Basic and Clinical Pharmacology, 13th Ed.

Skeletal Muscle Relaxants

Marieke Kruidering-Hall, PhD,

& Lundy Campbell, MD


A 30-year-old woman is rushed to the emergency department at a major trauma center after a motor vehicle crash. Although in significant pain, she is awake, alert, and able to give a brief history. She states that she was the driver and was wearing a seatbelt. There were no passengers in the car. Her past medical history is significant only for asthma, for which she has been intubated once in the past. She has no allergies to medications. There are multiple lacerations on her face and extremities and a large open fracture of her right femur. An orthopedic surgeon has scheduled immediate operative repair of the femur fracture, and the plastic surgeon wants to suture the facial lacerations at the same time. You decide to intubate the patient for the procedure. What muscle relaxant would you choose? Would you choose the same agent if she had experienced a 30% total body burn in a fire at the time of the accident? What if the past medical history included right-sided hemiparesis of 10 years’ duration?

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). 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, a spasmolytic agent that has no significant central effects and is used primarily to treat a rare anesthetic-related complication, malignant hyperthermia, is also discussed in this chapter.



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, d-tubocurarine, 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/μm*. 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 α-β and δ-α 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 excitation-contraction 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 the one of five subunits of the AChR in the end plate surface of adult mammalian muscle. Each subunit contains four helical domains labeled M1 to 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 α-β and the δ-α 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 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.



All of the available neuromuscular blocking drugs bear a structural resemblance to acetylcholine. For example, succinylcholine is two acetylcholine molecules linked end-to-end (Figure 27–2). In contrast to the single linear structure of succinylcholine and other depolarizing drugs, the nondepolarizing agents (eg, pancuronium) conceal the “double-acetylcholine” structure in one of two types of bulky, semirigid ring systems (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 acetylcholine-like 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 27–4 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 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 half-life. Drugs that are excreted by the kidney typically have longer half-lives, leading to longer durations of action (> 35 minutes). Drugs eliminated by the liver tend to have shorter half-lives and durations of action (Table 27–1). All steroidal muscle relaxants are metabolized to their 3-hydroxy, 17-hydroxy, or 3,17-dihydroxy products in the liver. The 3-hydroxy 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 3-hydroxy metabolite may accumulate and cause prolonged paralysis because it has a longer half-life than the parent compound. The remaining metabolites possess minimal neuromuscular blocking properties.

TABLE 27–1 Pharmacokinetic and dynamic properties of neuromuscular blocking drugs.


The intermediate-acting 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 long-acting steroid-based drugs (eg, pancuronium). The duration of action of these relaxants may be prolonged significantly in patients with impaired liver function.

Atracurium (Figure 27–3) is an intermediate-acting 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 half-life (ie, 150 minutes). It readily crosses the blood-brain 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 L-cysteine. 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 succinylcholine-induced 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 at-risk 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 dibucaine-related 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 receptor-end 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). Top: 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.

A. Nondepolarizing Relaxant Drugs

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 (Figure 27–1) 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 train-of-four (TOF) pattern, four stimuli are applied at 2 Hz. The TOF ratio (TOF-R) is calculated from the strength of the fourth contraction divided by that of the first. In the double-burst 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).


B. Depolarizing Relaxant Drugs

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 contractions of muscle motor units. Data from single-channel 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 excitation-contraction coupling requires end plate repolarization (“repriming”) and repetitive firing to maintain muscle tension, a flaccid paralysis results. In contrast to the nondepolarizing drugs, this so-called phase I (depolarizing) block is augmented, not reversed, by cholinesterase inhibitors.


FIGURE 27–7 Action of succinylcholine on single-channel 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 [Lond] 1990;428:155.)

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 (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) (Figure 27–6), with possible reversal by acetylcholinesterase inhibitors.


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 (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) single-twitch stimulation, (2) train-of-four (TOF) stimulation, and (3) tetanic stimulation. Two other modalities are also available to monitor neuromuscular transmission: double-burst stimulation and posttetanic count.

With single-twitch 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 dose-related 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 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, so-called 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 no-twitch response (by TOF) of about 10–15 minutes (Figure 27–6, bottom panel).

The double-burst 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 single-twitch, 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 double-burst stimulation than to TOF stimulation. The absence of fade in response to double-burst 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.

A. Nondepolarizing Relaxant Drugs

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.

B. Depolarizing 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 tends 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 duration of neuromuscular block typically lasts less than 10 minutes (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 tubocurarine-induced 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 pancuronium-induced 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.


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, ganglionic-blocking 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 dose-dependent 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) (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 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 P-type 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 acetylcholine-induced muscle contractions as a result of blockade of the nicotinic receptor ion channels. Experimentally, similar effects can be demonstrated with sodium channel-blocking 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 plate-depolarizing 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, d-tubocurarine, 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, “pre-curarization” 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 7Neostigmine and pyridostigmineantagonize nondepolarizing neuromuscular ablockade 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 novel reversal agent approved in Europe. It is still in phase 3 clinical trials and not yet approved for use in the USA. Its approval has been delayed over concerns that it may induce coagulopathy and hypersensitivity reactions. Sugammadex is a modified γ-cyclodextrin (a macro-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. Sugammadex will bind to and can reverse effects of other steroidal neuromuscular blockers such as vecuronium and pancuronium, but to a lesser extent.

Clinical trials studying the safety and efficacy of sugammadex have used doses varying between 0.5 and 16 mg/kg. These trials reported no difference in prevalence of untoward effects among sugammadex, placebo, and neostigmine. Currently, three dose ranges are recommended: 2 mg/kg to reverse shallow neuromuscular blockade, 4 mg/kg to reverse profound blockade (1–2 posttetanic count), and 1 mg/kg for immediate reversal following administration of rocuronium. The sugammadex-rocuronium complex is typically excreted unchanged in the urine within 24 hours in patients with normal renal function. In patients with renal insufficiency, complete urinary elimination may take much longer. However, due to the strong complex formation with rocuronium, no signs of recurrence of neuromuscular blockade have been noted up to 48 hours after use in such patients.

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 intra-abdominal 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 blood-brain barrier.


Spasticity may be defined as “disordered sensorimotor control resulting from an upper motor neuron lesion, presenting as intermittent or sustained involuntary activation of muscles.” 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. These conditions often involve abnormal function of the bowel and bladder as well as skeletal muscle. As described by the definition above, the mechanisms underlying clinical spasticity appear to involve not only the stretch reflex arc itself but also higher centers in the CNS (ie, upper motor neuron lesion), with damage to descending pathways in the spinal cord resulting in hyperexcitability of the alpha motor neurons in the cord. 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). The important components involved in these processes are shown in Figure 27–9.


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 edition. McGraw-Hill, 2009. Copyright © The McGraw-Hill Companies, Inc.)

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.

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).


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.


Baclofen (p-chlorophenyl-GABA) was designed to be an orally active GABA-mimetic 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 (see Figure 24–2 and Figure 27–10). 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. 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 in reducing spasticity and causes less sedation. In addition, baclofen does not reduce overall muscle strength as much as dantrolene. It is rapidly and completely absorbed after oral administration and has a plasma half-life of 3–4 hours. Dosage is started at 15 mg twice daily, increasing as tolerated to 100 mg daily. Adverse effects of this drug include drowsiness; however, patients become tolerant to the sedative effect with chronic administration. Increased seizure activity has been reported in epileptic patients. Therefore, 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.

Studies have confirmed that intrathecal 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, long-term intrathecal baclofen therapy can improve the quality of life for patients with severe spastic disorders. Adverse effects of high-dose baclofen include excessive somnolence, respiratory depression, and coma.

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).


As noted in Chapter 11, α2 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 α2-adrenoceptor agonist 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 pressure-lowering 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, dizziness, dry mouth, asthenia, and hepatotoxicity. The drowsiness can be managed by taking the drug at night. Tizanidine displays linear pharmacokinetics, and dosage requirements vary considerably among patients. Dosage must be adjusted in patients with hepatic or renal impairment. Tizanidine is involved in drug-drug 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.


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 blood-brain barrier. Idrocilamide and riluzole are newer drugs for the treatment of amyotrophic lateral sclerosis (ALS) that appear to have spasm-reducing effects, possibly through inhibition of glutamatergic transmission in the CNS.


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 excitation-contraction 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 slower-responding 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 one third of an oral dose of dantrolene is absorbed, and the elimination half-life 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 (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.


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 single-chain 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 (BoNT-A, BoNT-E) or synaptobrevin-2 (BoNT-B, BoNT-D, BoNT-F). Local facial injections of botulinum toxin are widely used for the short-term 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. Future research developing other serotypes such as BoNT-C and BoNT-F is expected to result in the development of new agents that can provide chemodenervation with long-term benefits and at lower cost.


A large number of less well-studied, centrally active drugs (eg, carisoprodol, chlorphenesin, 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 injury-related muscle spasm is 20–40 mg/d orally in divided doses.

*The authors thank Paul F. White, PhD, MD, and Bertram G. Katzung, MD, PhD, for contributions to this chapter in previous editions.

*SNAP, Soluble N-ethylmaleimide sensitive factor Attachment Protein.

SUMMARY Skeletal Muscle Relaxants






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Because of trauma and associated pain, it is assumed that gastric emptying will be significantly delayed. To avoid possible aspiration at the time of intubation, a very rapid-acting muscle relaxant should be used so the airway can be secured with an endotracheal tube. Therefore, succinylcholine is the agent of choice in this case. Despite its adverse effects, succinylcholine has the fastest onset of action of any currently available skeletal muscle relaxant. An alternative to succinylcholine is high-dose (up to 1.2 mg/kg) rocuronium, a nondepolarizing muscle relaxant. At this dose, rocuronium has a very rapid onset, which approaches but does not quite equal that of succinylcholine.

Both burns and neurologic injuries result in the expression of extrajunctional acetylcholine receptors. In patients with recent burns, succinylcholine use can lead to life-threatening hyperkalemia. Although the drug would not result in dangerous hyperkalemia if given immediately after a severe neurologic injury, in a patient with a chronic paralysis, its use may lead to hyperkalemia. Therefore, succinylcholine would also be contraindicated in a patient with long-standing hemiparesis.