Pharmacology of Neuromuscular Blocking Drugs

Key Points

▪
Two different populations of nicotinic acetylcholine receptors exist at the mammalian neuromuscular junction. In the adult, the nicotinic acetylcholine receptor at the postsynaptic (muscular) membrane is composed of α ₂ βδε subunits, while the fetal (immature) receptor is composed of α ₂ βγδ. The presynaptic (neuronal) nicotinic receptor is a pentameric complex composed of α ₃ β ₂ subunits. Each of the two α subunits of the postsynaptic receptors has a ligand (acetylcholine) binding site.
▪
Nondepolarizing muscle relaxants produce neuromuscular blockade by competing with acetylcholine for the postsynaptic α subunits. In contrast, succinylcholine acts directly with the recognition sites and produces prolonged depolarization that results in decreased sensitivity of the postsynaptic nicotinic acetylcholine receptor and inactivation of sodium channels so that propagation of the action potential across the muscle membrane is inhibited.
▪
Different patterns of stimulation examine neuromuscular blockade at different areas of the motor end plate. Depression of the response to single twitch stimulation is likely caused by blockade of postsynaptic nicotinic acetylcholine receptors, whereas fade in the response to tetanic and train-of-four stimuli results from blockade of presynaptic nicotinic receptors.
▪
Succinylcholine is the only available depolarizing neuromuscular blocking drug for clinical use. It is characterized by rapid onset of effect and ultrashort duration of action because of its rapid hydrolysis by butyrylcholinesterase.
▪
Available nondepolarizing neuromuscular blocking drugs can be classified according to chemical class (aminosteroid, benzylisoquinolinium, or other compounds) or by duration of action (long-, intermediate-, and short-acting drugs) of equipotent doses.
▪
The speed of onset is inversely proportional to the potency of nondepolarizing neuromuscular blocking drugs. With the exception of atracurium, molar potency is highly predictive of a drug’s rate of onset of effect. Rocuronium has a molar potency that is approximately 13% that of vecuronium and 9% that of cisatracurium. Its onset of effect is more rapid than either of these muscle relaxants.
▪
Neuromuscular blockade develops faster, lasts a shorter time, and recovers faster in the more centrally located neuromuscular units (e.g., laryngeal adductors, diaphragm, and masseter muscle) than in the more peripherally located adductor pollicis muscle.
▪
Many long-acting neuromuscular blocking drugs undergo minimal or no metabolism, and they are primarily eliminated, largely unchanged, by renal excretion. Neuromuscular blocking drugs of intermediate duration of action have faster distribution and more rapid clearances than the long-acting drugs because of multiple pathways of degradation, metabolism, and elimination. Mivacurium, a short-acting neuromuscular blocking drug, is cleared rapidly and almost exclusively by metabolism by butyrylcholinesterase.
▪
After the administration of nondepolarizing neuromuscular blocking drugs, it is essential to ensure adequate return of normal neuromuscular function using objective (quantitative) means of monitoring. Residual neuromuscular paralysis decreases upper esophageal tone, coordination of the esophageal musculature during swallowing, and hypoxic ventilatory drive. Residual paralysis can increase healthcare costs and the patient hospital length of stay, morbidity, and mortality.

Acknowledgment

The editors and publisher would like to thank Drs. Mohamed Naguib and Cynthia A. Lien for contributing a chapter on this topic in the prior edition of this work. It has served as the foundation for the current chapter.

History and Clinical Use

In 1942, Griffith and Johnson described d -tubocurarine (dTc) as a safe drug to provide skeletal muscle relaxation during surgery. One year later, Cullen described the use of this drug in 131 patients who had received general anesthesia for surgery. In 1954, Beecher and Todd reported a six-fold increase in mortality in patients receiving dTc compared with patients who had not received a muscle relaxant. The increased mortality resulted from a general lack of understanding of the clinical pharmacology and effects of neuromuscular blocking drugs (NMBDs). The effect of residual neuromuscular blockade postoperatively was not appreciated, guidelines for monitoring muscle strength had not been established, and the importance of pharmacologically antagonizing residual blockade was not understood.

Succinylcholine, introduced by Thesleff and Foldes and associates in 1952, rapidly gained widespread use and changed anesthetic practice drastically because the drug’s rapid onset of effect and ultrashort duration of action allowed for both rapid endotracheal intubation and rapid recovery of neuromuscular strength.

In 1967, Baird and Reid reported on the clinical administration of the first synthetic aminosteroid, pancuronium. The development of the intermediate-acting NMBDs was based on the compounds’ metabolism and resulted in the introduction of vecuronium, an aminosteroid, and atracurium, a benzylisoquinolinium, into clinical practice in the 1980s. Vecuronium was the first muscle relaxant to have an intermediate duration of action and minimal cardiovascular actions. Mivacurium, the first short-acting nondepolarizing NMBD, was introduced into clinical practice in the 1990s, as was rocuronium, an intermediate-acting NMBD with a very rapid onset of neuromuscular blockade. Other NMBDs have been introduced into clinical practice since the use of dTc was first advocated. These include pipecuronium, doxacurium, cisatracurium, and rapacuronium. Although not all remain in clinical use today, each represented an advance or improvement in at least one aspect over its predecessors. Still other NMBDs, such as CW 002 ¹¹ and CW 1759-50 are undergoing investigation.

NMBDs should be administered only to anesthetized individuals to provide relaxation of skeletal muscles. Because this class of drugs lacks analgesic or amnestic properties, NMBDs should not be administered to prevent patient movement. Awareness during surgery and in the intensive care unit (ICU) has been described in multiple publications. As stated by Cullen and Larson, “muscle relaxants given inappropriately may provide the surgeon with optimal [operating] conditions in…a patient [who] is paralyzed but not anesthetized—a state that [is] wholly unacceptable for the patient.” Additionally, “muscle relaxants used to cover up deficiencies in total anesthetic management…represent an…inappropriate use of the valuable adjuncts to anesthesia.” Administration of NMBDs intraoperatively to maintain neuromuscular block requires that the time course of block be monitored and the depth of anesthesia be assessed continuously.

NMBDs have been integrated into most anesthetic techniques for major surgery and have become key components in the continuous improvement of safe anesthetic practice and the development of advanced surgical techniques. As earlier stated by Foldes and colleagues, “…[the] first use of…muscle relaxants…not only revolutionized the practice of anesthesia but also started the modern era of surgery and made possible the explosive development of cardiothoracic, neurologic, and organ transplant surgery.” Certainly, NMBDs are now used routinely to facilitate endotracheal intubation and mechanical ventilation, and are commonly used to maintain neuromuscular blockade through any number of different surgical procedures. This chapter reviews the pharmacology and clinical use of NMBDs and anticholinesterases in anesthesia and intensive care settings.

Principles of Action of Neuromuscular Blocking Drugs at the Neuromuscular Junction

A brief description of the physiology of neuromuscular blockade is presented in this chapter. A more comprehensive overview is provided in Chapter 12 .

Postjunctional Effects

Nicotinic acetylcholine receptors (nAChRs) belong to a large pentameric family of ligand-gated ion channel receptors that include the 5-hydoxytryptamine ₃ (5-HT ₃ ), glycine, and γ-aminobutyric acid (GABA) receptors. They are synthetized in muscle cells and anchored to the end plate membrane by a special protein called rapsyn. Development of innervation in the first weeks of life leads to the replacement of the γ subunit by ε subunit. In adult mammalian skeletal muscle, the nAChR is a pentameric complex of two α subunits in association with single β, δ, and ε subunits ( Fig. 27.1 ). Stoichiometrically, the receptor is represented as α2βεδ, while organizationally it is αεαδβ.

Fig. 27.1, Subunit composition of the nicotinic acetylcholine receptor (nAChR) in the end plate surface of adult mammalian muscle. The adult AChR is an intrinsic membrane protein with five distinct subunits (α 2 βδε) . Each subunit contains four helical domains, labeled M 1 to M 4 . The M 2 domain forms the channel pore. The upper panel shows a single α subunit with its N and C termini on the extracellular surface of the membrane lipid bilayer. Between the N and C termini, the α subunit forms four helices (M 1 , M 2 , M 3 , and M 4 ), which span the membrane bilayer. The lower panel shows the pentameric structure of the nAChR of adult mammalian muscle. The N termini of two subunits cooperate to form two distinct binding pockets for acetylcholine. These pockets occur at the ε-α and the δ-α subunit interface. The M 2 membrane-spanning domain of each subunit lines the ion channel. The doubly liganded ion channel has equal permeability to sodium (Na) and potassium (K) ; calcium (Ca) contributes approximately 2.5% to the total permeability.

The subunits are organized to form a transmembrane pore, or channel, as well as extracellular binding pockets for acetylcholine and other agonists or antagonists. The receptors are clustered on the crests of the junctional folds; the receptor density in this area is 10,000 to 30,000/μm ² . Each of the two α subunits has an acetylcholine-binding site. These sites are located in pockets within the receptor protein, approximately 3.0 nm above the surface membrane at the interfaces of the α _H -ε and α _L -δ subunits. αH and αL indicate the high- and low-affinity binding sites for dTc; the difference in affinity probably results from the contribution of the different neighboring subunits.18 For instance, the binding affinity of dTc for the αH-ε site is approximately 100 to 500 times higher than that for the αL-δ site. The fetal nAChR contains a γ subunit instead of an adult ε subunit. Once activated by acetylcholine, the mature nAChR has a shorter opening time and a higher conductance to sodium (Na ⁺ ), potassium (K ⁺ ), and calcium (Ca ²⁺ ) than the fetal nAChR, which has a smaller, single-channel conductance and a much longer open channel time.

Functionally, the ion channel of the acetylcholine receptor is closed in the resting state. Simultaneous binding of two acetylcholine molecules to the α subunits is required to initiate conformational changes that open the channel. If one molecule of a nondepolarizer NMBD (i.e., a competitive antagonist) is bound to a subunit at the AChR, two agonist molecules of acetylcholine cannot bind simultaneously, and neuromuscular transmission is inhibited.

Succinylcholine, a depolarizing NMBD, produces prolonged depolarization of the end plate region, which is similar to, but more persistent than, the depolarization induced by acetylcholine. This mechanism results in (1) desensitization of the nAChR, (2) inactivation of voltage-gated Na ⁺ channels at the neuromuscular junction, and (3) increases in K ⁺ permeability in the surrounding membrane. The end results are failure of action potential generation and neuromuscular blockade.

The fetal nAChR is a low-conductance channel, in contrast to the high-conductance channel of the adult nAChR and upregulation of nAChRs found in states of functional or surgical denervation is characterized by the spreading of predominantly fetal-type nAChRs. These receptors are resistant to nondepolarizing NMBDs and are more sensitive to succinylcholine.

Prejunctional Effects

Prejunctional receptors are involved in the modulation of acetylcholine release in the neuromuscular junction. The existence of both nicotinic and muscarinic receptors on the motor nerve endings has been described. Prejunctional nicotinic receptors are activated by acetylcholine and function in a positive-feedback control system, which could mediate mobilization of the reserve store into the readily releasable store in case of high-frequency stimulation; this mobilization serves to maintain availability of acetylcholine when demand for it is high (e.g., during tetanic stimulation). These presynaptic receptors are α ₃ β ₂ neuronal subtype receptors. Although most nondepolarizing NMBDs have a distinct affinity for the α ₃ β ₂ cholinergic receptor, succinylcholine lacks this affinity. The action of nondepolarizing versus depolarizing NMBDs at this neuronal cholinergic receptor explains the typical fade phenomenon after any nondepolarizing drugs, and the lack of such effect in the clinical dose range for succinylcholine. The G-protein–coupled muscarinic receptors also are involved in the feedback modulation of acetylcholine release.24 The prejunctional M1 and M2 receptors are involved in facilitation and inhibition of acetylcholine release, respectively, by modulating Ca2+ influx. The prejunctional nicotinic receptors are involved with mobilization of acetylcholine but not directly with its release process. Hence, blockade of the prejunctional nicotinic receptors by nondepolarizing NMBDs prevents acetylcholine from being made available fast enough to support tetanic or train-of-four (TOF) stimulation. In contrast, the prejunctional muscarinic receptors are involved with up-modulation or down-modulation of the release mechanism.

Pharmacology of Succinylcholine

Structure-Activity Relationships

All NMBDs contain quaternary ammonium compounds and as such are structurally closely related to acetylcholine. Positive charges at the quaternary ammonium sites of NMBDs mimic the quaternary nitrogen atom of acetylcholine and are the structural reason for the attraction of these drugs to muscle- and neuronal-type nAChRs at the neuromuscular junction. These receptors are also located at other sites throughout the body where acetylcholine is the transmitter. These sites include the neuronal-type nicotinic receptors in autonomic ganglia and as many as five different muscarinic receptors on both the parasympathetic and sympathetic sides of the autonomic nervous system. In addition, populations of neuronal nicotinic and muscarinic receptors are located prejunctionally at the neuromuscular junction.

The depolarizing NMBD, succinylcholine, is composed of two molecules of acetylcholine linked through the acetate methyl groups ( Fig. 27.2 ). As described by Bovet, succinylcholine is a small, flexible molecule, and like the natural ligand acetylcholine, succinylcholine stimulates cholinergic receptors at the neuromuscular junction and muscarinic autonomic sites, thus opening the ionic channel in the acetylcholine receptor.

Fig. 27.2, Structural relationship of succinylcholine, a depolarizing neuromuscular blocking drug, and acetylcholine. Succinylcholine consists of two acetylcholine molecules linked through the acetate methyl groups. Like acetylcholine, succinylcholine stimulates nicotinic receptors at the neuromuscular junction.

Pharmacokinetics and Pharmacodynamics

Succinylcholine is the only available NMBD with a rapid onset of effect and an ultrashort duration of action. The ED ₉₅ (the dose causing on average 95% suppression of neuromuscular response) of succinylcholine is 0.51 to 0.63 mg/kg. Using cumulative dose-response techniques, Kopman and coworkers estimated that its potency is far greater, and it has an ED ₉₅ of less than 0.3 mg/kg.

Administration of 1 mg/kg of succinylcholine results in complete suppression of response to neuromuscular stimulation in approximately 60 seconds. In patients with genotypically normal butyrylcholinesterase (also known as plasma cholinesterase or pseudocholinesterase), recovery to 90% muscle strength following administration of 1 mg/kg succinylcholine requires 9 to 13 minutes.

The ultrashort duration of action of succinylcholine results from its rapid hydrolysis by butyrylcholinesterase to succinylmonocholine and choline. Butyrylcholinesterase has a large enzymatic capacity to hydrolyze succinylcholine, and only 10% of the intravenously administered drug reaches the neuromuscular junction. The initial metabolite, succinylmonocholine, is a much weaker NMBD than succinylcholine and is metabolized much more slowly to succinic acid and choline. The elimination half-life of succinylcholine is estimated to be 47 seconds.

Because little or no butyrylcholinesterase is present at the neuromuscular junction, the neuromuscular blockade induced by succinylcholine is terminated by its diffusion away from the neuromuscular junction into the circulation. Butyrylcholinesterase therefore influences the onset and duration of action of succinylcholine by controlling the rate at which the drug is hydrolyzed before it reaches, and after it leaves, the neuromuscular junction.

Butyrylcholinesterase Activity

Butyrylcholinesterase is synthesized by the liver and found in the plasma. The neuromuscular blockade induced by succinylcholine is prolonged when the concentration or activity of the enzyme is decreased. The activity of the enzyme refers to the number of substrate molecules (μmol) hydrolyzed per unit of time, and it is often expressed in International Units. Because the normal range of butyrylcholinesterase activity is quite large, significant decreases in activity result in only modest increases in the time required to return to 100% of baseline muscle strength ( Fig. 27.3 ).

Factors that lower butyrylcholinesterase activity include liver disease, advanced age, malnutrition, pregnancy, burns, oral contraceptives, monoamine oxidase inhibitors, echothiophate, cytotoxic drugs, neoplastic disease, anticholinesterase drugs, tetrahydroaminacrine, hexafluorenium, and metoclopramide. Bambuterol, a prodrug of terbutaline, produces marked inhibition of butyrylcholinesterase activity and causes prolongation of succinylcholine-induced blockade. The β-blocker esmolol inhibits butyrylcholinesterase but causes only a minor prolongation of succinylcholine-induced blockade.

Decreased butyrylcholinesterase enzyme activity is not a major concern in clinical practice because even large decreases in butyrylcholinesterase activity result in only modest increases in the duration of action of succinylcholine. Even when butyrylcholinesterase activity is reduced to 20% of normal by severe liver disease, the duration of apnea after the administration of succinylcholine increases from a normal duration of 3 minutes to only 9 minutes. When glaucoma treatment with echothiophate decreased butyrylcholinesterase activity from 49% of control to no activity, the increase in the duration of neuromuscular blockade varied from 2 to 14 minutes. In no patient did the total duration of neuromuscular blockade exceed 23 minutes.

Dibucaine Number and Atypical Butyrylcholinesterase Activity

Succinylcholine-induced neuromuscular blockade can be significantly prolonged if a patient has an abnormal genetic variant of butyrylcholinesterase. Kalow and Genest discovered a variant that responded to dibucaine differently than it did to normal butyrylcholinesterase. Dibucaine inhibits normal butyrylcholinesterase to a far greater extent than the abnormal enzyme. This observation led to the establishment of the dibucaine number. Under standardized test conditions, dibucaine inhibits the normal enzyme by approximately 80% and the abnormal enzyme by approximately 20% ( Table 27.1 ). Many other genetic variants of butyrylcholinesterase have since been identified, although the dibucaine-resistant variants are the most important. A review by Jensen and Viby-Mogensen provides more detailed information on this topic.

Table 27.1

Relationship Between Dibucaine Number and Duration of Succinylcholine or Mivacurium Neuromuscular Blockade

Type of Butyrylcholinesterase	Genotype	Incidence	Dibucaine Number ∗	Response to Succinylcholine or Mivacurium
Homozygous typical	E ₁ ^u E ₁ ^u	Normal	70-80	Normal
Heterozygous atypical	E ₁ ^u E ₁ ^a	1/480	50-60	Lengthened by 50%-100%
Homozygous atypical	E ₁ ^a E ₁ ^a	1/3200	20-30	Prolonged to 4-8 h

∗ The dibucaine number indicates the percentage of enzyme inhibited.

Although the dibucaine number indicates the genetic makeup of an individual with respect to butyrylcholinesterase, it does not measure the concentration of the enzyme in the plasma substrate. This is determined by measuring butyrylcholinesterase activity in plasma, and it may be influenced by comorbidities, medications, and genotype.

The molecular biology of butyrylcholinesterase is well understood. The amino acid sequence of the enzyme is known, and the coding errors responsible for most genetic variations have been identified. Most variants result from a single amino acid substitution error or sequencing error at or near the active site of the enzyme. For example, in the case of the “atypical” dibucaine-resistant (A) gene, a mutation occurs at nucleotide 209, where guanine is substituted for adenine. The resultant change in this codon causes substitution of glycine for aspartic acid at position 70 in the enzyme. In the case of the fluoride-resistant (F) gene, two amino acid substitutions are possible, namely, methionine for threonine at position 243, and valine for glycine at position 390. Table 27.1 summarizes many of the known genetic variants of butyrylcholinesterase: the amino acid substitution at position 70 is written as Asp ∅ Gly. New variants of butyrylcholinesterase genotypes continue to be discovered.

Side Effects

Cardiovascular Effects

Succinylcholine-induced cardiac dysrhythmias are many and varied. The drug stimulates cholinergic autonomic receptors on both sympathetic and parasympathetic ganglia and muscarinic receptors in the sinus node of the heart. At low doses, both negative inotropic and chronotropic responses may occur. These responses can be attenuated by prior administration of atropine. With large doses of succinylcholine, these effects may become positive, causing tachycardia. The clinical manifestation of generalized autonomic stimulation is the development of sinus bradycardia, junctional rhythms, and ventricular dysrhythmias. Clinical studies have described these dysrhythmias under various conditions in the presence of the intense autonomic stimulus of tracheal intubation. It is not entirely clear whether the cardiac irregularities are caused by the action of succinylcholine alone or by the added presence of extraneous autonomic stimulation. An in vitro study using ganglionic acetylcholine receptors subtype α ₃ β ₄ expressed in Xenopus laevis oocytes suggested that succinylcholine at clinically relevant concentrations had no effect on the expressed receptors. Only high doses of succinylcholine caused inhibition of ganglionic acetylcholine receptors. Whether or not these findings are applicable to clinical practice is unclear because the methodology ( X. laevis oocytes expression model) has no clinical equivalent.

Sinus Bradycardia

Stimulation of cardiac muscarinic receptors in the cardiac sinus node causes sinus bradycardia. This side effect is particularly problematic in individuals with predominantly vagal tone, such as in children who have not received atropine. Sinus bradycardia can occur in adults and appears more commonly after a second dose of the drug administered approximately 5 minutes after the initial dose. The bradycardia may be prevented by administration of atropine, ganglion-blocking drugs, and nondepolarizing NMBDs. The ability of these drugs to prevent bradycardia implies that direct myocardial effects, increased muscarinic stimulation, and ganglionic stimulation may all be involved in the bradycardic response. The greater incidence of bradycardia after a second dose of succinylcholine suggests that the hydrolysis products of succinylcholine (succinylmonocholine and choline) may sensitize the heart to a subsequent dose.

Nodal (Junctional) Rhythms

Nodal rhythms occur commonly following administration of succinylcholine. The mechanism responsible for this likely involves relatively greater stimulation of muscarinic receptors in the sinus node, thus suppressing the sinus mechanism and allowing the emergence of the atrioventricular node as the pacemaker. The incidence of junctional rhythm is greater after a second dose of succinylcholine, and may be prevented by prior administration of dTc.

Ventricular Dysrhythmias

Under stable anesthetic conditions, succinylcholine decreases the threshold of the ventricle to catecholamine-induced dysrhythmias in monkeys and dogs. Circulating catecholamine concentrations increase fourfold, and K ⁺ concentrations increase by one third, following succinylcholine administration in dogs. Similar increases in catecholamine levels occur following administration of succinylcholine to humans. Other autonomic stimuli, such as endotracheal intubation, hypoxia, hypercarbia, and surgery, may be additive to the effect of succinylcholine. The possible influence of drugs such as digitalis, tricyclic antidepressants, monoamine oxidase inhibitors, exogenous catecholamines, and anesthetic drugs such as halothane, which may lower the ventricular threshold for ectopic activity or increase the arrhythmogenic effect of the catecholamines, should also be considered. Ventricular escape beats may also occur as a result of severe sinus bradycardia and atrioventricular nodal slowing secondary to succinylcholine administration. The incidence of ventricular dysrhythmias is further increased by the release of K ⁺ from skeletal muscle as a consequence of the depolarizing action of the drug.

Hyperkalemia

The administration of succinylcholine to an otherwise healthy individual increases the plasma K ⁺ levels by approximately 0.5 mEq/dL. This slight increase in K ⁺ is well tolerated by most individuals and generally does not cause dysrhythmias. The increase in K ⁺ results from the depolarizing action of succinylcholine. With activation of the acetylcholine channels, movement of Na ⁺ into the cells is accompanied by movement of K ⁺ out of the cells.

Patients with renal failure are no more susceptible to an exaggerated response to succinylcholine than are those with normal renal function. Patients who have uremic neuropathy may possibly be susceptible to succinylcholine-induced hyperkalemia, although the evidence supporting this view is scarce.

However, severe hyperkalemia may follow the administration of succinylcholine to patients with severe metabolic acidosis and hypovolemia. In experimental animals (rabbit), the combination of metabolic acidosis and hypovolemia results in a high resting K ⁺ level and an exaggerated hyperkalemic response to succinylcholine. In this situation, the K ⁺ originates from the gastrointestinal tract, rather than from muscle. In patients with metabolic acidosis and hypovolemia, correction of the acidosis by hyperventilation and sodium bicarbonate administration should be attempted before succinylcholine administration. Should severe hyperkalemia occur, it can be treated with immediate hyperventilation, infusion of 500-1,000 mg calcium chloride or calcium gluconate over 3 minutes intravenously, and 10 units of regular insulin in 50 mL of 50% glucose for adults or, for children, 0.15 units/kg of regular insulin in 1.0 mL/kg of 50% glucose intravenously.

Kohlschütter and associates found that four of nine patients with severe abdominal infections had an increase in serum K ⁺ levels of as much as 3.1 mEq/L after succinylcholine administration. The likelihood of a hyperkalemic response to succinylcholine increases in patients who have had intraabdominal infections for longer than 1 week.

Stevenson and Birch described a single, well-documented case of a marked hyperkalemic response to succinylcholine in a patient with a closed head injury without peripheral paralysis.

Hyperkalemia after administration of succinylcholine is also a risk in patients who have had physical trauma. The risk of hyperkalemia occurs 1 week after the injury, at which time a progressive increase in serum K ⁺ occurs during an infusion of succinylcholine. The risk of hyperkalemia can persist. Three weeks after injury, three of the patients studied in this series, who had especially severe injuries, became markedly hyperkalemic with an increase in serum K ⁺ of more than 3.6 mEq/L. Birch and coworkers also found that the prior administration of 6 mg of dTc prevented the hyperkalemic response to succinylcholine. In the absence of infection or persistent degeneration of tissue, a patient is likely susceptible to the hyperkalemic response for at least 60 days after massive trauma or until adequate healing of damaged muscle has occurred.

Additionally, patients with conditions that result in the proliferation of extrajunctional acetylcholine receptors, such as upper or lower motor denervation, immobilization, burn injuries, and neuromuscular disease, are likely to have an exaggerated hyperkalemic response following the administration of succinylcholine. The response of patients with neuromuscular disease to NMBDs is reviewed in detail later in this chapter. Some of these disease states include cerebrovascular accident with resultant hemiplegia or paraplegia, muscular dystrophies, and Guillain-Barré syndrome. The hyperkalemia following administration of succinylcholine may be severe enough that cardiac arrest ensues. For a review of succinylcholine-induced hyperkalemia in acquired pathologic states, see Martyn and Richtsfeld.

Increased Intraocular Pressure

Succinylcholine may cause an increase in intraocular pressure (IOP). The increased IOP develops within 1 minute of injection, peaks at 2 to 4 minutes, and subsides by 6 minutes. The mechanism by which succinylcholine increases IOP has not been clearly defined, but it is known to involve contraction of tonic myofibrils and/or transient dilatation of choroidal blood vessels. Sublingual administration of nifedipine may attenuate the increase in IOP caused by succinylcholine, a finding suggesting a circulatory mechanism. Despite this increase in IOP, the use of succinylcholine for eye operations is not contraindicated unless the anterior chamber is open. Although Meyers and colleagues were unable to confirm the efficacy of small (0.09 mg/kg) doses of dTc (“precurarization”) in attenuating increases in IOP following succinylcholine, numerous other investigators have found that prior administration of a small dose of nondepolarizing NMBD (e.g., 3 mg of dTc or 1 mg of pancuronium) prevents a succinylcholine-induced increase in IOP. Furthermore, Libonati and associates described the anesthetic management of 73 patients with penetrating eye injuries who received succinylcholine. Among these 73 patients, no extrusion of vitreous occurred. Thus, despite the potential concerns, the use of succinylcholine in patients with penetrating eye injuries, after pretreatment with a nondepolarizing NMBD and with a carefully controlled rapid-sequence induction of anesthesia, can be considered. Succinylcholine is only one of many factors that may increase IOP. Other factors include endotracheal intubation and “bucking” on the endotracheal tube once it is positioned. Of prime importance in minimizing the chance of increasing IOP is ensuring that the patient is well anesthetized and is not straining or coughing. For instance, coughing, vomiting and maximal forced lid closure may induce increases in intraocular pressure that are 3-4 times greater (60-90 mm Hg) than those induced by succinylcholine administration. Because a nondepolarizing NMBD with a rapid onset of effect, rocuronium, is available, it is possible to perform a rapid sequence induction of anesthesia and endotracheal intubation without administering succinylcholine. Finally, should a patient become too lightly anesthetized during intraocular surgery, succinylcholine should not be given to immobilize the patient. Rather, the surgeon should be asked to pause while anesthesia is deepened. If necessary, the depth of neuromuscular blockade can also be increased with nondepolarizing NMBDs.

Increased Intragastric Pressure

Unlike the rather consistent increase in IOP following administration of succinylcholine, increases in intragastric pressure (IGP) are much more variable. The increase in IGP from succinylcholine is presumed to result from fasciculations of the abdominal skeletal muscle. This is not surprising because more coordinated abdominal skeletal muscle activity (e.g., straight-leg raising) may increase the IGP to values as high as 120 cm H ₂ O (88 mm Hg). In addition to skeletal muscle fasciculations, the acetylcholine-like effect of succinylcholine may be partly responsible for the observed increases in IGP. Greenan observed consistent increases in IGP of 4 to 7 cm H ₂ O (3-5 mm Hg) with direct vagal stimulation.

Miller and Way found that 11 of 30 patients had essentially no increase in IGP after succinylcholine administration, yet 5 of the 30 had an increase in IGP of greater than 30 cm H ₂ O (22 mm Hg). The increase in IGP from succinylcholine appeared to be related to the intensity of the fasciculations of the abdominal skeletal muscles. Accordingly, when fasciculations were prevented by prior administration of a nondepolarizing NMBD, no increase in IGP was observed.

Whether the increases in IGP following succinylcholine administration are sufficient to cause incompetence of the gastroesophageal junction are debatable. Generally, an IGP greater than 28 cm H ₂ O (21 mm Hg) is required to overcome the competence of the gastroesophageal junction. However, when the normal oblique angle of entry of the esophagus into the stomach is altered, as may occur with pregnancy or an abdomen distended by ascites, bowel obstruction, or a hiatus hernia, the IGP required to cause incompetence of the gastroesophageal junction is frequently less than 15 cm H ₂ O (11 mm Hg). In these circumstances, regurgitation of stomach contents following succinylcholine administration is a distinct possibility, and precautionary measures should be taken to prevent fasciculations. Endotracheal intubation may be facilitated with administration of either a nondepolarizing NMBD or a defasciculating dose of nondepolarizing relaxant before succinylcholine use. Although the increase in IGP from succinylcholine is well documented, the evidence of clinical harm is not clear.

Succinylcholine does not increase IGP appreciably in infants and children. This may be related to the minimal or absent fasciculations from succinylcholine in these young patients.

Increased Intracranial Pressure

Succinylcholine has the potential to increase intracranial pressure. The mechanisms and clinical significance of this transient increase are unknown, but pretreatment with nondepolarizing NMBDs prevents intracranial pressure increases.

Myalgia

The incidence of muscle pain following administration of succinylcholine varies widely, from 0.2% to 89%. Muscle pain occurs more frequently after minor surgery, especially in women and in ambulatory, rather than bedridden, patients. Waters and Mapleson postulated that pain is secondary to damage produced in muscle by the unsynchronized contractions of adjacent muscle fibers just before the onset of paralysis. This concept has been substantiated by finding myoglobinemia and increases in serum creatine kinase following succinylcholine administration. Prior administration of a small (“defasciculating”) dose of a nondepolarizing NMBD clearly prevents fasciculations from succinylcholine. The efficacy of this approach in preventing muscle pain is not clear; however, most investigators report that pretreatment with a nondepolarizing NMBD has minimal effect. Pretreatment with a prostaglandin inhibitor (e.g., lysine acetyl salicylate) has been shown effective in decreasing the incidence of muscle pain after succinylcholine. This finding suggests a possible role for prostaglandins and cyclooxygenases in succinylcholine-induced myalgias. Other investigators have found that myalgias following outpatient laparoscopic surgery (and atracurium administration) occur even in the absence of succinylcholine. Other investigators reported a significant reduction in postoperative myalgia in elective oral surgery patients pretreated with rocuronium (20%) compared with vecuronium (42%) and placebo (70%).

Masseter Muscle Rigidity

An increase in tone of the masseter muscle is a frequent response to succinylcholine in adults as well as in children. Several studies have reported that an increase in masseter muscle tone of up to 500 g lasting 1 to 2 minutes is a normal finding in adults. Most cases of the so-called masseter muscle rigidity (MMR) may represent simply the extreme of a spectrum of muscle tension changes that occur in response to succinylcholine. Meakin and associates suggested that the high incidence of spasm in children may result from inadequate dosage of succinylcholine. In all likelihood, this increase in tone is an exaggerated contractile response at the neuromuscular junction and cannot be used to establish a diagnosis of malignant hyperthermia. Although an increase in tone of the masseter muscle may be an early indicator of malignant hyperthermia, this finding is not consistently associated with that syndrome. Currently, no indication exists to change to a “nontriggering” anesthetic technique in instances of isolated MMR.

Anaphylaxis

There is some controversy concerning the incidence of anaphylaxis following succinylcholine. The incidence of anaphylactic reactions may be close to 0.06%. Almost all cases of anaphylaxis have been reported in Europe or Australia. When the muscle relaxant cross-links with IgE, degranulation and release of histamine, neutrophil chemotactic factor, and platelet-activating factor occur. The release of these mediators can induce cardiovascular collapse, bronchospasm, and skin reaction. Patients with a history of anaphylactic reaction to succinylcholine may exhibit a cross-reaction, at least in vitro, with other NMBDs. The cross-reactivity is related to the common structural features of these drugs, all of which contain quaternary ammonium ions.

Clinical Uses

In spite of its many adverse effects, succinylcholine remains in clinical use. Its popularity is likely the result of its rapid onset of effect, the profound depth of neuromuscular blockade it produces, and its short duration of action. Succinylcholine is not used as regularly as in the past for routine endotracheal intubation, but it is still a muscle relaxant frequently used for rapid-sequence induction of anesthesia and tracheal intubation. Although 1.0 mg/kg of succinylcholine is recommended to facilitate endotracheal intubation at 60 seconds, as little as 0.5 to 0.6 mg/kg may result in adequate intubating conditions 60 seconds after administration. Reduction in the succinylcholine dose from 1.0 to 0.6 mg/kg decreases the incidence of hemoglobin desaturation but does not shorten the time to spontaneous diaphragmatic movements. Decreasing the dose of succinylcholine is appealing as long as it does not interfere with provision of adequate conditions for endotracheal intubation and subsequent adequate ventilation.

Typically, after administering succinylcholine for tracheal intubation, a nondepolarizing NMBD is given to maintain neuromuscular blockade. Prior administration of succinylcholine enhances the depth of blockade caused by a subsequent dose of nondepolarizing NMBD. However, the effect on duration of action is variable. Succinylcholine has no effect on the duration of pancuronium, but it increases the duration of atracurium and rocuronium. The reasons for these differences are not clear.

With administration of large doses of succinylcholine, the nature of the block, as determined by a monitor of neuromuscular blockade, changes from that of a depolarizing drug (phase 1 block) to that of a nondepolarizing drug (phase 2 block). Clearly, both the dose and the duration of administration of succinylcholine contribute to this change. The relative contribution of each factor has not been established, however.

Posttetanic potentiation and fade in response to TOF and tetanic stimuli can be demonstrated after bolus administration of different doses of succinylcholine. It seems that some characteristics of phase 2 blockade are evident from an initial dose (i.e., as small as 0.3 mg/kg) of succinylcholine. Fade in response to TOF stimulation has been attributed to the presynaptic effects on NMBDs. The etiology of the appearance of fade phenomenon in the TOF response following excessive administration of succinylcholine has been suggested to be dependent on a concentration-dependent affinity for succinylcholine to the presynaptic α ₃ β ₂ neuronal subtype AChR in concentrations exceeding the normal clinical concentration range seen after routine doses.

Interactions With Anticholinesterases

Neostigmine and pyridostigmine inhibit butyrylcholinesterase, as well as acetylcholinesterase. If succinylcholine is administered after antagonism of residual neuromuscular block, as it may be with postextubation laryngospasm, the effect of succinylcholine will be pronounced and significantly prolonged. The effect of succinylcholine (1 mg/kg) was prolonged from 11 to 35 minutes when it was given 5 minutes after administration of neostigmine (5 mg). Ninety minutes after neostigmine administration, butyrylcholinesterase activity will have returned to less than 50% of its baseline value.

Nondepolarizing Neuromuscular Blocking Drugs

The use of NMBDs in anesthesia has its origin in the arrow poisons or curares of South American Indians. Several nondepolarizing NMBDs were purified from naturally occurring sources. For example, dTc can be isolated from the Amazonian vine Chondodendron tomentosum . Similarly, the intermediates for the production of metocurine and alcuronium, which are semisynthetic, are obtained from Chondodendron and Strychnos toxifera . Malouetine, the first steroidal NMBD, was originally isolated from Malouetia bequaertiana , which grows in the jungles of the Democratic Republic of Congo in central Africa. The NMBDs pancuronium, vecuronium, pipecuronium, rocuronium, rapacuronium, atracurium, doxacurium, mivacurium, cisatracurium, gantacurium, and gallamine are all synthetic compounds.

Available nondepolarizing NMBDs can be classified according to chemical class, based on structure (steroids, benzylisoquinoliniums, fumarates, and other compounds), or, alternatively, according to onset or duration of action (long-, intermediate-, and short-acting drugs) of equipotent doses ( Table 27.2 ).

Table 27.2

Classification of Nondepolarizing Neuromuscular Blockers According to Duration of Action (Time to T1 = 25% of Control) after Twice the Dose Causing on Average 95% Suppression of Neuromuscular Response

	Clinical Duration
	Long-acting (>50 min)	Intermediate-acting (20-50 min)	Short-acting (10-20 min)	Ultrashort-acting (<10 min)
Steroidal compounds	Pancuronium	Vecuronium Rocuronium
Benzylisoquinolinium compounds	d -Tubocurarine	Atracurium Cisatracurium	Mivacurium
Asymmetric mixed-onium fumarates		CW 002		Gantacurium

Most nondepolarizing neuromuscular blockers are bisquaternary ammonium compounds. d -Tubocurarine, vecuronium, and rocuronium are monoquaternary compounds.

T1, First twitch of train-of-four.

Structure-Activity Relationships

Nondepolarizing NMBDs were originally classified by Bovet as pachycurares, or bulky molecules having the amine functions incorporated into rigid ring structures. Two extensively studied chemical series of synthetic nondepolarizing NMBDs are the aminosteroids, in which the interonium distance is maintained by an androstane skeleton, and the benzylisoquinolinium series, in which the distance is maintained by linear diester-containing chains or, in the case of curare, by benzyl ethers. For a detailed account on structure-activity relationships, see Lee.

Benzylisoquinolinium Compounds

dTc is an NMBD in which the amines are present in the form of two benzyl substituted tetrahydroisoquinoline structures ( Fig. 27.4 ). Using nuclear magnetic resonance spectroscopy and methylation–demethylation studies, Everett and associates demonstrated that dTc contains three N -methyl groups. One amine is quaternary (i.e., permanently charged with four nitrogen substituents), and the other is tertiary (i.e., pH-dependent charge with three nitrogen substituents). At physiologic pH, the tertiary nitrogen is protonated so that it is positively charged. The structure-activity relationships of the bis-benzylisoquinolines (see Fig. 27.4 ) have been described by Waser and by Hill and associates, and these relationships are as follows:

1.
The nitrogen atoms are incorporated into isoquinoline ring systems. This bulky molecule favors a nondepolarizing rather than a depolarizing activity.
2.
The interonium distance (distance between charged amines) is approximately 1.4 nm.
3.
Both the ganglion-blocking and the histamine-releasing properties of dTc probably result from the presence of the tertiary amine function.
4.
When dTc is methylated at the tertiary amine and at the hydroxyl groups, the result is metocurine, a compound of greater potency (by a factor of two in humans) with much weaker ganglion-blocking and histamine-releasing properties than dTc (see Fig. 27.4 ). Metocurine contains three additional methyl groups, one of which quaternizes the tertiary nitrogen of dTc; the other two form methyl ethers at the phenolic hydroxyl groups.
5.
Bisquaternary compounds are more potent than their monoquaternary analogues. The bisquaternary derivative of dTc, chondocurine, is more than twice as potent as dTc (see Fig. 27.4 ).
6.
Substitution of the methyl groups on the quaternary nitrogen with bulkier groups causes a reduction in both potency and duration of action.

Fig. 27.4, Chemical structures of d -tubocurarine, metocurine, and chondocurine.

Atracurium is a bis-benzyltetrahydroisoquinolinium with isoquinolinium nitrogens connected by a diester-containing hydrocarbon chain ( Fig. 27.5 ). The presence (in duplicate) of two-carbon separations between quaternary nitrogen and ester carbonyl renders it susceptible to the Hofmann elimination reaction. The compound can also undergo ester hydrolysis. In a Hofmann elimination reaction, a quaternary ammonium group is converted into a tertiary amine through cleavage of a carbon-nitrogen bond. This is a pH- and temperature-dependent reaction in which higher pH and temperature favor elimination.

Fig. 27.5, Chemical structures of atracurium, cisatracurium, mivacurium, and doxacurium. The asterisk indicates the chiral centers; arrows show cleavage sites for Hofmann elimination.

Atracurium has 4 chiral centers at each of the chiral carbons adjacent to the two amines. It is composed of 10 isomers. These isomers have been separated into three geometric isomer groups that are designated cis-cis , cis-trans , and trans-trans according to their configuration about the tetrahydroisoquinoline ring system. The ratio of the cis-cis , cis-trans , and trans-trans isomers is approximately 10:6:1, corresponding to 50% to 55% cis-cis , 35% to 38% cis-trans , and 6% to 7% trans-trans isomers.

Cisatracurium, the 1R cis– 1′R cis isomer of atracurium, comprises approximately 15% of atracurium by weight but more than 50% in terms of neuromuscular blocking activity (see Fig. 27.5 ). R designates the absolute stereochemistry of the benzyl tetrahydroisoquinoline rings, and cis represents the relative geometry of the bulky dimethoxy and 2-alkyester groups at C(1) and N(1), respectively. Like atracurium, cisatracurium undergoes Hofmann elimination. It is approximately four times as potent as atracurium, and in contrast to atracurium, it does not cause histamine release, thus indicating that histamine release may be stereospecific.

Mivacurium differs from atracurium by the presence of an additional methylated phenolic group (see Fig. 27.5 ). Compared with other isoquinolinium NMBDs, the interonium chain of mivacurium is longer (16 atoms). Mivacurium consists of a mixture of three stereoisomers. The two most active are the trans-trans and cis-trans isomers (57% and 37% weight/weight, respectively), which are equipotent; the cis-cis isomer (6% weight/weight) has only one tenth the neuromuscular blocking activity of the more potent isomers in cats and monkeys. Mivacurium is metabolized by butyrylcholinesterase to a monoester and a dicarboxylic acid at 70% to 88% the rate at which succinylcholine is metabolized by the same enzyme.

Steroidal Neuromuscular Blockers

For the steroidal compounds to have neuromuscular blocking potential, it is likely that one of the compound’s two nitrogen atoms be quaternized. The presence of an acetyl ester (acetylcholine-like moiety) facilitates their interaction with nAChRs at the postsynaptic muscle membrane.

Pancuronium is characterized by the presence of two acetyl ester groups on the A and D rings of the steroidal molecule. Pancuronium is a potent NMBD with vagolytic properties. It is also an inhibitor of butyrylcholinesterase ( Fig. 27.6 ). Deacetylation at the 3 or 17 positions decreases its potency.

Fig. 27.6, Chemical structures of different steroidal neuromuscular blockers.

Vecuronium, in which the 2-piperidine substituent is not methylated, is the N -demethylated derivative of pancuronium (see Fig. 27.6 ). At physiologic pH, the tertiary amine is largely protonated, as it is in dTc. The minor molecular modification results in the following: (1) a slight increase in the potency when compared with pancuronium; (2) a marked reduction in its vagolytic properties; (3) molecular instability in solution; and (4) increased lipid solubility, which results in a greater biliary elimination of vecuronium than pancuronium.

Vecuronium is degraded by the hydrolysis of the acetyl esters at the C3 and the C17 positions. Hydrolysis at the C3 position is the primary degradation pathway because the acetate at the 3 position is more susceptible to hydrolysis in aqueous solutions than the acetate at the 17 position. This is because of the adjacent basic piperidine at the 2 position that facilitates hydrolysis of the 3-acetate. Therefore vecuronium cannot be prepared as a ready-to-use solution with a sufficient shelf life, even as a buffered solution. In contrast, the 2-piperidine of pancuronium is quaternized and no longer alkaline and therefore does not facilitate hydrolysis of the 3-acetate.

Rocuronium lacks the acetyl ester that is found in the A ring of the steroid nucleus of pancuronium and vecuronium (see Fig. 27.6 ). The introduction of cyclic substituents other than piperidine at the 2 and 16 positions results in a compound with a more rapid onset of effect than vecuronium or pancuronium. The methyl group attached to the quaternary nitrogen of vecuronium and pancuronium is replaced by an allyl group in rocuronium. As a result of this change, rocuronium is approximately 6 and 10 times less potent than pancuronium and vecuronium, respectively. The replacement of the acetyl ester attached to the A ring by a hydroxy group means that rocuronium is stable in solution. At room temperature, rocuronium is stable for 60 days. In contrast, pancuronium is stable for 6 months. The reason for this difference in shelf life is related to the fact that rocuronium is terminally sterilized in manufacturing, and pancuronium is not. Terminal sterilization causes some degree of degradation.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here