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.
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 .
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.
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 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
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.
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 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.
|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|
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.
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.
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.
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.
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.
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.
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.
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 ).
|Long-acting (>50 min)||Intermediate-acting (20-50 min)||Short-acting (10-20 min)||Ultrashort-acting (<10 min)|
|Steroidal compounds||Pancuronium||Vecuronium |
|Benzylisoquinolinium compounds||d -Tubocurarine||Atracurium |
|Asymmetric mixed-onium fumarates||CW 002||Gantacurium|
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.
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:
The nitrogen atoms are incorporated into isoquinoline ring systems. This bulky molecule favors a nondepolarizing rather than a depolarizing activity.
The interonium distance (distance between charged amines) is approximately 1.4 nm.
Both the ganglion-blocking and the histamine-releasing properties of dTc probably result from the presence of the tertiary amine function.
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.
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 ).
Substitution of the methyl groups on the quaternary nitrogen with bulkier groups causes a reduction in both potency and duration of action.
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.
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.
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.
Asymmetric Mixed-Onium Fumarates and Analogues
These compounds share some structural properties with mivacurium. Gantacurium and CW 002 represent a new class of bisquaternary nondepolarizing NMBDs ( Fig. 27.7 ). Gantacurium, an asymmetric mixed-onium chlorofumarate, is unique among nondepolarizing compounds in terms of its rapid onset of effect, its short duration of action, and its unique means of inactivation. Because of the presence of three methyl groups between the quaternary nitrogen and oxygen atom at each end of the carbon chain, this compound does not undergo Hofmann elimination.
Gantacurium has an ultrashort duration of action in human volunteers and in different animal species. In human volunteers receiving a nitrous oxide–opioid anesthetic, the ED 95 of gantacurium is 0.19 mg/kg. Onset of and recovery from block resemble those of succinylcholine. Following administration of approximately 2.5 times the ED 95 dose, onset of maximal block occurs in 1.5 minutes. Spontaneous recovery to a TOF of 0.9 or greater occurs 10 minutes after administration of an ED 95 dose, and complete spontaneous recovery occurs in 14 to 15 minutes after administration of doses ranging from 2 to 3.5 times the ED 95 . Recovery is accelerated by administration of edrophonium at the beginning of spontaneous recovery. Transient hypotension and tachycardia occur following administration of doses three times the ED 95 and greater, a finding suggesting that histamine release occurs with administration of these doses.
Gantacurium appears to undergo two pathways of inactivation. One is a slower ester hydrolysis, and the second one, which occurs much more quickly, occurs through the adduction of cysteine, a nonessential amino acid, to create a new compound that can no longer bind to the nAChR of the neuromuscular junction. This unique means of inactivation likely accounts for the drug’s ultrashort duration of effect. It also provides a novel means of shortening recovery from gantacurium-induced neuromuscular block. Administration of l -cysteine (10 mg/kg) 1 minute after administration of gantacurium results in rapid return to complete neuromuscular function within 1 to 2 minutes.
An analogue of the asymmetric fumarate gantacurium, CW 002 has been synthesized to undergo slower l -cysteine adduction. Because of its slower metabolism, it has an intermediate duration of action. In animals, it causes a nondepolarizing block that can be antagonized by neostigmine. Administration of l -cysteine 1 minute after administration of CW 002 effectively speeds recovery of neuromuscular function, whereas neostigmine does not. Volunteer trials are required to determine whether onset, recovery, and ease of antagonism are improved over those using compounds that are currently available.
CW 011 (an asymmetrical maleate) is a nonhalogenated olefinic diester analogue of gantacurium that can undergo l -cysteine adduction in animal models. Because this adduction reaction is slower than that of gantacurium, its duration of neuromuscular block is longer (approximately 21 minutes). Exogenous l -cysteine (50 mg/kg) administration can induce full recovery of neuromuscular block (after five times ED 95 dose of CW 011) in 2 to 3 minutes.
The clinical development of gantacurium was suspended in 2006, but since then, several other compounds similar to gantacurium have been tested. CW 1759-50 is a fast-onset, ultrashort-acting NMBA that is devoid of histaminoid side effects in animal testing. 11a,11b CW 1759-50 is ultrashort acting because it is inactivated by plasma l -cysteine. Spontaneous recovery (5%-95% interval) from either bolus or infusion was similar (5-6 minutes), and reversal by l -cysteine required about 2 minutes.
Potency of Nondepolarizing Neuromuscular Blocking Drugs
Drug potency is commonly expressed by the dose-response relationship. The dose of an NMBD required to produce an effect (e.g., 50%, 90%, or 95% depression of baseline twitch height, commonly expressed as ED 50 , ED 90 , and ED 95 , respectively) defines its potency. The NMBDs have different potencies, as illustrated in Table 27.3 and Fig. 27.8 . For factors affecting the potency of NMBDs, see the section on drug interactions later in this chapter. The dose-response relationship for nondepolarizing NMBDs is sigmoidal (see Fig. 27.8 ) and has been derived in various ways. The simplest method is to perform linear regression over the approximately linear portion of a semilogarithmic plot between 25% and 75% neuromuscular blockade. Alternatively, the curve can be subjected to probit or logit transformation to linearize it over its whole length, or the data can be subjected to nonlinear regression using the sigmoid E max model of this form:
|ED 50 (mg/kg)||ED 90 (mg/kg)||ED 95 (mg/kg)||References|
|Pancuronium||0.036 (0.022-0.042)||0.056 (0.044-0.070)||0.067 (0.059-0.080)||98, 103|
|d -Tubocurarine||0.23 (0.16-0.26)||0.41 (0.27-0.45)||0.48 (0.34-0.56)||103|
|Rocuronium||0.147 (0.069-0.220)||0.268 (0.200-0.419)||0.305 (0.257-0.521)||98, 104-106|
|Vecuronium||0.027 (0.015-0.031)||0.042 (0.023-0.055)||0.043 (0.037-0.059)||103|
|Atracurium||0.12 (0.08-0.15)||0.18 (0.19-0.24)||0.21 (0.13-0.28)||103|
|Cisatracurium||0.026 (0.015-0.031)||—||0.04 (0.032-0.05)||107-109, 371|
|Mivacurium||0.039 (0.027-0.052)||—||0.067 (0.045-0.081)||9, 110-112|
More complex models relating the concentration of NMBDs at the neuromuscular junction to their pharmacologic effect have been developed, and are discussed later.
Factors that govern duration of action of NMBDs.
There is ample evidence that potent NMBDs have slower onset times than less potent drugs with similar physicochemical properties. These facts can be explained by the concept of the margin of safety. A critical number of receptors at the neuromuscular junction must be occupied before appearance of neuromuscular block, and at least 90% of the receptors must be occupied before block is complete at the adductor pollicis. When the drug reaches the synaptic cleft, most molecules will bind to receptors that are present with a high density. As the concentration of free drug decreases, more molecules are driven in and the process will continue until the concentrations of free drug within and outside the synaptic cleft are equal. When a potent drug is administered, fewer molecules are given than in a case of a less potent drug, and the onset will be slower compared to onset of lower potency NMBD. Nondepolarizing NMBDs of low potency (e.g., rocuronium) have more molecules to diffuse from the central compartment into the effect compartment. Once in the effect compartment, all molecules act promptly. Weaker binding of the low-potency drugs to receptors prevents buffered diffusion, a process that occurs with more potent drugs. Buffered diffusion causes repetitive binding and unbinding to receptors, thus keeping potent drugs in the neighborhood of the effector sites and potentially lengthening the duration of effect. This phenomenon is probably what contributes to the slower onset time for cisatracurium than atracurium. However, for very short-acting drugs, the ideal ED 95 might be greater (0.5-1.0 mg/kg) because rapid metabolism in the plasma destroys some of the administered muscle relaxant before it reaches the neuromuscular junction. This phenomenon can explain the relatively slow onset time for mivacurium.
Plasma concentrations have only modest influence on onset time. Arterial plasma concentrations peak 25 to 35 seconds after administration, thus before onset of neuromuscular block. This paradox can be explained by assuming that the site of action, the neuromuscular junction, is represented by the effect compartment in which the concentration of the NMBD is directly related to the magnitude of neuromuscular blockade. The rate constant for transfer into the effect compartment is similar for most intermediate duration action NMBDs and corresponds approximately to neuromuscular junction blood flow divided by neuromuscular junction/plasma partition coefficient. Whatever muscle relaxant, the limiting factor appears to be the time required for the drug to reach the neuromuscular junction, which in turn depends on cardiac output, the distance of the muscle (and neuromuscular junction) from the central circulation, and muscle blood flow. Therefore in most cases, the onset time will be dependent on blood flow to muscle. Under normal circumstances, muscle blood flow increases when cardiac output increases, with a direct relationship between speed of onset and cardiac output. This may explain why infants and children have a faster onset of neuromuscular block, and elderly patients have a slower onset than younger individuals.
It is obvious that the intensity of maximum blockade is affected directly by the administered dose. However, when the dose increases in the subparalyzing range (that is, when maximum blockade is between 0% and 100%), time to reach maximum effect is dose-independent. This is because the time to peak concentration at the effect compartment is independent of the dose. When the administered dose, however, is sufficient to effect complete disappearance of neuromuscular response, time to maximum blockade becomes dose-dependent.
Duration of Action
Although it is commonly believed that the rate of decline of NMBD plasma concentrations during recovery from neuromuscular blockade determines the duration of action and the rate of recovery, further explanations are needed. It has been suggested that muscle blood flow is, to a certain extent, a limiting factor in the termination of action. For long-acting NMBDs, the dominant effect for the recovery from neuromuscular blockade is the rate of decrease of plasma concentration because there is pseudo-equilibrium between concentrations at the neuromuscular junction and plasma. Therefore changing blood flow will not affect the duration of action. For intermediate duration of action NMBD, after a single bolus dose, plasma concentrations decrease at a rate that differs slightly from the equilibrium half-life with muscle. It can induce a significant concentration gradient between neuromuscular junction and plasma during recovery, but provided that recovery rate is constant, the ratio of concentrations between the neuromuscular junction and plasma will remain relatively constant.
The most important factor is that the rate of decline of plasma concentration during recovery is not always related to the NMBD terminal half-life because after initial administration, plasma concentrations will decrease because of redistribution. It is only when redistribution will be complete that the decrease in plasma concentrations will be dependent on the terminal half-life and will decrease more slowly. For long-acting NMBD such as pancuronium, the recovery time will take place during the terminal half-life. In this situation the duration of action will be dependent on the rate of decrease of plasma concentrations. This is different for intermediate duration of action NMBDs. The terminal half-life of atracurium is around 20 minutes, whereas the elimination half-lives of both vecuronium and rocuronium are between 60 and 120 minutes. Although such differences can be observed, the duration of action and recovery from neuromuscular block of these three drugs are very similar. These apparent discrepancies can be explained by the fact that the distribution phase is the most important factor and extends for a much longer period than for long-acting NMBDs. If their duration of action and recovery rates are almost identical, it is due to the decrease of plasma concentrations to levels compatible with recovery during the redistribution phase.
The main goal of neuromuscular blockade during induction of anesthesia includes paralysis of the vocal cords and muscles of the jaw to facilitate endotracheal intubation. Relaxation of the respiratory muscles, particularly the diaphragm, allows controlled ventilation. Paralysis of the abdominal muscles and the diaphragm is often required intraoperatively, particularly during abdominal, robotic, or laparoscopic surgery. During recovery from neuromuscular block, restoration of complete neuromuscular strength is essential to ensure adequate spontaneous ventilation with normal regulation of breathing during hypoxia and the patency of the musculature of the upper airway with maintained airway protection. The choice of the initial dose of NMBD, timing of readministration of NMBD, timing of administration of anticholinesterase, and interpretation of monitoring require an understanding of the varying sensitivities of different muscle groups to NMBDs.
Although the practice of administering an NMBD to facilitate tracheal intubation may be routine, it has been suggested that the combination of propofol with a rapid-acting opioid may provide good to excellent intubating conditions in most patients. However, relatively large doses of opioids are required to obtain satisfactory intubating conditions. Mencke and coworkers demonstrated that adding atracurium to a propofol-fentanyl induction regimen significantly improved the quality of intubating conditions and decreased the frequency of vocal cord lesions following intubation from 42% to 8%. The rate of postoperative hoarseness was also significantly decreased to 16% from 44%. Combes and associates confirmed that the use of NMBD for tracheal intubation decreased the incidence of adverse postoperative upper airway symptoms, resulted in better intubating conditions, and also reduced the rate of adverse hemodynamic effects caused by deeper levels of anesthesia. Patients intubated without an NMBD had three to four times more Cormack scores of 3 to 4, and difficult intubation was more common (12% vs. 1%). In a cohort of more than 100,000 patients, Lundstrom and colleagues demonstrated that avoidance of NMBD was associated with more difficult tracheal intubation conditions compared with NMBD use, with an odds ratio of 1.5. A recent Cochrane review supported the use of an NMBD (vs. avoidance of NMBD) in order to create the best intubating conditions.
Several alternative approaches are available to enhance surgical relaxation when administration of additional NMBDs may be inappropriate. These options include increasing the depth of general anesthesia with a drug such as a volatile anesthetic or propofol, administering lidocaine, using regional anesthesia, positioning the patient properly on the operating table, and appropriately adjusting the depth of neuromuscular blockade. The choice of one or several of these options is determined by the estimated remaining duration of surgery, the anesthetic technique, and the surgical maneuver required. Importantly, the single best (and only) method to ensure appropriate dosing and timing of additional NMBD is assessment of the depth of neuromuscular block by objective (quantitative) means.
It is important to keep these options in mind to avoid relying on only neuromuscular blockade to achieve a desired degree of surgical relaxation.
Varying Sensitivities of Different Muscle Groups
The sensitivity of the neuromuscular junctions to the effects of neuromuscular relaxants among various muscle groups varies greatly. Paton and Zaimis demonstrated in 1951 that some of the muscles of respiration, such as the diaphragm, were more resistant to curare than others. The dose of nondepolarizing NMBDs needed to block the diaphragm is 1.5 to 2 times that of the adductor pollicis. Thus complete paralysis of the diaphragm is not expected with doses of NMBDs used to block neuromuscular transmission at the adductor pollicis. Similarly, the laryngeal adductor muscles are more resistant to nondepolarizing NMBDs than the more peripheral muscles such as the adductor pollicis, at which all dosing recommendations for NMBDs and their antagonists have been made. The sparing effect of NMBDs on the laryngeal adductor muscles has been documented with vecuronium, rocuronium, cisatracurium, and mivacurium. Plaud and colleagues studied the pharmacokinetic-pharmacodynamic relationship of NMBDs at the adductor pollicis and the laryngeal adductors. These investigators found that the concentration in the effect compartment producing 50% of the maximum block was significantly greater at the laryngeal adductor muscles (1.5 μg/mL) than that at the adductor pollicis muscle (0.8 μg/mL). Convincing evidence indicates that the EC 50 for almost all drugs is 50% to 100% higher at the diaphragm or larynx than it is at the adductor pollicis. These differences may be caused by any of several factors. Waud and Waud found that following curare administration, neuromuscular transmission occurs when approximately 18% of the receptors are free at the diaphragm, whereas it does not occur at the peripheral muscles unless 29% of receptors are free. The reason may be higher receptor density, greater release of acetylcholine, or less acetylcholinesterase activity. The lower density of acetylcholine receptors in slow muscle fibers, such as found in the peripheral muscles, explains, in part, the lower margin of safety for neuromuscular transmission when compared with that in the faster muscle fibers in the laryngeal adductors. Muscle sensitivity to succinylcholine is different from that of other NMBDs. Succinylcholine is the only muscle relaxant that, at equipotent doses, causes greater neuromuscular block at the vocal cords than at the adductor pollicis. Some data suggest that in contrast to nondepolarizing NMBDs, succinylcholine is more effective in blocking the muscles composed of primarily fast-contracting fibers.
In spite of the relative resistance to NMBDs, the onset of neuromuscular block is significantly faster at the diaphragm and the laryngeal adductors than at the adductor pollicis. Fisher and associates postulated that more rapid equilibration (shorter effect site equilibration half-life [ t ½ k e0 ]) of the NMBD between plasma and the effect compartment at these more centrally located muscles was the explanation for this observation. The accelerated rate of equilibrium probably represents little more than differences in regional blood flow. Therefore muscle blood flow (i.e., the rate of drug delivery to the tissue), rather than a drug’s intrinsic potency, may be more important in determining the onset and offset time of nondepolarizing NMBDs. Greater blood flow per gram of muscle at the diaphragm or larynx results in delivery of a higher peak plasma concentration of drug in the brief period of time before rapid redistribution occurs. Plaud and colleagues confirmed this hypothesis by demonstrating a faster transfer rate constant (i.e., t ½ k e0 ) at the laryngeal adductors (2.7 minutes) than at the adductor pollicis (4.4 minutes). Greater resistance to neuromuscular blockade accounts for the faster recovery of the respiratory muscles and the muscles of the abdominal wall than at the adductor pollicis muscle. Recovery occurs more rapidly because blood concentration of the NMBD must decrease more in the muscles of respiration than in the adductor pollicis for recovery of neuromuscular function to begin.
In contrast, the muscles of the upper airway are particularly sensitive to the effects of muscle relaxants. The masseter is 15% more sensitive to nondepolarizing NMBDs than is the adductor pollicis. Significant weakness of the muscles of the upper airway may exist even when strength at the adductor pollicis has recovered almost to baseline values. A TOF ratio less than 0.9 at the adductor pollicis (with a calibrated neuromuscular monitor) is associated with impaired pharyngeal function, reduced resting tone in the upper esophageal sphincter muscle, and decreased coordination of the muscles involved in swallowing, all of which cause an increased incidence of misdirected swallows, or aspiration. Because of the resistance of the diaphragm and laryngeal muscles to neuromuscular block, patients may be weak in pharyngeal muscle groups while being able to breathe as long as an endotracheal tube is in place. Once the trachea is extubated, however, patients may not be able to maintain a patent airway or protect their airway. This is likely the reason that patients with a TOF less than 0.9 in the postanesthesia care unit (PACU) are more likely to develop critical respiratory events than those whose TOF ratio is 0.9 or greater. Some investigators have demonstrated that among patients who received NMBD, those who did not receive reversal were more than twice as likely to develop pneumonia after surgery.
The increase in ventilation during hypoxia is mainly governed by afferent neuronal input from peripheral chemoreceptors of the carotid body. Acetylcholine is involved in the transmission of afferent neuronal activity from the carotid body to the central nervous system (CNS). Eriksson and associates have shown that partial neuromuscular block (TOF ratio of 0.7) reduces specifically the ventilatory responses to isocapnic hypoxia without altering the response to hypercapnia. The ventilatory response to hypoxia returns to control values after recovery of a TOF ratio to above 0.9. The mechanism behind this interaction seems to be a spontaneous, reversible depression of carotid body chemoreceptor activity during hypoxia.
General Dosage Guidelines
Proper selection of the dose of nondepolarizing NMBD and quantitative monitoring are required to ensure that the desired effect is achieved without overdose of the relaxant ( Tables 27.4 and 27.5 ).
|Dosage For Relaxation|
|ED 95 Under N 2 O/O 2||Dose for Intubation||Supplemental Dose after Intubation||N 2 O||Anesthetic Vapors ∗|
|Continuous Infusion Dosage ( μ g/kg/min) Required to Maintain 90%-95% Twitch Inhibition Under N 2 O/O 2 With Intravenous Agents|
∗ The potentiation of nondepolarizing relaxants by different anesthetic vapors has been reported to vary from 20% to 50%. More recent data suggest, however, that this variation may be much less, particularly in the case of the intermediate- and short-acting relaxants. Therefore for the sake of simplicity, this table assumes a potentiation of 40% in the case of all volatile anesthetics.
|Anesthesia||Intubating Dose (mg/kg)||Approximate ED 95 Multiples||Maximum Block (%)||Time to Maximum Block (min)||Clinical Duration ∗ (min)||References|
|Succinylcholine||Opioids or halothane||0.5||1.7||100||—||6.7||372|
|Succinylcholine||Opioids or halothane||1.0||2||100||—||11.3||372|
|BENZYLISOQUINOLINIUM COMPOUNDS †|
The intensity of maximum blockade is directly affected by dose. If a small dose of NMBD is administered, neuromuscular block may not occur because the amount administered is inadequate to overcome the margin of safety at the neuromuscular junction. When doses lower than those required to cause 100% neuromuscular blockade are administered, the time required to reach maximum effect is a function of the NMBD and blood flow to the muscles. It is independent of the dose administered. However, if the administered dose is high enough to cause 100% neuromuscular blockade, the time required for maximum block will depend on the dose of NMBD administered. Larger doses will, up to a certain point, produce a faster onset of effect. Increasing the dose of NMBD beyond that point will not further decrease the time to onset of maximal effect, and may significantly prolong the total duration of neuromuscular blockade, contributing to residual postoperative paralysis.
In addition to a general knowledge of the pharmacodynamics and pharmacokinetics of NMBDs and understanding of the guidelines for dosing, optimal practice requires that dosing be adjusted to account for variability in individual patients’ responses to NMBDs. This adjustment cannot be made without using a quantitative (objective) monitor of neuromuscular blockade any time that an NMBD is administered to a patient. Overdosage must be avoided for several reasons: to limit the duration of drug effect so that it matches the anticipated length of surgery; to avoid unwanted cardiovascular side effects associated with large NMBD doses; and to minimize residual neuromuscular block postoperatively.
Initial and Maintenance Dosage
The initial dose of NMBD is determined by the reason for administration. Traditionally, doses used to facilitate tracheal intubation are twice the ED 95 (see Table 27.4 ). If, however, the trachea has been intubated without the use of an NMBD and the purpose in administering an NMBD is to produce surgical relaxation, a dose that is slightly less than the ED 95 (see Table 27.5 ) may be sufficient in most surgical settings. Administration of NMBDs solely for surgical relaxation does not prevent vocal cord injury and postoperative hoarseness caused by intubation without NMBD. Additionally, ensuring maximal neuromuscular block by using quantitative means (e.g., a TOF count of zero) rather than being guided by clinical judgment will result in less hemodynamic instability during laryngoscopy and better intubating conditions. Administering a smaller initial dose may be sufficient in the presence of any of the potent inhalational anesthetics (see the later section on drug interactions), but the dosing should always be guided by quantitative monitoring.
To avoid prolonged residual paralysis, inadequate antagonism of residual blockade, or both, the main goal in dosing NMBDs should be to use the lowest possible dose that provides adequate relaxation for surgery. Moreover, clinical management of individual patients should be guided by monitoring of the neuromuscular block, ideally with an objective neuromuscular monitoring technique, to allow safe intraoperative administration of the NMBD and its antagonism by neostigmine or sugammadex (see also Chapter 43 , Neuromuscular Monitoring).
In an adequately anesthetized and monitored patient, little reason exists to abolish the TOF responses to peripheral nerve stimulation completely. However, if deep levels of block are required to maintain paralysis of the diaphragm and the abdominal wall muscles, response of the adductor pollicis to stimulation of the ulnar nerve may disappear. In this case, monitoring the depth of neuromuscular block can be accomplished using the posttetanic count (PTC) at the adductor pollicis or TOF ratio at the corrugator supercilii. Supplemental (maintenance) doses of NMBDs should be approximately one tenth (in case of long-acting NMBDs) to one fourth (in the case of intermediate- and short-acting NMBDs) the initial dose and should not be given until quantitative evidence of beginning recovery from the previous dose is present.
Relaxation can be maintained by continuous infusion of intermediate- and short-acting drugs. This approach is useful in maintaining a stable depth of neuromuscular blockade and allows adjustment of the depth of relaxation according to surgical needs. The depth of neuromuscular blockade maintained is moderate, if possible, to ensure complete spontaneous recovery of neuromuscular function at the end of a surgical procedure or prompt antagonism of residual effects. Suggested definitions of the depth of neuromuscular block are listed in Table 27.6 . Table 27.4 lists the approximate dose ranges that are typically required during infusions to maintain 90% to 95% blockade of the twitch (one twitch visible on TOF stimulation) during a nitrous oxide–oxygen anesthetic supplemented with intravenous anesthetics. Infusion dosage is usually decreased by 30% to 50% in the presence of potent volatile anesthetics.
|Depth of Block||Posttetanic Count||Train-of-Four Count||Subjective Train-of-Four Ratio||Measured Train-of-Four Ratio|
|Intense (profound) block||0||0||0||0|
|Light (shallow) block||NA||4||Fade present||0.1-0.4|
|Minimal block (near recovery)||NA||4||No fade||>0.4 but <0.90|
|Full recovery (normal function)||NA||4||No fade||≥0.90-1.0|
Neuromuscular Blocking Drugs and Tracheal Intubation
Rapid onset of neuromuscular blockade is one of the requirements for securing an airway promptly. It is affected by several factors, including muscle blood flow, rate of delivery of the drug to the neuromuscular junction, receptor affinity, plasma clearance of the NMBD, and the mechanism of neuromuscular blockade (depolarizing vs. nondepolarizing) (see Table 27.5 and Fig. 27.9 ). Onset time decreases as ED 50 increases. When a potent NMBD is administered, fewer molecules are administered than in the case of an equipotent dose of a less potent drug. Because of this lower concentration gradient, more time is required for sufficient molecules of a potent drug to be delivered to the neuromuscular junction. Thus onset time is longer. This concept was verified by Kopman and colleagues, who demonstrated that, when giving equipotent doses of gallamine, dTc, and pancuronium, onset time was slower with the more potent pancuronium and faster with the less potent gallamine. Except for atracurium, the molar potency (the ED 50 or ED 95 expressed as μM/kg) is highly predictive of a drug’s initial rate of onset of effect (at the adductor pollicis muscle). A drug’s measured molar potency is the end result of many contributing factors: the drug’s intrinsic potency (the CE 50 , which is the biophase concentration resulting in 50% twitch depression), the rate of equilibration between plasma and biophase (k e0 ), the initial rate of plasma clearance, and probably other factors as well. Notably, rocuronium has a molar potency (ED 95 ) of 0.54 μM/kg, which is approximately 13% that of vecuronium and only 9% that of cisatracurium; this finding illustrates the expected faster onset of rocuronium at the adductor pollicis muscle, as opposed to vecuronium and cisatracurium. Donati and Meistelman proposed a model to explain this inverse potency–onset relationship.
The times to 95% blockade at the adductor pollicis after administration of the ED 95 dose of succinylcholine, rocuronium, vecuronium, atracurium, mivacurium, and cisatracurium are shown in Fig. 27.10 . The illustration shows that the most potent compound, cisatracurium, has the slowest onset, and the least potent compound, rocuronium, has the most rapid onset. Bevan also proposed that rapid plasma clearance is associated with a rapid onset of action. The fast onset of succinylcholine’s action is related to its rapid metabolism and plasma clearance.
The onset of neuromuscular blockade is much faster in the muscles that are relevant to obtaining optimal intubating conditions (laryngeal adductors, diaphragm, and masseter) than in the muscle that is typically monitored (adductor pollicis) ( Fig. 27.11 ). Thus neuromuscular blockade develops faster, has a shorter maximum depth and duration of effect, and recovers more quickly in these central muscles ( Table 27.7 ).
|Dose (mg/kg)||Anesthesia||Laryngeal Adductors||Adductor Pollicis||Reference|
|Onset Time (s)||Maximum Block (% Depression)||Clinical Duration (min)||Onset Time (s)||Maximum block (% Depression)||Clinical Duration (min)|
|Succinylcholine, 1.0||Propofol-fentanyl||34 ± 12||100 ± 0||4.3 ± 1.6||56 ± 15||100 ± 0||8 ± 2||122|
|Rocuronium, 0.25||Propofol-fentanyl||96 ± 6||37 ± 8||—||180 ± 18||69 ± 8||—||121|
|Rocuronium, 0.4||Propofol-fentanyl||92 ± 29||70 ± 15||—||155 ± 40||99 ± 3||24 ± 7||122|
|Rocuronium, 0.5||Propofol-fentanyl||84 ± 6||77 ± 5||8 ± 3||144 ± 12||98 ± 1||22 ± 3||121|
|Vecuronium, 0.04||Propofol-fentanyl||198 ± 6||55 ± 8||—||342 ± 12||89 ± 3||11 ± 2||120|
|Vecuronium, 0.07||Propofol-fentanyl||198 ± 12||88 ± 4||9 ± 2||342 ± 18||98 ± 1||22 ± 2||120|
|Mivacurium, 0.14||Propofol-alfentanil||137 ± 20||90 ± 7||5.7 ± 2.1||201 ± 59||99 ± 1||16.2 ± 4.6||138|
|Mivacurium, 0.2||Propofol-alfentanil||89 ± 26||99 ± 4||10.4 ± 1.5||202 ± 45||99 ± 2||20.5 ± 3.9||139|
Paralysis following intravenous administration does not occur instantaneously even with large doses of muscle relaxants. Onset of blockade occurs 1 to 2 minutes earlier in the laryngeal muscles than at the adductor pollicis after administration of nondepolarizing NMBDs. The pattern of blockade (onset, depth, and speed of recovery) in the corrugator supercilii muscle is similar to that in the larynx, the diaphragm, and the muscles of the abdominal wall. By monitoring the onset of neuromuscular blockade at the corrugator supercilii, one can predict the quality of tracheal intubating conditions. Good to excellent intubating conditions are observed in more than 90% of patients after disappearance of the TOF responses (a TOF count of zero) at the corrugator supercilii. The onset of maximal blockade in the larynx also corresponds with the point at which the adductor pollicis muscle begins to show palpable evidence of weakening.
Rapid Tracheal Intubation
Rocuronium in high dose (0.9-1.2 mg/kg) or succinylcholine 1.5 mg/kg can be used interchangeably for rapid tracheal intubation because they provide adequate intubating conditions within 60 to 90 seconds. Hence if succinylcholine is considered undesirable or contraindicated, high doses of rocuronium can be administered. The onset of action of other nondepolarizing NMBDs can be accelerated by administering a priming dose of the NMBD or by using combinations of NMBDs. Although combinations of mivacurium and rocuronium can achieve rapid onset without undue prolongation of action and without undesirable side effects, combinations of compounds of different structures may result in a marked prolongation of neuromuscular blockade. Additionally, combining different NMBDs may not consistently result in a rapid onset of neuromuscular block.
This technique entails administration of a single intubating dose (two times the ED 95 ) of a rapid-onset NMBD such as rocuronium to an awake patient, followed by the administration of the anesthetic induction agent at the onset of clinical signs of weakness such as ptosis or loss of ability to maintain the raised arm. Using this technique, 0.6 mg/kg rocuronium can provide good to excellent intubating conditions within 45 seconds after induction of anesthesia. Because of the potential for unpleasant symptoms and recall associated with neuromuscular paralysis in awake patients, this technique is no longer used clinically.
Since the introduction of rocuronium into clinical practice, the use of priming technique has almost disappeared. When priming, a small, subparalyzing dose of the nondepolarizer (≈20% of the ED 95 or ≈10% of the intubating dose) is administered 2 to 4 minutes before the intubating dose of the compound. This procedure accelerates the onset of blockade for most nondepolarizing NMBDs only by 30 to 60 seconds, thereby indicating that intubation can be performed within 90 seconds of the second dose. However, the intubating conditions that occur after priming are only marginally improved and do not match those that occur after succinylcholine. The size of the priming dose is limited by its effects on the awake patient, since the anesthetic induction agent is administered only immediately prior to the intubating dose of NMBD. Further, priming doses can cause subtle degrees of neuromuscular blockade and increase the patient’s discomfort, the risks of aspiration, and difficulty swallowing and breathing. This technique is contraindicated in patients with abnormal airway anatomy or increased sensitivity to NMBDs such as patients with myasthenia gravis or those taking magnesium.
Large-Dose Regimen for Rapid Tracheal Intubation
Large doses of NMBDs are usually recommended when intubation must be accomplished in less than 90 seconds. High-dose regimens are associated with considerably prolonged duration of action and potentially increased cardiovascular side effects, however (see Table 27.5 ). Increasing the dosage of rocuronium from 0.6 mg/kg (twice the ED 95 ) to 1.2 mg/kg (four times the ED 95 ) shortens the onset time of complete neuromuscular block from 89 to 55 seconds but essentially doubles the clinical duration of action of the compound (the recovery of the first twitch of TOF [T1] to 25% of baseline values) from 37 to 73 minutes.
Small-Dose Relaxants for Tracheal Intubation
Small doses of NMBDs can be used for routine tracheal intubation. The use of smaller doses of NMBDs has the following two possible advantages: (1) it shortens the time to recovery from neuromuscular blockade, and (2) it reduces the requirement for anticholinesterase drugs. Rocuronium has the shortest onset time of all the nondepolarizing NMBDs currently available. The maximal effect of either 0.25 or 0.5 mg/kg of rocuronium at the laryngeal muscles occurs after 1.5 minutes. This interval is shorter than the 3.3 minutes reported after administration of equipotent doses of vecuronium (0.04 or 0.07 mg/kg), and it is only slightly longer than the 0.9 minutes reported after 0.25 or 0.5 mg/kg of succinylcholine (see Table 27.7 ).
With a better understanding of the multiple factors that contribute to satisfactory conditions for intubation, it is now possible to administer NMBDs thoughtfully in this fashion. Intubating conditions are related more closely to the degree of neuromuscular blockade of the laryngeal adductor muscles than to the degree of blockade typically monitored at the adductor pollicis. Fig. 27.12 demonstrates this principle. In the presence of an adequate depth of anesthesia, complete blockade at the larynx or diaphragm, or both, may not be a prerequisite for satisfactory intubating conditions. Kopman and colleagues noted that 0.5 mg/kg of rocuronium (1.5 times the ED 95 ) provided satisfactory conditions for intubation in patients anesthetized with 12.5 μg/kg of alfentanil and 2.0 mg/kg of propofol if laryngoscopy was delayed for 75 seconds after drug administration. It was furthermore estimated that 1.5 times the ED 95 of rocuronium would produce at least 95% blockade in 98% of the population. A similar or lower multiple of rocuronium’s ED 95 was shown to have a faster onset and shorter duration of action than those of atracurium or cisatracurium. In most patients receiving 15 μg/kg of alfentanil followed by 2.0 mg/kg of propofol and 0.45 mg/kg of rocuronium, good to excellent conditions for intubation are present 75 to 90 seconds after the completion of drug administration.
Metabolism and Elimination
The specific pathways of the metabolism (biotransformation) and elimination of NMBDs are summarized in Table 27.8 . Of the nondepolarizing NMBDs listed, pancuronium, pipecuronium, vecuronium, atracurium, cisatracurium, and mivacurium are the only drugs that are metabolized or degraded. Nearly all nondepolarizing NMBD molecules contain ester linkages, acetyl ester groups, and hydroxy or methoxy groups. These substitutions, especially the quaternary nitrogen groups, confer a high degree of water solubility with only slight lipid solubility. The hydrophilic nature of relaxant molecules enables easy elimination in the urine through glomerular filtration, with no tubular resorption or secretion. Therefore all nondepolarizing NMBDs show elimination of the parent molecule in the urine as the basic route of elimination; those with a long duration of action thus have a clearance rate that is limited by the glomerular filtration rate (1-2 mL/kg/min).
|Drug||Duration||Metabolism (%)||Kidney (%)||Liver (%)||Metabolites|
|Succinylcholine||Ultrashort||Butyrylcholinesterase (98%-99%)||<2%||None||Monoester (succinyl monocholine) and choline; the monoester is metabolized much more slowly than succinylcholine|
|Gantacurium||Ultrashort||Cysteine (fast) and ester hydrolysis (slow)||?||?||Inactive cysteine adduction product, chloroformate monoester, and alcohol|
|Mivacurium||Short||Butyrylcholinesterase (95%-99%)||<5%||None||Monoester and quaternary alcohol; the metabolites are inactive and most likely are not metabolized any further|
|(Metabolites eliminated in urine and bile)|
|Atracurium||Intermediate||Hofmann elimination and nonspecific ester hydrolysis (60%-90%)||10%-40%||None||Laudanosine, acrylates, alcohols, and acids; although laudanosine has CNS-stimulating properties, the clinical relevance of this effect is negligible|
|(Metabolites eliminated in urine and bile)|
|Cisatracurium||Intermediate||Hofmann elimination (77%?)||Renal clearance is 16% of total||Laudanosine and acrylates; ester hydrolysis of the quaternary monoacrylate occurs secondarily; because of the greater potency of cisatracurium, laudanosine quantities produced by Hofmann elimination are 5-10 times lower than in the case of atracurium, thus making this a nonissue in practice|
|Vecuronium||Intermediate||Liver (30%-40%)||40%-50%||50%-60% ≈60%||The 3-OH metabolite accumulates, particularly in renal failure; it has ≈80% the potency of vecuronium and may be responsible for delayed recovery in ICU patients|
|(Metabolites excreted in urine and bile) ≈40%|
|Pancuronium||Long||Liver (10%-20%)||85%||15%||The 3-OH metabolite may accumulate, particularly in renal failure; it is approximately two thirds as potent as the parent compound|
|d -Tubocurarine||Long||None||80% (?)||20%||None|
Long-Acting Neuromuscular Blocking Drugs
Pancuronium is cleared largely by the kidney and, to a limited extent, by hepatic uptake and elimination. A small amount (15%-20%) is deacetylated at the 3 position in the liver, but this makes a minimal contribution to the total clearance. Deacetylation also occurs at the 17 position, but to such a small extent as to be clinically irrelevant. The three known metabolites have been individually studied in anesthetized humans. The 3-OH metabolite is the most potent of the three, being approximately half as potent as pancuronium, and is the only one present in detectable concentrations in the plasma. This metabolite has pharmacokinetics and duration of action similar to those of pancuronium. The 3-OH metabolite is most likely excreted largely by the kidney. The parent compound and the 3-OH metabolite are also cleared in small amounts through a minor liver pathway. The total clearance is delayed, and the duration of action is significantly lengthened, by severe disorders of renal or hepatic function.
Intermediate-Acting Neuromuscular Blockers
Vecuronium, the 2-desmethyl derivative of pancuronium, is more lipid soluble than pancuronium because of the absence of the quaternizing methyl group at the 2 position. It undergoes two to three times more metabolism than pancuronium. Vecuronium is taken up into the liver by a carrier-mediated transport system, and it is then deacetylated at the 3 position by liver microsomes. Approximately 12% of vecuronium clearance is through conversion to 3-desacetylvecuronium, and 30% to 40% of the drug is cleared in the bile as the parent compound. Although the liver is the principal organ of elimination for vecuronium, the drug also undergoes significant (up to 25%) renal excretion, and this combined organ elimination gives it a clearance rate of 3 to 6 mL/kg/min.
The principal metabolite of vecuronium, 3-desacetylvecuronium, is a potent NMBD (≈80% of the potency of vecuronium). The metabolite, however, has slower plasma clearance and longer duration of action than vecuronium. 3-Desacetylvecuronium has a clearance rate of 3.5 mL/kg/min, and renal clearance accounts for approximately one sixth of its elimination. In patients with renal failure in the ICU, 3-desacetylvecuronium can accumulate and produce prolonged neuromuscular blockade. Other putative metabolites are 17-desacetylvecuronium and 3,17-bisdesacetylvecuronium, neither of which occurs in clinically significant amounts.
Rocuronium is eliminated primarily by the liver, with a small fraction (≈10%) eliminated in the urine. It is taken up into the liver by a carrier-mediated active transport system. The putative metabolite, 17-desacetylrocuronium, has low (5%-10%) neuromuscular blocking activity of the parent drug and it has not been detected in significant quantities. The elimination of rocuronium occurs predominately through its biliary excretion. The organic anion transporting peptide 1A2 (OATP1A2) mediates the hepatocellular uptake of a variety of drugs, including rocuronium. The peptide is encoded by the SLCO1A2 gene and is expressed in the bile duct cells (cholangiocytes) of the liver. Genetic polymorphism of the SLCO1A2 gene has recently been reported, and was shown to reduce the clearance of rocuronium in patients undergoing elective surgeries. [CR] This reduction in the biliary excretion may partially explain the marked prolongation in the duration of action of rocuronium in some patients.
Short-Acting Neuromuscular Blocking Drugs
Mivacurium is hydrolyzed in the plasma by butyrylcholinesterase to a monoester and an amino alcohol, which are excreted in urine and bile. They have less than 1% of the neuromuscular blocking activity of the parent compound. Less than 5% of mivacurium is excreted in the urine as the parent compound.
Mivacurium consists of three stereoisomers, and the clearances of the two most pharmacologically active isomers, the cis-trans and trans-trans , are approximately 100 and 50 to 70 mL/kg/min, respectively. These two isomers show elimination half-lives of 2 to 3 minutes. The third stereoisomer, the cis-cis , is present as only 4% to 8% of the mivacurium mixture and has less than 10% of the neuromuscular blocking potency of the other two isomers. Consequently, even though it has a much longer elimination half-life (55 minutes) and lower clearance (≈4 mL/kg/min) than the two other isomers, it does not contribute significantly to the duration of action of mivacurium. This rapid enzymatic clearance of mivacurium accounts for its short duration of action. When butyrylcholinesterase activity is significantly decreased, however, as in the rare patient who is homozygous for genetically atypical enzymes, the duration of action of mivacurium is prolonged for up to several hours.
CW 1759-50 is an ultrashort-acting nondepolarizing NMBD that was developed to minimize the histaminoid side effects associated with gantacurium. In laboratory animals, the ED 95 of CW 1759-50 is 0.03 mg/kg (cat) and 0.069 mg/kg (rhesus monkey). Its total duration of action (spontaneous recovery) is approximately 8 minutes, and it is minimally prolonged (12 minutes) after administration of doses four times its ED 95 . 11a,11b It can be antagonized rapidly (2 minutes) by l -cysteine. Its development for clinical use is undergoing.
Intermediate-Acting Neuromuscular Blocking Drugs
Atracurium is metabolized through two pathways: Hofmann elimination and nonspecific ester hydrolysis. Hofmann elimination is a purely chemical process that results in loss of the positive charges by molecular fragmentation to laudanosine (a tertiary amine) and a monoquaternary acrylate, compounds that are thought to have no neuromuscular and little or no cardiovascular activity of clinical relevance.
Because it undergoes Hofmann elimination, atracurium is relatively stable at pH 3.0 and 4°C and becomes unstable when it is injected into the bloodstream. Early observations of the breakdown of the drug in buffer and plasma showed faster degradation in plasma, a finding suggesting a possible enzymatic hydrolysis of the ester groups. Further evidence suggested that ester hydrolysis may be more important than originally realized in the breakdown of atracurium. By using a pharmacokinetics analysis, Fisher and associates concluded that a significant amount of clearance of atracurium may be by routes other than ester hydrolysis and Hofmann elimination. Thus it appears that atracurium’s metabolism is complicated and may not be completely understood.
Laudanosine, a metabolite of atracurium, has CNS-stimulating properties. Because it crosses the blood-brain barrier, laudanosine was thought to cause excitement and seizure activity. However, plasma concentrations of this metabolite are very low, and adverse effects are unlikely to occur with atracurium (or cisatracurium) use in either the operating room or the ICU.
Atracurium is a mixture of 10 optical isomers. Cisatracurium is the 1R cis– 1′R cis isomer of atracurium. Like atracurium, cisatracurium is metabolized by Hofmann elimination to laudanosine and a monoquaternary acrylate. In contrast, however, no ester hydrolysis of the parent molecule occurs. Hofmann elimination accounts for 77% of the total clearance of 5 to 6 mL/kg/min. Twenty-three percent of the drug is cleared through organ-dependent means, and renal elimination accounts for 16% of this. Because cisatracurium is approximately four or five times as potent as atracurium, approximately five times less laudanosine is produced, and, as with atracurium, accumulation of this metabolite is not thought to be of any consequence in clinical practice.
Long-Acting Neuromuscular Blocking Drugs
dTc has no active metabolism and the kidney is the major pathway of elimination, with approximately 50% of a dose eliminated through renal pathways. The liver is likely a secondary route of elimination.
Asymmetric Mixed-Onium Fumarates
Gantacurium and CW 002 are degraded by two chemical mechanisms, neither of which is enzymatic: (1) rapid formation of an apparently inactive cysteine adduction product and (2) slower hydrolysis of the ester bond to presumably inactive hydrolysis products (see Fig. 27.7 ). CW 1759-50 is degraded nonenzymatically by endogenous l- cysteine at physiological pH and temperature, which accounts for its ultrashort duration of action.
In summary, the only short-acting nondepolarizing NMBD, mivacurium, is cleared rapidly and almost exclusively by metabolism by butyrylcholinesterase, thus resulting in much greater plasma clearance than that of any other nondepolarizing NMBD. NMBDs of intermediate duration, such as vecuronium, rocuronium, atracurium, and cisatracurium, have clearance rates in the range of 3 to 6 mL/kg/min because of multiple pathways of degradation, metabolism, and/or elimination. Atracurium is cleared two to three times more rapidly than the long-acting drugs. Similar clearance values have been obtained for rocuronium and cisatracurium. The long-acting NMBDs undergo minimal or no metabolism, and they are eliminated largely unchanged, mostly by renal excretion. Hepatic pathways are less important in their metabolism.
Adverse Effects of Neuromuscular Blocking Drugs
NMBDs seem to play a prominent role in the incidence of adverse reactions that occur during anesthesia. The Committee on Safety of Medicines in the United Kingdom reported that 10.8% (218 of 2014) of adverse drug reactions and 7.3% of deaths (21 of 286) were attributable to the NMBDs.
While NMBDs have little penetration through the blood-brain barrier, they may interact with nicotinic and muscarinic cholinergic receptors within the peripheral nervous system, in particular the sympathetic and parasympathetic nervous systems and at the nicotinic receptors of the neuromuscular junction.
Dose-response ratios comparing the neuromuscular blocking potencies of these drugs (the ED 95 ) with their potencies in blocking vagal (parasympathetic) or sympathetic ganglionic transmission (the ED 50 ) can be constructed ( Table 27.9 ). These ratios are termed the autonomic margin of safety of the relaxant in question. The higher the dose ratio, the lower is the likelihood of, or the greater the safety ratio for, the occurrence of the particular autonomic effect. The side effect is considered absent (none) in clinical practice if the safety ratio is greater than 5; it is weak or slight if the safety ratio is 3 or 4, moderate if 2 or 3, and strong or prominent if the ratio is 1 or less.
|Drugs||Vagus ∗||Sympathetic Ganglia ∗||Histamine Release †|
These autonomic responses are not reduced by slower injection of the muscle relaxant. They are dose related and additive over time if divided doses are given. If identical to the original dose, subsequent doses will produce a similar response (i.e., no tachyphylaxis will occur). This is not the case, however, when the side effect of histamine release is in question. Cardiovascular responses secondary to histamine release are decreased by slowing the injection rate, and the response undergoes rapid tachyphylaxis. The autonomic effects of NMBDs are summarized in Table 27.10 .
|Drug Type||Autonomic Ganglia||Cardiac Muscarinic Receptors||Histamine Release|
Quaternary ammonium compounds (e.g., NMBDs) are generally weaker histamine-releasing substances than are tertiary amines such as morphine. Nevertheless, when large doses of certain NMBDs are administered rapidly, erythema of the face, neck, and upper torso may develop, as well as a brief decrease in arterial pressure and a slight to moderate increase in heart rate. Bronchospasm in this setting is very rare. The clinical effects of histamine are seen when plasma concentrations increase 200% to 300% of baseline values, and these effects involve chemical displacement of the contents of mast cell granules containing histamine, prostaglandin, and possibly other vasoactive substances. The serosal mast cell, located in the skin and connective tissue and near blood vessels and nerves, is principally involved in the degranulation process.
The side effect of histamine release is most often noted following administration of the benzylisoquinolinium class of muscle relaxants, although it has also been noted in steroidal relaxants of low potency. The effect is usually of short duration (1-5 minutes), is dose related, and is clinically insignificant in healthy patients. The hypotensive cardiovascular response to 0.6 mg/kg of dTc in humans is prevented both by antihistamines and by nonsteroidal antiinflammatory drugs (e.g., aspirin). The final step in dTc-induced hypotension is modulated by prostaglandins that are vasodilators. This side effect can be reduced considerably by using a slower injection rate that results in lower peak plasma concentrations of dTc. It is also prevented by prophylaxis with combinations of histamine 1 and histamine 2 blockers. If a minor degree of histamine release such as described earlier occurs after an initial dose of an NMBD, subsequent doses will generally cause no response at all, as long as they are no larger than the original dose. This is clinical evidence of tachyphylaxis, an important characteristic of histamine release. A much more significant degree of histamine release occurs during anaphylactoid or anaphylactic reactions, but these are very rare.
Clinical Cardiovascular Manifestations of Autonomic Mechanisms
The hypotension seen with the use of atracurium and mivacurium results from histamine release, whereas dTc causes hypotension by histamine release and ganglionic blockade. The effects of dTc occur closer to the dose required to achieve neuromuscular blockade. The safety margin for histamine release is approximately three times greater for atracurium and mivacurium than it is for dTc. Rapid administration of atracurium in doses greater than 0.4 mg/kg and of mivacurium in doses greater than 0.15 mg/kg has been associated with transient hypotension secondary to histamine release ( Fig. 27.13 ).
Pancuronium causes a moderate increase in heart rate and, to a lesser extent, in cardiac output, with little or no change in systemic vascular resistance. Pancuronium-induced tachycardia has been attributed to the following: (1) vagolytic action, probably from inhibition of M 2 receptors; and (2) sympathetic stimulation that involves both direct (blockade of neuronal uptake of norepinephrine) and indirect (release of norepinephrine from adrenergic nerve endings) mechanisms. In humans a decrease in plasma norepinephrine levels was surprisingly found after administration of either pancuronium or atropine. The investigators postulated that the increase in heart rate or rate-pressure product occurs because pancuronium (or atropine) acts through baroreceptors to reduce sympathetic outflow. More specifically, the vagolytic effect of pancuronium increases heart rate and hence blood pressure and cardiac output, in turn influencing the baroreceptors to decrease sympathetic tone. Support for this concept is provided by the finding that prior administration of atropine attenuates or eliminates the cardiovascular effects of pancuronium. However, a positive chronotropic effect that places emphasis on the vagolytic mechanism has not been found in humans. The tachycardia seen with benzylisoquinolinium compounds is the result of histamine release.
Succinylcholine and dTc actually reduce the incidence of epinephrine-induced dysrhythmias. Possibly because of enhanced atrioventricular conduction, the incidence of dysrhythmias caused by pancuronium appears to increase during halothane anesthesia. There are reports of rapid tachycardia (>150 beats/min) that progressed to atrioventricular dissociation in two patients anesthetized with halothane who also received pancuronium. The only other factor common to those two patients was that both were taking tricyclic antidepressant drugs.
Several case reports described the occurrence of severe bradycardia and even asystole after vecuronium or atracurium administration. All these cases were also associated with opioid coadministration. Subsequent studies indicated that administration of vecuronium or atracurium alone does not cause bradycardia. When combined with other drugs that do cause bradycardia (e.g., fentanyl), however, the nonvagolytic relaxants such as vecuronium, cisatracurium, and atracurium allow this mechanism to occur unopposed. Thus the moderate vagolytic effect of pancuronium is often used to counteract opioid-induced bradycardia.
The muscarinic cholinergic system plays an important role in regulating airway function. Five muscarinic receptors have been cloned, three of which (M 1 to M 3 ) exist in the airways. M 1 receptors are under sympathetic control, and they mediate bronchodilation. M 2 receptors are located presynaptically ( Fig. 27.14 ), at the postganglionic parasympathetic nerve endings, and they function in a negative-feedback mechanism to limit the release of acetylcholine. The M 3 receptors, which are located postsynaptically (see Fig. 27.14 ), mediate contraction of the airway smooth muscles (i.e., bronchoconstriction). Nondepolarizing NMBDs have different antagonistic activities at both M 2 and M 3 receptors. For example, blockade of M 3 receptors on airway smooth muscle inhibits vagally induced bronchoconstriction (i.e., causes bronchodilation), whereas blockade of M 2 receptors results in increased release of acetylcholine that acts on M 3 receptors, thus causing bronchoconstriction.
The affinity of the compound rapacuronium to block M 2 receptors is 15 times higher than its affinity to block M 3 receptors. This explains the high incidence (>9%) of severe bronchospasm reported with this drug that resulted in its withdrawal from the market. In laboratory animals (guinea pig), CW 1759-50 is reported to have five times greater safety at both M 2 and M 3 receptors than rapacuronium. [CR]
The administration of benzylisoquinolinium NMBDs (with the exception of cisatracurium) is associated with histamine release, which may result in increased airway resistance and bronchospasm in patients with hyperactive airway disease.
The frequency of life-threatening anaphylactic (immune-mediated) or anaphylactoid reactions occurring during anesthesia has been estimated at 1 in 10,000 to 20,000 anesthetic procedures, whereas it is estimated at 1 in 6500 administrations of NMBDs in some countries. In France, the most common causes of anaphylaxis in patients who experienced allergic reactions were reported to be NMBDs (60.6%), antibiotics (18.2%), dyes (5.4%), and latex (5.2%). Patients were sensitized to 2 or more NMBDS in approximately 50% of the cases and no cross-sensitivity could be predicted without skin testing. Anaphylactic reactions are mediated through immune responses involving immunoglobulin E (IgE) antibodies fixed to mast cells. Anaphylactoid reactions are not immune mediated and represent exaggerated pharmacologic responses in very rare and very sensitive individuals.
However, anaphylaxis to nondepolarizing NMBDs is not uncommon in patients without any previous exposure to any nondepolarizing NMBDs. Cross-reactivity occurs between NMBDs and food, cosmetics, disinfectants, and industrial materials. Sensitization to nondepolarizing NMBDs may also be related to pholcodine, a cough-relieving medicine. Cross-reactivity is seen in 70% of patients with a history of anaphylaxis to an NMBD. Six years after the withdrawal of pholcodine from the Norwegian market, the prevalence of IgE sensitization to NMBDs (succinylcholine) decreased significantly.
Steroidal compounds (e.g., rocuronium, vecuronium, or pancuronium) result in no significant histamine release. For example, four times the ED 95 of rocuronium (1.2 mg/ kg) causes no significant histamine release. Nevertheless, rocuronium and succinylcholine are reportedly associated with a 43.1% and 22.6% incidence, respectively, of anaphylaxis in France. Rose and Fisher classified rocuronium and atracurium as having intermediate levels of risk for causing allergic reactions. These investigators also noted that the increased number of reports of anaphylaxis with rocuronium is in line with the market share of that drug’s usage. Watkins stated, “The much higher incidence of rocuronium reactions reported in France is currently inexplicable and is likely to remain so if investigators continue to seek a purely antibody-mediated response as an explanation of all anaphylactoid reaction presentations.” All nondepolarizing NMBDs may elicit anaphylaxis. More recent publications have highlighted the need for standardization of diagnostic procedures of anaphylactic reactions. Biochemical tests should be performed rapidly after occurrence of an anaphylactic reaction. An early increase in plasma histamine is observed 60 to 90 minutes after anaphylactic reactions. Serum tryptase concentration typically reaches a peak between 15 and 120 minutes, depending on the severity of the reaction, and is much more specific than histamine as a marker of anaphylactic reaction. It is highly suggestive of mast cell activation. Skin testing remains the gold standard for detection of the culprit agent. For many years, dilution thresholds have been debated. For instance, Laxenaire used a 1:10 dilution of rocuronium for interdermal skin testing, whereas Rose and Fisher used a 1:1000 dilution. Levy and associates showed that rocuronium in a 1:10 dilution can produce false-positive results in intradermal testing and suggested that rocuronium be diluted at least 100-fold to prevent such results. The authors also reported that high concentrations (≥10 –4 M) of both rocuronium and cisatracurium were capable of producing a wheal-and-flare response to intradermal testing, which was associated with mild to moderate mast cell degranulation in the cisatracurium group only. However, in contrast to control patients, skin tests with nondepolarizing NMBDs that were performed in patients who had an anaphylactic reaction were considered reliable. In the case of suspected anaphylactic reaction to any NMBD, it is mandatory to complete investigation for cross-reactivity with other commercially available NMBDs to identify safe alternative regimens.
All NMBDs can cause noncompetitive inhibition of histamine- N -methyltransferase, but the concentrations required for that inhibition greatly exceed those that would be used clinically, except in the case of vecuronium, with which the effect becomes manifest at 0.1 to 0.2 mg/kg. This finding could explain the occurrence of occasional severe bronchospasm in patients after receiving vecuronium. For goals of treatment of anaphylactic reactions, see Chapters 5 and 6.
Drug Interactions and Other Factors Affecting Response to Neuromuscular Blockers
A drug-drug interaction is an in vivo phenomenon that occurs when the administration of one drug alters the effects or kinetics of another drug. In vitro physical or chemical incompatibilities are not considered drug interactions.
Many drugs interact with NMBDs or their antagonists, or both, and it is beyond the scope of this chapter to review them all. Some of the more important drug interactions with NMBDs and their antagonists are discussed in the following sections.
Interactions Among Nondepolarizing Neuromuscular Blocking Drugs
Mixtures of two nondepolarizing NMBDs are considered to be either additive or synergistic. Antagonistic interactions have not been reported in this class of drugs. Additive interactions have been demonstrated after administration of chemically related drugs, such as atracurium and mivacurium, or after coadministration of various pairs of steroidal NMBDs. Conversely, combinations of structurally dissimilar (e.g., a steroidal with a benzylisoquinolinium) NMBDs, such as the combinations of pancuronium and dTc, pancuronium and metocurine, rocuronium and mivacurium, or rocuronium and cisatracurium, produce a synergistic response. An additional advantage (rapid onset and short duration) is noted for mivacurium-rocuronium combinations. Although the precise mechanisms underlying a synergistic interaction are not known, hypotheses that have been put forward include the existence of multiple binding sites at the neuromuscular junction (presynaptic and postsynaptic receptors) and the nonequivalence of binding affinities of the two α subunits (α H and α L ). Further, inhibition of butyrylcholinesterase by pancuronium results in decreased plasma clearance of mivacurium and marked potentiation of the neuromuscular blockade.
The pharmacodynamic response to the use of two different nondepolarizing NMBDs during the course of anesthesia depends not only on the specific drugs used but also on the sequence of their administration. Approximately three half-lives are required for a clinical changeover (so that 95% of the first drug has been cleared) and for the duration of the blockade to begin to take on the characteristics of the second drug. After the administration of pancuronium, recovery from the first two maintenance doses of vecuronium is reportedly prolonged, although this effect becomes negligible by the third dose. Similarly, Naguib and colleagues noted that the mean duration of the first maintenance dose of mivacurium to 10% recovery of the first twitch was significantly longer after atracurium (25 minutes) than after mivacurium (14.2 minutes). However, the duration of the second maintenance dose of mivacurium after atracurium (18.3 minutes) was similar to that of mivacurium after mivacurium (14.6 minutes).
The apparent prolongation of action of the first maintenance dose of mivacurium administered after atracurium, and of those reported with vecuronium after pancuronium, is not related to synergism. Combinations of atracurium and mivacurium and of vecuronium and pancuronium are simply additive. However, this prolongation in the duration of action could be attributed to the relative concentrations of these drugs at the receptor site. Because most receptors remain occupied by the drug administered initially, the clinical profile depends on the kinetics or dynamics (or both) of the drug administered first, rather than on those of the second (maintenance) drug. However, with further incremental doses of the second drug, a progressively larger proportion of the receptors is occupied by that second drug, and its clinical profile becomes evident.
Interactions Between Succinylcholine and Nondepolarizing Neuromuscular Blocking Drugs
The interaction between succinylcholine and nondepolarizing NMBDs depends on the order of administration and the doses used. Small doses of different nondepolarizing NMBDs administered before succinylcholine to prevent fasciculations have an antagonistic effect on the development of subsequent depolarizing block produced by succinylcholine. Therefore it is recommended that the dose of succinylcholine be increased after the administration of a defasciculating dose of a nondepolarizing NMBD.
Studies of the effects of administering succinylcholine before nondepolarizing NMBDs have produced conflicting results. Several investigators reported potentiation of the effects of pancuronium, vecuronium, and atracurium by prior administration of succinylcholine. In contrast, other investigators found no significant influence of succinylcholine on subsequent administration of pancuronium, rocuronium, or mivacurium.
Interactions With Inhaled Anesthetics
Deep anesthesia induced with potent volatile anesthetics (in the absence of neuromuscular blockade) may cause a slight reduction of neuromuscular transmission, as measured by depression of sensitive indicators of clinical neuromuscular function, such as tetanus and TOF ratio. Inhaled anesthetics also enhance the neuromuscular blocking effects of nondepolarizing NMBDs. Inhaled anesthetics decrease the required dose of NMBDs, and prolong both the duration of action of the NMBD and recovery from neuromuscular block, depending on the duration of anesthesia, the specific inhaled anesthetic, and the concentration (dose) given. The rank order of potentiation is desflurane > sevoflurane > isoflurane > halothane > nitrous oxide/barbiturate/opioid or propofol anesthesia ( Fig. 27.15 ).
The greater clinical muscle-relaxing effect produced by less potent anesthetics is mainly caused by their larger aqueous concentrations. Desflurane and sevoflurane have low blood-gas and tissue-gas solubility, so equilibrium between the end-tidal concentration and the neuromuscular junction is reached more rapidly with these anesthetics than with older inhaled anesthetics.
The interaction between volatile anesthetics and NMBDs is one of pharmacodynamics, not pharmacokinetics. The proposed mechanisms behind this interaction include (1) a central effect on α motoneurons and interneuronal synapses, (2) inhibition of postsynaptic nAChR, and (3) augmentation of the antagonist’s affinity at the receptor site.
Interactions With Antibiotics
Most antibiotics can cause neuromuscular blockade in the absence of NMBDs. The aminoglycoside antibiotics, the polymyxins, and lincomycin and clindamycin primarily inhibit the prejunctional release of acetylcholine and also depress postjunctional nAChR sensitivity to acetylcholine. The tetracyclines, in contrast, exhibit postjunctional activity only. When combined with NMBDs, the aforementioned antibiotics can potentiate neuromuscular blockade. The cephalosporins and penicillins have not been reported to potentiate neuromuscular blockade. Because antagonism of neuromuscular blockade with neostigmine has been reported to be more difficult after the administration of aminoglycosides, ventilation should be controlled until the neuromuscular blockade terminates spontaneously. Ca 2+ should not be used to hasten the recovery of neuromuscular function for two reasons: the antagonism it produces is not sustained, and it may prevent the antibacterial effect of the antibiotics.
Hypothermia prolongs the duration of action of nondepolarizing NMBDs. The force of contraction of the adductor pollicis decreases by 10% to 16% per degree Celsius decrease in muscle temperature lower than 35.2°C. To maintain the muscle temperature at or higher than 35.2°C, the central temperature must be maintained above 36.0°C. The mechanical response recovery to 10% twitch height with 0.1 mg/kg of vecuronium increases from 28 minutes at a mean central temperature of 36.4°C to 64 minutes at 34.4°C. The mechanism or mechanisms underlying this prolongation may be pharmacodynamic or pharmacokinetic, or both. They include diminished renal and hepatic excretion, changing volumes of distribution, altered local diffusion receptor affinity, changes in pH at the neuromuscular junction, and the net effect of cooling on the various components of neuromuscular transmission. Hypothermia decreases the plasma clearance and prolongs the duration of action of rocuronium and vecuronium. Temperature-related differences in the pharmacodynamics of vecuronium have also been reported. The k e0 decreases (0.023/min/°C) with lower temperature, a finding suggesting slightly delayed equilibration of drug between the circulation and the neuromuscular junction during hypothermia. The Hofmann elimination process of atracurium is slowed by a decrease in pH and especially by a decrease in temperature. In fact, atracurium’s duration of action is markedly prolonged by hypothermia. For instance, the duration of action of a dose of 0.5 mg/kg atracurium is 44 minutes at 37°C but 68 minutes at 34.0°C when evoked mechanical responses are monitored.
Changes in temperature also affect the interpretation of the results of monitoring neuromuscular blockade. For example, the duration of action of vecuronium measured in an arm cooled to a skin temperature of 27°C is prolonged, and monitoring by PTC in that arm is unreliable. In the same patient, TOF responses are different if the arms are at different temperatures, and the correlation of responses in the two arms becomes progressively poorer as the temperature difference between the arms increases.
The efficacy of neostigmine is not altered by mild hypothermia. Hypothermia does not change the clearance, maximum effect, or duration of action of neostigmine in volunteers. Mild hypothermia prolonged sugammadex reversal of deep rocuronium block by 46 seconds, a prolongation considered clinically acceptable.
Interactions With Magnesium and Calcium
Magnesium sulfate, given for treatment of preeclampsia and eclamptic toxemia, potentiates the neuromuscular blockade induced by nondepolarizing NMBDs. After a dose of 40 mg/kg of magnesium sulfate, the ED 50 of vecuronium was reduced by 25%, the onset time was nearly halved, and the recovery time nearly doubled. Neostigmine-induced recovery is also attenuated in patients treated with magnesium. The mechanisms underlying the enhancement of nondepolarizing block by magnesium probably involve both prejunctional and postjunctional effects. High magnesium concentrations inhibit Ca 2+ channels at the presynaptic nerve terminals that trigger the release of acetylcholine. Further, magnesium ions have an inhibitory effect on postjunctional potentials and cause decreased excitability of muscle fiber membranes. In patients receiving magnesium, the dose of nondepolarizing NMBDs must be reduced and carefully titrated using an objective monitor to ensure adequate recovery of neuromuscular function prior to tracheal extubation.
The interaction between magnesium and succinylcholine is controversial, with some reports suggesting that magnesium antagonizes the block produced by succinylcholine. Ca 2+ triggers the release of acetylcholine from the motor nerve terminal and enhances excitation-contraction coupling in muscle. Increasing Ca 2+ concentrations decreased the sensitivity to dTc and pancuronium in a muscle-nerve model. In hyperparathyroidism, hypercalcemia is associated with decreased sensitivity to atracurium and thus a shortened time course of neuromuscular blockade.
Interactions With Lithium
Lithium is used for treatment of bipolar affective disorder (manic-depressive illness). The lithium ion resembles Na + , K + , magnesium, and Ca 2+ ions, and therefore may affect the distribution and kinetics of all these electrolytes. Lithium enters cells via Na + channels and tends to accumulate within the cells.
By its activation of K + channels, lithium inhibits neuromuscular transmission presynaptically and muscular contraction postsynaptically. The combination of lithium and pipecuronium results in a synergistic inhibition of neuromuscular transmission, whereas the combination of lithium and succinylcholine results in additive inhibition. Prolongation of neuromuscular blockade was reported in patients taking lithium carbonate and receiving both depolarizing and nondepolarizing NMBDs. Only one report did not demonstrate prolongation of recovery from succinylcholine in patients receiving lithium. In patients who are stabilized on lithium therapy and undergoing surgery, NMBDs should be administered in incremental and reduced doses and titrated to the degree of blockade required.
Interactions With Local Anesthetic and Antidysrhythmic Drugs
Local anesthetics act on the presynaptic and postsynaptic part of the neuromuscular junction. In large intravenous doses, most local anesthetics block neuromuscular transmission; in smaller doses, they enhance the neuromuscular blockade produced by both nondepolarizing and depolarizing NMBDs. The ability of neostigmine to antagonize a combined local anesthetic–neuromuscular blockade has not been studied. Procaine also inhibits butyrylcholinesterase and may augment the effects of succinylcholine and mivacurium by decreasing their hydrolysis by the enzyme.
In small intravenous doses, local anesthetics depress posttetanic potentiation, and this is thought to be a neural prejunctional effect. With larger doses, local anesthetics block acetylcholine-induced muscular contractions, a finding suggesting that local anesthetics have a stabilizing effect on the postjunctional membrane. Procaine displaces Ca 2+ from the sarcolemma and thus inhibits caffeine-induced contracture of skeletal muscle. Most of these mechanisms of action probably apply to all local anesthetics.
Several drugs used for the treatment of dysrhythmias augment the blockade induced by NMBDs. Single-fiber electromyography found that verapamil and amlodipine impair neuromuscular transmission in subjects without neuromuscular disease. Clinical reports suggested potentiation of neuromuscular block with verapamil and impaired reversal of vecuronium in a patient receiving disopyramide. However, the clinical significance of these interactions is probably minor.
Interactions With Antiepileptic Drugs
Anticonvulsants have a depressant action on acetylcholine release at the neuromuscular junction. Patients receiving long-term anticonvulsant therapy demonstrated resistance to nondepolarizing NMBDs (except mivacurium and probably atracurium as well ), as evidenced by accelerated recovery from neuromuscular blockade and the need for increased doses to achieve complete neuromuscular blockade. Vecuronium clearance is increased two-fold in patients receiving long-term carbamazepine therapy. Other investigators, however, attribute this resistance to the increased binding (i.e., decreased free fraction) of the NMBDs to α 1 -acid glycoproteins or to upregulation of neuromuscular acetylcholine receptors (or to both mechanisms). The latter could also explain the hypersensitivity seen with succinylcholine. The slight prolongation of succinylcholine’s action in patients taking anticonvulsants has few clinical implications. Conversely, the potential hyperkalemic response to succinylcholine in the presence of receptor upregulation is of concern.
Interactions With Diuretics
Early results showed that in patients undergoing renal transplantation, the intensity and duration of dTc neuromuscular blockade was increased after a dose of furosemide (1 mg/kg intravenously).
Furosemide reduced the concentration of dTc required to achieve 50% twitch tension depression in the indirectly stimulated rat diaphragm and intensified the neuromuscular blockade produced by dTc and succinylcholine. Furosemide appears to inhibit the production of cyclic adenosine monophosphate. In addition, the breakdown of adenosine triphosphate is inhibited, resulting in reduced output of acetylcholine. Acetazolamide antagonized the effects of anticholinesterases in the rat phrenic-diaphragm preparation. However, in one report, 1 mg/kg of furosemide facilitated recovery of the evoked twitch response after pancuronium. Long-term furosemide treatment had no effect on either dTc- or pancuronium-induced neuromuscular blockade.
In contrast, mannitol appears to have no effect on a nondepolarizing neuromuscular blockade. Increasing urine output by the administration of mannitol or other osmotic or tubular diuretics has no effect on the rate at which dTc and presumably other NMBDs are eliminated in the urine.
Interactions With Other Drugs
Dantrolene, a drug used for the treatment of malignant hyperthermia, prevents Ca 2+ release from the sarcoplasmic reticulum and blocks excitation-contraction coupling. Although dantrolene does not block neuromuscular transmission, the mechanical response to stimulation is depressed, resulting in potentiation of nondepolarizing neuromuscular blockade.
Azathioprine, an immunodepressant drug that is used in patients undergoing renal transplantation, has a minor antagonistic action on muscle relaxant–induced neuromuscular blockade.
Steroids antagonize the effects of nondepolarizing NMBDs in both humans and animals. Possible mechanisms for this interaction include facilitation of acetylcholine release because of the effect of steroids on the presynaptic motor nerve terminal. Other reports, however, described a noncompetitive inhibition and channel blockade of the nAChR. Endogenous steroids act noncompetitively on nAChRs. Prolonged treatment with a combination of corticosteroids and NMBDs can result in prolonged weakness in patients receiving critical care (see the later section on NMBDs and weakness syndromes in critically ill patients).
Antiestrogenic drugs such as tamoxifen appear to potentiate the effects of nondepolarizing NMBDs.