Cardiovascular Effects

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

Hyperkalemia

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

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

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

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

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

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

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

Increased Intraocular Pressure

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

Increased Intragastric Pressure

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

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

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

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

Increased Intracranial Pressure

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

Myalgia

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

Masseter Muscle Rigidity

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

Anaphylaxis

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

Benzylisoquinolinium Compounds

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

• 1.
  

  The nitrogen atoms are incorporated into isoquinoline ring systems. This bulky molecule favors a nondepolarizing rather than a depolarizing activity.

  
  
• 2.
  

  The interonium distance (distance between charged amines) is approximately 1.4 nm.

  
  
• 3.
  

  Both the ganglion-blocking and the histamine-releasing properties of dTc probably result from the presence of the tertiary amine function.

  
  
• 4.
  

  When dTc is methylated at the tertiary amine and at the hydroxyl groups, the result is metocurine, a compound of greater potency (by a factor of two in humans) with much weaker ganglion-blocking and histamine-releasing properties than dTc (see Fig. 27.4 ). Metocurine contains three additional methyl groups, one of which quaternizes the tertiary nitrogen of dTc; the other two form methyl ethers at the phenolic hydroxyl groups.

  
  
• 5.
  

  Bisquaternary compounds are more potent than their monoquaternary analogues. The bisquaternary derivative of dTc, chondocurine, is more than twice as potent as dTc (see Fig. 27.4 ).

  
  
• 6.
  

  Substitution of the methyl groups on the quaternary nitrogen with bulkier groups causes a reduction in both potency and duration of action.

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

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

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

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

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

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

Steroidal Neuromuscular Blockers

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

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

Chemical structures of different steroidal neuromuscular blockers.

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

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

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

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.

Chemical structure of gantacurium (a mixed-onium chlorofumarate). In whole human blood, two pathways of deactivation occur, neither of which is enzymatic: (1) rapid formation of an apparently inactive cysteine adduction product, with cysteine replacing chlorine; and (2) slower hydrolysis of the ester bond adjacent to the chlorine substitution to chlorofumarate monoester and alcohol.

From Boros EE, Samano V, Ray JA, et al. Neuromuscular blocking activity and therapeutic potential of mixed-tetrahydroisoquinolinium halofumarates and halosuccinates in rhesus monkeys. J Med Chem. 2003;46:2502–2515.

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.

Onset

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.

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 ).

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.

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.

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.

A computer simulation based on Sheiner’s model and data reported by Wierda and colleagues. The dose causing on average 95% suppression of neuromuscular response (ED ₉₅ ) of rocuronium at the adductor pollicis from this model is 0.33 mg/kg. Rocuronium, 0.45 mg/kg is given as a bolus at time zero. Muscle X represents a muscle (e.g., the diaphragm or the laryngeal adductors) that is less sensitive to the effects of nondepolarizing relaxants than the adductor pollicis but has greater blood flow. In this example, the concentration of rocuronium producing 50% block (EC ₅₀ ) of muscle X is 2.5 times that of the adductor pollicis, but the half-life of transport between the plasma and effect compartment (t _½ k _e0 ) of muscle X is only half as long. The rapid equilibration between plasma concentrations of rocuronium and muscle X results in the more rapid onset of blockade of muscle X than of the adductor pollicis. The greater EC ₅₀ at muscle X explains the faster recovery of this muscle than of the adductor pollicis from neuromuscular blockade. Lower blood concentrations of rocuronium must be achieved at the adductor pollicis than at muscle X before recovery begins. T1, First twitch of train-of-four.

From Naguib M, Kopman AF. Low dose rocuronium for tracheal intubation. Middle East J Anesthesiol. 2003;17:193–204, with permission from the Middle East Journal of Anesthesiology.

Steroidal Compounds

Benzylisoquinolinium Compounds

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.

Autonomic Effects

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.

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 .

Clinical Cardiovascular Manifestations of Autonomic Mechanisms

Hypotension

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 ).

Dose response to mivacurium in patients under nitrous oxide–oxygen-opioid anesthesia. Maximum changes at each dose are shown; n = 9 subjects per group. (A) With fast injection, a 15% to 20% decrease in arterial pressure occurred at 2.5 to 3 times the ED ₉₅ (0.20-0.25 mg/kg). (B) The changes were less than 10% when slower injection (30 seconds) was done.

From Savarese JJ, Ali HH, Basta SJ, et al. The cardiovascular effects of mivacurium chloride [BW B1090U] in patients receiving nitrous oxide–opiate-barbiturate anesthesia. Anesthesiology. 1989;70:386–394.

Tachycardia

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.

Dysrhythmias

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.

Bradycardia

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.

Respiratory Effects

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 muscarinic (M ₃ ) receptors are located postsynaptically on airway smooth muscle. Acetylcholine (ACh) stimulates M ₃ receptors to cause contraction. M ₂ muscarinic receptors are located presynaptically at the postganglionic parasympathetic nerve endings, and they function in a negative-feedback mechanism to limit the release of ACh.

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.

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 ).

Cumulative dose-response curves for rocuronium-induced neuromuscular blockade during 1.5 minimum alveolar concentration anesthesia with desflurane, sevoflurane, isoflurane, and total intravenous anesthesia (TIVA) .

From Wulf H, Ledowski T, Linstedt U, et al. Neuromuscular blocking effects of rocuronium during desflurane, isoflurane, and sevoflurane anaesthesia. Can J Anaesth. 1998;45:526–532, with permission from the Canadian Journal of Anaesthesia.

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.

Temperature

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.