Chapter 27 - Skeletal Muscle Relaxants

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Katzung’s Basic & Clinical Pharmacology, 16th Edition
Chapter 27: Skeletal Muscle Relaxants
Marieke KruideringHall; Lundy J. Campbell
CASE STUDY
CASE STUDY
An 80kg 35yearold woman with a BMI of 32 is undergoing right knee surgery for a meniscus tear. The surgeon and the patient both request
general anesthesia for the procedure. In addition to obesity, the patient has hypertension (treated with hydrochlorothiazide) and insulindependent
diabetes, and she takes an oral contraceptive pill. She has no known drug allergies. Her physical examination is remarkable only for obesity and a
Mallampati class 3 airway (indicating extremely limited space from tongue base to roof of mouth and probable difficulty in intubating). Because of
her diabetes and risk for delayed gastric emptying, you elect to use endotracheal intubation to protect her airway during the procedure.
After induction of anesthesia with propofol, you administer a dose of rocuronium to achieve skeletal muscle relaxation and to facilitate
endotracheal intubation. Once fully relaxed, you attempt direct laryngoscopy but are unable to visualize her airway. You make changes to the
patient’s position, and use a different technique, but you are still unable to perform intubation.
You switch back to bag/mask ventilation, but it has now become more difficult to achieve adequate tidal volumes. You decide to reverse the
neuromuscular blockade and wake the patient. (1) What agents could be used to reverse the neuromuscular blockade? (2) What would be the most
appropriate agent to use in this scenario? (3) What problems may occur with your chosen agent?
Drugs that affect skeletal muscle function include two different therapeutic groups: those used during surgical procedures and in the intensive care
unit (ICU) to produce muscle paralysis (ie, neuromuscular blockers), and those used to reduce spasticity in a variety of painful conditions (ie,
spasmolytics and antispasmodics). Neuromuscular blocking drugs interfere with transmission at the neuromuscular end plate and lack central
nervous system (CNS) activity. These compounds are used primarily as adjuncts during general anesthesia to optimize surgical conditions and to
facilitate endotracheal intubation in order to ensure adequate ventilation. Drugs in the spasmolytic group have traditionally been called “centrally
acting” muscle relaxants and are used primarily to treat chronic back pain and painful fibromyalgic conditions. Dantrolene, an agent that has no
significant central effects and is used primarily to treat a rare anestheticrelated complication, malignant hyperthermia, is also discussed in this
chapter.
NEUROMUSCULAR BLOCKING DRUGS

History
During the 16th century, European explorers found that natives in the Amazon Basin of South America were using curare, an arrow poison that
produced skeletal muscle paralysis, to kill animals. The active compound, dtubocurarine, and its modern synthetic analogs have had a major
influence on the practice of anesthesia and surgery and have proved useful in understanding the basic mechanisms involved in neuromuscular
transmission.
Normal Neuromuscular Function
The mechanism of neuromuscular transmission at the motor end plate is similar to that described for preganglionic cholinergic nerves in Chapter 6.
The arrival of an action potential at the motor nerve terminal causes an influx of calcium and release of the neurotransmitter acetylcholine.
Acetylcholine then diffuses across the synaptic cleft to activate nicotinic receptors located on the motor end plate, present at a density of 10,000/μm2 in
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on the αβ and δα subunits causes opening of the channel. The
subsequent movement of sodium and potassium through the channel is associated with a graded depolarization of the end plate membrane (see
Figure 7–4, panel B). This change in voltage is termed the motor end plate potential. The magnitude of the end plate potential is directly related to the
Normal Neuromuscular Function
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The mechanism of neuromuscular transmission at the motor end plate is similar to that described for preganglionic cholinergic nerves in Chapter 6.
The arrival of an action potential at the motor nerve terminal causes an influx of calcium and release of the neurotransmitter acetylcholine.
Acetylcholine then diffuses across the synaptic cleft to activate nicotinic receptors located on the motor end plate, present at a density of 10,000/μm2 in
some species. As noted in Chapter 7, the adult NM receptor is composed of five peptides: two alpha peptides, one beta, one gamma, and one delta
peptide (Figure 27–1). The binding of two acetylcholine molecules to receptors on the αβ and δα subunits causes opening of the channel. The
subsequent movement of sodium and potassium through the channel is associated with a graded depolarization of the end plate membrane (see
Figure 7–4, panel B). This change in voltage is termed the motor end plate potential. The magnitude of the end plate potential is directly related to the
amount of acetylcholine released. If the potential is small, the permeability and the end plate potential return to normal without an impulse being
propagated from the end plate region to the rest of the muscle membrane. However, if the end plate potential is large, the adjacent muscle membrane
is depolarized, and an action potential will be propagated along the entire muscle fiber. Muscle contraction is then initiated by excitationcontraction
coupling. The released acetylcholine is quickly removed from the end plate region by both diffusion and enzymatic destruction by the local
acetylcholinesterase enzyme.
FIGURE 27–1
The adult nicotinic acetylcholine receptor (nAChR) is an intrinsic membrane protein with five distinct subunits (α2 β δ γ). ( A ) Cartoon of one of five
subunits of the AChR in the end plate surface of adult mammalian muscle. Each subunit contains four helical domains labeled M1–M4. The M2 domains
line the channel pore. (B) Cartoon of the full nAChR. The N termini of two subunits cooperate to form two distinct binding pockets for acetylcholine
(ACh). These pockets occur at the αβ and the δα subunit interfaces. Binding of one molecule of ACh enhances the receptor’s affinity for the second
molecule, followed by multiple intermediate steps leading to channel opening. These steps are the subject of intense investigation.

Chapter 27: Skeletal Muscle Relaxants, Marieke KruideringHall; Lundy J. Campbell Page 2 / 29
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subunits of the AChR in the end plate surface of adult mammalian muscle. Each subunit contains four helical domains labeled M1–M4. The M2 domains
line the channel pore. (B) Cartoon of the full nAChR. The N termini of two subunits cooperate to form two distinct binding pockets for acetylcholine
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(ACh). These pockets occur at the αβ and the δα subunit interfaces. Binding of one molecule of ACh enhances the receptor’s affinity for the second
molecule, followed by multiple intermediate steps leading to channel opening. These steps are the subject of intense investigation.
At least two additional types of acetylcholine receptors are found within the neuromuscular apparatus. One type is located on the presynaptic motor
axon terminal, and activation of these receptors mobilizes additional transmitter for subsequent release by moving more acetylcholine vesicles toward
the synaptic membrane. The second type of receptor is found on extrajunctional cells and is not normally involved in neuromuscular transmission.
However, under certain conditions (eg, prolonged immobilization, thermal burns), these receptors may proliferate sufficiently to affect subsequent
neuromuscular transmission. This proliferation of extrajunctional acetylcholine receptors may be clinically relevant when using depolarizing or
nondepolarizing skeletal muscle relaxant drugs and is described later.
Skeletal muscle relaxation and paralysis can occur from interruption of function at several sites along the pathway from the CNS to myelinated somatic
nerves, unmyelinated motor nerve terminals, nicotinic acetylcholine receptors, the motor end plate, the muscle membrane, and the intracellular
muscular contractile apparatus itself.
Blockade of end plate function can be accomplished by two basic mechanisms. First, pharmacologic blockade of the physiologic agonist acetylcholine
is characteristic
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27: Skeletal Muscle Relaxants, Marieke depolarization. Lundy J. Campbell
The prototype Page
of this nondepolarizing subgroup is d tubocurarine. The 3 / 29
second
mechanism of blockade can be produced by an excess of a depolarizing agonist, such as acetylcholine. This seemingly paradoxical effect of
acetylcholine also occurs at the ganglionic nicotinic acetylcholine receptor. The prototypical depolarizing blocking drug is succinylcholine. A similar
nondepolarizing skeletal muscle relaxant drugs and is described later.
Skeletal muscle relaxation and paralysis can occur from interruption of function at several sites along the pathway from the CNS to myelinated somatic
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nerves, unmyelinated motor nerve terminals, nicotinic acetylcholine receptors, the motor end plate, the muscle membrane, and the intracellular
muscular contractile apparatus itself.
Blockade of end plate function can be accomplished by two basic mechanisms. First, pharmacologic blockade of the physiologic agonist acetylcholine
is characteristic of the antagonist neuromuscular blocking drugs (ie, nondepolarizing neuromuscular blocking drugs). These drugs prevent access of
the transmitter to its receptor and thereby prevent depolarization. The prototype of this nondepolarizing subgroup is d tubocurarine. The second
mechanism of blockade can be produced by an excess of a depolarizing agonist, such as acetylcholine. This seemingly paradoxical effect of
acetylcholine also occurs at the ganglionic nicotinic acetylcholine receptor. The prototypical depolarizing blocking drug is succinylcholine. A similar
depolarizing block can be produced by acetylcholine itself when high local concentrations are achieved in the synaptic cleft (eg, by cholinesterase
inhibitor intoxication) and by nicotine and other nicotinic agonists. However, the neuromuscular block produced by depolarizing drugs other than
succinylcholine cannot be precisely controlled and is of no clinical value.
BASIC PHARMACOLOGY OF NEUROMUSCULAR BLOCKING DRUGS

Chemistry
All of the available neuromuscular blocking drugs bear a structural resemblance to acetylcholine. For example, succinylcholine is two acetylcholine
molecules linked endtoend (Figure 27–2). In contrast to the linear structure of succinylcholine and other depolarizing drugs, the nondepolarizing
agents (eg, pancuronium) conceal the “doubleacetylcholine” structure in one of two types of bulky, semirigid ring systems (see Figure 27–2).
Examples of the two major families of nondepolarizing blocking drugs—the isoquinoline and steroid derivatives—are shown in Figures 27–3 and 27–4.
Another feature common to all currently used neuromuscular blockers is the presence of one or two quaternary nitrogens, which makes them poorly
lipid soluble and limits entry into the CNS.
FIGURE 27–2
Structural relationship of succinylcholine, a depolarizing agent, and pancuronium, a nondepolarizing agent, to acetylcholine, the neuromuscular
transmitter. Succinylcholine, originally called diacetylcholine, is simply two molecules of acetylcholine linked through the acetate methyl groups.
Pancuronium may be viewed as two acetylcholinelike fragments (outlined in color) oriented on a steroid nucleus.

FIGURE 27–2
Structural relationship of succinylcholine, a depolarizing agent, and pancuronium, a nondepolarizing agent, to acetylcholine, the neuromuscular
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transmitter. Succinylcholine, originally called diacetylcholine, is simply two molecules of acetylcholine linked through the acetate methyl groups.
Pancuronium may be viewed as two acetylcholinelike fragments (outlined in color) oriented on a steroid nucleus.
FIGURE 27–3
Structures of two isoquinoline neuromuscular blocking drugs. These agents are nondepolarizing muscle relaxants.

FIGURE 27–3
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Structures of two isoquinoline neuromuscular blocking drugs. These agents are nondepolarizing muscle relaxants.
FIGURE 27–4
Structures of steroid neuromuscular blocking drugs (steroid nucleus in color). These agents are all nondepolarizing muscle relaxants.

FIGURE 27–4
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Structures of steroid neuromuscular blocking drugs (steroid nucleus in color). These agents are all nondepolarizing muscle relaxants.
Pharmacokinetics of Neuromuscular Blocking Drugs
All of the neuromuscular blocking drugs are highly polar compounds and inactive orally; they must be administered parenterally.
A. Nondepolarizing Relaxant Drugs

The rate of
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KruideringHall; Lundydrug from the blood is characterized by a rapid initial distributionPage
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bound in peripheral tissues. Therefore, their volume of distribution (80–140 mL/kg) is only slightly larger than the blood volume.
Pharmacokinetics of Neuromuscular Blocking Drugs University Of Rijeka
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All of the neuromuscular blocking drugs are highly polar compounds and inactive orally; they must be administered parenterally.
The rate of disappearance of a nondepolarizing neuromuscular blocking drug from the blood is characterized by a rapid initial distribution phase
followed by a slower elimination phase. Neuromuscular blocking drugs are highly ionized, do not readily cross cell membranes, and are not strongly
bound in peripheral tissues. Therefore, their volume of distribution (80–140 mL/kg) is only slightly larger than the blood volume.
The duration of neuromuscular blockade produced by nondepolarizing relaxants is strongly correlated with the elimination halflife. Drugs that are
excreted by the kidney typically have longer halflives, leading to longer durations of action (>35 minutes). Drugs eliminated by the liver tend to have
shorter halflives and durations of action (Table 27–1). All steroidal muscle relaxants are metabolized to their 3hydroxy, 17hydroxy, or 3,17dihydroxy
products in the liver. The 3hydroxy metabolites are usually 40–80% as potent as the parent drug. Under normal circumstances, metabolites are not
formed in sufficient quantities to produce a significant degree of neuromuscular blockade during or after anesthesia. However, if the parent
compound is administered for several days in the ICU setting, the 3hydroxy metabolite may accumulate and cause prolonged paralysis because it has
a longer halflife than the parent compound. The remaining metabolites possess minimal neuromuscular blocking properties.
TABLE 27–1
Pharmacokinetic and dynamic properties of neuromuscular blocking drugs.
Clearance Approximate Duration of Action Approximate Potency Relative to

Drug Elimination
(mL/kg/min) (minutes) Tubocurarine
Isoquinoline derivatives
Atracurium Spontaneous1 6.6 20–35 1.5
Cisatracurium Mostly spontaneous 5–6 25–44 1.5
Tubocurarine Kidney (40%) 2.3–2.4 >50 1
Steroid derivatives
Pancuronium Kidney (80%) 1.7–1.8 >35 6
Rocuronium Liver (75–90%) and 2.9 20–35 0.8

kidney
Vecuronium Liver (75–90%) and 3–5.3 20–35 6

kidney
Depolarizing agent
Succinylcholine Plasma ChE2 (100%) >100 <8 0.4
1Nonenzymatic and enzymatic hydrolysis of ester bonds.
2Butyrylcholinesterase (pseudocholinesterase).
The intermediateacting steroid muscle relaxants (eg, vecuronium and rocuronium) tend to be more dependent on biliary excretion or hepatic
metabolism for their elimination. These muscle relaxants are more commonly used clinically than the longacting steroidbased drugs (eg,
pancuronium). The duration of action of these relaxants may be prolonged significantly in patients with impaired liver function.
Atracurium (see Figure 27–3) is an intermediateacting isoquinoline nondepolarizing muscle relaxant that is no longer in widespread clinical use. In
addition to hepatic metabolism, atracurium is inactivated by a form of spontaneous breakdown known as Hofmann elimination. The main breakdown
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acid, neither of which possesses neuromuscular blocking properties. Laudanosine is slowly
metabolized by the liver and has a longer elimination halflife (ie, 150 minutes). It readily crosses the bloodbrain barrier, and high blood
concentrations may cause seizures and an increase in the volatile anesthetic requirement. During surgical anesthesia, blood levels of laudanosine
typically range from 0.2 to 1 mcg/mL; however, with prolonged infusions of atracurium in the ICU, laudanosine blood levels may exceed 5 mcg/mL.
The intermediateacting steroid muscle relaxants (eg, vecuronium and rocuronium) tend to be more dependent on biliary excretion or hepatic
metabolism for their elimination. These muscle relaxants are more commonly used clinically than the longacting steroidbased drugs (eg,
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pancuronium). The duration of action of these relaxants may be prolonged significantly in patients with impaired liver function.
Atracurium (see Figure 27–3) is an intermediateacting isoquinoline nondepolarizing muscle relaxant that is no longer in widespread clinical use. In
addition to hepatic metabolism, atracurium is inactivated by a form of spontaneous breakdown known as Hofmann elimination. The main breakdown
products are laudanosine and a related quaternary acid, neither of which possesses neuromuscular blocking properties. Laudanosine is slowly
metabolized by the liver and has a longer elimination halflife (ie, 150 minutes). It readily crosses the bloodbrain barrier, and high blood
concentrations may cause seizures and an increase in the volatile anesthetic requirement. During surgical anesthesia, blood levels of laudanosine
typically range from 0.2 to 1 mcg/mL; however, with prolonged infusions of atracurium in the ICU, laudanosine blood levels may exceed 5 mcg/mL.
Atracurium has several stereoisomers, and the potent isomer cisatracurium has become one of the most common muscle relaxants in use today.
Although cisatracurium resembles atracurium, it has less dependence on hepatic inactivation, produces less laudanosine, and is much less likely to
release histamine. From a clinical perspective, cisatracurium has all the advantages of atracurium with fewer adverse effects. Therefore, cisatracurium
has virtually replaced atracurium in clinical practice.
Gantacurium represents a new class of nondepolarizing neuromuscular blockers, called asymmetric mixed onium chlorofumarates. It is degraded
nonenzymatically by adduction of the amino acid cysteine and ester bond hydrolysis. Gantacurium is currently in phase 3 clinical trials and not yet
available for widespread clinical use. Preclinical and clinical data indicate gantacurium has a rapid onset of effect and predictable duration of action
(very short, similar to succinylcholine) that can be reversed with neostigmine or more quickly (within 1–2 minutes), with administration of Lcysteine. At
doses above three times the ED95, cardiovascular adverse effects (eg, hypotension) have occurred, probably due to histamine release. No
bronchospasm or pulmonary vasoconstriction has been reported at these higher doses.
B. Depolarizing Relaxant Drugs
The extremely short duration of action of succinylcholine (5–10 minutes) is due to its rapid hydrolysis by butyrylcholinesterase and
pseudocholinesterase in the liver and plasma, respectively. Plasma cholinesterase metabolism is the predominant pathway for succinylcholine
elimination. The primary metabolite of succinylcholine, succinylmonocholine, is rapidly broken down to succinic acid and choline. Because plasma
cholinesterase has an enormous capacity to hydrolyze succinylcholine, only a small percentage of the original intravenous dose ever reaches the
neuromuscular junction. In addition, because there is little if any plasma cholinesterase at the motor end plate, a succinylcholineinduced blockade is
terminated by its diffusion away from the end plate into extracellular fluid. Therefore, the circulating levels of plasma cholinesterase influence the
duration of action of succinylcholine by determining the amount of the drug that reaches the motor end plate.
Neuromuscular blockade produced by succinylcholine can be prolonged in patients with an abnormal genetic variant of plasma cholinesterase. The
dibucaine number is a measure of the ability of a patient to metabolize succinylcholine and can be used to identify atrisk patients. Under
standardized test conditions, dibucaine inhibits the normal enzyme by 80% and the abnormal enzyme by only 20%. Many genetic variants of plasma
cholinesterase have been identified, although the dibucainerelated variants are the most important. Given the rarity of these genetic variants, plasma
cholinesterase testing is not a routine clinical procedure but may be indicated for patients with a family history of plasma cholinesterase deficiency.
Another reasonable strategy is to avoid the use of succinylcholine where practical in patients with a possible family history of plasma cholinesterase
deficiency.
Mechanism of Action
The interactions of drugs with the acetylcholine receptorend plate channel have been described at the molecular level. Several modes of action of
drugs on the receptor are illustrated in Figure 27–5.
FIGURE 27–5
Schematic diagram of the interactions of drugs with the acetylcholine receptor on the end plate channel (structures are purely symbolic). T o p : The
action of the normal agonist, acetylcholine (red) in opening the channel. Bottom, left: A nondepolarizing blocker, eg, rocuronium (yellow), is shown
as preventing the opening of the channel when it binds to the receptor. Bottom, right: A depolarizing blocker, eg, succinylcholine (blue), both
occupying the receptor and blocking the channel. Normal closure of the channel gate is prevented, and the blocker may move rapidly in and out of the
pore. Depolarizing blockers may desensitize the end plate by occupying the receptor and causing persistent depolarization. An additional effect of
drugs on the end plate channel may occur through changes in the lipid environment surrounding the channel (not shown). General anesthetics and
alcohols may impair neuromuscular transmission by this mechanism.

occupying the receptor and blocking the channel. Normal closure of the channel gate is prevented, and the blocker may move rapidly in and out of the
pore. Depolarizing blockers may desensitize the end plate by occupying the receptor and causing persistent depolarization. An additional effect of
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drugs on the end plate channel may occur through changes in the lipid environment surrounding the channel (not shown). General anesthetics and
alcohols may impair neuromuscular transmission by this mechanism.
All the neuromuscular blocking drugs in current use in the USA except succinylcholine are classified as nondepolarizing agents. Although it is no
longer in widespread clinical use, d tubocurarine is considered the prototype neuromuscular blocker. When small doses of nondepolarizing muscle
relaxants are administered, they act predominantly at the nicotinic receptor site by competing with acetylcholine. The least potent nondepolarizing
relaxants (eg, rocuronium) have the fastest onset and the shortest duration of action. In larger doses, nondepolarizing drugs can enter the pore of the
ion channel (see Figure 27–5) to produce a more intense motor blockade. This action further weakens neuromuscular transmission and diminishes
the ability of the acetylcholinesterase inhibitors (eg, neostigmine, edrophonium, pyridostigmine) to antagonize the effect of nondepolarizing muscle
relaxants.
Nondepolarizing relaxants can also block prejunctional sodium channels. As a result of this action, muscle relaxants interfere with the mobilization of
acetylcholine at the nerve ending and cause fade of evoked nerve twitch contractions (Figure 27–6 and described below). One consequence of the
surmountable nature of the postsynaptic blockade produced by nondepolarizing muscle relaxants is the fact that tetanic stimulation (rapid delivery of
electrical stimuli to a peripheral nerve) releases a large quantity of acetylcholine and is followed by transient posttetanic facilitation of the twitch
strength (ie, relief of blockade). An important clinical consequence of this principle is the reversal of residual blockade by cholinesterase inhibitors.
The characteristics of a nondepolarizing neuromuscular blockade are summarized in Table 27–2 and Figure 27–6.
FIGURE 27–6
Muscle contraction responses to different patterns of nerve stimulation used in monitoring skeletal muscle relaxation. The alterations produced by a
nondepolarizing blocker and depolarizing and desensitizing blockade by succinylcholine are shown. In the trainoffour (TOF) pattern, four stimuli are
applied at 2 Hz. The TOF ratio (TOFR) is calculated from the strength of the fourth contraction divided by that of the first. In the doubleburst pattern,
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a 700 ms rest period and then repeated. In the posttetanic potentiation pattern, several seconds of 50 Hz
stimulation
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twitches is the posttetanic count (PTC),* first posttetanic contraction.
FIGURE 27–6
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Muscle contraction responses to different patterns of nerve stimulation used in monitoring skeletal muscle relaxation. The alterations produced by a
nondepolarizing blocker and depolarizing and desensitizing blockade by succinylcholine are shown. In the trainoffour (TOF) pattern, four stimuli are
applied at 2 Hz. The TOF ratio (TOFR) is calculated from the strength of the fourth contraction divided by that of the first. In the doubleburst pattern,
three stimuli are applied at 50 Hz, followed by a 700 ms rest period and then repeated. In the posttetanic potentiation pattern, several seconds of 50 Hz
stimulation are applied, followed by several seconds of rest and then by single stimuli at a slow rate (eg, 0.5 Hz). The number of detectable posttetanic
twitches is the posttetanic count (PTC),* first posttetanic contraction.
TABLE 27–2
Comparison of a typical nondepolarizing muscle relaxant (rocuronium) and a depolarizing muscle relaxant (succinylcholine).
Succinylcholine
Rocuronium Phase I Phase II
Administration of tubocurarine Additive Antagonistic Augmented1
Administration of succinylcholine Antagonistic Additive Augmented1
Effect of neostigmine Antagonistic Augmented1 Antagonistic
Initial excitatory effect on skeletal muscle None Fasciculations None
Response to a tetanic stimulus Unsustained (fade) Sustained2 (no fade) Unsustained (fade)
Posttetanic facilitation Yes No Yes
Rate of recovery 30–60 min3 4–8 min >20 min3
1It is not known whether this interaction is additive or synergistic (super additive).
2The amplitude is decreased, but the response is sustained.

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TABLE 27–2
Comparison of a typical nondepolarizing muscle relaxant (rocuronium) and a depolarizing muscle relaxant (succinylcholine).
Succinylcholine
Rocuronium Phase I Phase II
Administration of tubocurarine Additive Antagonistic Augmented1
Administration of succinylcholine Antagonistic Additive Augmented1
Effect of neostigmine Antagonistic Augmented1 Antagonistic
Initial excitatory effect on skeletal muscle None Fasciculations None
Response to a tetanic stimulus Unsustained (fade) Sustained2 (no fade) Unsustained (fade)
Posttetanic facilitation Yes No Yes
Rate of recovery 30–60 min3 4–8 min >20 min3
1It is not known whether this interaction is additive or synergistic (super additive).
2The amplitude is decreased, but the response is sustained.
3The rate depends on the dose and on the completeness of neuromuscular blockade.
1 . Phase I block (depolarizing)
Succinylcholine is the only clinically useful depolarizing blocking drug. Its neuromuscular effects are like those of acetylcholine except that
succinylcholine produces a longer effect at the myoneural junction. Succinylcholine reacts with the nicotinic receptor to open the channel and cause
depolarization of the motor end plate, and this in turn spreads to the adjacent membranes, causing transient contractions of muscle motor units. Data
from singlechannel recordings indicate that depolarizing blockers can enter the channel to produce a prolonged “flickering” of the ion conductance
(Figure 27–7). Because succinylcholine is not metabolized effectively at the synapse, the depolarized membranes remain depolarized and
unresponsive to subsequent impulses (ie, a state of depolarizing blockade). Furthermore, because excitationcontraction coupling requires end plate
repolarization (“repriming”) and repetitive firing to maintain muscle tension, a flaccid paralysis results. In contrast to the nondepolarizing drugs, this
socalled phase I (depolarizing) block is augmented, not reversed, by cholinesterase inhibitors.
FIGURE 27–7
Action of succinylcholine on singlechannel end plate receptor currents in frog muscle. Currents through a single AChR channel were recorded using
the patch clamp technique. The upper trace was recorded in the presence of a low concentration of succinylcholine; the downward deflections
represent openings of the channel and passage of inward (depolarizing) current. The lower trace was recorded in the presence of a much higher
concentration of succinylcholine and shows prolonged “flickering” of the channel as it repetitively opens and closes or is “plugged” by the drug.
(Reproduced with permission from Marshall CG, Ogden DC, Colquhoun D. The actions of suxamethonium (succinyldicholine) as an agonist and
channel blocker at the nicotinic receptor of frog muscle. J Physiol. 1990;428:155–174.)

represent openings of the channel and passage of inward (depolarizing) current. The lower trace was recorded in the presence of a much higher
concentration of succinylcholine and shows prolonged “flickering” of the channel as it repetitively opens and closes or is “plugged” by the drug.
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(Reproduced with permission from Marshall CG, Ogden DC, Colquhoun D. The actions of suxamethonium (succinyldicholine) as an agonist and
channel blocker at the nicotinic receptor of frog muscle. J Physiol. 1990;428:155–174.)
The characteristics of a depolarizing neuromuscular blockade are summarized in Table 27–2 and Figure 27–6.
2 . Phase II block (desensitizing)
With prolonged exposure to succinylcholine, the initial end plate depolarization decreases, and the membrane becomes repolarized. Despite this
repolarization, the membrane cannot easily be depolarized again because it is desensitized. The mechanism for this desensitizing phase is unclear,
but some evidence indicates that channel block may become more important than agonist action at the receptor in phase II of succinylcholine’s
neuromuscular blocking action. Regardless of the mechanism, the channels behave as if they are in a prolonged closed state (see Figure 27–6). Later in
phase II, the characteristics of the blockade are nearly identical to those of a nondepolarizing block (ie, a nonsustained twitch response to a tetanic
stimulus) (see Figure 27–6), with possible reversal by acetylcholinesterase inhibitors.
CLINICAL PHARMACOLOGY OF NEUROMUSCULAR BLOCKING DRUGS

Skeletal Muscle Paralysis
Before the introduction of neuromuscular blocking drugs, profound skeletal muscle relaxation for intracavitary operations could be achieved only by
producing levels of volatile (inhaled) anesthesia deep enough to produce profound depressant effects on the cardiovascular and respiratory systems.
The adjunctive use of neuromuscular blocking drugs makes it possible to achieve adequate muscle relaxation for all types of surgical procedures
without the cardiorespiratory depressant effects produced by deep anesthesia.
Assessment of Neuromuscular Transmission
Monitoring the effect of muscle relaxants during surgery (and recovery following the administration of cholinesterase inhibitors) typically involves the
use of a device that produces transdermal electrical stimulation of one of the peripheral nerves to the hand or facial muscles and recording of the
evoked contractions (ie, twitch responses). The motor responses to different patterns of peripheral nerve stimulation can be recorded in the operating
room during the procedure (see Figure 27–6). The standard approach for monitoring the clinical effects of muscle relaxants during surgery uses
peripheral nerve stimulation to elicit motor responses, which are visually observed by the anesthesiologist. The three most commonly used patterns
include (1) singletwitch stimulation, (2) trainoffour (TOF) stimulation, and (3) tetanic stimulation. Two other modalities are also available to monitor
neuromuscular transmission: doubleburst stimulation and posttetanic count.
With singletwitch stimulation, a single supramaximal electrical stimulus is applied to a peripheral nerve at frequencies from 0.1 Hz to 1.0 Hz. The
higher frequency is often used during induction and reversal to more accurately determine the peak (maximal) drug effect. TOF stimulation involves
four successive supramaximal stimuli given at intervals of 0.5 second (2 Hz). Each stimulus in the TOF causes the muscle to contract, and the relative
magnitude of the response of the fourth twitch compared with the first twitch is the TOF ratio. With a depolarizing block, all four twitches are reduced
in a doserelated fashion. With a nondepolarizing block, the TOF ratio decreases (“fades”) and is inversely proportional to the degree of blockade.
During recovery from nondepolarizing block, the amount of fade decreases and the TOF ratio approaches 1.0. Recovery to a TOF ratio greater than 0.7
is typically necessary for resumption of spontaneous ventilation. However, complete clinical recovery from a nondepolarizing block is considered to
require a TOF greater than 0.9. Fade in the TOF response after administration of succinylcholine signifies the development of a phase II block.
Tetanic stimulation consists of a very rapid (30–100 Hz) delivery of electrical stimuli for several seconds. During a nondepolarizing neuromuscular
block (and a phase II block after succinylcholine), the response is not sustained, and fade of the twitch responses is observed. Fade in response to
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tetanic stimulation 7:4 Aconsidered
is normally Your IP isa161.53.41.15
presynaptic event. However, the degree of fade depends primarily on the degree of neuromuscular
blockade. During a partial nondepolarizing blockade, tetanic nerve stimulation is followed by an increase in the posttetanic twitch response, socalled
posttetanic facilitation of neuromuscular transmission. During intense neuromuscular blockade, there is no response to either tetanic or posttetanic
stimulation. As the intensity of the block diminishes, the response to posttetanic twitch stimulation reappears. The reappearance of the first response
During recovery from nondepolarizing block, the amount of fade decreases and the TOF ratio approaches 1.0. Recovery to a TOF ratio greater than 0.7
is typically necessary for resumption of spontaneous ventilation. However, complete clinical recovery from a nondepolarizing block is considered to
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require a TOF greater than 0.9. Fade in the TOF response after administration of succinylcholine signifies the development of a phase II block.
Tetanic stimulation consists of a very rapid (30–100 Hz) delivery of electrical stimuli for several seconds. During a nondepolarizing neuromuscular
block (and a phase II block after succinylcholine), the response is not sustained, and fade of the twitch responses is observed. Fade in response to
tetanic stimulation is normally considered a presynaptic event. However, the degree of fade depends primarily on the degree of neuromuscular
blockade. During a partial nondepolarizing blockade, tetanic nerve stimulation is followed by an increase in the posttetanic twitch response, socalled
posttetanic facilitation of neuromuscular transmission. During intense neuromuscular blockade, there is no response to either tetanic or posttetanic
stimulation. As the intensity of the block diminishes, the response to posttetanic twitch stimulation reappears. The reappearance of the first response
to twitch stimulation after tetanic stimulation reflects the duration of profound (clinical) neuromuscular blockade. To determine the posttetanic count,
5 seconds of 50 Hz tetany is applied, followed by 3 seconds of rest, followed by 1 Hz pulses for about 10 seconds (10 pulses). The counted number of
muscle twitches provides an estimation of the depth of blockade. For instance, a posttetanic count of 2 suggests no twitch response (by TOF) for about
20–30 minutes, and a posttetanic count of 5 correlates to a notwitch response (by TOF) of about 10–15 minutes (see Figure 27–6, bottom panel).
The doubleburst stimulation pattern is another mode of electrical nerve stimulation developed with the goal of allowing for manual detection of
residual neuromuscular blockade when it is not possible to record the responses to singletwitch, TOF, or tetanic stimulation. In this pattern, three
nerve stimuli are delivered at 50 Hz followed by a 700 ms rest period and then by two or three additional stimuli at 50 Hz. It is easier to detect fade in the
responses to doubleburst stimulation than to TOF stimulation. The absence of fade in response to doubleburst stimulation implies that clinically
significant residual neuromuscular blockade does not exist.
A more quantitative approach to neuromuscular monitoring involves monitoring using a force transducer for measuring the evoked response (ie,
movement) of the thumb to TOF stimulation over the ulnar nerve at the wrist. This device has the advantage of being integrated in the anesthesia
machine and also provides a more accurate graphic display of the percentage of fade to TOF stimulation.
During anesthesia, administration of tubocurarine, 0.1–0.4 mg/kg IV, initially causes motor weakness, followed by the skeletal muscles becoming
flaccid and inexcitable to electrical stimulation (Figure 27–8). In general, larger muscles (eg, abdominal, trunk, paraspinous, diaphragm) are more
resistant to neuromuscular blockade and recover more rapidly than smaller muscles (eg, facial, foot, hand). The diaphragm is usually the last muscle
to be paralyzed. Assuming that ventilation is adequately maintained, no adverse effects occur with skeletal muscle paralysis. When administration of
muscle relaxants is discontinued, recovery of muscles usually occurs in reverse order, with the diaphragm regaining function first. The pharmacologic
effect of tubocurarine, 0.3 mg/kg IV, usually lasts 45–60 minutes. However, subtle evidence of residual muscle paralysis detected using a
neuromuscular monitor may last for another hour, increasing the likelihood of adverse outcomes, eg, aspiration and decreased hypoxic drive. Potency
and duration of action of the other nondepolarizing drugs are shown in Table 27–1. In addition to the duration of action, the most important property
distinguishing the nondepolarizing relaxants is the time to onset of the blocking effect, which determines how rapidly the patient’s trachea can be
intubated. Of the currently available nondepolarizing drugs, rocuronium has the most rapid onset time (60–120 seconds).
FIGURE 27–8
Neuromuscular blockade from tubocurarine during equivalent levels of isoflurane and halothane anesthesia in patients. Note that isoflurane
augments the block far more than does halothane. MAC, minimal alveolar concentration.
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Relaxant Drugs
Following the administration of succinylcholine, 0.75–1.5 mg/kg IV, transient muscle fasciculations occur over the chest and abdomen within 30
seconds, although general anesthesia and the prior administration of a small dose of a nondepolarizing muscle relaxant tend to attenuate them. As
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Following the administration of succinylcholine, 0.75–1.5 mg/kg IV, transient muscle fasciculations occur over the chest and abdomen within 30
seconds, although general anesthesia and the prior administration of a small dose of a nondepolarizing muscle relaxant tend to attenuate them. As
paralysis develops rapidly (<90 seconds), the arm, neck, and leg muscles are initially relaxed followed by the respiratory muscles. As a result of
succinylcholine’s rapid hydrolysis by cholinesterase in the plasma (and liver), the neuromuscular block typically lasts less than 10 minutes (see Table
27–1).
Cardiovascular Effects
Vecuronium, cisatracurium, and rocuronium have minimal, if any, cardiovascular effects. The other nondepolarizing muscle relaxants (ie,
pancuronium and atracurium) produce cardiovascular effects that are mediated by autonomic or histamine receptors (Table 27–3). Tubocurarine and,
to a lesser extent, atracurium can produce hypotension as a result of systemic histamine release, and with larger doses, ganglionic blockade may occur
with tubocurarine. Premedication with an antihistaminic compound attenuates tubocurarineinduced hypotension. Pancuronium causes a moderate
increase in heart rate and a smaller increase in cardiac output, with little or no change in systemic vascular resistance. Although pancuroniuminduced
tachycardia is primarily due to a vagolytic action, release of norepinephrine from adrenergic nerve endings and blockade of neuronal uptake of
norepinephrine may be secondary mechanisms. Bronchospasm may be produced by neuromuscular blockers that release histamine (eg, atracurium),
but after induction of general anesthesia, insertion of an endotracheal tube is the most common cause of bronchospasm.
TABLE 27–3
Effects of neuromuscular blocking drugs on other tissues.
Drug Effect on Autonomic Ganglia Effect on Cardiac Muscarinic Receptors Tendency to Cause Histamine Release
Isoquinoline derivatives
Atracurium None None Slight
Cisatracurium None None None
Tubocurarine Weak block None Moderate
Steroid derivatives
Pancuronium None Moderate block None
Rocuronium1 None Slight None
Vecuronium None None None
Other agents
Gallamine None Strong block None
Succinylcholine Stimulation Stimulation Slight
1Allergic reactions have been reported.
Succinylcholine can cause cardiac arrhythmias, especially when administered during halothane anesthesia. The drug stimulates autonomic
cholinoceptors, including the nicotinic receptors at both sympathetic and parasympathetic ganglia and muscarinic receptors in the heart (eg, sinus
node). The negative
Downloaded inotropic
20241011 andYour
7:4 A chronotropic responses to succinylcholine can be attenuated by administration of an anticholinergic drug (eg,
IP is 161.53.41.15
Chapter 27: Skeletal
glycopyrrolate, Muscle
atropine). WithRelaxants,
large dosesMarieke KruideringHall;
of succinylcholine, Lundy
positive J. Campbell
inotropic Page 15 / 29
and chronotropic effects may be observed. On the other hand,
bradycardia has been repeatedly observed when a second dose of succinylcholine is given less than 5 minutes after the initial dose. This transient
bradycardia can be prevented by thiopental, atropine, and ganglionicblocking drugs, and by pretreating with a small dose of a nondepolarizing
1Allergic reactions have been reported.
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Succinylcholine can cause cardiac arrhythmias, especially when administered during halothane anesthesia. The drug stimulates autonomic
cholinoceptors, including the nicotinic receptors at both sympathetic and parasympathetic ganglia and muscarinic receptors in the heart (eg, sinus
node). The negative inotropic and chronotropic responses to succinylcholine can be attenuated by administration of an anticholinergic drug (eg,
glycopyrrolate, atropine). With large doses of succinylcholine, positive inotropic and chronotropic effects may be observed. On the other hand,
bradycardia has been repeatedly observed when a second dose of succinylcholine is given less than 5 minutes after the initial dose. This transient
bradycardia can be prevented by thiopental, atropine, and ganglionicblocking drugs, and by pretreating with a small dose of a nondepolarizing
muscle relaxant (eg, rocuronium). Direct myocardial effects, increased muscarinic stimulation, and ganglionic stimulation contribute to this
bradycardic response.
Other Adverse Effects of Depolarizing Blockade
A. Hyperkalemia
Patients with burns, nerve damage or neuromuscular disease, closed head injury, and other trauma may develop proliferation of extrajunctional
acetylcholine receptors. During administration of succinylcholine, potassium is released from muscles, likely due to fasciculations. If the proliferation
of extrajunctional receptors is great enough, sufficient potassium may be released to result in cardiac arrest. The exact time course of receptor
proliferation is unknown; therefore, it is best to avoid the use of succinylcholine in these cases.
B. Increased Intraocular Pressure
Administration of succinylcholine may be associated with the rapid onset of an increase in intraocular pressure (<60 seconds), peaking at 2–4 minutes,
and declining after 5 minutes. The mechanism may involve tonic contraction of myofibrils or transient dilation of ocular choroidal blood vessels.
Despite the increase in intraocular pressure, the use of succinylcholine for ophthalmologic operations is not contraindicated unless the anterior
chamber is open (“open globe”) due to trauma.
C. Increased Intragastric Pressure
In heavily muscled patients, the fasciculations associated with succinylcholine may cause an increase in intragastric pressure ranging from 5 to 40 cm
H2O, increasing the risk for regurgitation and aspiration of gastric contents. This complication is more likely to occur in patients with delayed gastric
emptying (eg, those with diabetes), traumatic injury (eg, an emergency case), esophageal dysfunction, and morbid obesity.
D. Muscle Pain
Myalgias are a common postoperative complaint of heavily muscled patients and those who receive large doses (>1.5 mg/kg) of succinylcholine. The
true incidence of myalgias related to muscle fasciculations is difficult to establish because of confounding factors, including the anesthetic technique,
type of surgery, and positioning during the operation. However, the incidence of myalgias has been reported to vary from less than 1% to 20%. It
occurs more frequently in ambulatory than in bedridden patients. The pain is thought to be secondary to the unsynchronized contractions of adjacent
muscle fibers just before the onset of paralysis. However, there is controversy over whether the incidence of muscle pain following succinylcholine is
actually higher than with nondepolarizing muscle relaxants when other potentially confounding factors are taken into consideration.
Interactions with Other Drugs
A. Anesthetics
Inhaled (volatile) anesthetics potentiate the neuromuscular blockade produced by nondepolarizing muscle relaxants in a dosedependent fashion. Of
the general anesthetics that have been studied, inhaled anesthetics augment the effects of muscle relaxants in the following order: isoflurane (most),
sevoflurane, desflurane, halothane, and nitrous oxide (least) (see Figure 27–8). The most important factors involved in this interaction are the
following: (1) nervous system depression at sites proximal to the neuromuscular junction (ie, CNS); (2) increased muscle blood flow (ie, due to
peripheral vasodilation produced by volatile anesthetics), which allows a larger fraction of the injected muscle relaxant to reach the neuromuscular
junction; and (3) decreased sensitivity of the postjunctional membrane to depolarization.
A rare interaction of succinylcholine with volatile anesthetics results in malignant hyperthermia, a condition caused by abnormal release of calcium
from stores in skeletal muscle. This condition is treated with dantrolene and is discussed below under Spasmolytic & Antispasmodic Drugs and in
Chapter 16.

B. Antibiotics
Numerous reports have described enhancement of neuromuscular blockade by antibiotics (eg, aminoglycosides). Many of the antibiotics have been
shown to cause a depression of evoked release of acetylcholine similar to that caused by administering magnesium. The mechanism of this
junction; and (3) decreased sensitivity of the postjunctional membrane to depolarization.
A rare interaction of succinylcholine with volatile anesthetics results in malignant hyperthermia, a condition caused by abnormalAccess
release of calcium
Provided by:
from stores in skeletal muscle. This condition is treated with dantrolene and is discussed below under Spasmolytic & Antispasmodic Drugs and in
Chapter 16.
B. Antibiotics
Numerous reports have described enhancement of neuromuscular blockade by antibiotics (eg, aminoglycosides). Many of the antibiotics have been
shown to cause a depression of evoked release of acetylcholine similar to that caused by administering magnesium. The mechanism of this
prejunctional effect appears to be blockade of specific Ptype calcium channels in the motor nerve terminal.
C. Local Anesthetics and Antiarrhythmic Drugs
In small doses, local anesthetics can depress posttetanic potentiation via a prejunctional neural effect. In large doses, local anesthetics can block
neuromuscular transmission. With these higher doses, local anesthetics block acetylcholineinduced muscle contractions as a result of blockade of the
nicotinic receptor ion channels. Experimentally, similar effects can be demonstrated with sodium channelblocking antiarrhythmic drugs such as
quinidine. However, at the doses used for cardiac arrhythmias, this interaction is of little or no clinical significance. Higher doses of bupivacaine have
been associated with cardiac arrhythmias independent of the muscle relaxant used.
D. Other Neuromuscular Blocking Drugs
The end platedepolarizing effect of succinylcholine can be antagonized by administering a small dose of a nondepolarizing blocker. To prevent the
fasciculations associated with succinylcholine administration, a small nonparalyzing dose of a nondepolarizing drug can be given before
succinylcholine (eg, dtubocurarine, 2 mg IV, or pancuronium, 0.5 mg IV). Although this dose usually reduces fasciculations and postoperative
myalgias, it can increase the amount of succinylcholine required for relaxation by 50–90% and can produce a feeling of weakness in awake patients.
Therefore, “precurarization” before succinylcholine is no longer widely practiced.
Effects of Diseases & Aging on the Neuromuscular Response
Several diseases can diminish or augment the neuromuscular blockade produced by nondepolarizing muscle relaxants. Myasthenia gravis enhances
the neuromuscular blockade produced by these drugs. Advanced age is associated with a prolonged duration of action from nondepolarizing
relaxants as a result of decreased clearance of the drugs by the liver and kidneys. As a result, the dosage of neuromuscular blocking drugs should be
reduced in older patients (>70 years).
Conversely, patients with severe burns and those with upper motor neuron disease are resistant to nondepolarizing muscle relaxants. This
desensitization is probably caused by proliferation of extrajunctional receptors, which results in an increased dose requirement for the
nondepolarizing relaxant to block a sufficient number of receptors.
Reversal of Nondepolarizing Neuromuscular Blockade
The cholinesterase inhibitors effectively antagonize the neuromuscular blockade caused by nondepolarizing drugs. Their general pharmacology is
discussed in Chapter 7. Neostigmine and pyridostigmine antagonize nondepolarizing neuromuscular blockade by increasing the availability of
acetylcholine at the motor end plate, mainly by inhibition of acetylcholinesterase. To a lesser extent, these cholinesterase inhibitors also increase the
release of this transmitter from the motor nerve terminal. In contrast, edrophonium antagonizes neuromuscular blockade purely by inhibiting
acetylcholinesterase activity. Edrophonium has a more rapid onset of action but may be less effective than neostigmine in reversing the effects of
nondepolarizing blockers in the presence of profound neuromuscular blockade. These differences are important in determining recovery from
residual block, the neuromuscular blockade remaining after completion of surgery and movement of the patient to the recovery room. Unsuspected
residual block may result in hypoventilation, leading to hypoxia and even apnea, especially if patients have received central depressant medications in
the early recovery period.
Sugammadex is a reversal agent approved for rapid reversal of the steroid neuromuscular blocking agents rocuronium and vecuronium. Although it
has been in clinical use in Europe since 2008, its approval in the USA was delayed because of concerns that it causes a low incidence of anaphylaxis and
hypersensitivity reactions. Sugammadex is a modified gcyclodextrin (a large ring structure with 16 polar hydroxyl groups facing inward and 8 polar
carboxyl groups facing outward) that binds tightly to rocuronium in a 1:1 ratio. By binding to plasma rocuronium, sugammadex decreases the free
plasma concentration and establishes a concentration gradient for rocuronium to diffuse away from the neuromuscular junction back into the
circulation, where it is quickly bound by free sugammadex.
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Currently, three 7:4are
dose ranges A recommended
Your IP is 161.53.41.15
for sugammadex: 2 mg/kg to reverse shallow neuromuscular blockade (spontaneous recovery has
reached the second twitch in TOF stimulation), 4 mg/kg to reverse deeper blockade (1–2 posttetanic count and no response to TOF stimulation), and
16 mg/kg for immediate reversal following administration of a single dose of 1.2 mg/kg of rocuronium. In patients with normal renal function (defined
as a creatinine clearance [CrCl] > 80 mL/min), the sugammadexrocuronium complex is typically excreted unchanged in the urine within 24 hours. In
has been in clinical use in Europe since 2008, its approval in the USA was delayed because of concerns that it causes a low incidence of anaphylaxis and
hypersensitivity reactions. Sugammadex is a modified gcyclodextrin (a large ring structure with 16 polar hydroxyl groups facing inward and 8 Of
University polar
Rijeka
carboxyl groups facing outward) that binds tightly to rocuronium in a 1:1 ratio. By binding to plasma rocuronium, sugammadex decreases the free
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plasma concentration and establishes a concentration gradient for rocuronium to diffuse away from the neuromuscular junction back into the
circulation, where it is quickly bound by free sugammadex.
Currently, three dose ranges are recommended for sugammadex: 2 mg/kg to reverse shallow neuromuscular blockade (spontaneous recovery has
reached the second twitch in TOF stimulation), 4 mg/kg to reverse deeper blockade (1–2 posttetanic count and no response to TOF stimulation), and
16 mg/kg for immediate reversal following administration of a single dose of 1.2 mg/kg of rocuronium. In patients with normal renal function (defined
as a creatinine clearance [CrCl] > 80 mL/min), the sugammadexrocuronium complex is typically excreted unchanged in the urine within 24 hours. In
patients with renal insufficiency, complete urinary elimination may take much longer. The plasma halflife of sugammadex in patients with renal
impairment increases significantly as CrCl is reduced. In mild to moderate renal insufficiency (CrCl between 30 and 80 mL/min), the halflife varies
between 4 and 6 hours. This increases dramatically in patients with severe renal impairment (CrCl > 30 mL/min), in whom the halflife is extended to 19
hours. The ability to dialyze sugammadex is variable, although some studies have demonstrated the ability to dialyze it using a highflux method.
Therefore, sugammadex is not recommended for use in patients with severe renal impairment unless absolutely necessary.
Sugammadex is associated with a few significant adverse reactions. Most importantly, sugammadex may cause anaphylaxis, which occurred in 0.3% of
patients who received the 16 mg/kg dose in the US Food and Drug Administration (FDA) studies. Hypersensitivity reactions, such as nausea, pruritus,
and urticaria, are more common than anaphylaxis, and also occur more frequently with higher doses of sugammadex. Other significant adverse
reactions include marked bradycardia that may progress to cardiac arrest within minutes of administration and coagulopathy, with an approximately
25% elevation of activated partial thromboplastin time and prothrombin time/international normalized ratio values that may last up to 1 hour.
Because sugammadex binds the steroidal neuromuscular blocking agents rocuronium and vecuronium, it is not surprising that it can also block other
steroidal drugs. The two most important of these drugs are progesteronebased contraceptives and the selective estrogen receptor modulator
toremifene. When sugammadex is administered to a woman who is taking hormonal contraceptives that contain progesterone, the progesterone may
be bound by sugammadex, and the efficacy of the contraceptive is decreased as if the woman missed one or two doses. The manufacturer
recommends that an alternative nonhormonal contraceptive be used for 7 days following sugammadex administration. Sugammadex also very tightly
binds toremifene, which may be used to treat metastatic breast cancer (see Chapter 40). Not only will the efficacy of toremifene be reduced, but
displacement of rocuronium from sugammadex may result, and prolonged neuromuscular blockade could occur.
Uses of Neuromuscular Blocking Drugs
A. Surgical Relaxation
One of the most important applications of the neuromuscular blockers is in facilitating intracavitary surgery, especially in intraabdominal and
intrathoracic procedures.
B. Endotracheal Intubation
By relaxing the pharyngeal and laryngeal muscles, neuromuscular blocking drugs facilitate laryngoscopy and placement of an endotracheal tube.
Endotracheal tube placement ensures an adequate airway and minimizes the risk of pulmonary aspiration during general anesthesia.
C. Control of Ventilation
In critically ill patients who have ventilatory failure from various causes (eg, severe bronchospasm, pneumonia, chronic obstructive airway disease), it
may be necessary to control ventilation to provide adequate gas exchange and to prevent atelectasis. In the ICU, neuromuscular blocking drugs are
frequently administered to reduce chest wall resistance (ie, improve thoracic compliance), decrease oxygen utilization, and improve ventilator
synchrony.
D. Treatment of Convulsions
Neuromuscular blocking drugs (ie, succinylcholine) are occasionally used to attenuate the peripheral (motor) manifestations of convulsions
associated with status epilepticus, local anesthetic toxicity, or electroconvulsive therapy. Although this approach is effective in eliminating the
muscular manifestations of the seizures, it has no effect on the central processes because neuromuscular blocking drugs do not cross the bloodbrain
barrier.
SPASMOLYTIC & ANTISPASMODIC DRUGS

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Skeletal muscle 7:4 A Your
relaxants include IP is 161.53.41.15
neuromuscular blockers, spasmolytics, and antispasmodics. Spasmolytics and antispasmodics are used to treat two
Chapter 27: Skeletal Muscle Relaxants, Marieke KruideringHall;
conditions: spasms from peripheral musculoskeletal Lundy J. Campbell
conditions (antispasmodics) Page 18 / 29
and spasticity from upper motor neuron lesions (spasmolytics).
Spasticity presents as intermittent or sustained involuntary contraction of skeletal muscle, causing stiffness that interferes with mobility and speech. It
is characterized by an increase in tonic stretch reflexes and flexor muscle spasms (ie, increased basal muscle tone) together with muscle weakness. It is
muscular manifestations of the seizures, it has no effect on the central processes because neuromuscular blocking drugs do not cross the bloodbrain
barrier.
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SPASMOLYTIC & ANTISPASMODIC DRUGS

Skeletal muscle relaxants include neuromuscular blockers, spasmolytics, and antispasmodics. Spasmolytics and antispasmodics are used to treat two
conditions: spasms from peripheral musculoskeletal conditions (antispasmodics) and spasticity from upper motor neuron lesions (spasmolytics).
Spasticity presents as intermittent or sustained involuntary contraction of skeletal muscle, causing stiffness that interferes with mobility and speech. It
is characterized by an increase in tonic stretch reflexes and flexor muscle spasms (ie, increased basal muscle tone) together with muscle weakness. It is
often associated with spinal injury, cerebral palsy, multiple sclerosis, and stroke. The mechanisms underlying clinical spasticity appear to involve not
only the stretch reflex arc itself but also higher centers in the CNS, with damage to descending pathways in the spinal cord resulting in hyperexcitability
of the alpha motor neurons in the cord. The important components involved in these processes are shown in Figure 27–9. Pharmacologic therapy may
ameliorate some of the symptoms of spasticity by modifying the stretch reflex arc or by interfering directly with skeletal muscle (ie, excitation
contraction coupling).
FIGURE 27–9
Schematic illustration of the structures involved in the stretch reflex (right half) showing innervation of extrafusal (striated muscle) fibers by alpha
motor neurons and of intrafusal fibers (within muscle spindle) by gamma motor neurons. The left half of the diagram shows an inhibitory reflex arc,
which includes an intercalated inhibitory interneuron. (Reproduced with permission from Waxman SG: Clinical Neuroanatomy, 26th ed. New York, NY:
McGraw Hill; 2009.)
Drugs that modify the reflex arc may modulate excitatory or inhibitory synapses (see Chapter 21). Thus, to reduce the hyperactive stretch reflex, it is
desirable to reduce the activity of the Ia fibers that excite the primary motor neuron or to enhance the activity of the inhibitory internuncial neurons.
These structures are shown in greater detail in Figure 27–10.
FIGURE 27–10
Postulated sites of spasmolytic action of tizanidine (α2), benzodiazepines (GABAA), and baclofen (GABAB) in the spinal cord. Tizanidine may also have a
postsynaptic inhibitory effect. Dantrolene acts on the sarcoplasmic reticulum in skeletal muscle. Glu, glutamatergic neuron.

FIGURE 27–10
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Postulated sites of spasmolytic action of tizanidine (α2), benzodiazepines (GABAA), and baclofen (GABAB) in the spinal cord. Tizanidine may also have a
postsynaptic inhibitory effect. Dantrolene acts on the sarcoplasmic reticulum in skeletal muscle. Glu, glutamatergic neuron.
A variety of pharmacologic agents described as depressants of the spinal “polysynaptic” reflex arc (eg, barbiturates [phenobarbital] and glycerol
ethers [mephenesin]) have been used to treat these conditions of excess skeletal muscle tone. However, as illustrated in Figure 27–10, nonspecific
depression of synapses involved in the stretch reflex could reduce the desired GABAergic inhibitory activity, as well as the excitatory glutamatergic
transmission. Currently available drugs can provide significant relief from painful muscle spasms, but they are less effective in improving meaningful
function (eg, mobility and return to work).
Diazepam
As described in Chapter 22, benzodiazepines facilitate the action of GABA in the CNS. Diazepam acts at GABAA synapses, and its action in reducing
spasticity is at least partly mediated in the spinal cord because it is somewhat effective in patients with cord transection. Although diazepam can be
used in patients with muscle spasm of almost any origin (including local muscle trauma), it also produces sedation at the doses required to reduce
muscle tone. The initial dosage is 4 mg/d, and it is gradually increased to a maximum of 60 mg/d. Other benzodiazepines have been used as
spasmolytics (eg, midazolam), but clinical experience with them is limited.
Meprobamate and carisoprodol are sedatives that have been used as central muscle relaxants, although evidence for their efficacy without sedation is
lacking. Carisoprodol is a schedule IV drug; it is metabolized to meprobamate, which is also a schedule IV drug. Withdrawal of carisoprodol and
meprobamate after extensive use elicits physical withdrawal, with anxiety, tremors, muscle twitching, insomnia, and auditory and visual hallucinations.
Baclofen
Baclofen (pchlorophenylGABA) was designed to be an orally active GABAmimetic agent and is an agonist at GABAB receptors. Activation of these
receptors by baclofen results in hyperpolarization by three distinct actions: (1) closure of presynaptic calcium channels, (2) increased postsynaptic K+
conductance, and (3) inhibition of dendritic calcium influx channels. Through reduced release of excitatory transmitters in both the brain and the
spinal cord, baclofen suppresses activity of Ia sensory afferents, spinal interneurons, and motor neurons (see Figure 27–10). Baclofen may also reduce
pain in patients with spasticity, perhaps by inhibiting the release of substance P (neurokinin 1) in the spinal cord.
Baclofen is at least as effective as diazepam and tizanidine (discussed below) in reducing spasticity and is less sedating than diazepam. Baclofen does
not reduce overall muscle strength as much as dantrolene. It is rapidly and completely absorbed after oral administration and has a plasma halflife of
3–4 hours.
Chapter 27:Dosage is started
Skeletal MuscleatRelaxants,
15 mg twice daily, increasing
Marieke as tolerated
KruideringHall; LundytoJ.100 mg daily. Studies have confirmed that intrathecal catheter Page 20 / 29
Campbell
administration
©2024 McGrawofHill.
baclofen can control
All Rights severe
Reserved. spasticity
Terms and
of Use muscle Policy
• Privacy pain that is not responsive
• Notice to medication by other routes of administration. Owing
• Accessibility
to the poor egress of baclofen from the spinal cord, peripheral symptoms are rare. Therefore, higher central concentrations of the drug may be
tolerated. Partial tolerance to the effect of the drug may occur after several months of therapy but can be overcome by upward dosage adjustments to
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Baclofen is at least as effective as diazepam and tizanidine (discussed below) in reducing spasticity and is less sedating than diazepam. Baclofen does
not reduce overall muscle strength as much as dantrolene. It is rapidly and completely absorbed after oral administration and has a plasma halflife of
3–4 hours. Dosage is started at 15 mg twice daily, increasing as tolerated to 100 mg daily. Studies have confirmed that intrathecal catheter
administration of baclofen can control severe spasticity and muscle pain that is not responsive to medication by other routes of administration. Owing
to the poor egress of baclofen from the spinal cord, peripheral symptoms are rare. Therefore, higher central concentrations of the drug may be
tolerated. Partial tolerance to the effect of the drug may occur after several months of therapy but can be overcome by upward dosage adjustments to
maintain the beneficial effect. This tolerance was not confirmed in a recent study and decreased response may represent unrecognized catheter
malfunctions. Although a major disadvantage of this therapeutic approach is the difficulty of maintaining the drug delivery catheter in the
subarachnoid space, risking an acute withdrawal syndrome upon treatment interruption, longterm intrathecal baclofen therapy can improve the
quality of life for patients with severe spastic disorders. Adverse effects of highdose baclofen include excessive somnolence, respiratory depression,
and coma. Patients can become tolerant to the sedative effect with chronic administration. Increased seizure activity has been reported in epileptic
patients. Withdrawal from baclofen must be done very slowly. Baclofen should be used with caution during pregnancy; although there are no reports
of baclofen directly causing human fetal malformations, animal studies using high doses show that it causes impaired sternal ossification and
omphalocele.
Oral baclofen has been studied in many other medical conditions, including patients with intractable low back pain, stiff person syndrome, trigeminal
neuralgia, cluster headache, intractable hiccups, tic disorder, gastroesophageal reflux disease, and cravings for alcohol, nicotine, and cocaine (see
Chapter 32). Efficacy of oral baclofen has not been established in patients with stroke, Parkinson disease, or cerebral palsy.
TIZANIDINE
As noted in Chapter 11, α2adrenoceptor agonists such as clonidine and other imidazoline compounds have a variety of effects on the CNS that are not
fully understood. Among these effects is the ability to reduce muscle spasm. Tizanidine is a congener of clonidine that has been studied for its
spasmolytic actions. Tizanidine has significant α2agonist effects, but it reduces spasticity in experimental models at doses that cause fewer
cardiovascular effects than clonidine or dexmedetomidine. Tizanidine has approximately one tenth to one fifteenth of the blood pressurelowering
effects of clonidine. Neurophysiologic studies in animals and humans suggest that tizanidine reinforces both presynaptic and postsynaptic inhibition
in the cord. It also inhibits nociceptive transmission in the spinal dorsal horn. Tizanidine’s actions are believed to be mediated via restoration of
inhibitory suppression of the group II spinal interneurons without inducing any changes in intrinsic muscle properties.
Clinical trials with oral tizanidine report efficacy in relieving muscle spasm comparable to diazepam, baclofen, and dantrolene. Tizanidine causes
markedly less muscle weakness but produces a different spectrum of adverse effects, including drowsiness, hypotension in 16–33%, dizziness, dry
mouth, asthenia, and hepatotoxicity, requiring monitoring of liver function, blood pressure, and renal function. The drowsiness can be managed by
taking the drug at night. Tizanidine displays linear pharmacokinetics, and dosage requirements vary considerably among patients. Treatment is
initiated at 2 mg every 6–8 hours and can be titrated up to a maximum of 36 mg/d. Dosage must be adjusted in patients with hepatic or renal
impairment. Tizanidine is involved in drugdrug interactions; plasma levels increase in response to CYP1A2 inhibition. Conversely, tizanidine induces
CYP11A1 activity, which is responsible for converting cholesterol to pregnenolone. In addition to its effectiveness in spastic conditions, tizanidine also
appears to be effective for management of chronic migraine. Abrupt withdrawal should be avoided because it results in rebound hypertension,
tachycardia, and increased spasms.
OTHER CENTRALLY ACTING SPASMOLYTIC DRUGS
Gabapentin is an antiepileptic drug (see Chapter 24) that has shown considerable promise as a spasmolytic agent in several studies involving patients
with multiple sclerosis. Pregabalin is a newer analog of gabapentin that may also prove useful in relieving painful disorders that involve a muscle
spasm component. Progabide and glycine have also been found in preliminary studies to reduce spasticity. Progabide is a GABAA and GABAB agonist
and has active metabolites, including GABA itself. Glycine is another inhibitory amino acid neurotransmitter (see Chapter 21) that appears to possess
pharmacologic activity when given orally and readily passes the bloodbrain barrier. Idrocilamide and riluzole are newer drugs for the treatment of
amyotrophic lateral sclerosis (ALS) that appear to have spasmreducing effects, possibly through inhibition of glutamatergic transmission in the CNS,
although several other mechanisms have been proposed—such as stabilizing the inactivated state of voltagedependent sodium channels.
BOTULINUM TOXIN
The therapeutic use of botulinum toxin (BoNT) for ophthalmic purposes and for local muscle spasm was mentioned in Chapter 6. This neurotoxin
Downloaded 20241011 7:4and
produces chemodenervation A Your
localIP is 161.53.41.15
paralysis when injected into a muscle. Seven immunologically distinct toxins share homologous subunits. The
singlechain polypeptide BoNT has little activity until Lundy
it is cleaved into J. Campbell
a heavy
Page 21 / 29
chain (100 kDa) and a light chain (50 kDa). The light chain, a zinc
dependent protease, prevents release of acetylcholine by interfering with vesicle fusion, through proteolytically cleaving SNAP*25 (BoNTA, BoNTE) or
synaptobrevin2 (BoNTB, BoNTD, BoNTF). Local facial injections of botulinum toxin are widely used for the shortterm treatment (1–3 months per
amyotrophic lateral sclerosis (ALS) that appear to have spasmreducing effects, possibly through inhibition of glutamatergic transmission in the CNS,
although several other mechanisms have been proposed—such as stabilizing the inactivated state of voltagedependent sodium channels.
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BOTULINUM TOXIN
The therapeutic use of botulinum toxin (BoNT) for ophthalmic purposes and for local muscle spasm was mentioned in Chapter 6. This neurotoxin
produces chemodenervation and local paralysis when injected into a muscle. Seven immunologically distinct toxins share homologous subunits. The
singlechain polypeptide BoNT has little activity until it is cleaved into a heavy chain (100 kDa) and a light chain (50 kDa). The light chain, a zinc
dependent protease, prevents release of acetylcholine by interfering with vesicle fusion, through proteolytically cleaving SNAP*25 (BoNTA, BoNTE) or
synaptobrevin2 (BoNTB, BoNTD, BoNTF). Local facial injections of botulinum toxin are widely used for the shortterm treatment (1–3 months per
treatment) of wrinkles associated with aging around the eyes and mouth. Local injection of botulinum toxin has also become a useful treatment for
generalized spastic disorders (eg, cerebral palsy). Most clinical studies to date have involved administration in one or two limbs, and the benefits
appear to persist for weeks to several months after a single treatment. BoNT has virtually replaced anticholinergic medications used in the treatment of
dystonia. More recently, FDA approval was granted for treatment of incontinence due to overactive bladder and for chronic migraine. Most studies
have used several formulations of type A BoNT, but type B is also available.
Adverse effects include respiratory tract infections, muscle weakness, urinary incontinence, falls, fever, and pain. While immunogenicity is currently of
much less concern than in the past, experts still recommend that injections not be administered more frequently than every 3 months. Studies to
determine safety of more frequent administration are underway. Besides occasional complications, a major limitation of BoNT treatment is its high
cost. In addition, postmarketing reports of systemic and potentially fatal effects from spread of the toxin, generated a black box warning. The risk is
greatest for children treated for spasticity, but toxicity can occur in adults as well.
DANTROLENE
Dantrolene is a hydantoin derivative related to phenytoin that has a unique mechanism of spasmolytic activity. In contrast to the centrally acting drugs,
dantrolene reduces skeletal muscle strength by interfering with excitationcontraction coupling in the muscle fibers. The normal contractile response
involves release of calcium from its stores in the sarcoplasmic reticulum (see Figures 13–1 and 27–10). This activator calcium brings about the tension
generating interaction of actin with myosin. Calcium is released from the sarcoplasmic reticulum via a calcium channel, called the ryanodine
receptor (RyR) channel because the plant alkaloid ryanodine combines with a receptor on the channel protein. In the case of the skeletal muscle
RyR1 channel, ryanodine facilitates the open configuration.
Dantrolene interferes with the release of activator calcium through this sarcoplasmic reticulum calcium channel by binding to the RyR1 and blocking
the opening of the channel. Motor units that contract rapidly are more sensitive to the drug’s effects than are slowerresponding units. Cardiac muscle
and smooth muscle are minimally depressed because the release of calcium from their sarcoplasmic reticulum involves a different RyR channel (RyR2).
Treatment with dantrolene is usually initiated with 25 mg daily as a single dose, increasing to a maximum of 100 mg four times daily as tolerated. Only
about onethird of an oral dose of dantrolene is absorbed, and the elimination halflife of the drug is approximately 8 hours. Major adverse effects are
generalized muscle weakness, sedation, and occasionally hepatitis.
A special application of dantrolene is in the treatment of malignant hyperthermia, a rare heritable disorder that can be triggered by a variety of
stimuli, including general anesthetics (eg, volatile anesthetics) and neuromuscular blocking drugs (eg, succinylcholine; see also Chapter 16). Patients
at risk for this condition have a hereditary alteration in Ca2+induced Ca2+ release via the RyR1 channel or impairment in the ability of the sarcoplasmic
reticulum to sequester calcium via the Ca2+ transporter (see Figure 27–10). Several mutations associated with this risk have been identified. After
administration of one of the triggering agents, there is a sudden and prolonged release of calcium, with massive muscle contraction, lactic acid
production, and increased body temperature. Prompt treatment is essential to control acidosis and body temperature and to reduce calcium release.
The latter is accomplished by administering intravenous dantrolene, starting with a dose of 1 mg/kg IV, and repeating as necessary to a maximum dose
of 10 mg/kg.
ANTISPASMODICS: DRUGS USED TO TREAT ACUTE LOCAL MUSCLE SPASM
A large number of less wellstudied, centrally active drugs (eg, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol,
and orphenadrine)
Downloaded 20241011are promoted forIP
7:4 A Your theisrelief of acute muscle spasm caused by local tissue trauma or muscle strains. It has been suggested that
161.53.41.15
these drugs act primarily at the level of the brainstem. Lundy
Cyclobenzaprine may be regarded as the prototype of the group. Cyclobenzaprine isPage
J. Campbell 22 / 29
structurally
related to the tricyclic antidepressants and produces antimuscarinic side effects. It is ineffective in treating muscle spasm due to cerebral palsy or
spinal cord injury. As a result of its strong antimuscarinic actions, cyclobenzaprine may cause significant sedation, as well as confusion and transient
The latter is accomplished by administering intravenous dantrolene, starting with a dose of 1 mg/kg IV, and repeating as necessary to a maximum dose
of 10 mg/kg.
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ANTISPASMODICS: DRUGS USED TO TREAT ACUTE LOCAL MUSCLE SPASM
A large number of less wellstudied, centrally active drugs (eg, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol,
and orphenadrine) are promoted for the relief of acute muscle spasm caused by local tissue trauma or muscle strains. It has been suggested that
these drugs act primarily at the level of the brainstem. Cyclobenzaprine may be regarded as the prototype of the group. Cyclobenzaprine is structurally
related to the tricyclic antidepressants and produces antimuscarinic side effects. It is ineffective in treating muscle spasm due to cerebral palsy or
spinal cord injury. As a result of its strong antimuscarinic actions, cyclobenzaprine may cause significant sedation, as well as confusion and transient
visual hallucinations. The dosage of cyclobenzaprine for acute injuryrelated muscle spasm is 20–40 mg/d orally in divided doses. This drug class
carries risks of significant adverse events and abuse potential.
SUMMARY Skeletal Muscle Relaxants
Clinical Pharmacokinetics, Toxicities,

Subclass, Drug Mechanism of Action Effects
Applications Interactions
DEPOLARIZING NEUROMUSCULAR BLOCKING AGENT
Succinylcholine Agonist at nicotinic Initial depolarization causes Placement of Rapid metabolism by plasma
acetylcholine (ACh) transient contractions, endotracheal tube at cholinesterase • normal duration
receptors, especially at followed by prolonged start of anesthetic ∼5 min • Toxicities: Arrhythmias •
neuromuscular junctions • flaccid paralysis • procedure • rarely, hyperkalemia • transient increased
depolarizes • may stimulate depolarization is then control of muscle intraabdominal, intraocular
ganglionic nicotinic ACh and followed by repolarization contractions in pressure • postoperative muscle
cardiac muscarinic ACh that is also accompanied by status epilepticus pain
receptors paralysis
NONDEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS
dTubocurarine Competitive antagonist at Prevents depolarization by Prolonged relaxation Renal excretion • duration, ∼40–60
nACh receptors, especially at ACh, causes flaccid paralysis • for surgical min • Toxicities: Histamine release •
neuromuscular junctions can cause histamine release procedures • hypotension • prolonged apnea
with hypotension • weak superseded by newer
block of cardiac muscarinic nondepolarizing
ACh receptors agents
Cisatracurium Similar to tubocurarine Like tubocurarine but lacks Prolonged relaxation Not dependent on renal or hepatic
histamine release and for surgical function • duration ∼25–45 min •
antimuscarinic effects procedures • Toxicities: Prolonged apnea but
relaxation of less toxic than atracurium
respiratory muscles
to facilitate
mechanical
ventilation in
intensive care unit
Rocuronium Similar to cisatracurium Like cisatracurium but slight Like cisatracurium • Hepatic metabolism • duration
antimuscarinic effect useful in patients ∼20–35 min • Toxicities: Like
with renal cisatracurium
impairment
Vecuronium: Intermediate duration; metabolized in liver

ChapterCENTRALLY
27: SkeletalACTING
MuscleSPASMOLYTIC
Relaxants, Marieke
DRUGSKruideringHall; Lundy J. Campbell
Page 23 / 29
Baclofen GABAB agonist, facilitates Pre and postsynaptic Severe spasticity due Oral, intrathecal • Toxicities:
antimuscarinic effect useful in patients ∼20–35 min • Toxicities: Like
with renal cisatracurium University Of Rijeka
impairment Access Provided by:
Vecuronium: Intermediate duration; metabolized in liver
CENTRALLY ACTING SPASMOLYTIC DRUGS
Baclofen GABAB agonist, facilitates Pre and postsynaptic Severe spasticity due Oral, intrathecal • Toxicities:
spinal inhibition of motor inhibition of motor output to cerebral palsy, Sedation, weakness; rebound
neurons multiple sclerosis, spasticity upon abrupt withdrawal

stroke
Diazepam Facilitates GABAergic Increases interneuron Chronic spasm due Hepatic metabolism • duration
transmission in central inhibition of primary motor to cerebral palsy, ∼12–24 h • Toxicities: See Chapter
nervous system (see Chapter afferents in spinal cord • stroke, spinal cord 22
22) central sedation injury • acute spasm
due to muscle injury
Tizanidine α2Adrenoceptor agonist in Pre and postsynaptic Spasm due to Oral • renal and hepatic elimination
the spinal cord inhibition of reflex motor multiple sclerosis, • duration 3–6 h • Toxicities:
output stroke, amyotrophic Weakness, sedation, hypotension,
lateral sclerosis hepatotoxicity (rare), rebound
hypertension upon abrupt
withdrawal
CENTRALLY ACTING ANTISPASMODIC DRUGS
Cyclobenzaprine Poorly understood inhibition Reduction in hyperactive Acute spasm due to Hepatic metabolism • duration, ∼4–
of muscle stretch reflex in muscle reflexes • muscle injury • 6 h • Toxicities: Strong
spinal cord antimuscarinic effects inflammation antimuscarinic effects
Methocarbamol, orphenadrine, others: Like cyclobenzaprine with varying degrees of antimuscarinic effect. Class side effect: strong central nervous
system depression; note carisoprodol is a schedule IV drug.
DIRECTACTING MUSCLE RELAXANTS
Dantrolene Blocks RyR1 Ca2+release Reduces actinmyosin IV: Malignant IV, oral • duration 4–6 h • Toxicities:
channels in the sarcoplasmic interaction • weakens hyperthermia • Oral: Muscle weakness • Black box
reticulum of skeletal muscle skeletal muscle contraction Spasm due to warning: hepatotoxicity
cerebral palsy, spinal
cord injury, multiple
sclerosis
Botulinum toxin Inhibits synaptic exocytosis Flaccid paralysis Upper and lower Direct injection into muscle •
through clipping of vesicle limb spasm due to duration 2–3 months • Toxicities:
fusion proteins in cerebral palsy, Muscle weakness, falls • Black box
presynaptic nerve terminal multiple sclerosis; warning: potential spread of toxin
cervical dystonia, leading to excessive weakness
overactive bladder, reported after use for cerebral
migraine, palsy with spasticity
hyperhidrosis

migraine, palsy with spasticity
hyperhidrosis
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PREPARATIONS AVAILABLE
GENERIC NAME AVAILABLE AS
NEUROMUSCULAR BLOCKING DRUGS
Atracurium Generic
Cisatracurium Generic, Nimbex
Pancuronium Generic
Rocuronium Generic, Zemuron
Succinylcholine Generic, Anectine, Quelicin
Tubocurarine Generic
Vecuronium Generic, Norcuron
REVERSAL AGENTS
Neostigmine Generic
Edrophonium Generic
Sugammadex Bridion
SPASMOLYTICS, ANTISPASMODICS
Baclofen Generic, Gablofen, Lioresal
Botulinum toxin type A Botox, Dysport, Xeomin
Botulinum toxin type B Myobloc
Carisoprodol Generic, Soma
Chlorzoxazone Generic
Cyclobenzaprine Generic, Amrix, Fexmid, Flexeril
Dantrolene Generic, Dantrium, Revonto
Diazepam Generic, Valium, Diastat
Gabapentin Generic, Fanatrex FusePaq, Gabarone, Gralise, Neurontin

Chapter 27: Skeletal
Note: Muscle
This drug Relaxants,
is labeled Marieke
for use only KruideringHall;
in epilepsy Lundy
and postherpetic J. Campbell
neuralgia. Page 25 / 29
Metaxalone Generic, Skelaxin
Dantrolene Generic, Dantrium, Revonto
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Diazepam Generic, Valium, Diastat
Gabapentin Generic, Fanatrex FusePaq, Gabarone, Gralise, Neurontin
Note: This drug is labeled for use only in epilepsy and postherpetic neuralgia.
Metaxalone Generic, Skelaxin
Methocarbamol Generic, Robaxin
Orphenadrine Generic, Antiflex, Banflex, Norflex, Flexoject, Flexon, MioRel, Myolin, Norflex Injectable, Orfro, Orphenate
Riluzole Generic, Rilutek, Tiglutik
Note: This drug is labeled only for use in amyotrophic lateral sclerosis.
Tizanidine Generic, Zanaflex
CASE STUDY ANSWER
This patient presents problems that make her management more difficult than the average. She is at higher risk of difficulty with airway
management because of obesity, and both obesity and diabetes raise the risk of aspiration. Therefore, the decision to use an endotracheal tube for
her airway management is reasonable.
As the case progresses, you are experiencing difficulty with mask ventilation, and the decision to abort the procedure and awaken the patient is
probably the best response. In order to do so, the neuromuscular blockade must be fully reversed so she will be able to breathe on her own once
awakened.
There are two options for reversal of neuromuscular blockade with rocuronium (and with vecuronium): sugammadex, or neostigmine combined
with glycopyrrolate. Sugammadex would be the most appropriate agent. As described in Chapter 7, neostigmine works to increase the level of
acetylcholine at the neuromuscular junction by inhibiting the enzymatic breakdown of acetylcholine. Glycopyrrolate (Chapter 8) is given to block the
bradycardia associated with increased cholinergic activity. However, if the patient is still fully relaxed with rocuronium, neostigmine will not
sufficiently increase acetylcholine to allow full reversal. In contrast, sugammadex actively binds rocuronium and removes it from the neuromuscular
junction. In order to fully reverse an intubating dose of rocuronium, a sugammadex dose of 16 mg/kg should be administered. This will reverse the
effect of rocuronium within 1.5–3.0 minutes. Sugammadex is renally cleared, so it should not be used in patients in renal failure (creatinine
clearance less than 30 mL/min) unless absolutely necessary. This patient has insulindependent diabetes, so her creatinine clearance may be
abnormally low. If this were the case, the benefit of sugammadex would still outweigh its potential risk. In addition, some studies have found that
sugammadex may be dialyzable, and could therefore be removed by that method if needed. This patient is also taking an oral contraceptive agent,
and it would be necessary to counsel her that sugammadex may interfere with the efficacy of that agent and the FDA recommends use of another
method of contraception for the following 7 days. Other issues that may occur with sugammadex use include anaphylaxis, especially when using the
maximum dose of 16 mg/kg, marked bradycardia, hypotension, nausea and vomiting, and headache.
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Chapter 27 - Skeletal Muscle Relaxants

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Katzung’s Basic & Clinical Pharmacology, 16th Edition

Chapter 27: Skeletal Muscle Relaxants

Marieke Kruidering­Hall; Lundy J. Campbell

NEUROMUSCULAR BLOCKING DRUGS

Normal Neuromuscular Function

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BASIC PHARMACOLOGY OF NEUROMUSCULAR BLOCKING DRUGS

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Pharmacokinetics of Neuromuscular Blocking Drugs

A. Nondepolarizing Relaxant Drugs

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A. Nondepolarizing Relaxant Drugs

Clearance Approximate Duration of Action Approximate Potency Relative to

Atracurium Spontaneous1 6.6 20–35 1.5

Cisatracurium Mostly spontaneous 5–6 25–44 1.5

Tubocurarine Kidney (40%) 2.3–2.4 >50 1

Pancuronium Kidney (80%) 1.7–1.8 >35 6

Rocuronium Liver (75–90%) and 2.9 20–35 0.8

Vecuronium Liver (75–90%) and 3–5.3 20–35 6

Succinylcholine Plasma ChE2 (100%) >100 <8 0.4

1Nonenzymatic and enzymatic hydrolysis of ester bonds.

B. Depolarizing Relaxant Drugs

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A. Nondepolarizing Relaxant Drugs

Rocuronium Phase I Phase II

Administration of tubocurarine Additive Antagonistic Augmented1

Administration of succinylcholine Antagonistic Additive Augmented1

Effect of neostigmine Antagonistic Augmented1 Antagonistic

Initial excitatory effect on skeletal muscle None Fasciculations None

Posttetanic facilitation Yes No Yes

Rate of recovery 30–60 min3 4–8 min >20 min3

2The amplitude is decreased, but the response is sustained.

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B. Depolarizing Relaxant Drugs

Rocuronium Phase I Phase II

Administration of tubocurarine Additive Antagonistic Augmented1

Administration of succinylcholine Antagonistic Additive Augmented1

Effect of neostigmine Antagonistic Augmented1 Antagonistic

Initial excitatory effect on skeletal muscle None Fasciculations None

Posttetanic facilitation Yes No Yes

Rate of recovery 30–60 min3 4–8 min >20 min3

2The amplitude is decreased, but the response is sustained.

B. Depolarizing Relaxant Drugs

1 . Phase I block (depolarizing)

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2 . Phase II block (desensitizing)

CLINICAL PHARMACOLOGY OF NEUROMUSCULAR BLOCKING DRUGS

Assessment of Neuromuscular Transmission

A. Nondepolarizing Relaxant Drugs

B. Depolarizing Relaxant Drugs

Atracurium None None Slight

Cisatracurium None None None

Tubocurarine Weak block None Moderate

Pancuronium None Moderate block None

Rocuronium1 None Slight None

Marieke KruideringHall; Lundy J. Campbell

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DIRECTACTING MUSCLE RELAXANTS

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