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Cisatracurium
Cisatracurium is a benzylisoquinolinium neuromuscular-blocking drug that is metabolized by
plasma esterases;
From: Cardiothoracic Critical Care, 2007

Related terms:
Muscle Relaxant Agent, Neuromuscular Blocking, Neuromuscular Blocking Agent, Drug,
Atracurium Besilate, Pancuronium, Rocuronium, Vecuronium, Suxamethonium, Liver Disease

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Pharmacokinetics and Pharmacology of Drugs Used in Children

Charles J. Coté, ... Nishan Goudsouzian, in A Practice of Anesthesia for Infants and Children (Fourth Edition), 2009

Cisatracurium
Cisatracurium (Nimbex) is one of the 10 stereoisomers of atracurium (1R-Cis, 1“R-Cis). Cisatracurium is three times more potent than
atracurium with the same duration of action.873 Similar to other nondepolarizing relaxants its onset can be accelerated by increasing the
dose (see Tables 6-15 and 6-16); as with the other relaxants, this will increase the duration of the action. Cisatracurium, like atracurium, is a
noncumulative agent with recovery occurring during the elimination phase rather than during the distribution phase.
Cisatracurium has a slightly slower onset of action than atracurium, consistent with its relative potency. Twice the ED95 dose (80 μg/kg) of
cisatracurium leads to complete suppression of the twitch response in 2.5 minutes. The recovery to 25% and 95% of control response
occurs in 31 and 53 minutes, respectively.873–876 Its histamine releasing effects are minimal; its duration and recovery profile are essentially
the same as atracurium.
The distribution and elimination half-lives of cisatracurium in children are 3.5 and 23 minutes in children. The Vdss and the total body
clearance are significantly greater than in adults, thus explaining the faster recovery in children.877 In adults with renal failure, the clearance
of cisatracurium is reduced by 13%; plasma laudanosine levels were greater but were only about 10% of those reported with atracurium.878
The duration of action of cisatracurium in renal failure patients is not significantly prolonged.879 It should be noted that patients receiving
chronic anticonvulsant therapy (carmazepine or phenytoin) can develop a moderate resistance to the action of cisatracurium.880

Pharmacokinetics and Pharmacology of Drugs Used in Children

Brian J. Anderson, ... Charles J. Coté, in A Practice of Anesthesia for Infants and Children (Sixth Edition), 2019

Cisatracurium
Cisatracurium (Nimbex) is one of the 10 stereoisomers of atracurium (1R-cis, 1′R-cis). Cisatracurium is three times more potent than
atracurium, with the same duration of action.1108 Similar to other nondepolarizing relaxants, its onset can be accelerated by increasing the
dose (see E-Table 7.7 and Table 7.10); as with the other relaxants, this will increase the duration of the action. Cisatracurium, like atracurium,
is a noncumulative agent with recovery occurring during the elimination phase rather than during the distribution phase.
Cisatracurium has a slightly slower onset of action than atracurium, consistent with its relative potency. Twice the ED95 dose (80 µg/kg) of
cisatracurium leads to complete suppression of the twitch response in 2.5 minutes. The recovery to 25% and 95% of control response
occurs in 31 and 53 minutes, respectively.1108–1111 Its histamine-releasing effects are minimal; its duration and recovery profile are similar to
atracurium.
The distribution and elimination half-lives of cisatracurium in children are 3.5 and 23 minutes, respectively. The Vdss and the total body
clearance of most drugs in children are greater (expressed as milligrams per kilogram; see the example of dexmedetomidine Fig. 7.5) than in
adults, thus explaining the faster recovery in children.1032 In adults with renal failure, the clearance of cisatracurium is reduced by 13%;
plasma laudanosine levels were greater but were only about 10% of those reported with atracurium.1112 The duration of action of
cisatracurium in patients with renal failure is not significantly prolonged.1113 It should be noted that patients receiving chronic
anticonvulsant therapy (carbamazepine or phenytoin) can develop a moderate resistance to the action of cisatracurium.1114

Use of Sedatives, Analgesics, and Neuromuscular Blockers

Michael J. Murray, ... William T. Browne, in Critical Care Medicine (Third Edition), 2008

Cisatracurium
Cisatracurium, an isomer of atracurium, is an intermediate-acting benzylisoquinolinium NMBA that is increasingly used in lieu of
atracurium. It produces few, if any, cardiovascular effects and has less of a tendency to produce mast cell degranulation than atracurium.
Bolus doses with 0.10 to 0.2 mg/kg result in paralysis in an average of 2.5 minutes, and recovery begins at approximately 25 minutes;
maintenance infusion rates should be started at 2.5 to 3 μg/kg/min. Cisatracurium also is metabolized by ester hydrolysis and Hofmann
elimination, so duration of block should not be affected by renal or hepatic dysfunction. There have not yet been reports of significantly
prolonged recovery associated with cisatracurium. The mean peak plasma laudanosine concentrations are lower in patients receiving
cisatracurium compared with patients receiving clinically equivalent doses of atracurium.

Pharmacology of Pediatric Anesthesia

Peter J. Davis, ... Susan Woelfel, in Smith's Anesthesia for Infants and Children (Eighth Edition), 2011

Cisatracurium
Cisatracurium is a metabolite of atracurium, a mixture of 10 optical and geometric isomers (Welch et al., 1995). The R-R1 optical isomer in
the cis-cis configuration, cisatracurium, is about 1.5 times more potent than atracurium and does not liberate histamine even at very high
doses (five times the ED95) (Soukup et al., 1997). Cisatracurium is primarily degraded by Hofmann degradation to laudanosine and a
monoquaternary acrylate, which is hydrolyzed by plasma esterases. The by-products of metabolism have no neuromuscular blocking effect,
and they are excreted by the liver and the kidneys (Neill et al., 1983).
Cisatracurium is equipotent in infants, children, and adults (Table 7-23). During nitrous oxide-narcotic thiopentone administration, the
ED50 and ED95 values for infants (29 ± 3 mcg/kg and 43 ± 9 mcg/kg, respectively) were similar for children (29 ± 2 mcg/kg and 47 ± 7
mcg/kg) (DeRuiter and Crawford, 2001).
With halothane anesthesia in children, the rate of recovery after a dose of one to two times the ED95 was rapid, with a recovery index from
T25 to T75 of 9 to 11 minutes and a recovery index from T5 to T95 25 to 30 minutes (Meretoja et al., 1996). In a separate study of infants and
children anesthetized with nitrous oxide and opioids, 0.15 mg/kg (three times the ED95) of cisatracurium had a mean onset time of
maximum blockade in infants of 2 ± 0.8 minutes, whereas that in children was less rapid at 3 ± 1.2 minutes. The clinical duration of action
of cisatracurium to T25 was significantly longer in infants (43.3 ± 6.2 minutes) than in children (36 ± 5.4 minutes); however, once
neuromuscular function started to recover, the rate of recovery was similar in both age groups (Taivainen et al., 2000). Another study with
0.1 mg/kg (two times ED95) of cisatracurium in 15 infants and 15 children with remifentanil and sevoflurane anesthesia (2% end-tidal) also
reported a significantly faster onset (74 vs. 198 seconds), longer clinical duration to T25 (55 vs. 41 minutes), and longer recovery to TOF
greater than 0.9, 73 (range 56 to 86) minutes vs. 59 (range 43 to 72) minutes in the infants than in children. Here, the inhalational agent
accelerated the onset and prolonged the recovery to T25 in spite of a smaller dose of cisatracurium. Again, the recovery index was
comparable in both infants and children at 21 vs. 16 minutes (Soltész et al., 2002). One of the benefits of cisatracurium is that once recovery
begins, full recovery is rapid and predictable in both infants and children. Also of note is that there were negligible changes in heart rate or
blood pressure for both age groups at the larger dose (Brandom, 1998; Taivainen et al., 2000; Meakin et al., 2007).
Cisatracurium infusions have a place in the ICU for postoperative care, especially in patients with organ failure. Postoperative cardiac
patients (younger than age 2 years) receiving cis- atracurium infusions had a high clearance, low duration of residual block, and a mean
return to TOF of greater than 0.9 of 30 minutes (Reich et al., 2004). Another ICU study in children (aged 3 months to 16 years) had an
average cisatracurium infusion rate of 3.9 ±1.3 mcg/kg per minute with a median time to recovery significantly shorter with cisatracurium
(52 minutes, with a range of 35 to 73 minutes) compared with vecuronium (123 minutes, with a range of 80 to 480 minutes) (Burmester and
Mok, 2005). Steady-state volume of distribution (207 ± 31 mL/kg) and total body clearance (6.8 ± 0.7 mL/min per kg) for cisatracurium are
significantly larger in children than those published for adults. Both renal failure and liver disease have minimal effects on the
pharmacodynamics of cisatracurium (Table 7-35) (Prielipp et al., 1995; DeWolf et al., 1996).

Neuromuscular Blocking Agents

Joseph D. Tobias, in Pediatric Critical Care (Fourth Edition), 2011

Cis-atracurium
Cis-atracurium is one of the 10 stereoisomers that comprise atracurium. It is six to eight times as potent as atracurium, but devoid of
clinically significant histamine release and hemodynamic effects.72 Cis-atracurium is available as a 2 mg/mL solution. Like atracurium, cis-
atracurium is an intermediate-acting neuromuscular blocking agent, with a duration of action of 20 to 30 minutes following a bolus dose of
0.2 mg/kg. Acceptable conditions for endotracheal intubation are provided in approximately 2 minutes. In a cohort of 80 adult patients, cis-
atracurium in doses of 0.1, 0.15, and 0.2 mg/kg provided acceptable conditions for endotracheal intubation in 4.6, 3.4, and 2.8 minutes with
a clinically effective duration of 45, 55, and 61 minutes.73 In a cohort of 27 infants (1 to 23 months of age) and 24 children (2 to 12.5 years of
age), the onset time to achieve maximal blockade following a dose of 0.15 mg/kg was more rapid in infants (2.0 ± 0.8 versus 3.0 ± 1.2
minutes, P = .0011).72 The clinical duration (recovery to 25% of baseline) was longer in infants (43.3 ± 6.2 versus 36.0 ± 5.4 minutes; P <
.0001). Once neuromuscular recovery began, the rate of recovery was similar between the two groups. However, de Ruiter et al.74 reported
no difference in the ED50, ED95, or the infusion rate required to maintain 90% to 99% block when comparing 32 infants (0.3 to 1 year of
age) and 32 children (3.1 to 9.6 years of age). The ED50 in the two groups was 29 ± 3 versus 29 ± 2 μg/kg, the ED95 was 43 ± 9 versus 47 ± 7
μg/kg, and the infusion rate required to maintain 90% to 99% blockade in the two groups was 1.9 ± 4 versus 2.0 ± 0.5 μg/kg/min.
A prospective study evaluated cis-atracurium dosing requirements in 15 PICU patients ranging in age from 10 months to 11 years and in
weight from 4 to 28 kg.75 The cis-atracurium infusion was adjusted to maintain one twitch of the TOF. Infusion requirements varied from
2.1 to 3.8 μg/kg/min (average, 3.1 ± 0.6 μg/kg/min) on day 1, from 2.9 to 8.1 μg/kg/min (average, 4.5 ± 1.6 μg/kg/min, P < .01 compared to
day 1) on day 3, and from 1.4 to 22.7 μg/kg/min during all patient days. The highest infusion requirements were noted following the
administration of the drug for prolonged periods of time (150 and 224 hours). When the infusion was discontinued, spontaneous return of
neuromuscular function was noted in 14 to 33 minutes. Effective neuromuscular blockade was provided and no adverse effects related to
cis-atracurium were noted. In particular, no hemodynamic changes were noted with bolus dosing. Odetola et al.76 evaluated the dosing
requirements of cis-atracurium in a cohort of 11 PICU patients, ranging in age from 0 to 2 years. The duration of the infusions varied from
14 to 122 hours (64.5 ± 36 hours). The infusion requirements to maintain 90% to 95% neuromuscular blockade were 5.36 ± 3.0 μg/kg/min.
Laudanosine concentrations during the infusion were 163.3 ± 116 ng/mL. As in the previous study, there was an increase in dose
requirements over time and no hemodynamic effects were noted with cis-atracurium.
Reich et al. compared vecuronium and cis-atracurium, administered by continuous infusion, to provide neuromuscular blockade following
surgery for congenital heart disease in a cohort of 19 patients less than 2 years of age.77 The NMBA was administered to maintain one
twitch of the TOF. Median infusion times were 64.5 hours for cis-atracurium and 46 hours for vecuronium (P = not significant). Median
recovery time, defined as a normal TOF without fade, was shorter with cis-atracurium than with vecuronium (30 minutes versus 180
minutes, P < .05). Recovery time was more than 4 hours in three of nine patients who received vecuronium. Two of these patients had high
vecuronium plasma concentrations, while the other had an elevated 3-OH vecuronium level. There was no difference in time to tracheal
extubation, intensive care unit stay, or hospital stay.
As with other NMBAs, resistance to the effects of cis-atracurium may be seen in patients treated with anticonvulsant agents.78 Time to
recovery of T1 to 25% of baseline was 69 ± 13 minutes in patients not receiving anticonvulsant medications, 64 ± 19 minutes in those
receiving acute therapy with anticonvulsants, and 59 ± 19 minutes in those receiving chronic anticonvulsant therapy. As with atracurium,
altered clearance and decreased infusion requirements occur with hypothermia.79 During induced hypothermia (34° C) to control increased
ICP, cis-atracurium infusion requirements were 1.7 μg/kg/min and increased to 3.4 μg/kg/min with return to normothermia.
Neuromuscular Blockers and Reversal Drugs
Cynthia A. Lien, Matthias Eikermann, in Pharmacology and Physiology for Anesthesia, 2013

Cisatracurium
Cisatracurium (Figure 19-9) is the 1 R-cis 1′R-cis stereoisomer of the 10 stereoisomers that comprise atracurium and has been available
since 1995. Its innovative development involved isolation and testing of individual stereoisomers from the parent mixture, with selection
and further development of the one with reduced side effects. It is approximately threefold more potent than atracurium (ED95 of
0.05 mg/kg) and, like atracurium, has an intermediate duration of action.95 Because of its greater potency, however, its onset of effect is
considerably slower.95 For this reason, doses of three to five times the ED95 are recommended for endotracheal intubation.96 In contrast to
atracurium, administration of such large doses is not associated with histamine release, and resultant hypotension or tachycardia.97

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Figure 19-9. Chemical structure of cisatracurium. It is the 1 R-cis 1′ R-cis stereoisomer, one of 10 stereoisomers comprising atracurium.

Like atracurium, cisatracurium undergoes Hofmann elimination. Clearance, elimination half-life, and volume of distribution are the same
when doses of the ED95 or twice the ED95 are administered.98 The clinical duration of action (the time required from administration of a
dose to recovery of 25% T1 height) defines the earliest time that reversal of residual neuromuscular block is recommended. The duration of
action of 0.1 mg/kg cisatracurium (2× ED95) is 45 minutes. Doubling the dose to 4× ED95 increases it to 68 minutes and doubling it again to
8× ED95 increases it by another 23 minutes, equivalent to the elimination half-life of the compound.95
Hofmann elimination accounts for 77% of total clearance of cisatracurium and renal elimination 16%.99 The slight dependence on renal
elimination likely contributes to the increase in elimination half-life of 14% and decrease in clearance of 13% observed in patients with renal
failure.100 Despite these pharmacokinetic changes in patients with renal dysfunction, no prolongation of the duration of action is found
following a bolus dose.101 As with atracurium, both volume of distribution and clearance of cisatracurium are increased in patients with
hepatic failure.102 Elimination half-life is unchanged, and thus the clinical duration of action and 25% to 75% recovery interval (the time
required to recover from 25% to 75% of baseline twitch height) is unchanged in patients with liver failure.102
Recovery from cisatracurium-induced neuromuscular block occurs over the same time course in older surgical patients as it does in young
adults.103 An increase in its volume of distribution and no change in its clearance in older adults likely account for a prolongation of
elimination half-life by up to 28%.103 The decrease in renal function that occurs with normal aging could account for these pharmacokinetic
differences. The prolonged elimination half-life of cisatracurium in the geriatric patient does not affect recovery from neuromuscular block
induced with a bolus dose of the NMBA.

Side Effects of Drugs Annual 32

C. Williams, M. Leuwer, in Side Effects of Drugs Annual, 2010

Comparative studies
The speed of reversal of rocuronium by sugammadex has been compared with reversal of cis-atracurium by neostigmine in 84 ASA I–III adults (15c).
Four patients who were given sugammadex group (nausea in one, shivering in one, increased urinary N-acetyl glucosaminidase in two, and altered
facial sensation in one patient) and one given neostigmine group (nausea) had at least one adverse reaction that the investigators attributed to the
study drugs. Most of the adverse events were not considered to be related to the study drugs. Nausea and shivering after anesthesia are common
adverse events. The authors did not explain their rationale for attributing nausea and shivering to sugammadex. Postoperative urinary N-acetyl
glucosaminidase was raised in seven of those who received sugammadex and one of those who received neostigmine. No inferential analysis was
performed on these data.
Neurology and the Neuromuscular System
Stan K. Bardal BSc (Pharm), MBA, PhD, ... Douglas S. Martin PhD, in Applied Pharmacology, 2011

Nondepolarizing Neuromuscular Blockers

Description
Nondepolarizing neuromuscular blockers are paralyzing drugs, also known as muscle relaxants or paralytics.
Prototype and Common Drugs
▪ Prototype: Vecuronium
▪ Others: Rocuronium, pancuronium, atracurium, cisatracurium, mivacurium
▪ Reversal agents (anti-cholinesterases):

▴ Neostigmine, edrophonium

MOA (Mechanism of Action)

▪ Voluntary skeletal muscle contraction occurs when a motor neuron is depolarized. The distal end of the motor neuron is part of the
NMJ, which is the anatomic connection between the neuron and muscle. The presynaptic membrane is the motor nerve, and the
postsynaptic membrane is the motor end plate of the muscle cell.
▪ The depolarizing motor neuron releases acetylcholine, and the ACh crosses the synapse and binds to nicotinic ACh receptors on the
muscle cell. The binding of ACh to the motor end plate induces small mini-depolarizations. When enough mini-depolarizations occur, a
full action potential is created in the muscle cell, which results in an increase in intracellular calcium levels and subsequent actin-myosin
interactions, resulting in contraction (Figure 21-6).
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Figure 21-6.

▪ NMJ blockers bind the nicotinic ACh receptor and competitively antagonize ACh, thereby preventing the signal from the neuron to be
communicated to the muscle. These drugs do not cause any depolarization of the muscle when they bind; therefore they are referred to
as nondepolarizing. This is in contrast to the other class of paralytics, which are depolarizing.
▪ Neuromuscular blockade can be partial or complete. If partial, then the strength of muscle contraction is reduced.
▪ All skeletal muscles become paralyzed, including muscles for breathing, speech, and eyelid movement and all other skeletal muscle.
Smooth muscles and cardiac muscle are not paralyzed because contraction is not dependent on the same neuromuscular transmission.
Therefore the heart does not stop beating and smooth muscle function such as pupillary reflexes to light and gastrointestinal motility
are not affected.
▪ Paralytics do not affect level of consciousness; it is very difficult to know the exact level of consciousness of a person who is paralyzed,
and therefore unconsciousness must be achieved before a patient is paralyzed.

Reversal of Blockade
▪ If the patient remains paralyzed for longer than desired, then reversal medication can be administered to facilitate return of muscle
strength.
▪ Because these drugs are all competitive antagonists of ACh, increasing the concentration of ACh in the synaptic cleft will result in more
ACh binding to ACh receptors on the motor end plate, and thus strength will be restored.
▪ Cholinesterase is the enzyme that breaks down ACh. Anticholinesterases are the drugs that inhibit cholinesterase, resulting in
increased levels of ACh everywhere in the body.

▴ Increased ACh is desirable only in the motor end plate. ACh, however, will stimulate all muscarinic and nicotinic receptors in the
body and can lead to the following cholinergic side effects (mediated by muscarinic receptors):

• Bradycardia
• Salivation
• Bronchospasm and increased airway secretions
• Nausea, vomiting, and diarrhea
• Urination

▴ Blocking the muscarinic receptors with an anticholinergic drug such as atropine or glycopyrrolate will reduce the incidence of
these muscarinic side effects without influencing the effects on nicotinic receptors. Anticholinergic drugs are therefore routinely
administered with anticholinesterase drugs.

Pharmacokinetics
▪ There are important differences in duration of action and method of metabolism among the different drugs in this class. See Table 21-4.

▴ Hoffman degradation is simply spontaneous breakdown of the molecule at physiologic pH and temperature. This process occurs
despite renal or hepatic failure, and therefore the duration of action of atracurium and cisatracurium is essentially unchanged in
patients with renal or hepatic impairment.
▴ Decreased metabolism or elimination results in prolonged duration of action for the drug. This is undesirable when the drug is
being used for surgery and the surgery is finished but the patient is still paralyzed; the anesthesiologist must then wait before
waking the patient. Reversal medications can be given, but if the degree of paralysis is too high, then full reversal cannot be
achieved.

TABLE 21-4. Nondepolarizing Neuromuscular Junction Blockers

Agent Duration Metabolism and Elimination Comments

Mivacurium Short Pseudocholinesterase Causes histamine release (hypotension)

Atracurium Intermediate Hoffman degradation Duration not affected by liver or renal disease

Cisatracurium Intermediate Hoffman degradation Duration not affected by liver or renal disease

Vecuronium Intermediate Biliary

Rocuronium Intermediate Biliary

Pancuronium Long Renal Is vagolytic (causes increased heart rate)

Duration is based on intubating dose: short = 15 to 20 minutes, intermediate = 30 to 45 minutes, long = 2 to 3 hours.

Indications
▪ Paralysis

▴ For surgery
▴ For intubation

Contraindications
▪ A conscious patient
▪ Lack of skill or equipment to provide respiratory resuscitation:

▴ Bag-mask ventilation
▴ Intubation (insertion of breathing tube into trachea)
Side Effects
▪ Side effects are drug specific:

▴ Mivacurium: hypotension from histamine release (causes vasodilation)

▴ Pancuronium: tachycardia from the vagolytic effect

Important Notes
▪ Potency and time to onset: Onset time is determined by the dose administered. For a given drug, giving a larger dose will result in a
faster onset of paralysis. For drugs that are more potent (e.g., pancuronium is the most potent), a smaller dose is required for paralysis,
but because a smaller dose is required, more potent drugs have a slower onset of action.
▪ Potency of muscle relaxants is measured using the effective dose in 95% of the population (ED95). For each drug, the ED95 dose is
different. As a general rule, an intubating dose (probably the most common indication for paralyzing drugs) is twice the ED95.
▪ The degree of paralysis can be measured with a small battery-powered device called a nerve stimulator. It essentially delivers a small
electric shock. Electrodes (usually just electrocardiographic patches) are applied on top of the motor nerve of interest (usually the ulnar
nerve at the wrist or the facial nerve at the temple). When the electrical shock is applied, a muscle that is not paralyzed will vigorously
contract; a partially paralyzed muscle will demonstrate a small twitch, and a fully paralyzed muscle will not contract at all.
▴ If four electrical shocks are applied in succession, the test is called a train of four. This is important because each successive shock
will release a slightly smaller amount of ACh from the presynaptic nerve; because the drugs are competitive antagonists, the
partially blocked muscle will demonstrate progressively smaller contractions, a phenomenon called fade. A patient can have zero fade
when as many as 50% of the nicotinic receptors are still occupied; therefore four full contractions with the nerve stimulator TOF
test does not guarantee that the patient will have 100% strength.
▴ If a patient has zero contractions with the TOF test, he or she is not likely to respond to reversal medication. The only way to reverse
paralysis in this patient is to wait until there are 1 to 2 twitches (the more the better) and then administer the reversal medication.
▴ Administering an excessive dose (in an attempt to overcome one's own impatience) of the reversal anticholinesterase will result in
muscarinic side effects and can also paradoxically reparalyze the patient!

Advanced
▪ Nondepolarizing muscle relaxant blockade is prolonged by inhaled anesthetics. This is relevant for anesthesiologists because inhaled
anesthetics are very commonly coadministered with muscle relaxants.
▪ During a long surgery a long-acting muscle relaxant might be used. However, near the end of surgery the anesthesiologist might want a
shorter-acting, more titratable drug. However, mixing drugs has an unexpected synergistic effect: one would expect that converting
from a long-duration to a short-duration drug would result in a shorter duration of action, but, in fact, in combination the two drugs
frequently potentiate each other and the result can be a much longer duration of block than would have been expected from either drug.
Mixing nondepolarizing drugs is not recommended.
▪ Reversal drugs are used for other indications:

▴ Myasthenia gravis is a condition whereby antibodies to nicotinic receptors exist. The antibodies function like paralyzing drugs and
cause weakness. Anticholinergic drugs are given to help antagonize the weakness effects of the antibodies.
▪ A new reversal drug called sugammadex is in clinical trials. It works by binding (essentially removing from circulation) rocuronium. It
appears to be safe and effective even when the patient is fully paralyzed with even a very large dose of rocuronium.

FYI
▪ Curare is the historical prototype of nondepolarization neuromuscular blockers, but it is no longer used clinically. Curare (also called D-
tubocurare) was the first paralytic used in anesthesia, but it has been replaced by newer agents. It was introduced to anesthesia around
1940. It was discovered in South America and was first used in poison arrows for hunting. It is harvested from the plant Strychnos
toxifera. The toxin strychnine is also from this genus of plant (but from a different species).
▪ SLUDGE is an acronym to help you remember the signs of cholinergic syndrome:

▴ Salivation
▴ Lacrimation
▴ Urination
 ▴ Diarrhea
▴ Gastrointestinal upset
▴ Emesis (vomiting)
▴ Unfortunately, the important bronchial signs (bronchospasm and secretions) are not included in the acronym.
▪ Take care not to confuse the following terms, which are polar opposites of each other: anticholinergic and anticholinesterase. The former
blocks muscarinic activity, whereas the latter increases both muscarinic and nicotinic receptor activity.
▪ Drugs that are GABA-mimetic (they increase the action of the inhibitory neurotransmitter GABA) are also muscle relaxants. However,
these drugs are not paralytic drugs. They act in the brain or spinal cord and reduce afferent transmission to the muscle. Examples of
these drugs include benzodiazepines (GABAA enhancers), baclofen (GABAB enhancers), cyclobenzaprine, and methocarbamol.
▪ The last nondepolarizing drug to come to market was rapacuronium. It had a very short time of onset and duration but was withdrawn
from clinical practice in 2001 because of the risk of fatal bronchospasm.

Endotracheal Intubation
Shepard B. Stone, in Essential Clinical Procedures (Second Edition), 2007

Nondepolarizing Neuromuscular Blockade Agents

The nondepolarizing NMB class includes curare, metocurine, pancuronium, vecuronium, atracurium, cis-atracurium, doxacurium,
pipecuronium, mivacurium, and rocuronium. Rocuronium offers the fastest onset (within 1 minute and maximal effect within 3 minutes,
with a duration of 30 minutes) at a dose of 1.2 mg/kg. The others have a slower onset. Increasing the dose enhances the onset of all these
drugs, increasing their duration of action. Increasing the dose also increases the likelihood of unwanted side effects. Some of the drugs
listed release histamine when given rapidly or in a large dose, which may cause flushing, hypotension, and bronchospasm.

Nondepolarizing Neuromuscular Relaxants

Maria A.K. Öhrn, in Complications in Anesthesia (Second Edition), 2007

Implications
It is known that some NDMRs (e.g., d-tubocurarine, atracurium, cisatracurium, doxacurium, metocurine, mivacurium) may cause
nonimmunologic histamine release. The magnitude of this response is species dependent (e.g., greater in cats than in rats or dogs) and
varies with the dose, the rapidity of injection, and, in clinical situations, the individual patient. Although the response may at first appear
anaphylactic, any histamine release is more direct (anaphylactoid), often self-limited, and easily managed with judicious use of short-lived
vasoconstrictors to counter the associated vasodilatation.
Recent studies indicate that NDMRs account for more than half of all anaphylactoid reactions during general anesthesia. NDMRs,
collectively, cause more such reactions than any other class of drugs commonly given during general anesthesia. However, the incidence of
true anaphylaxis during anesthesia is quite low (estimated at 1 in 5000 to 1 in 25,000 cases).
Concerning other NDMR complications, if these are recognized early enough, prolonged block can be managed without incident. If not
(e.g., those that occur at the end of anesthesia), the need for patient care and the health care costs increase. Prolonged block can also
increase operating room times, especially if patients must be extubated before admission to the postanesthetic care unit, as required in
some ambulatory surgery centers. With severe NDMR overdose, postoperative mechanical ventilatory support may be needed for some
time. If so, the patient must be sedated to avoid subsequent recall of unpleasant events due to partial or complete paralysis.
Unrecognized residual neuromuscular blockade can cause further complications. With partial block, patients may have insufficient motor
strength to protect the airway, increasing the risk for pulmonary aspiration. This can also cause respiratory insufficiency, hypercarbia, and
hypoxemia. Collectively, these conditions may cause hemodynamic instability, arrhythmias, or respiratory arrest.

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