Nondepolarizing Neuromuscular

Blocking Agents 21
Erin Bettendorf and Zhiling Xiong

CASE: 27-year-old man with a history of asthma presenting Where is the site of action of neuromuscular blocking
with 12 h of abdominal pain, anorexia, nausea, and vomiting drugs?
and found to have acute appendicitis. He is scheduled for an
Neuromuscular blockers act at the acetylcholine receptor,
emergent laparoscopic appendectomy.
located largely in the neuromuscular junction. The receptors
PMH: Asthma are composed of five subunits—two alpha subunits, one
PSH: Tonsillectomy and adenoidectomy, age 6 beta, one delta, and one epsilon. Acetylcholine binds to the
Allergies: NKDA alpha subunits, as do most neuromuscular blocking medi-
Medications: Albuterol, montelukast cations. There are two classes of acetylcholine receptors—
FH: Maternal aunt “took a long time to wake up” from nicotinic and muscarinic. Nicotinic receptors are located on
anesthesia skeletal muscle and autonomic ganglia and are the site of
action of neuromuscular blocking medications. Muscarinic
acetylcholine receptors are found throughout the body in
Questions smooth muscle, the SA and AV node in the heart and in the
secretory glands.
Is neuromuscular blockade beneficial in this case?
Describe the process of normal signaling at the neu-
Why or why not?
romuscular junction leading to muscle contraction.
Muscle relaxation is useful in a variety of surgeries including
The transmission of a signal begins with an action potential
laparoscopic cases such as this. When used during induction,
moving down a nerve causing calcium influx through volt-
muscle relaxants help provide optimal intubating conditions
age gated calcium channels. The sudden increase in intra-
by inhibiting contraction of the muscles attached to the vocal
cellular calcium leads to the movement of acetylcholine-
cords, allowing for ease of passage of the endotracheal tube.
containing storage vesicles from the cytoplasm to the cell
Additionally, neuromuscular blockers can improve surgical
membrane. At the cell membrane, the vesicles fuse and
conditions in many instances, facilitating the safe and effi-
release acetylcholine into the neuromuscular junction. The
cient completion of the surgery.
acetylcholine molecules cross the junction and bind to
nicotinic acetylcholine receptors at the motor end plate. In
order for a conformational change to occur in the nicotinic
acetylcholine receptor, both alpha subunits making up the
receptor must have an acetylcholine molecule bound to
them. Once two acetylcholine molecules are bound, the
E. Bettendorf (&)
Z. Xiong receptor conformational change opens an ion channel,
Department of Anesthesiology, Perioperative allowing sodium and calcium to move into the cell and for
and Pain Medicine, Brigham and Women’s Hospital,
potassium to move out. The movement of these ions causes a
75 Francis Street, Boston, MA 02115, USA
e-mail: ebettendorf@partners.org change in potential across the cellular membrane. When
enough receptors are triggered and a large enough potential
Z. Xiong
e-mail: zxiong@partners.org difference exists across the perijunctional membrane,

© Springer International Publishing AG 2017 149

L.S. Aglio and R.D. Urman (eds.), Anesthesiology,
DOI 10.1007/978-3-319-50141-3_21
150 E. Bettendorf and Z. Xiong

depolarization occurs. This leads to opening of sodium butyrylcholinesterase). The fraction that does reach the
channels on the muscle cell membrane, causing calcium to neuromuscular junction can then bind the acetylcholine
leave the sarcoplasmic reticulum. This sudden increase in receptor and cause its clinical effects. Subsequently, suc-
intracellular calcium allows actin and myosin to interact and cinylcholine will redistributes from the neuromuscular
cause muscle contraction. junction and is rapidly broken down.

What is the difference between a mature acetylcholine What can alter the duration of action of
receptor and an immature or fetal receptor? succinylcholine?

The immature acetylcholine receptor is found in fetal muscle The normal onset of succinylcholine is 30–90 s and the
and contains a gamma instead of epsilon subunit. Immature duration of action is 3–5 min. However, this can be signif-
acetylcholine receptors are also called extrajunctional icantly lengthened in a variety of situations. Pseudo-
receptors because they can also be located outside of the cholinesterase deficiency decreases the amount of enzyme
neuromuscular junction when found in adults. available to break down succinylcholine. For patients who
are heterozygous for an atypical pseudocholinesterase gene,
How is acetylcholine metabolized? the duration of succinylcholine can be 20–30 min. For
homozygous patients, a single dose of succinylcholine can
As acetylcholine molecules diffuse away from the nicotinic cause paralysis for several hours.
receptors on the motor end plate, the molecules are rapidly There are several acquired forms of prolonged action of
broken down in the neuromuscular junction by the enzyme succinylcholine. Decreased activity of butyrylcholinesterase
acetylcholinesterase into choline and acetate. The choline can be seen in patients with liver disease, pregnancy, kidney
can then be taken up by the presynaptic membrane and disease and from various medications (ex: cholinesterase
converted back into acetylcholine. Acetylcholinesterase is inhibitors, metoclopramide, esmolol, cyclophosphamide,
located at the motor end plate adjacent to the acetylcholine oral contraceptives, echothiophate). Patients with hypother-
receptors. mia will have prolonged duration of action. Giving a high
dose of succinylcholine or an infusion can also lengthen the
What are the two broad categories of neuromuscular action of succinylcholine.
blocking agents?
What are the side-effects of succinylcholine?
The two classes are depolarizing and nondepolarizing mus-
cle relaxants. Succinylcholine is the only depolarizing neu- Succinylcholine has several significant and potentially sev-
romuscular blocking drug in clinical use. There are several ere side-effects. However, with appropriate planning and
different nondepolarizing muscle relaxants, examples of patient selection, the risk of this medication can be reduced.
which include rocuronium, vecuronium, cisatracurium, and Histamine release can be seen in some patients, but is gen-
pancuronium. erally mild and transient.
Hyperkalemia occurs with succinylcholine administration
What is the mechanism of action of depolarizing as a result of efflux of potassium into the extracellular space
muscle relaxants? with muscle contraction. In some patients, this hyperkalemia
can cause life-threatening arrhythmias.
Structurally similar to acetylcholine, depolarizing neuromus-
Fasciculations are visible muscle contractions that can be
cular blockers (succinylcholine) bind at the acetylcholine
seen in many patients, indicating muscle relaxation. They
binding site (alpha subunits) and cause propagation of an
often do not occur in patients with low muscle mass, elderly
action potential. Unlike acetylcholine, however, depolarizing
patients, and children. Patients may develop myalgia as a
muscle relaxants are not broken down by acetylcholinesterase.
result of uncoordinated muscle contraction. Pretreatment
This results in longer binding, leading to which increases the
with a nondepolarizing neuromuscular blocker will decrease
time until the motor end plate can repolarize and causes a short
fasciculations, but its effect on myalgias is controversial.
period of muscle relaxation. Thus, they are competitive ago-
Contractions of the abdominal wall can lead to increased
nists at the acetylcholine receptor.
intragastric pressure. This is offset by increased lower eso-
phageal sphincter tone, resulting in no increased risk of
How is succinylcholine metabolized?
aspiration. Increased intracranial pressure occurs with suc-
When administered to a patient, the majority of a dose of cinylcholine, but can be reduced if with nondepolarizer
succinylcholine is metabolized before ever reaching the pretreatment. Increased intraocular pressure is not altered by
neuromuscular junction. It is broken down quickly and nondepolarizing medications and is independent of
efficiently by plasma pseudocholinesterase (also known as fasciculations.
21 Nondepolarizing Neuromuscular Blocking Agents 151

Succinylcholine is the only neuromuscular blocking What are the durations of action of the various clini-
medication that can be a trigger for malignant hyperthermia. cally available nondepolarizing muscle relaxants?
As a structural analog of acetylcholine, succinylcholine
can bind to and effect receptors in the parasympathetic and Rocuronium—at larger doses initial doses, onset is short
sympathetic nervous system. Smaller doses stimulate the (1–2 min) and intermediate duration of action
parasympathetic system predominantly, causing bradycardia Vecuronium—onset in 2–3 min and intermediate to long
and decreased inotropy. Larger doses can cause increased duration
heart rate. The cardiovascular effects are often limited in Pancuronium—onset in 2–3 min and long duration
adults. However, children are at increased risk for Atracurium—onset in 2–3 min and intermediate duration
succinylcholine-induced bradycardia, which can be severe. Cisatracurium—onset in 2–3 min and intermediate duration
Prior to administration of succinylcholine in children, atro-
pine can be given prophylactically. How are the nondepolarizing muscle relaxants each
metabolized and eliminated?
Which patients are at increased risk for hyperkalemia Rocuronium is not metabolized, only excreted. Excretion
from succinylcholine administration and why? occurs primarily through the liver with a contribution from
In patients with acute nerve or tissue damage, increased the kidneys. In patients with severe liver failure, decreased
production of immature acetylcholine receptors occurs at liver mass (i.e., elderly) or pregnancy, rocuronium duration
extrajunctional locations. When succinylcholine is given, of action can be prolonged.
these extrajunctional receptors depolarize along with the Vecuronium undergoes partial metabolism in the liver
mature acetylcholine receptors at neuromuscular junctions, and is eliminated via the kidneys and in bile. Renal failure
causing increased levels of potassium release from the can prolong its duration of action.
intracellular compartment. In a healthy patient, potassium Pancuronium is metabolized to a limited degree in the
levels can increase by 0.5 meq/L with the administration of liver and is excreted renally.
succinylcholine. In patients with preexisting tissue damage, Atracurium is broken down by Hofmann degradation and
this increase can be significant and potentially ester hydrolysis. Given this significant metabolism, only a
life-threatening. Conditions in which this increased risk small fraction ultimately is eliminated via the kidneys and bile.
exists include burn injuries, spinal cord injuries, cerebral Cisatracurium is exclusively metabolized by Hofmann
vascular accidents, severe trauma, intracerebral or spinal elimination. It is independent of kidney or renal function,
cord masses, severe infections, significant metabolic acido- giving it a consistent duration of action.
sis, prolonged immobilization and myopathies such as
Duchenne’s muscular dystrophy. What is Hofmann Elimination?
Hofmann degradation is a nonenzymatic, spontaneous
Describe the mechanism of action of nondepolarizing
breakdown of a compound. It occurs at normal physiologic
neuromuscular blockers.
pH and temperature in vivo. Both atracurium and cisa-
Nondepolarizing muscle relaxants bind the alpha subunit of tracurium undergo Hofmann elimination.
the acetylcholine receptors at the neuromuscular junction.
Hence, they are competitive inhibitors of the acetylcholine What are the side-effects of pancuronium?
receptor. By preventing the binding of acetylcholine, the Pancuronium can increase heart rate, blood pressure and
movement of ions and the change in potential across the cardiac output via vagolysis. It has increased risk of
postsynaptic membrane of the neuromuscular junction, arrhythmias compared to other medications in its class. It
paralysis occurs. also has a long duration of action, making it less useful in
many surgical settings compared to similar medications.
What are the two categories of nondepolarizing
muscle blockers used in clinical practice? What are the features of mivacurium?
One group is the benzylisoquinolines, which include the Mivacurium is a benzylisoquinoline derivative. It is a short
drugs mivacurium, atracurium and cisatracurium. The other acting neuromuscular blocking drug. The onset is usually
group includes the steroidal medications—rocuronium, 3–5 min and its duration of action is approximately
vecuronium, and pancuronium. 10–20 min. It is the only nondepolarizer that is metabolized
152 E. Bettendorf and Z. Xiong

by pseudocholinesterase. Thus, patients who have either nerve, evaluating the adductor pollicis and orbicularis oculi,
atypical plasma cholinesterase or pseudocholinesterase respectively. To determine a “train of four,” four electrical
deficiency will have a prolonged duration of action of stimuli of 2 Hz are given over 2 s. When four twitches are
mivacurium in a similar manner to succinylcholine. present, the ratio of the fourth twitch compared to the first
twitch gives an indication of the level of residual neuro-
Does neostigmine reverse the neuromuscular block- muscular blockade. A ratio of less than 0.9 is considered to
ade caused by mivacurium? be residual blockade.
Tetany involves a single stimulus that lasts at least 5
Because the anticholinesterase drug neostigmine not only
seconds. Sustained tetany is often done with 50–100 Hz.
inhibits true cholinesterase but also the pseudocholinesterase,
there is concern about the possibility that neostigmine might
What is post-tetanic potentiation?
paradoxically prolong the duration of mivacurium action.
However, most experts believe that the benefits of increasing After sustained tetany, there is a transient increase in twitch
the concentration of acetylcholine produced by neostigmine height, such as with a train of four, immediately afterward.
to compete for the binding sites on the nicotonic cholinergic The possible cause of this is increased acetylcholine in the
receptor in the neuromuscular junction should outweigh the neuromuscular junction.
inhibition of the activity of plasma pseudocholinesterase and
therefore the action of mivacurium may be reversed. Con- Which sources of neuromuscular blockade monitoring
ventional wisdom says that no reversal agent is needed given correlate with which muscle groups?
the fact that mivacurium is such a short acting drug.
Monitoring of the facial nerve and assessing a train of four in
the orbicularis oculi correlates with return of diaphragmatic
Which neuromuscular blocker(s) have active
function. The adductor pollicis correlates well with the
metabolites?
return of function of the muscles of the larynx.
Atracurium and cisatracurium metabolism produce lau-
danosine. Laudanosine has been shown to cause central How will you determine if the patient’s neuromuscu-
nervous system excitation. This excitation has the potential lar blockade is reversible?
to cause increased minimum alveolar concentration
When a patient has four twitches on train of four stimula-
requirements for inhalation anesthetics and may even cause
tions, they are reversible. Reversal agents can take up 10–
seizures. Laudanosine is metabolized in the liver and
15 min or even longer in the cases of more significant
excreted in urine and bile, so patients with hepatic failure are
muscle relaxation, to reach peak effect and to fully reverse
at increased risk of laudanosine toxicity.
the patient’s muscle relaxation.
Which nondepolarizing muscle relaxants cause his-
What will you use for reversal and why?
tamine release?
Reversal of neuromuscular blockade should include both a
Like succinylcholine, several nondepolarizers are capable of
cholinesterase inhibitor and an anticholinergic agent. The
triggering histamine release. They are tubocurarine >
most commonly used cholinesterase inhibitor is neostig-
metrocurine > atracurium = mivacurium. Slow administra-
mine. It is a lipid-insoluble agent that cannot cross the
tion of the medication and/or pretreatment with H1 and H2
blood–brain barrier. Its onset is 5–7 min and duration of
antihistamine drugs reduce this side effect.
action is approximately 1 hour. If neostigmine is used to
reverse a long-acting muscle relaxant, it is possible that its
Should any of the nondepolarizing muscle relaxants
reversal effect could wear off before the neuromuscular
be avoided in our patient? Why or why not?
blocking medication, resulting in recurarization.
Atracurium can cause bronchospasm and should be avoided
in asthmatic patients. It causes a dose-dependent release of What are potential side-effects of reversal agents?
histamine. There are also reports of atracurium-induced
Cholinesterase inhibitors can cause several significant
bronchospasm in patients without asthma.
side-effects through the resulting increased levels of acetyl-
choline stimulating muscarinic receptors. In the cardiovas-
How will you gage the depth of neuromuscular
cular system, they cause bradycardia. They lead to
blockade?
bronchospasm and increased secretions in the lungs. The
To determine the level of muscle relaxation, a peripheral gastrointestinal system will have increased secretions, sali-
nerve stimulator is commonly used at the ulnar or facial vation, and intestinal spasm. Increased rates of postoperative
21 Nondepolarizing Neuromuscular Blocking Agents 153

nausea and vomiting can result from cholinesterase inhibitor prolongation of neuromuscular blockade. Various medica-
administration. Constriction of the pupils is an ophthalmo- tions can contribute to weakness including amiodarone,
logical side effect. verapamil, some antiretrovirals (zidovudine, lamivudine),
Physostigmine is a cholinesterase inhibitor that can cross corticosteroids, statins, some antibiotics (penicillin, tetracy-
the blood–brain barrier. If given to patient, it can cause cline, aminoglycosides, and clindamycin), sulfonamides,
cerebral excitation. The most commonly used cholinesterase NSAIDs and dantrolene. Volatile anesthetics potentiate the
inhibitor, neostigmine, does not cross the blood–brain action of muscle relaxants. Hypothermia can worsen neu-
barrier. romuscular blockade. Multiple electrolyte disturbances can
play a role in muscle weakness, including hypophos-
How can the side-effects of cholinesterase inhibitors phatemia, hypermagnesemia, hypocalcemia, and
be minimized? hypokalemia.
The administration of anticholinergic medications helps to
What should be done to manage a patient with pro-
mitigate several side-effects of cholinesterase inhibitors such
longed neuromuscular blockade?
as neostigmine. Anticholinergic drugs used in combination
with cholinesterase inhibitors function by acting largely at If a patient has delayed recovery from muscle relaxation,
the muscarinic acetylcholine receptors (as opposed to neu- sedation should be continued and respiratory support pro-
romuscular blocking drugs, which are used for their effect on vided until the neuromuscular blockade has worn off. In a
nicotinic acetylcholine receptors). The recommended agent sedated patient, assessing for sustained tetany of at least 5 s
to use in conjunction with neostigmine is glycopyrrolate is recommended periodically to determine return of muscle
given their similar duration of action and the fact that they function.
do not cross the blood–brain barrier.

What is the difference between a phase I and phase II Further Reading

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Mackey DC, Wasnick JD, Butterworth, JF, IV, et al. Chapter 11.
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Additionally, there are several possible sources for