking the initial
75% of the receptors, the effect (twitch depression) with con-
tinued relaxant administration is relatively more rapid. This
phenomenon is referred to as the “iceberg phenomenon.” At
least 95% receptor occupancy is necessary for complete sup-
pression of twitch (Fig. 38.1). The percent receptor occupancy,
and not the absolute number blocked, varies with dose. There-
fore, concentrations reached at the neuromuscular junction
vary. In other words, if the receptor number is increased, and
if antagonists occupy the same percentage of receptors, the
absolute number of receptors remaining unblocked is still
high. In these instances, a given concentration or dose of
muscle relaxant will produce a smaller effect on twitch height,
provided that other factors such as acetylcholine release are
unaltered. Clinically, this can be described as a resistance to
antagonists (muscle relaxants).
Mechanisms of action of muscle
relaxants
Muscle paralysis by muscle relaxants in a clinical setting is
achieved primarily by blocking the function of the postsynaptic
acetylcholine receptor. In addition to the competitive block of the
acetylcholine receptor produced by nondepolarizing neuromus-
cular blocking drugs and the noncompetitive block by depolar-
izing muscle relaxants (Fig. 38.2), numerous other drugs can
effect neuromuscular transmission at the receptor level.
Competitive block
Similar to acetylcholine, the nondepolarizing neuromuscular
blocking drugs also bind to the a subunit of the acetylcholine
receptor. They do not, however, possess any intrinsic agonist
activity. That is, they do not cause a conformational change in
the receptor from the closed to the open state. One molecule of
nondepolarizing muscle relaxant is sufficient to occupy the
receptor and prevent opening of the ion channel and conse-
quent ion flow. Therefore, acetylcholine and the nondepolariz-
ing muscle relaxants compete for the binding site at the
receptor. Hence the term competitive block. The probability
of binding is solely dependent on the concentration of each
ligand present at the neuromuscular junction and its affinity
for the receptor. Once the neuromuscular blocking drug dif-
fuses out of the junction, the probability that acetylcholine will
bind to the receptor rises and the muscle-blocking effect of the
muscle relaxant diminishes.
Noncompetitive block
The neuromuscular block (paralysis) produced by the depolar-
izing neuromuscular blocking drugs, typified by succinylcholine,
is noncompetitive. Succinylcholine, which is structurally two
molecules of acetylcholine bound together, is a partial agonist
609
 Section 3: Essential drugs in anesthetic practice

Figure 38.1. The “iceberg phenomenon” and defin-

Injection
Time to 95% recovery
itions of duration of action (see text for explanation).

Time to 25% recovery

onset Recovery index (25% – 75%)

100
Transmission [%]
Neuromuscular

0
Injection

95
Blocked Acetylcholine

75
Receptors [%]

Time

DRUG: acetylcholine succinylcholine High or repetitive Benzylisoquinolones Figure 38.2. Agonistic and antagonistic interac-
doses of Steroid muscle relaxants tions at the nicotinic acetylcholine receptor (nAChR).
succinylcholine

ACTION: Agonist Partial Agonist Partial Antagonist Antagonist

Phase I-block +
Non-competitve Phase II-block
Competitive block
EFFECT: Contraction block and (non-competitive
with paralysis
paralysis and competitive)
with paralysis

Intrinsic agonist activity

of the acetylcholine receptor and depolarizes (opens) the ion
channel. This opening requires the binding of only one molecule
of succinylcholine to the a subunit. The other a subunit of the
receptor can be occupied by either acetylcholine or succinylcho-
line. Succinylcholine cannot be hydrolyzed by acetylcholinester-
ase (AChE); it can therefore detach from the receptor and
repeatedly bind to other acetylcholine receptors until it is cleared
from the junctional area into the plasma, where it is hydrolyzed
by plasma (pseudo-)cholinesterase. Since succinylcholine is an
agonist of the acetylcholine receptor, binding induces muscle
fasciculation (uncoordinated mini-contractions), which occur
only during the initial phase, followed by a relaxation period.
Since the endplate membrane is continuously depolarized by the
presence of succinylcholine, the voltage-gated sodium ion

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channels in the perijunctional region, which initiate the muscle
action potential, are not activated after the initial depolarization.
The musculature relaxes after the initial fasciculation, although
the cell membrane beyond the perijunctional area is repolarized.
Therefore, muscle contraction can be elicited by direct electrical
stimulation of the muscle.
Phase II block
A phase II block is a complex phenomenon observed not only
after high single or cumulative doses of succinylcholine, but also
after normal doses of succinylcholine during lack of, or func-
tional inefficiency of, pseudocholinesterase (the metabolizing
enzyme of succinylcholine). In the latter situation, the initial
phase I (depolarization) block is converted into a phase II
(noncompetitive) block [13]; the decreased metabolism of suc-
cinylcholine is a relative overdose causing an increased concen-
tration in the synaptic cleft. The exact mechanism underlying a
phase II block remains unclear. It is probably due to an electrical
imbalance at the junctional membrane caused by the repeated
opening of the channels by succinylcholine. The junction is
depolarized by the initial action of succinylcholine. Thereafter,
the muscle membrane potential returns to a normal resting
potential, even though the junction is still exposed to the drug.
Clinically, a phase II block is characterized by a tetanic or train-
of-four (TOF) fade. Usually, acetylcholinesterase inhibitors can
reverse a phase II block, but they also can worsen it.
Desensitization block
The acetylcholine receptor is capable of existing in a number of
conformational states. When it has been desensitized, the
acetylcholine receptor cannot be activated to open its channel.
It is likely that the desensitized state is a physiologic response,
in which the desensitized acetylcholine receptors are in equi-
librium with the sensitive receptors so as to prevent excessive
muscle response to extreme neural stimulation [13]. An
increase in desensitized receptors can be induced by an
unphysiologically high concentration of agonist, e.g., high
acetylcholine levels caused by inhibition of acetylcholinesterase
enzyme, or high doses of succinylcholine after repetitive
administration or decreased metabolism. Nicotine itself can
also cause a desensitization of the receptor. The exact mechan-
ism that induces a desensitization block is not fully under-
stood. However, it is believed that it might be due to a certain
acetylcholine receptor subtype that contains a8b2 subunits
instead of a1b1. This receptor subtype is especially stimulated
at high concentrations of agonists, at which the ion channel
opens with a high selectivity for calcium ions. Calcium acti-
vates protein kinase C on the inside of the postjunctional
membrane, which in turn phosphorylates the “normal”
(2a1b1de) acetylcholine receptor, thereby desensitizing it [14].
In addition to the high levels of agonists or cholinesterase
inhibitors, desensitization can also be caused by certain inhal-
ation anesthetics, barbiturates, alcohols, local anesthetics
including cocaine, phenothiazines, verapamil, or polymyxin B.
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Chapter 38: Neuromuscular blocking drugs
The decrease in the margin of safety, or the increase in the
ability of nondepolarizing muscle relaxants to block transmis-
sion, a concomitant feature of desensitization block, is inde-
pendent of the classical effect based on a competitive inhibition
of acetylcholine. These effects are mediated by allosteric inhib-
ition of receptors by binding of the drug to sites other than
acetylcholine binding sites. The presence of desensitized recep-
tors means that fewer functional receptor channels than usual
are available to induce a transmembrane current. Therefore, the
production of desensitized receptors decreases the efficacy or
margin of safety of neuromuscular transmission. This increases
the susceptibility to antagonists, i.e., nondepolarizing neuro-
muscular blocking drugs. If many receptors are desensitized,
insufficient nondesensitized normal receptors are left to
depolarize the motor endplate, and effective neuromuscular
transmission will not occur.
Channel block
A noncompetitive method for blocking the physiologic
opening and closing of the acetylcholine receptor channel,
and thus depolarization, is by means of direct channel block.
Direct channel blocking is said to occur when molecules that
bind to the acetylcholine receptor change its conformation in
such a way that any further binding of acetylcholine to the a
subunit is prevented. Since the site of action is not located at
the acetylcholine binding site, this mechanism is distinct from
competitive antagonism with acetylcholine and therefore
cannot be reversed by acetylcholinesterase inhibitors, which
increase the concentration of acetylcholine in the synaptic
cleft. Channel block is believed to play a role in some drug-
induced alterations of neuromuscular function. These include
antibiotics, cocaine, quinidine, piperocaine, tricyclic anti-
depressants, naltraxone, naloxone, and histrionicotoxin.
Muscle relaxants in high concentrations can also cause
channel block [15,16]. Acetylcholine receptors are also suscep-
tible to channel block if a profound (deep) paralysis by a
nondepolarizing neuromuscular relaxant is antagonized by
acetylcholinesterase inhibitors. The increased number of
acetylcholine molecules displaces the muscle-relaxant mol-
ecules, and the acetylcholine competitively prevents the muscle
relaxant from binding to the a subunit. The channel is, how-
ever, kept open by acetylcholine. The muscle-relaxant mol-
ecules, which are still present at a high concentration, can
then enter the open channel and block the receptor for a longer
duration than the original block produced by binding at the
a subunit. Additionally, acetylcholinesterase inhibitors by
themselves can cause a channel block.
Acetylcholinesterase enzyme
Acetylcholinesterase hydrolyzes acetylcholine to acetate and
choline within 1 millisecond after its release from the presy-
naptic nerve terminal. By specific inhibition of acetylcholines-
terase, the metabolism of acetylcholine can be prevented and
611
 Section 3: Essential drugs in anesthetic practice

Acetylcholine Figure 38.3. Chemical structure of acetylcholine and succinyl-

choline (diacetylcholine).
O CH3
+
CH3 C O CH2 CH2 N CH3
CH3

Succinylcholine
( = Diacetylcholine)

CH3 O O CH3
+ +
CH3 N CH2 CH2 O C CH2 CH2 C O CH2 CH2 N CH3
CH3 CH3

its concentration in the synaptic cleft increased. This is used to A O

advantage in the clinical setting to reverse the effect of non- H3C C
depolarizing neuromuscular blocking drugs (see Chapter 39).
O CH3
CH3

Chemical structure and specific CH3

CH3
N+

properties of muscle relaxants N+

Structure–activity relationship
Analogous to acetylcholine, all muscle relaxants have at least one
quaternary amine group, which is involved in binding to the a
subunit of the nicotinic acetylcholine receptor. Succinylcholine
consists of two acetylcholine molecules bound together to form
diacetylcholine (Fig. 38.3). Succinylcholine retains the depolar-
izing capacity of acetylcholine but is not susceptible to hydrolysis
by acetylcholinesterase. Degradation is only achieved by plasma
cholinesterase after succinylcholine has diffused from the synap-
tic cleft into the plasma. The delayed degradation of diacetylcho-
line (compared with acetylcholine) results in a sustained high
concentration within the synaptic cleft.
Most nondepolarizing neuromuscular blocking drugs also
contain two amine groups. Some, but not all, of these com-
pounds have two quaternary amines. D-Tubocurarine, vecuro-
nium, and rocuronium are monoquaternary at a physiological
pH. The second amine group is protonated and is therefore
present in an uncharged state as a tertiary amine (Fig. 38.4). The
bisquaternary structure of the steriodal muscle relaxants favors
the block of postganglionic muscarinic acetylcholine receptors
and therefore has a vagolytic effect. The vagolytic effect is much
weaker with monoquaternary drugs (e.g. vecuronium, rocuro-
nium). The stereochemical aspects of a compound also have a
role in structure–activity relationships. Muscle relaxants of the
benzylisoquinoline type, including D-tubocurarine, mivacur-
ium, and atracurium, tend to have histaminergic side effects.
Some stereoisomers of atracurium have histaminergic proper-
ties, in contrast to several other isomers (e.g., cisatracurium,
Fig. 38.5), which have no histaminergic side effects in clinical
doses.
The affinity to the nicotinic acetylcholine receptor is
important for the onset time of a muscle relaxant [17]. This
O
Vecuronium
H3C C O Pancuronium
B O
Vecuronium
H3C C
Rocuronium
O CH3
CH3
O N+
CH3
N
CH2
O CH
H3C C O CH2
HO
Figure 38.4. (A) Chemical structure of the steroidal muscle relaxants vecur-
onium and pancuronium. The bisquaternary structure of pancuronium blocks
the postganglionic muscarinic acetylcholine receptors (vagolysis), unlike the
monoquaternary vecuronium. (B) Chemical structure of the steroid muscle
relaxants vecuronium and rocuronium. The longer aliphatic tail at the quater-
nary amine reduces the affinity towards the acetylcholine receptor. The
hydroxyl tail at position 3 (A-ring) ensures an adequate molecular stability of
rocuronium during storage in the ampullas.
principle was utilized when developing rocuronium from
vecuronium (Fig. 38.4). Muscle relaxants with a lower affinity
need to be administered in higher doses to achieve complete
neuromuscular block. The high initial bolus dose required for
this low-affinity drug, however, is associated with a higher
concentration gradient between the central compartment and
the neuromuscular junction, and this results in rapid diffusion
of drug from the central compartment to the acetylcholine
receptor, resulting in faster onset of paralysis [18].

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 Chapter 38: Neuromuscular blocking drugs

Table 38.1. Effect of muscle relaxants on (a) the autonomic nervous

system and (b) histamine release. The ratios provided are the quotients
of the dose that has a 50% chance for producing side effects (ED50SE)
divided by the effective dose for 95% twitch depression (ED95NMB). The
higher the ratio ED50SE/ ED95NMB, the safer the drug. Values below 3
may be considered as having a low therapeutic window

Ganglion Vagolysisa Histamine

blockadea liberationb
Steroid compounds
Pancuronium > 100 3 none
Rocuronium > 100 3 none
Vecuronium > 100 20 none
Figure 38.5. Chemical structure of cisatracurium. Cisatracurium is one of the
16 possible isomers of atracurium. The R-cis, R0 -cis- conformation is approxi- Benzylisoquinolines
mately five times more potent than the racemate and induces almost no
histamine. Mivacurium > 100 > 50 ~3
Atracurium 40 16 ~ 2.5
cis- > 50 > 50 none
Intrinsic activity at the neuromuscular Atracurium
nicotinic acetylcholine receptors Others
Molecules that bind to the nicotinic acetylcholine receptor,
depending on their intrinsic activity, induce either agonistic, Alcuronium ~3 ~4 none
partial agonistic, or antagonistic activity (Fig. 38.2). The clas- a
Determined in cats.
b
sic agonist of the acetylcholine receptor is acetylcholine: after Estimated from the clinical signs of histamine liberation.
binding of two acetylcholine molecules (one to each of the
a subunits), the receptor-associated ion channel opens. Suc-
The postganglionic parasympathetic muscarinic receptors,
cinylcholine acts as a partial agonist: it opens the ion channel
because of their helical structure and seven transmembrane
after binding to the receptor; however, it elicits only an initial
domains, have a greater similarity to adrenoceptors than to
depolarization with an associated muscle contraction (fasci-
the nicotinic acetylcholine receptor and, like the adrenoceptors,
culation). In the presence of high concentrations, succinyl-
they belong to the class of G-protein-coupled receptors. When
choline induces a phase II block. During phase II block,
succinylcholine is administered, whether or not the sympathetic
repetitive stimulation will give rise to fade, simulating a non-
or parasympathetic action in the autonomic nervous system
depolarizing relaxant block. For practical purposes, nondepo-
dominates is dependent on the pre-existing dynamic equilib-
larizing muscle relaxants display minimal intrinsic agonist
rium. Children, for example, often have elevated vagal tone and
activity (i.e., they are antagonists or competitive blockers of
therefore are prone to react with bradycardia or arrhythmia
the acetylcholine receptor). When recording twitch responses
during the administration of succinylcholine. To prevent this,
on a mechanomyograph, however, one may observe an initial
prophylactic block of the muscarinic receptors with atropine
transient increase in twitch height followed by twitch
can be attempted. Bradycardia also may be evidenced in adults
depression.
when a repeat dose of succinylcholine is administered. Of the
currently used nondepolarizing muscle relaxants, only pancur-
Effects on acetylcholine receptors in the onium blocks muscarinic receptors in clinically relevant doses.
central and autonomic nervous system The cardiac vagolytic effect of pancuronium is evidenced as
Ganglia of the autonomic nervous system transduce either tachycardia after injection (Table 38.1).
sympathetic or parasympathetic signals. In both ganglia, acetyl-
choline is the neurotransmitter. Succinylcholine stimulates the Effects on the carotid body
sympathetic as well as the parasympathetic ganglia, and add- Neuronal-type nicotinic acetylcholine receptors are important
itionally the postganglionic parasympathetic muscarinic recep- in signaling of hypoxia from the peripheral chemoreceptors of
tors. Thus it is common to have increased salivary secretions the carotid body to the central nervous system. Structurally,
and bradycardia, even in adults but more often in children, they differ in subunit composition (a3b2, a3b4, a4b2, and a7)
especially with repetitive doses of succinylcholine. Therapeutic from muscle-type acetylcholine receptors (a1b1de/g and a7).
doses of newer nondepolarizing neuromuscular blocking drugs Inhibition of neuronal acetylcholine receptors at the carotid
have no effect on autonomic ganglia (Table 38.1). High doses of body by muscle relaxants reduces the acute hypoxic ventilatory
D-tubocurarine, however, can result in ganglionic block giving response, which normally compensates for a decrease in oxygen
rise to hypotension and pupillary dilation. saturation by increasing the respiratory minute volume. In

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 Section 3: Essential drugs in anesthetic practice
clinically relevant concentrations, muscle relaxants such as
atracurium and vecuronium are able to inhibit neuronal acetyl-
choline signaling in the carotid body, attenuating chemorecep-
tor responses to hypoxia [21,22].
Effects on bronchial smooth muscle
Muscarinic acetylcholine receptors belong to the family of
G-protein-coupled receptors. However, they share the same
ligand used by nicotinic acetylcholine receptors at the neuro-
muscular junction, i.e., acetylcholine. Muscarinic receptors are
found not only on the postganglionic parasympathetic nerves
but also on smooth muscle of the bronchi. M2 and M3 mus-
carinic receptor subtypes are present on the bronchial smooth
muscle. The M3 receptor facilitates contraction, postsynapti-
cally. The M2 subtype plays a role in the auto-feedback mode
to inhibit or enhance the release of acetylcholine. Antagonism
(block) of the M2 receptor, which is presynaptic, enhances
acetylcholine release. The released acetylcholine acts on the
M3 receptor, causing bronchoconstriction. Irritation of the
airway by a foreign body, such as an endotracheal tube, can
lead to parasympathetic activation and release of acetylcholine
resulting in bronchoconstriction.
Since muscle relaxants are not specific to nicotinic acetyl-
choline receptors of the neuromuscular junction, they also are
able to exert effects on muscarinic receptors. Although mus-
carinic-receptor control of airway tone is complicated, the net
effect of neuromuscular relaxant-induced effects on airways
depends on the relative block of M2 and M3 muscarinic recep-
tors. Because M3 muscarinic receptor activation is associated
with initiation of airway smooth-muscle contraction, agents
that are potent antagonists at the M3 muscarinic receptor
should inhibit bronchoconstriction despite the M2 muscarinic
receptor block and the increased release of acetylcholine from
parasympathetic postganglionic nerves. Therefore, pancuro-
nium, a potent M2 antagonist, is not associated with broncho-
constriction since it is also a potent M3 antagonist at doses in the
clinical range [23]. On the other hand, rapacuronium, which
was taken off the US market owing to severe bronchospasm,
blocks M2 receptors but activates M3 receptors by allosteric
binding, thereby increasing smooth-muscle tone and adding
to its ability to provoke bronchospasm [24]. Vecuronium also
can exert a similar muscarinic receptor activation pattern. Quite
in contrast to rapacuronium, however, since the recommended
intubation doses of vecuronium are 15–20 times smaller than
rapacuronium, it exhibits no affinity for, or effect on, M2 or M3
muscarinic receptors at clinical concentrations [25]. Rocuro-
nium also does not potentiate vagally induced bronchoconstric-
tion; neither does cisatracurium or mivacurium [25].
Histamine release and anaphylaxis
Histamine release from mast cells can be induced either by an
antigen–antibody reaction as a result of true anaphylaxis
(mediated by IgE), by activation of the complement system
(IgG or IgM), or by direct action of molecules on the surface of
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mast cells. Two types of mast cells are differentiated: mucosal
(in the bronchial system and gastrointestinal tract) and serosal
(vascular endothelium, skin, connective tissue) [26].
Direct effects on mast cells
In comparison to tertiary amines (e.g., morphine), the quater-
nary ammonium structure of muscle relaxants presents a weak
histaminergic effect on mast cells. In clinical doses, succinyl-
choline and benzylisoquinolines (D-tubocurarine, atracurium,
mivacurium) can directly liberate histamine from serosal mast
cells. Clinical symptoms are erythema, rash, tachycardia, and
in rare cases hypotension. The pharmacologically selective and
more potent cisatracurium isoform, on the other hand, has no
direct histaminergic effects [27]. Neither do any of the com-
monly used steroidal muscle relaxants (pancuronium, vecur-
onium, rocuronium). The direct effect on the surface of mast
cells is subject to tachyphylaxis, meaning that slower, gradu-
ated, or repetitive administration of the drug decreases the
histaminergic side effect. Prophylactic administration of hista-
mine (H1 and H2) receptor blockers can suppress the clinical
side effects of histamine release [28].
Anaphylactic reactions
Anaphylactic reactions to muscle relaxants are very rare, and
probably are not related to other drug allergies, atopic dispos-
ition, or a sensitivity to direct mast-cell activation by individ-
ual substances. Anaphylactic reactions also have been observed
at first contact with a drug, and very often crossover allergies
are present. Females have a higher disposition to anaphylactic
reactions with muscle relaxants (male:female ratio ¼ 2.5:1).
A causal relationship with cosmetics and cleaning chemicals,
which often have quaternary ammonium structures, is specu-
lated. Relative to the frequency with which they are used, the
incidence of anaphylactic reactions after succinylcholine is
approximately three times greater than after administration
of nondepolarizing neuromuscular blocking drugs. The indi-
vidual neuromuscular blocking drugs do not differ in their
potential to elicit anaphylaxis (Table 38.1) [29].
Preclinical pharmacology and
pharmacological variables
of neuromuscular block
The neuromuscular blocking action of muscle relaxants is
characterized by a decreased contractile response to stimula-
tion of the respective motor nerve. Depending on the individ-
ual muscle group and blood supply, the onset, maximal effect,
and duration of block following muscle relaxants differ. Usu-
ally, to determine the clinical (pharmacologic) response to a
muscle relaxant, the twitch depression of a skeletal muscle
(e.g., adductor pollicis) in response to its nerve stimulation is
measured following incremental or single dose of the muscle

relaxant. A twitch of 100% is the response in the absence of
any neuromuscular block, while 0% indicates complete
paralysis. Although there is tremendous variability between
patients in terms of response to muscle relaxants, the com-
pounds are characterized by determining the following phar-
macologic variables as endpoints in large groups of patients
(Fig. 38.1):
(1) Potency – The potency of a muscle relaxant is described
by its effective dose (ED). ED95 and ED50 are the doses of
muscle relaxant necessary to suppress the twitch response
by 95% (5% twitch height) or 50% (50% twitch height) of
baseline (100%) twitch height, respectively.
(2) Onset – Onset describes the interval between injection of
the muscle relaxant and development of maximal neuro-
muscular block.
(3) Clinical duration of action (dur25 or dur95) – The
clinical duration of action is the interval between injec-
tion of the muscle relaxant and recovery of the twitch to
25% or 95% of baseline twitch height (i.e., 75% or 5%
twitch suppression). If the surgical conditions require
continued relaxation, re-injection of the muscle relaxant
becomes necessary at or before 25% recovery.
(4) Recovery index – The recovery index describes the speed
of the offset of effect of a muscle relaxant, and is defined
as the time taken for recovery from 25% to 75% twitch
height.
(5) Total duration of action – The total duration of action is
described by the interval between injection of the muscle
relaxant and recovery of the TOF ratio to  0.9 [30].
Pharmacokinetics (distribution
and elimination)
Muscle relaxants are usually administered intravenously, to
ensure rapid onset, fast distribution, and predictable elimin-
ation. The desired paralytic effect after subcutaneous or intra-
muscular application (as with poisoned arrows in the Amazon)
can only be achieved with high doses of muscle relaxants.
Furthermore, the pharmacodynamics of the intramuscular
nondepolarizing relaxants are unpredictable. Muscle relaxants
are not absorbed through the gastrointestinal tract. Succinyl-
choline, however, is absorbed effectively and rapidly via the
intramuscular route and therefore can be used in an emergency
setting to treat laryngospasm in the absence of an intravenous
line, provided there is no contraindication to its use.
Factors influencing pharmacokinetics
Volume of distribution
All muscle relaxants have a more or less positively charged
quaternary ammonium group, which remains ionized inde-
pendent of the pH value. The positive charge makes it almost
impossible for muscle relaxants to bind to lipids. Therefore the
volume of distribution (Vd) of muscle relaxants is almost
exclusively in the extracellular space and consists of 0.2–0.5
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Chapter 38: Neuromuscular blocking drugs
L kg–1. If muscle relaxants are administered over a prolonged
period of time (> 24 hours), distribution into less perfused
tissue occurs. resulting in a volume of distribution that can
then increase up to 10-fold [31].
Plasma protein binding
After injection, muscle relaxants bind to plasma proteins, par-
ticularly to albumin and g-globulins. The published values for
percentage of protein binding of individual muscle relaxants are
inconsistent and highly dependent on the method of determin-
ation. In the presence of inflammation, a protein called a1-acid
glycoprotein (AAG, orosomucoid), a component of a1-globulin,
increases in plasma. This protein binds to all muscle relaxants,
resulting in a decreased free fraction in plasma.
Pharmacologic potency
The pharmacologic potency of a muscle relaxant is described
by its affinity to the acetylcholine receptor. Many relaxants
exhibit a reciprocal relationship between pharmacologic
potency and onset time. If a low-affinity drug requires a high
dose (e.g., higher ED95) to achieve a defined twitch depression,
the concentration gradient between central compartment and
biophase will be high, resulting in faster delivery of the drug to
the receptor. In contrast, if the drug has a high affinity for the
acetylcholine receptor, it will be administered in smaller doses
(lower ED95) and the gradient for transfer of drug will be
lower, resulting in slower onset [17,18]. Even though muscle
relaxants do not all share these characteristics [18], pharma-
ceutical research follows this assumption when developing and
synthesizing new muscle relaxants (e.g., rocuronium).
Speed of injection
Fast injection of muscle relaxant generates a high concentra-
tion gradient between the central compartment and the bio-
phase (i.e., neuromuscular junction), and therefore expedites
onset time. However, in the case of the benzylisoquinolines,
especially atracurium and mivacurium, the histaminergic side
effects can be associated with rapid injection [32].
Perfusion
Intravenously administered muscle relaxants must be trans-
ported via the bloodstream to their effect compartments. If the
cardiac output is reduced for whatever reason, onset of the
neuromuscular block is delayed [33]. Differences in regional
blood flow result in different onset times in the individual
muscle groups (diaphragm < laryngeal muscles < orbicular
ocular muscle < adductor pollicis muscle) [34].
Obesity
At normal doses, the positive charge of the muscle relaxant
prevents its absorption into fat tissue. Therefore, the body-
weight-related volume of distribution (Vd kg–1), and clearance
in obese patients is markedly reduced compared to normal
615
 Section 3: Essential drugs in anesthetic practice

Table 38.2. Metabolism and elimination of muscle relaxants

Metabolism Renal elimination Biliary elimination

Succinylcholine 98–99% (plasma cholinesterase) < 2% high elimination in presence of —
plasma cholinesterase deficiency
Mivacurium 95–99% (plasma cholinesterase) < 5% (metabolites) high elimination in —
presence of plasma cholinesterase
deficiency
Atracurium 70–90% (Hofmann elimination und esterases) 10–30% (laudanosine) (laudanosine)
Cisatracurium 70–90% (Hofmann elimination and esterases) 10–30% (laudanosine) (laudanosine)
Alcuronium — 80–90% 10–20%
Vecuronium 30–40% (hepatic) ~ 40% (metabolites) 10–20% (metabolites)
Pancuronium 10–20% (hepatic) 60–80% 10%
Rocuronium Minimal (hepatic) 30–40% ~ 60%

Table 38.3. Pharmacokinetic parameters of muscle relaxants at different ages

Plasma clearance (mL kg–1 min–1) Volume of distribution (mL kg–1) Elimination half-life (min)
children adults elderly children adults elderly children adults elderly
Atracurium 5.1–9.1 5.0–6.2 5.4–6.5 113–210 100–140 150–190 14–20 17–23 22–23
Cisatracurium 4.1–6.5 110–180 19–25
Mivacurium 40–120 54 120–410 290 1–3 2
Vecuronium 2.8–5.9 4.2–6.3 2.6–3.7 130–360 210–280 180–440 28–123 50–90 58–125
Rocuronium 11.4–13.5 2.2–3.5 3.4 220–300 140–220 620 38–56 70–106 137
Pancuronium 1.7 1.0–2.0 0.8–1.2 200 100–280 220–320 103 115–155 151–204

patients. The elimination half-life, however, remains almost dependent metabolism and elimination of aminosteroidal
unaltered [35]. muscle relaxants that are affected by age (Tables 38.2, 38.3).

Age
Volume of distribution for muscle relaxants is larger in
children than in adults. Therefore, in children a higher dose
of muscle relaxant must be injected to achieve a given
concentration of relaxant. The neuromuscular junction is
also more sensitive in the younger child than in the adoles-
cent [36]. Thus the higher dose can result in prolonged
duration of action. With aminosteroidal derivatives, the
higher Vd of the drug can result in a prolonged duration
of action and elimination [37]. The higher heart rate and
cardiac index in children also shortens the onset time of
neuromuscular block compared with adults. Despite the
widening of the neuromuscular junction and decrease of
acetylcholine receptors with aging [38,39], the sensitivity to
neuromuscular blocking drugs remains unaltered [38,40,41].
However, distribution and elimination kinetics are often
prolonged in the elderly. This is largely the consequence of
impaired organ function, for example of heart, liver, and
kidneys. Of the drugs in current use, it is usually the organ-
Pregnancy
During pregnancy, the pharmacokinetics and pharmacodynamics
of muscle relaxants remain virtually unaltered. However, increased
potency and duration of action should be considered with the use
of nondepolarizing muscle relaxants when magnesium is used as
treatment for premature uterine contractions or pre-eclampsia.
The ionized state of muscle relaxants minimizes the passage of
drug through the blood–placenta barrier. Only after extended use,
for example during prolonged mechanical ventilation with relax-
ants in an ICU, do muscle relaxants reach the fetus in sufficient
concentrations to significantly affect muscle function [42].
Temperature
Duration of action of muscle relaxants is prolonged during
hypothermia because of delayed metabolic breakdown by the
organs of metabolism, as well as delayed hepatic and renal clear-
ances [43]. In the case of atracurium and cisatracurium, it is also
due to a delay in the spontaneous degradation (Hofmann elim-
ination) [44]. The differentiation between pharmacodynamic

616
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 Chapter 38: Neuromuscular blocking drugs

and pharmacokinetic causes is difficult to determine during Metabolism: ester hydrolysis

reduced body temperature. A possible exception is mivacur-
ium, which is degraded by temperature-independent plasma
cholinesterase [44,45].
Elimination and metabolism
of relaxants
The neuromuscular effect of a single dose of muscle relaxant is
primarily terminated by redistribution of drug from the
neuromuscular junction and central compartment to the per-
ipheral compartment. After repeated injection or continuous
infusion, however, the redistribution capacity may become
saturated, and the muscle relaxants and their active metabolites
may be distributed back into the central compartment. In this
case, neuromuscular recovery is determined primarily by the
elimination of the drug.
Renal elimination
All muscle relaxants can be eliminated through the
kidney, although this route may not be the primary pathway
(Fig. 38.6). At physiological pH, muscle relaxants are ionized
as quaternary amines. Patients with healthy renal function can
eliminate muscle relaxants at a rate of approximately 1–2 mL
kg–1 min–1, which is equivalent to the normal glomerular
filtration rate. Reabsorption from the tubules does not take
place. Decreased renal function prolongs the elimination half-
life of muscle relaxants that are excreted by the kidneys, such
as pancuronium, rocuronium, and alcuronium.
Succinylcholine and mivacurium are the only nondepolarizing
neuromuscular blocking drugs inactivated through enzymatic
cleavage by plasma cholinesterase. This inactivation takes place
as long as the molecules are in the extracellular space or diffuse
back into it from the synaptic cleft.
Atypical plasma cholinesterases
The incidence of individuals with heterozygous atypical
plasma cholinesterase is 1/480. The duration of action of
succinylcholine and mivacurium in these cases is delayed only
minimally. Homozygous carriers of the atypical plasma choli-
nesterase (incidence 1/3200), however, can experience pro-
longed neuromuscular block lasting up to 3–6 hours.
Numerous genotypes of plasma cholinesterase, in hetero- or
homozygous form, can be differentiated: e.g., E1u (usual:
normal form), E1a (atypical form: dibucaine-resistant), E1f
(fluoride-resistant), E1s (silent form: no enzyme activity at
all). The dibucaine test, introduced in 1957 by Kalow and
Genest, uses the local anesthetic dibucaine to inhibit plasma
cholinesterase in vitro [46]. Normal isoforms of plasma choli-
nesterase are more easily inhibited than the atypical isoforms.
The percentage of inhibition of plasma cholinesterase is
referred to as the dibucaine number. Normal plasma cholines-
terases will be inhibited about 70% by dibucaine, whereas
abnormal cholinesterases are less inhibited (Table 38.4).
Acquired cholinesterase deficiency
Different drugs can inhibit the activity of plasma cholinester-
ase, and thereby decrease the metabolism of succinylcholine

Figure 38.6. Schematic illustration of the distribu-

Injection k01

tion of muscle relaxants in the different compart-

ments. The propagated model can be used to
mathematically determine pharmacokinetic param-
eters. kxy describes the redistribution constants
between the different compartments.
11
2 k21
k0e Effect
Central Compartment Compartment
ke0
k12 (Biophase)
Peripheral Compartment

k20 k10 k10 k10

Elimination Elimination
Degradation: Renal: All
plasma cholinesterase: additionally
mivacurium, succinylcholine Hepatic: Steroids
Hofmann degradation: Degradation in plasma by Hofmann
cisatracurium or plasma cholinesterase:
cisatracurium, succinylcholine

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 Section 3: Essential drugs in anesthetic practice
Table 38.4. Dibucaine number, atypical plasma cholinesterase, and
neuromuscular recovery after succinylcholine or mivacurium
Dibucaine Plasma Neuromuscular
number cholinesterase recovery
 70 Normal Normal
35–65 Heterozygous Minimal increase
atypical
 30 Homozygous Prolonged by
atypical hours
and mivacurium. This is most obvious with the cholinesterase
inhibitors neostigmine and pyridostigmine. Several other
drugs, including pancuronium, antiemetic metoclopramide,
echothiopate (a topical drug used to treat glaucoma), and some
antiasthmatic drugs, have considerable capacity to inhibit cho-
linesterase. If the plasma cholinesterase activity is reduced to
values around 500 IUL–1 (e.g., during liver failure or burn
injury), the neuromuscular block induced by succinylcholine
or mivacurium can be prolonged up to 2.5 times [47]. Patients
with renal insufficiency, and pregnant women, may also dis-
play reduced plasma cholinesterase activity.
Metabolism: nonenzymatic decay
(Hofmann elimination)
Atracurium and its isomer cisatracurium are inactivated by
spontaneous temperature- and pH-dependent degradation by
the so-called Hofmann elimination. They are degraded into
laudanosine and monacrylate, which are inactive metabolites
at the neuromuscular junction. Hofmann elimination takes
place in the central and peripheral compartment and in the
synaptic cleft. In addition, atracurium is degraded via ester
hydrolysis into a quaternary acid and quaternary alcohol.
Metabolism: hepatic elimination
The steroidal relaxants rocuronium, pancuronium, and vecur-
onium are eliminated through the kidneys and the liver. Hepatic
elimination of the drugs and their metabolites can be important
during renal failure, but this pathway is still slightly slower than
the dissipation of action due to redistribution of the drug
following a single dose. Therefore, the duration of action of
each repetitive injection increases, or the dose of muscle relax-
ant required to establish a defined neuromuscular block
decreases, because the distribution volume of the drug is small.
This accumulation during repetitive dosing, however, in no way
compares with the accumulation of parent drug and metabolites
during liver and/or kidney failure. In contrast to the benzyliso-
quinolines, the deacetylation by the liver of steroidal muscle
relaxants in position 3 and 17 leads to metabolites, which have
their own neuromuscular blocking effects and are slowly elim-
inated. This is of clinical relevance when these muscle relaxants
are used over a long period of time (e.g., in the ICU), since the
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Table 38.5. Adverse effects of succinylcholine
Stimulation of muscarinic acetylcholine receptors of the
Incidence cardiac sinoatrial node
Bradycardia
—
Atrioventricular node rhythm
1/480
Ventricular arrhythmia
Depolarization of the endplate
1/3200
Increased intracranial pressure
Increased intraocular pressure
Increased intragastric pressure
Release of intracellular potassium
Myalgia
Masseter spasm
Trigger for malignant hyperthermia (MH)
Allergic reactions
accumulation of the metabolites can potentiate the paralysis
and delay neuromuscular recovery.
Clinical pharmacology of
the depolarizing relaxant
succinylcholine
Succinylcholine is the only depolarizing muscle relaxant cur-
rently in clinical use, having gained international acceptance
based on research by Foldes [48]. The molecular size is smaller
than that of the nondepolarizing muscle relaxants. Both nitro-
gen atoms are quaternary, i.e., positively charged and therefore
polar, water-soluble, and almost fat-insoluble. The pH of a 2%
solution is around 2–3. The commercially available solutions
also contain stabilizers and buffers (benzylalcohol, benzoate,
and sodium chloride), which might account for some of the
side effects (Table 38.5). The absolute and relative contraindi-
cations for use of succinylcholine are based on its side effects
(Table 38.6). In current clinical practice, succinylcholine is
used almost exclusively for rapid sequence intubation in
patients with increased risk for aspiration of gastric contents,
or to relieve laryngospasm.
After intravenous injection, most of the succinylcholine is
immediately metabolized by the plasma cholinesterases to
succinylmonocholine and choline, even before it reaches the
synaptic cleft. Thus, only a fraction reaches the neuromuscular
junction and it displays a depolarizing effect within 20–40
seconds. Clinically, this can be visualized within the first
minute after injection as a series of muscle fasciculations,
followed by complete muscle relaxation. The ED95 for succi-
nylcholine is 0.3 mg kg–1 body weight [49]. In clinical practice,

Table 38.6. Contraindications to succinylcholine
Neuromuscular diseases
Denervation (after 2 days)
Immobilization (after 3 days)
Burns (after 2 days)
Chronic use of muscle relaxants (after 3 days)
Sepsis/severe inflammation (after 3 days)
Disposition to malignant hyperthermia
Allergy against succinylcholine
Homozygous for atypical plasma cholinesterase
to ensure fast and complete paralysis, very often 1.0 mg kg–1
(3  ED95) of succinylcholine is given. More recent studies,
however, advocate a reduction in the intubating dose to 2 
ED95 (0.6 mg kg–1), which provides acceptable intubating
conditions after 60 seconds, with a shortening of the duration
of effect by more than 90 seconds [49]. Regardless of these
dosing guidelines, in clinical situations where maximal para-
lyzing effect is needed quickly and good intubating conditions
are mandatory, 1 mg kg–1 might still be a better choice. The
“ideal” dose of succinylcholine therefore remains an individual
decision.
Neuromuscular recovery begins after succinylcholine dif-
fuses out of the neuromuscular junction into the extracellular
space where it is enzymatically metabolized by plasma choli-
nesterase. Despite the development of newer nondepolarizing
neuromuscular blocking drugs with faster onset times (rocur-
onium) or shorter duration of action (mivacurium), succinyl-
choline remains the only muscle relaxant that combines both
properties: short onset time (< 1 minute) and short duration
of action (5–10 minutes). To prevent some of the unwanted
side effects of succinylcholine, related to the general muscle
fasciculations, the concept of precurarization was introduced.
To achieve this effect, a small dose of nondepolarizing neuro-
muscular blocking drug (e.g., vecuronium 0.01 mg kg–1 or
cisatracurium 0.01 mg kg–1 in an adult [50,51]), which occu-
pies a fraction of the acetylcholine receptors, is administered
before giving succinylcholine. However, since some acetylchol-
ine receptors are blocked, the total succinylcholine dose has to
be increased to achieve the same neuromuscular blocking
effect. Some patients may show signs of muscle weakness
(e.g., diplopia) after the precurarizing dose of the nondepolar-
izing relaxant. Precurarization is therefore inadvisable in
patients with existing muscle weakness (e.g., myasthenia
gravis). Additionally, when administering such small doses of
nondepolarizing neuromuscular blocker, one has to consider
that a long precurarization interval (e.g., 3–6 minutes for
cisatracurium [52] owing to the small gradient between the
central and effect compartment (biophase) (Fig. 38.6). The
utility of administering a small dose of nondepolarizing
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Chapter 38: Neuromuscular blocking drugs
relaxant in clinical practice has recently been questioned
because of the unwanted respiratory side effects [53].
Side effects of succinylcholine on autonomic
ganglia and muscarinic receptors
The effect of succinylcholine on the cardiovascular system is
very diverse, since it binds to all of the cholinergic receptors of
the autonomic nervous system (Table 38.5). Complete sup-
pression of the sinoatrial node (bradycardia), idioventricular
rhythm, and ventricular arrhythmias can occur as a result of
stimulation of the autonomic ganglia or the vagal muscarinic
receptors, especially after second and subsequent injections.
These dysrhythmic effects often are observed when high vagal
tone is present, which is common in pediatric patients or after
vagal stimulation induced by the laryngoscopy blade. Stimula-
tion of other parasympathetically innervated structures (dila-
tion of cervix, stimulation of carotid body or eyeballs) can
potentiate the bradycardia. High succinylcholine-induced
levels of catecholamines and serum potassium can potentiate
these dysrhythmias. By premedicating with atropine, bradyar-
rhythmias can be prevented; however, ventricular arrhythmias
are not attenuated by atropine pretreatment. Additionally, a
preceding injection of a small dose of succinylcholine (“self-
taming”) [54], or the injection of lidocaine [55] or opioids
[56], cannot attenuate these unwanted cardiovascular effects,
but may attenuate the side effects related to fasciculations,
namely myalgia.
Effects of succinylcholine at the
neuromuscular junction
By depolarizing the endplate, succinylcholine induces fascicu-
lation (uncoordinated contraction) of all skeletal muscles and
causes a variety of unwanted side effects (Table 38.5).
Although a causative relationship has not yet been estab-
lished, the potential to increase intragastric, intracranial, and
intraocular pressures and myalgia has been attributed to the
fasciculations. The relationship between fasciculations and
side effects is controversial, because the precurarizing dose
can weaken the intensity of the fasciculations but does not
reduce the side effects overall. It is especially difficult to
explain the underlying reason for elevated intracranial pres-
sure. It has been suggested that the increase in cerebral
perfusion due to an increase in afferent excitation in the
context of the generalized muscle fasciculations causes the
rise in intracranial pressure. Prior hyperventilation can
attenuate the rise in intracranial pressure. Other studies do
not confirm the rise in intracranial pressure [57]. A rise in
intraocular pressure has been attributed to sustained con-
traction of the extraocular muscles, where each muscle fiber
has multiple innervations. However, no published reports
have documented further eye damage with the administra-
tion of succinylcholine in patients with open eye injury [58].
Nonetheless, this catastrophic complication influences many
anesthesiologists to avoid succinylcholine [58]. The choice
619
 Section 3: Essential drugs in anesthetic practice
between succinylcholine and a nondepolarizer should therefore
be weighed against the danger of aspiration of gastric contents
and rise in intracranial or intraocular pressures. Inadequate
paralysis by a nondepolarizing relaxant can increase intracranial
and intraocular pressures from coughing or bucking during
laryngoscopy.
Succinylcholine leads to a temporary small increase in
serum potassium levels of approximately 0.5 mEq L–1 in healthy
patients. Pathologic states, which lead to quantitative increases
and/or qualitative changes in the acetylcholine receptor, often
are associated with larger succinylcholine-induced increases in
serum potassium. In certain pathologic states, the hyperkalemia
can reach life-threatening levels. If a patient has a pre-existing
hyperkalemia, succinylcholine is a relative contraindication.
However, succinylcholine has been used in chronic renal failure
patients with relatively normal potassium levels with no adverse
effects [59]. The potential for hyperkalemia with succinylcho-
line due to denervation induced by diabetic, ischemic, and renal
neuropathy should be kept in mind. The serum potassium level
does not reflect the potential for increased potassium release
from the muscle after succinylcholine injection. It is hoped that
this dilemma will become moot as techniques for rapid intub-
ation with other fast-onset nondepolarizing neuromuscular
blocking drugs are established.
Except for the volatile anesthetics, succinylcholine is the
strongest trigger of malignant hyperthermia. Masseter spasm
can be associated with succinylcholine in both adults and
(more frequently) in children. Although masseter muscle
spasm may be an early indicator of malignant hyperthermia,
it is not always predictive of malignant hyperthermia. It is not
necessary to abort the anesthetic or change to a nontriggering
drug when masseter spasm occurs in isolation.
Histamine release and allergic reactions
following succinylcholine
Although anaphylactic reactions are rare, succinylcholine is the
neuromuscular relaxant associated with their highest incidence.
Should severe cardiopulmonary side effects occur after injection
of succinylcholine, after excluding a hyperkalemic response, one
has to consider an allergic reaction and treat the patient accord-
ingly. Elevated serum tryptase levels will reflect the presence of
an anaphylactic reaction. Postoperatively, skin testing by a
dermatologist should be performed to confirm the allergen.
Clinical pharmacology of
nondepolarizing neuromuscular
blocking drugs
The nondepolarizing neuromuscular blocking drugs can be
classified in a number of ways (Table 38.7), but it is their
chemical structure that is most relevant when considering
PK/PD parameters and side effects.
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Standard intubation
One of the main reasons for using muscle relaxants in the context
of general anesthesia is to facilitate atraumatic and/or rapid trach-
eal intubation. If the muscles of the oral cavity, larynx, diaphragm,
and abdomen are completely relaxed that goal is achieved. In
clinical practice, little emphasis is put on neuromuscular moni-
toring when determining the optimal time-point of intubation.
Most anesthesiologists judge the time-point to be when adequate
depth of anesthesia and muscle relaxation is achieved by clinical
assessment. Others use the standard onset time provided by the
manufacturer. Normally a 2  ED95 dose of a muscle relaxant is
injected, and an intubation attempt is started after the standard
onset time (Table 38.8). Aside from muscle relaxation, the depth
of anesthesia determines the ease of intubation.
Rapid sequence induction with
nondepolarizing muscle relaxants
When there is substantial risk for aspiration of gastric contents,
an essential goal during induction of anesthesia is to secure the
airway as rapidly as possible, usually within 60–90 seconds after
loss of the protective airway reflexes. At present, succinylcholine
1 mg kg–1 and rocuronium 1.2 mg kg–1 are the only muscle
relaxants with the appropriate pharmacologic characteristics to
achieve this onset time. However, 1.2 mg kg–1 rocuronium has a
prolonged duration of muscle block. This prolonged duration of
action can be a serious problem if one gets into a “can’t intubate,
can’t ventilate” situation, and it can be fatal. Many anesthesiolo-
gists are reluctant to use such high doses of rocuronium. A short-
acting nondepolarizer, such as mivacurium, has a prolonged
onset of action, too long for rapid sequence induction. If contra-
indications to succinylcholine are present (Table 38.6), alterna-
tive techniques should be used (Table 38.9).
“Priming”
Two successive injections of a nondepolarizing muscle relaxant
can decrease the onset of muscle paralysis. Thus, a small
subparalytic (“priming”) dose is injected about 3 minutes
before the full intubating dose (Table 38.9). The priming dose,
by occupying a small number of receptors, decreases the
margin of safety of neurotransmission and therefore speeds
the onset of effect with the subsequent dose. By priming, it is
possible to achieve onset times in the range of 1 minute. Just as
with precurarization, some patients may show signs of muscle
weakness following the priming dose, which can increase the
risk for aspiration [53,60].
Increased intubating dose
By increasing the dose of nondepolarizing muscle relaxant, the
onset time for paralysis can be decreased. However, the chances
of unwanted cardiovascular side effects also are increased. Add-
itionally, the time to complete neuromuscular recovery is pro-
longed (Table 38.9). The limitations of currently available
nondepolarizing muscle relaxants for use in rapid sequence
 Chapter 38: Neuromuscular blocking drugs

Table 38.7. Classification of nondepolarizing muscle relaxants. Muscle relaxants can be classified according to their potency (ED95), date of introduction,
chemical structure, or duration of action

ED95 (mg kg–1) Clinical introduction Chemical classification Duration of action

Rocuronium 0.3 1992 Aminosteroid Intermediate
Vecuronium 0.05–0.06 1980 Aminosteroid Intermediate
Pancuronium 0.06–0.07 1960 Aminosteroid Long
Mivacurium 0.08 1997 Benzylisoquinoline Short
Atracurium 0.25 1980 Benzylisoquinoline Intermediate
Cisatracurium 0.05 1995 Benzylisoquinoline Intermediate
D-Tubocurarine 0.5 1942 Dibenzyl-tetrahydro-isoquinolone Long
Alcuronium 0.2–0.25 1964 Strychnine derivative Long

Table 38.8. Onset and duration of action after 2  ED95 dose of muscle Table 38.9. Muscle relaxants used for rapid sequence induction
relaxant
“Priming” Intubation Complete
Onset Dur25 Duration Recovery dose dose recovery
(min) (min) of action index (mg kg–1) (mg kg–1) (min)
until TOF (min)
 0.9 Succinylcholine None 0.8–1.0 5–10
(min) Succinylcholine Precurarization 1.5–2.0 5–10
Rocuronium 1.5–2.5 35–50 55–80 10–15 Rocuronium 0.3 1.0–1.2 90–120
Vecuronium 2–3 30–40 50–80 10–20 Vecuronium 0.01 0.15–0.4 90–180
Pancuronium 3.5–6 70–120 130–220 30–50 Mivacurium 0.02 0.25 25–40
Mivacurium 2.5–4.5 15–20 25–40 5–9 Atracurium 0.05 0.7–0.8 60–90
Atracurium 2–3 35–50 55–80 10–15 Cisatracurium 0.01 0.2–0.4 75–120
Cisatracurium 3–6 40–55 60–90 10–15 Primary goal of a rapid sequence induction is intubation within 60 seconds.
Alcuronium 3.5–6 80–120 170–240 45–60
See Fig. 38.1 and text for definitions of onset, dur25, TOF  0.9, and recovery
index.
recovery index in another muscle (e.g., diaphragm) within the
same subject, one can assess the sensitivity of different muscles
induction are (1) the relatively longer onset time for paralysis, groups to a drug. One also can compare the recovery index in
and therefore the longer time to intubation compared with the same muscle between individuals; however, this relation-
succinylcholine unless large doses of a nondepolarizing agents ship is used mainly for studying the effect of variables, such as
are given; and (2) prolonged duration of action, particularly age, drugs, diseases, and so on.
when given in high doses to speed onset of paralysis. The latter Residual neuromuscular block (postoperative residual cur-
can pose problems related to surgeries of shorter duration, and arization) is a common sequela of muscle relaxant use.
as indicated previously can result in a crisis when a “can’t Approximately 30–60% of all patients who receive a muscle
intubate, can’t ventilate” scenario occurs. For these reasons, relaxant have residual paralysis upon leaving the operating
many anesthesiologists prefer not to use nondepolarizing room, depending on the length of operation [61–63]. Residual
muscle relaxants for rapid sequence induction. The rapid rever- paralysis can be a serious, unrecognized, and relevant clinical
sal of rocuronium with sugammadex does have an advantage problem with a potential for severe cardiorespiratory compli-
over other drugs to produce rapid onset and offset of paralysis, cations. Older patients are more likely to be affected [64]. The
particularly in “can’t intubate, can’t ventilate” situations. clinical consequences include hypoventilation [65–67], atelec-
tasis, aspiration of gastric contents [60,68], lung infiltrates,
Neuromuscular recovery pneumonia, and even death [69]. The clinical importance of
from nondepolarizers monitoring neuromuscular block and its residual effects to
Clinical recovery from neuromuscular block is usually evaluate the need for prolonged intubation or reversal of the
described by the “recovery index.” By comparing the recovery neuromuscular block cannot be overemphasized. Simple meas-
index determined in one muscle (e.g., adductor pollicis) to the ures such as making neuromuscular monitoring available,

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 Section 3: Essential drugs in anesthetic practice
promoting its use, advocating the use of reversal drugs, and
training that emphasizes the negative effects of postoperative
residual curarization on patient outcome are highly effective
tools for reducing its incidence [59–69].
Factors confounding the
clinical pharmacology
of muscle relaxants
Renal insufficiency
If the renal function is impaired or completely absent, there is
reduced clearance (prolonged renal elimination) of relaxants.
However, since the neuromuscular effect of a single injection
of muscle relaxant is mainly terminated by redistribution, the
reduced renal elimination rate usually does not cause pro-
longed recovery times after a single dose. After repetitive
injections or continuous infusion, however, the decreased
renal clearance of relaxants prolongs the neuromuscular effect
of muscle relaxants eliminated primarily by the renal route.
The elimination (metabolic) pathways of (cis-)atracurium
and mivacurium are independent of kidney function. Rocur-
onium can be eliminated independent of the renal function.
However, even these primarily kidney-independent pathways
can be impaired during concomitant diseases (Table 38.10).
The activity of plasma cholinesterase is reduced in renal
failure, probably related to its loss via dialysis filter mem-
branes and as a consequence of reduced synthesis per se from
uremic hepatopathy. This leads to a prolonged effect of suc-
cinylcholine [71] and mivacurium [72]. Additionally, altered
fluid balances during dialysis change the Vd of the muscle
relaxants, making it difficult to predict the neuromuscular
blocking effect. Changes in acid–base balance as well as elec-
trolyte status also could influence the clinical response to
muscle relaxants.
Hepatic diseases
Liver failure is often associated with secondary hyperaldos-
teronism, which results in fluid retention and an increase in
the Vd of muscle relaxants. Consequently, larger than
normal doses must be administered to achieve a given par-
alysis. The higher dose, once administered, may stay in the
central compartment for a longer time because of poor
elimination by the liver. Therefore, patients with hepatobili-
ary diseases often have a prolonged duration of action of
muscle relaxants. After a single dose, however, the elimination
(clearance) times are relatively unimportant because redistri-
bution within the compartments is the major factor determin-
ing duration of action. However, after repetitive or continuous
administration of vecuronium, rocuronium, or pancuronium
accumulation occurs, because the elimination of these drugs is
partly dependent on hepatic function. These drugs also have
metabolites that are pharmacologically active. Plasma
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cholinesterase activity also is decreased in liver dysfunction
as a result of decreased synthesis; the ester hydrolysis of miva-
curium is proportionately reduced [47,73]. The elimination
times for atracurium and cisatracurium are independent of
hepatic function. Since cisatracurium, compared to atracur-
ium, is administered in lower doses owing to its higher
potency, a relatively smaller amount of laudanosine is pro-
duced. The plasma protein deficiency associated with liver
failure barely increases the free fraction of muscle relaxant,
since the overall plasma protein binding of relaxants to albu-
min is relatively low.
Neuromuscular diseases
The integrity and function of pre-, intra-, and postsynaptic
structures is important for development, function, and main-
tenance of the neuromuscular endplate. Any neuromuscular
disease that influences nerve conduction or electrical activity of
the muscle membrane therefore influences neuromuscular
architecture and receptor function. These changes in turn
affect the responses to relaxants (Fig. 38.8).
Increased expression of the acetylcholine
receptor
When innervation and electrical conductivity are established
between muscle and nerve, the mature receptors are local-
ized only to the neuromuscular junction. Deprivation of the
neural influences on muscle leads to an upregulation of
acetylcholine receptors, as well as a spread of the receptors
beyond the neuromuscular junction into the peri- and extra-
junctional areas. During this time, instead of the receptor
with an e subunit (2a1b1de) that is expressed in the normal
junction, new receptors containing a g subunit (2a1b1dg),
also termed fetal or immature receptors, are re-expressed as
seen in the fetus (see Postsynaptic physiology and pharmacol-
ogy, above) [10,11]. The ligand sensitivity and affinity of these
immature receptors are altered. Agonists such as succinylcho-
line depolarize immature receptors more easily, and can lead
to altered and exaggerated cation fluxes. Clinically, this means
that less succinylcholine is needed to open the receptor chan-
nels. Since potassium is transported from the intra- to extra-
cellular fluid during channel opening, the upregulated
acetylcholine receptors can efflux dangerously high levels of
potassium into the bloodstream because of the concentration
gradient. In addition a7-acetylcholine receptors are expressed,
which are depolarized not only by acetylcholine, or succinyl-
choline, but also by their degradation product choline [11,74].
The increased number of acetylcholine receptors and the
altered receptor isoforms in the perijunctional area, on
the other hand, increase the margin of safety for neuromuscu-
lar block in terms of response to muscle relaxants, leading
to a resistance to nondepolarizing neuromuscular blocking
drugs. Examples of conditions that induce an upregulation of
acetylcholine receptors include all forms of denervation,
 Chapter 38: Neuromuscular blocking drugs

Table 38.10. Comparative pharmacokinetics of muscle relaxants in normal subjects versus patients with liver or kidney failure

Plasma clearance (mL kg–1 min–1) Volume of distribution (mL kg–1) Elimination half-life (min)
normal kidney liver normal kidney liver normal kidney Liver
failure failure failure failure failure failure
Atracurium 6.8 5.5–7.0 6.5–8.0 172 140–220 200–280 21 18–25 20–25
Cisatracurium 4.3–5.3 3.8 6.6 195 161 161 22–30 25–34 24
Mivacurium 1.8 1.8 0.9 112 112 124 1–3 — —
Vecuronium 3.0–5.3 2.5–4.5 2.4–4.3 200–510 240–470 210–250 50–110 80–150 49–98
Rocuronium 2.9 3 3 175 260 320 87 97 97
Pancuronium 1.8 0–0.9 1.1–1.5 274 210–260 310–430 132 240–1050 208–270

Mivacurium

Quaternary
Amino alcohol

Dicarboxyl acid

Quaternary
Mono ester

Figure 38.7. Metabolism of mivacurium by the plasma cholinesterase. The charged products are eliminated via the kidney.

immobilization, burn injury, sepsis or systemic inflam-
mation, as well as chronic neuromuscular block (Fig. 38.8)
[8,10,11,74].
Lower and upper motor neuron lesion
The potential for succinylcholine-induced hyperkalemia after a
lower motor neuron lesion has been well established [75]. An
increase in sensitivity to succinylcholine is already present 3–4
days after denervation and reaches a critical level after 7–8
days. Patients who demonstrate increased sensitivity to agonist
(succinylcholine), due to upregulated receptors, usually also
display resistance to nondepolarizing neuromuscular blocking
drugs. The shorter the nerve segment distal to the lesion, the
earlier the receptors become upregulated [76]. However, even a
polyneuropathy in the absence of a complete transection of the
nerve can cause a high potassium response to succinylcholine
[77,78]. Lesions such as stroke, cerebral hemorrhage [79], head
trauma [80], multiple sclerosis [81], syringomyelia, and para-
plegia or quadriplegia [82] also result in upregulated acetyl-
choline receptors with the potential of demonstrating
hypersensitivity to succinylcholine and resistance to nondepo-
larizing neuromuscular blocking drugs. Upper motor neuron

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 Section 3: Essential drugs in anesthetic practice
Upper motor neuron lesions
Lower motor neuron lesions Up-regulation of AChR
Muscle trauma Increased requirement for non-
depolarizing muscle relaxants
Burn injury (resistance)
Immobilization
Hyperkalemia after succinylcholine
administration
Sepsis / Infection
Normal
Down-regulation of AChR
Myasthenia gravis
Organophosphate poisoning Decreased requirement with non-
depolarizing muscle relaxants
Chronic cholinesterase inhibition
(Increased sensitivity)
Figure 38.8. Conditions with altered acetylcholine receptor (AChR)
expression.
lesions can lead to unilateral or bilateral changes, whereas
lower motor neuron injury causes change only in the distribu-
tion of the affected nerve. The exact time period over which the
receptors remain upregulated is unclear. There have been
reports of increased succinylcholine sensitivity that persist for
several years after the nerve injury [79]. The risk of hyperka-
lemia following upper or lower motor neuron injury is prob-
ably absent once the resistance to nondepolarizing muscle
relaxants disappears, but no studies have defined this period.
Since it is difficult to predict how a patient with neurological
symptoms will react to muscle relaxants, succinylcholine
should be avoided and neuromuscular function monitored
when using nondepolarizing muscle relaxants.
Immobilization
The physiologic state of immobilization contrasts with dener-
vation syndromes in that there is no direct damage to cord or
nerve roots, and the muscle fibers remain innervated. How-
ever, immobilization (from isolated limbs with plaster cast to
total-body immobilization as in critical illness or total-body
cast) also induces an upregulation of acetylcholine receptors
[83–85]. The peak effect on acetylcholine receptor regulation
occurs at 14–21 days after onset of immobilization, but the
duration of this change is unclear in humans [84].
Burn injury
Burn injury induces an upregulation of acetylcholine receptors
in the musculature underneath the burn site, but usually not at
distant muscles [86]. The iatrogenically induced immobiliza-
tion of patients confined to bed, however, may cause receptor
changes even in distant muscles. There is evidence that the
burn injury per se leads to a direct chemical or physical
denervation, since the mRNAs for g subunits are increased,
as in denervation [86]. The extent to which circulating medi-
ators or the alterations of cell signaling pathways are involved
in upregulation remains to be investigated. Burn of a single
limb (8–9% body surface area) is sufficient to cause lethal
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hyperkalemia following succinylcholine [87]. The prolonged
administration of muscle relaxants to facilitate mechanical
ventilation can accentuate the upregulation [88]. Since it takes
some time to initiate the upregulation, it is safe to use succi-
nylcholine for up to 48–72 hours after acute burn injury. Any
use beyond this time should be avoided [74].
Infection and systemic inflammation
The effect of systemic infection and inflammation on the
acetylcholine receptor remains controversial. There have been
reports of hyperkalemia after succinylcholine administration
in septic patients [89,90]. An increase in acetylcholine recep-
tors in critically ill patients has been demonstrated; however,
patients receiving intensive care treatment may have concomi-
tant factors such as immobilization, long-term administration
of muscle relaxants, and steroid treatment. Other than an
increase in acetylcholine receptors, the resistance to nondepo-
larizing muscle relaxants also can be explained by the increased
binding of relaxants to acute-phase reactant protein, AAG,
which is increased in inflammatory processes. In rodents, both
causes for resistance to nondepolarizing muscle relaxants have
been demonstrated: inflammation alone was able to increase
acetylcholine receptors as well as AAG plasma levels [91,92].
Decreased number of acetylcholine receptors
Myasthenia gravis
Myasthenia gravis is an autoimmune disease associated with a
clinical picture of increasing muscle weakness and fatigue.
Antibodies against the acetylcholine receptor are present in
approximately 80% of the patients (“antibody-positive”). Some
of the “antibody-negative” patients have antibodies against a
receptor tyrosine kinase, muscle-specific kinase (MuSK),
which is important for the clustering and maturation of the
receptors at the neuromuscular junction [93]. It is therefore
likely that “antibody-negative” patients may have antibodies
against other proteins related to the neuromuscular junction.
The autoantibodies to the acetylcholine receptor in myasthenic
patients lead to a decrease in receptor number. Interestingly,
the levels of antibodies correlate poorly with the clinical status.
Symptoms of myasthenia gravis generally start with ptosis and
diplopia, and proceed to bulbar paralysis. Later disease stages
are marked by dysarthria, dysphagia, weakness of extremities,
and weakness of respiratory muscles [94]. The therapeutic
approach to myasthenia, aside from thymectomy (surgical
removal of the origin of the autoantibodies), is the adminis-
tration of cholinesterase inhibitors (mostly pyridostigmine).
Because of the downregulation of acetylcholine receptors,
patients with myasthenia are sensitive to nondepolarizing
muscle relaxants. If muscle relaxants are used during clinical
anesthesia, constant neuromuscular function monitoring for
the duration of anesthesia is advised. Preoperative determin-
ation of the train-of-four fade can be used to predict whether
or not the patient will have increased sensitivity to nondepo-
larizing muscle relaxants [95]. The reduced number of

acetylcholine receptors, however, renders succinylcholine less
capable of depolarizing the endplate effectively and raises the
dose requirements of succinylcholine. For rapid sequence
induction it is advisable to increase the dose of succinylcholine
to 1.5–2 mg kg–1. Higher doses may cause a nondepolarizing
type block (see Phase II block and Desensitation block, above).
The continuation of the treatment of myasthenics with choli-
nesterase inhibitors during the perioperative interval can cause
delayed hydrolysis of succinylcholine and prolong the neuro-
muscular block [96]. The discontinuation of cholinesterase
inhibitor therapy is, however, not recomended.
Lambert–Eaton myasthenic syndrome
Lambert–Eaton myasthenic syndrome is a paraneoplastic dis-
ease associated with small-cell carcinoma, usually of lung
origin. It is an autoimmune disorder caused by the presence
of antibodies directed against the PQ-type voltage-gated cal-
cium channels [97], possibly due to a cross-reaction with the
calcium channels on the carcinomatous cells [98]. More gen-
erally stated, the syndrome is caused by a prejunctional mech-
anism that results in the decreased quantal release of
acetylcholine. The acetylcholine receptor number on the post-
synaptic membrane remains normal. Clinically, patients with
Lambert–Eaton syndrome display an increased sensitivity to
both nondepolarizing and depolarizing muscle relaxants [99].
Again, monitoring neuromuscular function during the use of
muscle relaxants will provide continuous assessment. In con-
trast to myasthenia gravis, repetitive (e.g., train-of-four) stimu-
lation results in enhancement, and not fade, of twitch.
Interaction of relaxants with other drugs
Although some drugs have neuromuscular effects, because of
the high margin of safety of neuromuscular transmission the
effects often are seen only as a potentiation of the muscle
relaxant effect. Clinically relevant interactions between these
drugs and muscle relaxants can be classified into three main
areas: pharmacokinetic, junctional, and muscular effects.
Pharmacokinetic interaction of relaxants
with other drugs
Steroidal muscle relaxants are eliminated or metabolized by
the liver to varying extents (Table 38.2). Drugs that inhibit the
cytochrome P450 enzyme system (e.g., cimetidine) or reduce
liver perfusion delay hepatic elimination and prolong the effect
of muscle relaxants when high doses are administered [100].
Conversely, drugs that induce the cytochrome P450 system
(e.g., some antiepileptic drugs) increase the rate of elimination
of hepatic metabolized drugs. Thus the requirement for drugs
such as vecuronium and rocuronium is increased, while that
for mivacurium, which is metabolized independent of the liver
[101–104], is not. Acetylcholine receptor changes and
increased binding of relaxant to AAG may also play a role in
the increased requirement during treatment with antiepileptic
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Chapter 38: Neuromuscular blocking drugs
drugs [102]. The drugs known to cause this effect are barbit-
urates, carbamazepine, and dilantin [101–104].
Relaxant and nonrelaxant interaction
at the neuromuscular junction
Neuromuscular transmission can be influenced by drugs that
act on the nerve terminal or receptor. Presynaptically, three
mechanisms have been identified, all of which decrease the
release of acetylcholine. First, cyclic adenosine monophosphate
(cAMP) and adenosine triphosphate (ATP) are necessary to
synthesize acetylcholine. Furosemide is an example of a drug
that inhibits the synthesis of cAMP, thereby also decreasing
presynaptic acetylcholine synthesis. Second, volatile anesthet-
ics block presynaptic release of acetylcholine, which can be
evidenced during repetitive nerve stimulation. Finally, volatile
anesthetics, as well as magnesium [105,106], calcium antagon-
ists, and aminoglycoside antibiotics [107 ], reduce acetylchol-
ine release by blocking presynaptic calcium channels.
Postsynaptically, numerous drugs block the a subunit of the
acetylcholine receptor in a dose-dependent fashion. These
include inhalational anesthetics [108], aminoglycoside antibi-
otics [109], quinidine [110], tricyclic antidepressants [111],
ketamine [112], midazolam [113], and barbiturates [114].
Aside from binding to the a subunit, these drugs often also
block the channel itself, or desensitize the acetylcholine recep-
tor by allosteric mechanisms (see Phase II block, Desensitiza-
tion block, and Channel block, above). It is difficult to
determine, however, which of these mechanisms have the
greatest effect on their ability to potentiate muscle relaxants.
Muscular effects of other drugs
Dantrolene, which inhibits calcium release and reuptake into
the sarcoplasmic reticulum, is used for treatment of malignant
hyperthermia. It can potentiate the effect of the nondepolariz-
ing muscle relaxants at a muscular level without exerting an
effect on neuromuscular transmission [115]. The effects of
dantrolene cannot be monitored electromyographically.
Practical aspects of drug
administration
Few surgical procedures mandate continuous neuromuscular
paralysis. In many cases, it is unnecessary to continue the
paralysis after intubation. Operations in the abdomen usually
require muscle relaxation. If the depth of anesthesia is not
sufficient, or if appropriate anesthetic depth cannot be achieved
because of other factors (e.g., hemodynamic instability), the
patient might move or cough. If the surgeon or procedure
requires absolute paralysis, one can either give repetitive bolus
doses of muscle relaxant or start an infusion with close moni-
toring of neuromuscular function. The most convenient muscle
relaxants used for infusions are mivacurium or (cis-)
625
 Section 3: Essential drugs in anesthetic practice
Table 38.11. Infusion rates for a continuous neuromuscular block and
clinical recovery after continuous infusion
IR90–IR95 (μg Recovery time until T1/
kg–1 min–1) T4 > 0.9 (min)
Mivacurium 3–15 10–20a
Atracurium 4–12 30–70a
Cisatracurium 0.4–4 30–70a
Rocuronium 3–12 30–90b
IR90–IR95, infusion rate for a 90–95% neuromuscular block; Recovery until T1/T4
> 0.9 (min), time from end of infusion until complete neuromuscular recovery.
a
Independent of infusion time.
b
At infusion time of up to 2 hours, significantly increased compared
to single-shot injection.
atracurium, because they do not accumulate and the offset
indices are constant even after repetitive injection or continu-
ous infusion (Table 38.11) [116,117].
Differential diagnosis and therapy
of residual neuromuscular block
Before reversal of residual neuromuscular block, the presence
or absence of paralysis should be evaluated. The train-of-four
ratio is the most common method of assessing muscle weak-
ness, and a ratio of  0.9 is recommended for full recovery
from paralysis [30,61–68]. If a nondepolarizing neuromuscular
blocking drug is used, the muscle weakness beyond expected
duration may be due to delayed elimination of, or increased
sensitivity to, the drug. After the reversal drug has been admin-
istered, the patient should be closely monitored in the recovery
room, since the half-life of the reversal drug might be shorter
than that of the muscle relaxant, causing recurarization.
If succinylcholine or mivacurium was used, the underlying
cause for prolonged muscle weakness could be plasma choli-
nesterase deficiency or atypical plasma cholinesterase. In both
cases, antagonism with cholinesterase inhibitors will not be of
much benefit. These patients should be mechanically ventilated
until spontaneous recovery occurs, from renal elimination of
the drug. This may take as long as 4–6 hours. In these instances
of prolonged recovery of paralysis from succinylcholine or
mivacurium, the activity of the plasma cholinesterase should
be determined. If the activity of the plasma cholinesterase is
reduced because of genetic factors, the patient should be
advised of the results so as to avoid the same complication in
future anesthetic procedures.
Use of muscle relaxants during rapid
sequence induction
When inducing patients with an increased risk of aspiration
of gastric contents, one of the goals is to secure the airway as
early as possible. Succinylcholine continues to be the com-
monest drug used for this purpose. However, succinylcho-
line has clinically relevant side effects (Table 38.5). Myalgias
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are treated either with analgesics or by reducing muscle
fasciculations. The extent to which opioids are beneficial
for succinylcholine-induced myalgia remains to be answered
[56]. It is more common in clinical practice to treat myalgias
after the fact with nonsteroidal peripheral analgesics [118].
Prevention of muscle fasciculations not only reduces the
incidence of myalgias but also prevents increases in intrao-
cular [119] and intragastric [55] pressures. The importance
of increased intraocular or even intracranial pressure by
succinylcholine has been questioned [57,58]. “Precurariza-
tion,” by the administration of a small dose of nondepolar-
izing muscle relaxant preceding the administration of
succinylcholine, is the most used clinical technique for redu-
cing fasciculations. Alternative strategies include preadmi-
nistration of small doses of succinylcholine (“self-taming”)
[54], lidocaine (100 mg) [55], or opioids [56]. In one study,
37.5% of precurarized patients had paralytic symptoms such
as diplopia, heavy eyelids, difficulty with speech and swal-
lowing. In others, signs of respiratory insufficiency were
noted [53,120]. Therefore, precurarization has its own prob-
lems and side effects.
The efficacy of precurarization with nondepolarizing relax-
ant for reducing fasciculations is undisputed. The basis for this
that is the nondepolarizing muscle relaxant has blocking
effects at the pre- and postsynaptic acetylcholine receptors.
Since the antagonism by nondepolarizing relaxant also affects
the actual mechanism of action of succinylcholine, precurar-
ization leads to prolonged onset time, shorter duration of
action, and reduced maximal neuromuscular block by succi-
nylcholine [121]. To overcome these effects, an increased dose
of succinylcholine by approximately 25–75% is recommended
(1.5–2.0 mg kg–1) [122]. A higher dose of succinylcholine after
precurarization and a normal dose without precurarization
reveal no difference in terms of incidence of muscle
fasciculations.
Succinylcholine can induce bradycardia, especially in chil-
dren and particularly after the second dose. This side effect is
prevented by premedication with atropine, which at the same
time can cause tachycardia. Tachycardia can confound the
assessment of depth of anesthesia and fluid status. Precurar-
ization with nondepolarizing muscle relaxants does not affect
the muscarinic receptors and therefore does not prevent the
autonomic and cardiac effects of succinylcholine.
A systematic review published in 2008 revealed that there
was no statistical difference in intubation conditions when
succinylcholine 1.0 mg kg–1 was compared with 1.2 mg kg–1
rocuronium [123]. The primary drawback to administering
high doses of rocuronium is the slightly prolonged onset and
prolonged duration of action of approximately 2 hours versus
10 minutes after 1.0 mg kg–1 succinylcholine. The introduction
of sugammadex (available in Europe as of September 2008),
with its fast reversal of rocuronium-induced neuromuscular
block, might be a real step forward in eliminating the potential
hazards of succinylcholine [124–125].

Prolonged neuromuscular block
in the critically ill patient
Continuous administration of neuromuscular blocking
drugs in the ICU is practiced in some situations. The eti-
ology of prolonged muscle weakness in these critically ill
patients is certainly multifactorial. It is clear that extended
use of muscle relaxants leads to muscle weakness. Therefore,
the American College of Critical Care Medicine has pub-
lished clinical practice guidelines for the prolonged use of
muscle relaxants in the adult critically ill population [126].
Prolonged disruption of neuromuscular transmission by
muscle relaxants can cause profound changes at the neuro-
muscular junction that result in aberrant responses to the
future use of both depolarizing and nondepolarizing muscle
relaxants. When using muscle relaxants for long periods,
patients should be medicated with sedative and analgesic
drugs to provide adequate amnesia and analgesia. Only after
all other means have been tried without success should
neuromuscular blocking drugs be added to the armament-
arium. Indications for muscle relaxant therapy may include
facilitation of mechanical ventilation, prevention of increase
in intracranial or intrathoracic pressure during coughing
and suctioning, treatment of muscle spasms (e.g., tetanus),
and decrease of oxygen consumption. Other reasons for its
use may include prevention of injury during seizures, or to
prevent dislodgement of patient-care-related material (endo-
tracheal tubes, arterial lines, etc.) [8].
Pancuronium or vecuronium are popular choices for relax-
ants in the ICU, because they are inexpensive. However, when
vagolysis is contraindicated (i.e., cardiovascular disease)
neuromuscular blocking drugs other than pancuronium
should be used. Although the steroidal muscle relaxants may
have the potential to have a more profound effect on the
muscle wasting, by potentiating the effect of endogenous and
exogenous steroids, this hypothesis has not been proved con-
vincingly. In-vitro studies have documented that steroidal
relaxants have no effect on enhancing the activity of nuclear
steroidal receptors or the activity of steroids themselves [126].
Chemical denervation induced by muscle relaxants upregulates
steroidal receptors in muscle, aggravating the steroid-induced
myopathy [127]. For patients receiving neuromuscular
blocking drugs and corticosteroids, therefore, every effort
should be made to discontinue neuromuscular blocking drugs
as soon as possible. Because of the unique organ-independent
metabolism (Hofmann degradation) of atracurium and cisa-
tracurium, these drugs are preferred in patients with signifi-
cant hepatic or renal disease. If tachyphylaxis to one
neuromuscular blocking drug develops, a different neuromus-
cular blocking drug can be tried, although cross-tolerance does
exist. In general, all patients receiving neuromuscular blocking
drugs for prolonged periods in the ICU should have prophy-
lactic eye care, physical therapy, and prophylaxis for deep vein
thrombosis [128].
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Chapter 38: Neuromuscular blocking drugs
Summary
Muscle relaxants are mostly used to facilitate endotracheal
intubation and to improve operative conditions during sur-
gery. Less commonly, muscle relaxants are used in critically ill
ICU patients to facilitate mechanical ventilation, decrease
oxygen consumption, and attenuate rises in intracranial or
intrathoracic pressures during coughing or suctioning. Muscle
relaxants are also an integral part of the pharmacologic arma-
mentarium for sedative/hypnotic/analgesic (“balanced”)
anesthesia.
Muscle relaxants can be classified into depolarizing and
nondepolarizing drugs. The latter, based on chemical struc-
ture, can be subdivided into steroidal and benzylisoquinoline.
A depolarizing relaxant is typified by succinylcholine. Muscle
paralysis by nondepolarizing relaxants is achieved primarily by
blocking the function of the postsynaptic acetylcholine recep-
tor, although these drugs also block presynaptic acetylcholine
receptors. The nondepolarizers produce a competitive block by
binding to the a subunit of the acetylcholine receptor, inhibit-
ing the physiologic binding and action of the neurotransmitter
acetylcholine. The neuromuscular block produced by the
depolarizing relaxant is by partial agonism; succinylcholine
induces paralysis by binding to the receptor, and repetitively
depolarizing (opening) the ion channel until it moves out of
the receptor and is degraded in the extracellular fluid by
plasma (pseudo-) cholinesterase.
Muscle relaxants are administered intravenously, to ensure
rapid onset, fast distribution, and predictable elimination.
Muscle relaxants are not absorbed through the gastrointestinal
tract. Succinylcholine, however, is rapidly absorbed via the
intramuscular route and therefore can be used in an emer-
gency situation such as laryngospasm in children who do not
have intravenous access for drug administration. All muscle
relaxants can be eliminated via the kidney, although this route
may not be the primary pathway. The steroidal relaxants,
rocuronium, pancuronium, and vecuronium, can be elimin-
ated via the kidneys and the liver. The metabolic breakdown
products of steroidal relaxants are pharmacologically active,
although less potent. The benzylisoquinoline relaxants, atra-
curium and its isomer cisatracurium, are degraded into the
inactive metabolites laudanosine and monacrylate by spontan-
eous, temperature- and pH-dependent, Hofmann elimination.
Succinylcholine and mivacurium are inactivated through
enzymatic cleavage by plasma cholinesterase. The effect of
these two drugs can be prolonged in the presence of acquired
or congenital pseudocholinesterase deficiency. The neuromus-
cular effect of a single dose of nondepolarizing muscle relaxant
wanes with time primarily due to its redistribution from the
neuromuscular junction and central compartment to the per-
ipheral compartment.
Unwanted side effects of muscle relaxants can be due
to histamine release (hypotension) and anaphylaxis. The bron-
chial and cardiovascular side effects (bronchospasm and
627
 Section 3: Essential drugs in anesthetic practice

tachycardia) of nondepolarizing relaxants, particularly the
steroidal relaxants, are due to their binding to muscarinic
acetylcholine receptors on the bronchi and myocardium,
respectively. Succinylcholine can cause tachycardia or brady-
cardia by its ability to bind nicotinic receptors in the
autonomic ganglia and the postsynaptic parasympathetic mus-
carinic receptor. It also has the potential to cause hyperkalemia
and cardiac arrest when it is administered in the presence of
upregulated acetylcholine receptors, as seen in denervation,
burns, immobilization, sepsis and prolonged neuromuscular
block. The normal acetylcholine receptor has a subunit com-
position of 2a1b1de. In the upregulated state receptors consist-
ing of 2a1b1dg and 5a7 are expressed throughout the muscle
membrane. In the presence of upregulated acetylcholine recep-
tors, there is also resistance to the neuromuscular effects of
nondepolarizers.
The muscle relaxant effect of nondepolarizers can be con-
centration-dependently potentiated by volatile anesthetics,
magnesium, aminoglycoside antibiotics, quinidine, tricyclic
antidepressants, ketamine, midazolam, and barbiturates.
Myasthemia gravis is a condition in which downregulation of
the acetylcholine receptors occurs due to autoantibodies against
the receptor. In Lambert–Eaton myasthenic syndrome the
muscle weakness is caused by decreased release of acetylcholine
due to autoantibodies against the voltage-gated calcium channel
present on the nerve terminal. Myasthenia gravis and Lambert–
Eaton patients are more sensitive to nondepolarizing relaxants.
Neuromuscular monitoring is advocated when using
muscle relaxants. A train-of-four ratio of  0.9 confirms
adequate recovery from neuromuscular paralysis. In order to
reverse nondepolarizer-induced neuromuscular paralysis, cho-
linesterase inhibitors (neostigmine, edrophonium), which
increase acetylcholine levels, can be used. A steroidal muscle
relaxant encapsulator, sugammadex, which rapidly reverses
pancuronium-, rocuronium-, and vecuronium-induced neuro-
muscular block, is now available.

9. Fambrough DM. Control of 17. Bowmann WC, Rodger IW, Houston J,

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