Pharmacology of Succinylcholine Structure-Activity Relationships

All neuromuscular blockers, being quaternary ammonium compounds, are structurally related to acetylcholine. Positive charges at these sites in the molecules mimic the quaternary nitrogen atom of the transmitter acetylcholine and are the principal reason for the attraction of these drugs to muscleand neuronal-type nAChRs at the neuromuscular junction. These receptors are also located at other physiologic sites of acetylcholine in the body, such as 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 neuromuscular blocker succinylcholine is composed of two molecules of acetylcholine linked back to back through the acetate methyl groups ( Fig. 29-5 ). As described by Bovet,[27] succinylcholine is a long, thin, flexible molecule. Like acetylcholine, succinylcholine stimulates cholinergic receptors at the neuromuscular junction and at nicotinic (ganglionic) and muscarinic autonomic sites, thereby opening the ionic channel in the acetylcholine receptor.

Figure 29-5 Structural relationship of succinylcholine, a depolarizing neuromuscular blocking agent, and acetylcholine. Succinylcholine consists of two acetylcholine molecules linked through the acetate methyl groups. Like acetylcholine, succinylcholine stimulates nicotinic receptors at

the neuromuscular junction. Pharmacokinetics and Pharmacodynamics

Succinylcholine is the only available neuromuscular blocker with a rapid onset of effect and an ultrashort duration of action. The ED95 of succinylcholine (the dose causing on average 95% suppression of neuromuscular response) is 0.51 to 0.63 mg/kg.[28] Using cumulative dose-response techniques, Kopman and coworkers[29] estimated that its potency is far greater, with an ED95 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.[30] In patients with genotypically normal butyrylcholinesterase (also known as plasma cholinesterase or pseudocholinesterase) activity, recovery to 90% muscle strength after the administration of 1 mg/kg succinylcholine requires 9 to 13 minutes.[31]

The short duration of action of succinylcholine is due to its rapid hydrolysis by butyrylcholinesterase to succinylmonocholine and choline. Butyrylcholinesterase has an enormous capacity to hydrolyze succinylcholine, and only 10% of the administered drug reaches the neuromuscular junction.[32] The initial metabolite, succinylmonocholine, is a much weaker neuromuscular blocking agent 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.[33]

Because there is little or no butyrylcholinesterase at the neuromuscular junction, the neuromuscular blockade of succinylcholine is terminated by its diffusion away from the neuromuscular junction back 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. Dibucaine Number and Butyrylcholinesterase Activity

Butyrylcholinesterase is synthesized by the liver and found in plasma. The neuromuscular blockade induced by succinylcholine is prolonged by a decreased concentration or activity of the enzyme. The activity of the enzyme refers to the number of substrate molecules (mol) hydrolyzed per unit of time, often expressed in international units (IU). The normal range of butyrylcholinesterase activity is quite large[31]; significant decreases in butyrylcholinesterase activity result in modest increases in the time required to return to 100% twitch recovery ( Fig. 29-6 ).

Figure 29-6 Correlation between the duration of succinylcholine neuromuscular blockade and butyrylcholinesterase activity. The normal range of activity lies between the arrows. (From Viby-Mogensen J: Correlation of succinylcholine duration of action with plasma cholinesterase activity in subjects with the genotypically normal enzyme. Anesthesiology 53:517-520, 1980.)

Factors that have been described as lowering butyrylcholinesterase activity are liver disease,[34] advanced age,[35] malnutrition, pregnancy, burns, oral contraceptives, monoamine oxidase inhibitors, echothiophate, cytotoxic drugs, neoplastic disease, anticholinesterase drugs,[36] tetrahydroaminacrine,[37] hexafluorenium, and metoclopramide.[38] The histamine type 2 receptor antagonists have no effect on butyrylcholinesterase activity or the duration of succinylcholine's effect.[39] Bambuterol, a prodrug of terbutaline, produces marked inhibition of butyrylcholinesterase activity and causes prolongation of succinylcholine-induced blockade.[40] The -blocker esmolol inhibits butyrylcholinesterase but causes only minor prolongation of succinylcholine blockade.[41]

Despite all the publications and efforts to identify situations in which normal butyrylcholinesterase

enzyme activity may be low, this has not been a major concern in clinical practice because even large decreases in butyrylcholinesterase activity result in only moderate increases in the duration of action of succinylcholine. 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 just 9 minutes. Even when treatment of glaucoma with echothiophate decreased butyrylcholinesterase activity from 49% of control to no activity, the increase in duration of neuromuscular blockade varied from 2 to 14 minutes. In no patient did the total duration of neuromuscular blockade exceed 23 minutes.[42] Dibucaine Number and Atypical Butyrylcholinesterase Activity

Succinylcholine-induced neuromuscular blockade can be significantly prolonged if the patient has an abnormal genetic variant of butyrylcholinesterase. The variant was found by Kalow and Genest[43] to respond to dibucaine differently than normal butyrylcholinesterase does. Dibucaine inhibits normal butyrylcholinesterase to a far greater extent than it inhibits the abnormal enzyme. This observation led to development of the test for dibucaine number. Under standardized test conditions, dibucaine inhibits expression of the normal enzyme by about 80% and the abnormal enzyme by about 20% ( Table 29-1 ). Subsequently, many other genetic variants of butyrylcholinesterase have been identified, although the dibucaine-resistant variants are the most important. The review by Jensen and Viby-Mogensen[44] can be consulted for more detailed information on this topic. Table 29-1 -- Relationship between dibucaine number and duration of succinylcholine or mivacurium neuromuscular blockade Type of Genot Inciden Butyrylcholinesterase ype ce Homozygous typical Heterozygous atypical Homozygous atypical Dibucaine Number * Response to Succinylcholine or Mivacurium Normal Lengthened by 50%-100% Prolonged to 4-8 hr

E1uE1u Normal 70-80 E1uE1a 1/480 50-60

E1aE1a 1/3200 20-30

The dibucaine number indicates the percentage of enzyme inhibited.

Although the dibucaine number indicates the genetic makeup of an individual with respect to butyrylcholinesterase, it does not measure the concentration of the enzyme in plasma, nor does it indicate the efficiency of the enzyme in hydrolyzing a substrate such as succinylcholine or mivacurium. Both of the latter factors are determined by measuring butyrylcholinesterase activity, which may be influenced by 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.[44]

Most variants are due to 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 fluorideresistant (F) gene, two amino acid substitutions are possible, namely, methionine for threonine at position 243 and valine for glycine at position 390. Table 29-1 summarizes three 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.[45] Side Effects Cardiovascular Effects

Succinylcholine-induced cardiac dysrhythmias are many and varied. The drug stimulates all cholinergic autonomic receptors: nicotinic receptors on both sympathetic and parasympathetic ganglia[46] 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[47] and result in tachycardia. A prominent clinical manifestation of generalized autonomic stimulation is the development of cardiac dysrhythmias, principally manifested as 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 due to the action of succinylcholine alone or to the added presence of extraneous autonomic stimulation. An in vitro study using the ganglionic acetylcholine receptor subtype 34 expressed in Xenopus laevis oocytes suggested that at clinically relevant concentrations, succinylcholine had no effect on the expressed receptors.[48] Only at high doses of succinylcholine was inhibition of ganglionic acetylcholine receptors noted.[48] The significance of these findings is difficult to extrapolate into clinical practice because the method used (Xenopus laevis oocyte expression model) does not match clinical reality. SINUS BRADYCARDIA.

The autonomic mechanism involved in sinus bradycardia is stimulation of cardiac muscarinic receptors in the sinus node. This is particularly problematic in individuals with predominantly vagal tone, such as children who have not received atropine. Sinus bradycardia has also been noted in adults and appears more commonly after a second dose of the drug is given approximately 5 minutes after the first.[49] The bradycardia may be prevented by the administration of thiopental, atropine, ganglion-blocking drugs, and nondepolarizing neuromuscular blockers.[50] The implication of this information is that direct myocardial effects, increased muscarinic stimulation, and ganglionic stimulation may all be involved in the bradycardia response. The higher 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 commonly occur after the administration of succinylcholine. The mechanism probably involves relatively greater stimulation of muscarinic receptors in the sinus node, which suppresses the sinus mechanism and allows emergence of the atrioventricular node as the pacemaker. The incidence of junctional rhythm is greater after a second dose of succinylcholine but is prevented by prior administration of dTc.[50] VENTRICULAR DYSRHYTHMIAS.

Under stable anesthetic conditions, succinylcholine lowers the threshold of the ventricle to catecholamine-induced dysrhythmias in the monkey and dog. Circulating catecholamine concentrations increase fourfold and potassium concentrations increase by a third after administration of succinylcholine to dogs.[51] Similar increases in catecholamine levels after administration of succinylcholine to humans are also observed.[52] Other autonomic stimuli, such as endotracheal intubation, hypoxia, hypercapnia, 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 and cyclopropane, all of which may lower the ventricular threshold for ectopic activity or increase the arrhythmogenic effect of catecholamines, must also be considered. Ventricular escape beats may also occur as a result of severe sinus and atrioventricular nodal slowing secondary to succinylcholine administration. The development of ventricular dysrhythmias is further encouraged by the release of potassium from skeletal muscle as a consequence of the depolarizing action of the drug. Hyperkalemia

Administration of succinylcholine to an otherwise well individual for an elective surgical procedure increases plasma potassium levels by approximately 0.5 mEq/dL. This increase in potassium is due to the depolarizing action of the relaxant. With activation of the acetylcholine channels, movement of sodium into the cells is accompanied by movement of potassium out of the cells. This slight increase in potassium is well tolerated by most individuals and generally does not cause dysrhythmias.

Several early reports suggested that patients in renal failure may be susceptible to a hyperkalemic response to succinylcholine.[53] Nevertheless, more controlled studies have shown that such patients are no more susceptible to an exaggerated response to succinylcholine than those with normal renal function are.[54] One might postulate that patients who have uremic neuropathy may be susceptible to succinylcholine-induced hyperkalemia, although the evidence supporting this view is scarce. [53] [54]

However, severe hyperkalemia may follow the administration of succinylcholine to patients with severe metabolic acidosis and hypovolemia.[55] In rabbits, the combination of metabolic acidosis and hypovolemia results in a high resting potassium level and an exaggerated hyperkalemic response to succinylcholine.[56] In this situation, the potassium originates from the gastrointestinal tract, not from muscle as in the classic hyperkalemic response.[57] In patients with metabolic acidosis and hypovolemia, correction of the acidosis by hyperventilation and administration of sodium bicarbonate should be attempted before administration of succinylcholine. Should severe hyperkalemia occur, it can be treated

with immediate hyperventilation, 1.0 to 2.0 mg of calcium chloride intravenously, 1 mEq/kg of sodium bicarbonate, and 10 units of regular insulin in 50 mL of 50% glucose for adults or, for children, 0.15 units of regular insulin per kilogram in 1.0 mL/kg of 50% glucose.

Kohlschtter and associates[58] found that four of nine patients with severe abdominal infections had an increase in serum potassium levels of as much as 3.1 mEq/L after the administration of succinylcholine. These investigators found that in patients with intra-abdominal infections persisting for longer than 1 week, the possibility of a hyperkalemic response to succinylcholine should be considered.

Stevenson and Birch[59] described a single, well-documented case of a marked hyperkalemic response to succinylcholine in a patient with a closed head injury but no peripheral paralysis.

In studying soldiers who had undergone trauma during the Vietnam War, Birch and colleagues[60] found that a significant increase in serum potassium did not occur in 59 patients until about 1 week after the injury, at which time a progressive increase in the serum potassium level was noted after the infusion of succinylcholine. Three weeks after injury, three of these patients with especially severe trauma showed marked hyperkalemia with an increase in serum potassium of greater than 3.6 mEq/L, sufficient to cause cardiac arrest. Birch and coworkers[60] found that 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 susceptible to the hyperkalemic response for probably at least 60 days after massive trauma or until adequate healing of damaged muscle has occurred.

In addition, patients with any number of conditions that result in the proliferation of extrajunctional acetylcholine receptors, such as neuromuscular disease, are likely to have an exaggerated hyperkalemic response after the administration of succinylcholine. The response of these patients to neuromuscular blocking agents is reviewed in detail later in this chapter. These disease states include cerebrovascular accident with resultant hemiplegia or paraplegia, muscular dystrophies, and Guillain-Barr syndrome (see also Chapter 37 ). The hyperkalemia occurring after the administration of succinylcholine may be of such an extent that cardiac arrest ensues. For a recent review on succinylcholine-induced hyperkalemia in patients with acquired pathologic states, see Martyn and Richtsfeld.[61] Increased Intraocular Pressure

Succinylcholine usually causes an increase in intraocular pressure (IOP). The increased IOP is manifested within 1 minute after injection, peaks at 2 to 4 minutes, and subsides by 6 minutes.[62] The mechanism by which succinylcholine increases IOP has not been clearly defined, but it is known to involve contraction of tonic myofibrils or transient dilatation of choroidal blood vessels (or both). Sublingual administration of nifedipine has been reported to attenuate the increase in IOP from succinylcholine, thus suggesting a circulatory mechanism.[63] Despite this increase in IOP, the use of succinylcholine for eye operations is not contraindicated unless the anterior chamber is open. Although Meyers and associates[64] were unable to confirm the efficacy of precurarization in attenuating increases

in IOP after the administration of succinylcholine, numerous other investigators have found that prior administration of a small dose of nondepolarizing neuromuscular blocker (such as 3 mg of dTc or 1 mg of pancuronium) will prevent a succinylcholine-induced increase in IOP.[65] Furthermore, Libonati and coauthors[66] described the anesthetic management of 73 patients with penetrating eye injuries who received succinylcholine; no loss of global contents resulted. Thus, despite the potential concerns of Meyers and coworkers,[64] Libonati and colleagues[66] found that the use of succinylcholine in patients with penetrating eye injuries, after pretreatment with a nondepolarizing neuromuscular blocker and with carefully controlled, rapid-sequence induction of anesthesia, is an acceptable technique. Succinylcholine is only one of many factors, such as endotracheal intubation and bucking on the tube, that may elevate IOP.[64] Of prime importance is ensuring that the patient is well anesthetized and not straining or coughing. Because nondepolarizing neuromuscular blockers with shorter times to onset of effect are now available, providing an anesthetic that allows the trachea to be intubated rapidly without administering succinylcholine is now an option. Finally, should a patient's anesthesia become too light over the course of intraocular surgery, succinylcholine should not be given to immobilize the patient. Rather, the surgeon should be asked to pause while the anesthesia is deepened. If necessary, the depth of neuromuscular blockade can also be increased with nondepolarizing relaxants. Increased Intragastric Pressure

Unlike the rather consistent increase in IOP, the increase in intragastric pressure (IGP) caused by succinylcholine is quite variable. The increase in IGP from succinylcholine is presumed to be due to fasciculations of abdominal skeletal muscle. This is not surprising because more coordinated abdominal skeletal muscle activity (e.g., straight-leg raising) may increase IGP to values as high as 120 cm H2O. In addition to skeletal muscle fasciculations, the acetylcholine-like effect of succinylcholine may be partly responsible for the observed increases in IGP. Greenan[67] noted consistent increases in IGP of 4 to 7 cm H2O with direct vagal stimulation.

Miller and Way[68] found that 11 of 30 patients had essentially no increase in IGP after the administration of succinylcholine, yet 5 of the 30 had an increase in IGP of greater than 30 cm H2O. The increase in IGP from succinylcholine appeared to be related to the intensity of the abdominal skeletal muscle fasciculations. Accordingly, when fasciculations were prevented by prior administration of a nondepolarizing neuromuscular blocker, no increase in IGP was observed.

Are the increases in IGP after succinylcholine administration enough to cause incompetence of the gastroesophageal junction? Generally, an IGP of greater than 28 cm H2O 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, an abdomen distended by ascites, bowel obstruction, or a hiatal hernia, the IGP required to cause incompetence of the gastroesophageal junction is frequently less than 15 cm H2O.[68] In these circumstances, regurgitation of stomach contents after the administration of succinylcholine is a distinct possibility, and precautionary measures should be taken to prevent fasciculation. Endotracheal intubation may be facilitated by administration of either a nondepolarizing neuromuscular blocker or a defasciculating dose of a nondepolarizing relaxant before the succinylcholine.

Apparently, succinylcholine does not increase IGP appreciably in infants and children, which may be related to the minimal or absent fasciculations from succinylcholine in these age groups.[69] Increased Intracranial Pressure

Succinylcholine has the potential to increase intracranial pressure.[70] The mechanisms and clinical significance of this transient increase are unknown, but the rise in intracranial pressure does not occur after pretreatment with nondepolarizing neuromuscular blockers.[70] Myalgias

The incidence of muscle pain after the administration of succinylcholine varies from 0.2% to 89%.[71] It occurs more frequently after minor surgery, especially in women and in ambulatory rather than bedridden patients.[72] Waters and Mapleson[72] postulated that the pain is secondary to damage produced in muscle by the unsynchronized contractions of adjacent muscle fibers just before the onset of paralysis. That damage to muscle may occur has been substantiated by finding myoglobinemia and increases in serum creatine kinase after succinylcholine administration.[73] Prior administration of a small dose of a nondepolarizing neuromuscular blocker clearly prevents succinylcholine-related fasciculations.[73] However, the efficacy of this approach in preventing muscle pain is questionable. Although some investigators claim that pretreatment with a defasciculating dose of a nondepolarizing neuromuscular blocker has no effect,[71] many believe that the pain from succinylcholine is at least attenuated.[73] Pretreatment with a prostaglandin inhibitor (e.g., lysine acetyl salicylate) has been shown to be effective in decreasing the incidence of muscle pain after succinylcholine.[74] This suggests a possible role for prostaglandins and cyclooxygenases in succinylcholine-induced myalgias. Other investigators have found that myalgias after outpatient surgery occur even in the absence of succinylcholine.[75] Masseter Spasm

An increase in tone of the masseter muscle is a frequent response to succinylcholine in adults[76] and children.[77] Meakin and coworkers[77] suggested that the high incidence of spasm in children may be due to an 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, it is not consistently associated with that syndrome.[78] There is currently no indication to change to a nontriggering anesthetic in instances of isolated masseter spasm.[79] Clinical Uses

Despite its many adverse effects, succinylcholine remains in common use. Its popularity is probably due to its rapid onset of effect, the profound depth of neuromuscular blockade that it produces, and its short duration of action. Although it may be less commonly used than in the past for routine endotracheal intubation, it is the neuromuscular blocker of choice for rapid-sequence induction of anesthesia. In a study comparing intubating conditions after the administration of 1 mg/kg of

succinylcholine with those after the administration of 0.1 mg/kg of vecuronium or 0.1 mg/kg of pancuronium 30 seconds after administration of the relaxant and at 30-second intervals after that up for 120 seconds, intubation could be accomplished in all patients receiving succinylcholine at 30 seconds, in contrast with the other neuromuscular blockers studied.[80] Furthermore, at all time points studied up to 90 seconds, intubating conditions were better after the administration of succinylcholine than after either of the other neuromuscular blockers. Although 1.0 mg/kg of succinylcholine has long been recommended to facilitate endotracheal intubation at 60 seconds, a recent study indicated that 0.5 to 0.6 mg/kg of succinylcholine should allow adequate intubating conditions 60 seconds after administration. [81] Reduction of the succinylcholine dose from 1.0 mg/kg to 0.6 mg/kg decreased the incidence of hemoglobin saturation from 85% to 65% but did not shorten the time to spontaneous diaphragmatic movement.[82] However, a significant fraction of patients would be at risk if there were failure to intubate and ventilate regardless of whether succinylcholine is administered or the dose of succinylcholine administered.[82]

A small dose of nondepolarizing neuromuscular blocker is commonly given 2 minutes before the intubating dose of succinylcholine. This defasciculating dose of nondepolarizing neuromuscular blocker will attenuate any increases in IGP and intracranial pressure and minimize the incidence of fasciculations in response to succinylcholine. Prior administration of a nondepolarizing agent will render the muscle relatively resistant to succinylcholine, however, so the succinylcholine dose should be increased by 50%.[83] The use of a defasciculating dose of a nondepolarizing neuromuscular blocker may also slow the onset of succinylcholine and produce less favorable conditions for tracheal intubation.[73]

Typically after administration of succinylcholine for intubation, a nondepolarizing neuromuscular blocker is given to maintain neuromuscular blockade. Succinylcholine given first may enhance the depth of blockade induced by a subsequent dose of nondepolarizing neuromuscular blocker. [84] [85] [86] However, the effect on duration of action is variable. Succinylcholine has no effect on the duration of action of pancuronium, pipecuronium, or mivacurium [86] [87] but increases that of atracurium and rocuronium. [84] [85] The reasons for these differences are not clear.

The changing characteristics of succinylcholine neuromuscular blockade over the course of prolonged administration have been reviewed by Lee and Katz[88] and are summarized in Table 29-2. TOF stimulation is a very safe and useful guide for detecting the transition from a phase 1 to a phase 2 block. A phase 1 block has all the characteristics of a depolarizing block as described previously in the monitoring section. A phase 2 block has the characteristics of a nondepolarizing block. With the administration of large doses of succinylcholine, the nature of the block, as determined by a neuromuscular blockade monitor, changes from that of a depolarizing agent to that of a nondepolarizing agent. Clearly, both the dose and the duration of administration of succinylcholine are important variables, although the relative contribution of each has not been established. In practical terms, if administration of the drug is terminated shortly after TOF fading is clearly evident, rapid return of normal neuromuscular function should ensue. In addition, the decision whether to attempt antagonism of a phase 2 block has always been controversial. However, if the TOF ratio is less than 0.4, administration of edrophonium or neostigmine should result in prompt antagonism. Ramsey and associates[89] recommended that antagonism of a succinylcholine-induced phase 2 block with

edrophonium or neostigmine be attempted after spontaneous recovery of the twitch has been observed for 20 to 30 minutes and has reached a plateau phase with further recovery proceeding slowly. These researchers stated that in this situation, edrophonium and neostigmine invariably produce dramatic acceleration of the return of the TOF ratio toward normal.[89] In any event, monitoring neuromuscular function via TOF stimuli will help avoid succinylcholine overdose, detect the development of phase 2 blockade, observe its rate of recovery, and assess the effect of edrophonium or neostigmine on recovery. Table 29-2 -- Clinical characteristics of phase 1 and phase 2 neuromuscular blockade during succinylcholine infusion Characteristic Tetanic stimulation Post-tetanic facilitation Train-of-four fade Train-of-four ratio Edrophonium Recovery Dose requirements (mg/kg) * Tachyphylaxis Phase 1 No fade None No >0.7 Transition Slight fade Slight Moderate fade 0.4-0.7 Fade Yes Marked fade <0.4 Antagonizes Increasingly prolonged >6 Yes Phase 2

Augments Little effect Rapid 2-3 No Rapid to slow 4-5 Yes

Adapted from Lee C, Katz RL: Neuromuscular pharmacology. A clinical update and commentary. Br J Anaesth 52:173-188, 1980.
*

Cumulative dosage of succinylcholine by infusion under nitrous oxide anesthesia supplemented with intravenous agents. The dosage required to cause a phase 2 block is less in the presence of potent anesthetic vapors, such as isoflurane.

A recent study showed that post-tetanic potentiation and fade in response to TOF and tetanic stimuli are characteristics of neuromuscular blockade after bolus administration of different doses of succinylcholine.[25] It seems that some characteristics of phase 2 blockade are evident after an initial dose of succinylcholine (i.e., as small as 0.3 mg/kg).[25] Interactions with Anticholinesterases

Another interaction with succinylcholine involves neostigmine or pyridostigmine. For example, after dTc has been used for intra-abdominal surgery of long duration and the neuromuscular blockade has been reversed by neostigmine, the surgeon announces that another 15 minutes is needed to retrieve a missing sponge. Succinylcholine should not be administered to reestablish neuromuscular blockade because it produces relaxation that will last up to 60 minutes when given soon after the administration

of neostigmine. Sunew and Hicks[36] found that the effect of succinylcholine (1 mg/kg) was prolonged from 11 to 35 minutes when given 5 minutes after the administration of neostigmine (5 mg). This can be partly explained by the inhibition of butyrylcholinesterase by neostigmine and, to a lesser extent, by pyridostigmine. Ninety minutes after the administration of neostigmine, butyrylcholinesterase activity will have returned to less than 50% of its baseline value. Nondepolarizing Neuromuscular Blockers The use of neuromuscular blocking drugs in anesthesia has its origin in the South American Indians arrow poisons or curare. Several nondepolarizing neuromuscular blockers are still purified from naturally occurring sources. For example, although dTc can be synthesized, it is still less expensive to isolate from the Amazonian vine Chondodendron tomentosum. Similarly, intermediates for the production of metocurine and alcuronium, which are semisynthetic, are obtained from Chondodendron and Strychnos toxifera. Malouetine, the first steroidal neuromuscular blocking drug, was originally isolated from Malouetia bequaertiana, which grows in the jungles of the Democratic Republic of Congo in central Africa. The agents pancuronium, vecuronium, pipecuronium, rocuronium, rapacuronium, atracurium, doxacurium, mivacurium, cisatracurium, gantacurium, and gallamine are entirely synthetic.

The available nondepolarizing neuromuscular blockers can be classified according to chemical class (steroidal, benzylisoquinolinium, or other compounds) or, alternatively, according to onset or duration of action (long-, intermediate-, and short-acting drugs) of equipotent doses ( Table 29-3 ). Table 29-3 -- Classification of nondepolarizing neuromuscular blockers according to duration of action (time to T1 = 25% of control) after twice the ED95 Class of Blocker Clinical Duration LongActing (>50 min) Steroidal compounds IntermediateActing (20-50 min) Short-Acting Ultrashort-acting (15-20 min) (<10-12 min)

Pancuroniu Vecuronium m Rocuronium Pipecuroniu m dAtracurium Tubocurarin Cisatracurium e Metocurine Doxacurium Mivacurium

Benzylisoquinolinium compounds

Others Asymmetrical mixedonium chlorofumarates Gantacurium

Phenolic ether Diallyl derivative of toxiferine

Gallamine Alcuronium

A majority of nondepolarizing neuromuscular blockers are bisquaternary ammonium compounds. d-Tubocurarine, vecuronium, rocuronium, and rapacuronium are monoquaternary compounds, and gallamine is a trisquaternary ammonium compound.

Structure-Activity Relationships

Nondepolarizing neuromuscular blocking drugs were originally classified by Bovet[27] as pachycurares, or bulky molecules having the amine functions incorporated into rigid ring structures. Two extensively studied chemical series of synthetic nondepolarizing neuromuscular blockers are the aminosteroids (steroidal), 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 of structure-activity relationships, see Lee.[90] Benzylisoquinolinium Compounds

dTc is a neuromuscular blocker in which the amines are present in the form of two benzyl-substituted tetrahydroisoquinoline structures ( Fig. 29-7 ). The quaternary or tertiary nature of the two amines was initially questioned; however, with the use of nuclear magnetic resonance spectroscopy and methylation-demethylation studies, Everett and coworkers[91] demonstrated that dTc contains only 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 to render it positively charged. The structure-activity relationships of the bis-benzylisoquinolines (see Fig. 29-7 ) have been described by Waser[92] and by Hill and associates[93] as follows: 1. The nitrogen atoms are incorporated into isoquinoline ring systems. This bulky molecule favors nondepolarizing rather than 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 are probably due to 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 with greater potency (by a factor of 2 in humans) but much

weaker ganglion-blocking and histamine-releasing properties than dTc has (see Fig. 29-7 ). 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 analogs. The bisquaternary derivative of dTc, chondocurine, has more than double the potency of dTc ( Fig. 29-7 ). 6. Substitution of the methyl groups on the quaternary nitrogen with bulkier groups causes a reduction in both potency and duration of action.

Figure 29-7 Chemical structures of d-tubocurarine, metocurine, and chondocurine.

Atracurium is a bis-benzyltetrahydroisoquinolinium with isoquinolinium nitrogens connected by a diester-containing hydrocarbon chain ( Fig. 29-8 ). The presence (in duplicate) of two-carbon separations between quaternary nitrogen and ester carbonyl provides the basis for a Hofmann elimination reaction.[94] Furthermore, it can undergo ester hydrolysis. In a Hofmann elimination reaction, a quaternary ammonium group is converted to a tertiary amine by cleavage of a carbonnitrogen bond. This is a pH- and temperature-dependent reaction in which higher pH and temperature favor elimination. The actual structure of the quaternary centers is the laudanosinium moiety, as in metocurine. Atracurium has four chiral centers at each of the adjacent chiral carbons of the two amines. The marketed product has 10 isomers.[94] 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.[94] The ratio of the cis-cis, cis-trans, and trans-trans isomers is approximately 10:6:1, which corresponds to 50% to 55% cis-cis, 35% to 38% cis-trans, and 6% to 7% trans-trans isomers.

Figure 29-8 Chemical structures of atracurium, cisatracurium, mivacurium, and doxacurium. The asterisks indicate chiral centers; arrows show cleavage sites for Hofmann elimination.

Cisatracurium is the 1R cis1R cis isomer of atracurium and represents about 15% of the marketed atracurium mixture by weight but more than 50% in terms of potency or neuromuscular blocking

activity (see Fig. 29-8 ). 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. [95] [96] Cisatracurium is metabolized by Hofmann elimination. It is approximately four times as potent as atracurium, but unlike atracurium, it does not cause release of histamine in the clinical dose range. [95] [97] This indicates that the phenomenon of histamine release may be stereospecific. [95] [98] Cisatracurium is the second benzylisoquinolinium (after doxacurium) to be largely free of this side effect.

Mivacurium differs from atracurium by the presence of an additional methylated phenolic group (see Fig. 29-8 ). When compared with other isoquinolinium neuromuscular blockers, the interonium chain of mivacurium is longer (16 atoms).[93] Mivacurium consists of a mixture of three stereoisomers.[99] The two most active are the trans-trans and cis-trans isomers (57% and 37% wt/wt, respectively), which are equipotent; the cis-cis isomer (6% wt/wt) has only a 10th the activity of the others in cats and monkeys.[99] Mivacurium is metabolized by butyrylcholinesterase at 70% to 88% the rate of succinylcholine to a monoester, a dicarboxylic acid.[9]

Doxacurium is a bisquaternary benzylisoquinolinium diester of succinic acid (see Fig. 29-8 ). The interonium chain is shorter than that of either atracurium or mivacurium. Lee[90] pointed out that the number of methoxy groups on benzylisoquinolinium heads is increased from four (atracurium) and five (mivacurium) to six (doxacurium).[93] This increase was associated with both an increase in potency and a reduction in the propensity to release histamine. [90] [93] Steroidal Neuromuscular Blockers

In the steroidal compounds, it is probably essential that one of two nitrogen atoms in the molecule be quaternized. The presence of acetyl ester (acetylcholine-like moiety) is thought to facilitate its 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 neuromuscular blocking drug with both vagolytic and butyrylcholinesterase-inhibiting properties ( Fig. 29-9 ).[100] Deacetylation of the 3-OH or 17-OH groups decreases its potency.[101]

Figure 29-9 Chemical structures of different steroidal neuromuscular blockers.

Vecuronium is the N-demethylated derivative of pancuronium in which the 2-piperidine substituent is not methylated (i.e., vecuronium lacks the N-methyl group at position 2) (see Fig. 29-9 ).[7] At physiologic pH, the tertiary amine is largely protonated, as it is in dTc. The minor molecular modification relative to pancuronium results in (1) a slight change in potency; (2) a marked reduction in vagolytic properties; (3) molecular instability in solution, which explains in part the shorter duration of action of vecuronium than pancuronium; and (4) increased lipid solubility, which results in greater biliary elimination of vecuronium than pancuronium.[93]

Pancuronium and vecuronium are very similar in structure, yet vecuronium is prepared as a lyophilized powder. Vecuronium is degraded by the hydrolysis of acetyl esters at either or both the C3 and C17 positions. Hydrolysis at the C3 position is the primary degradation product. The acetate at position 3 is more susceptible to hydrolysis in aqueous solutions. Vecuronium is less stable in solution because of the group effect of the adjacent basic piperidine at position 2, which 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 pancuronium, the 2-piperidine is quaternized and no longer alkaline. Thus, it does not participate in catalysis of the 3-acetate hydrolysis.

Pipecuronium, like pancuronium, is a bisquaternary compound. Pipecuronium has piperazine rings attached to the A and D rings of the steroid nucleus, whereas pancuronium has piperidine rings (see Fig. 29-9 ).[93] Pipecuronium is a nonvagolytic substitute for pancuronium. Changes in the quaternary groups in which the quaternary nitrogen atoms are placed at the distal (4-position) aspect of the 2,16-substitutions lessen the vagolytic effects.[93] As a result, pipecuronium is about 10 times less vagolytic than pancuronium.

Rocuronium lacks the acetyl ester that is found in the steroid nucleus of pancuronium and vecuronium in the A ring (see Fig. 29-9 ). The introduction of cyclic substituents other than piperidine at the 2- and 16-positions results in a fast-onset compound.[102] The methyl group attached to the quaternary nitrogen of vecuronium and pancuronium is replaced by an allyl group in rocuronium. As a result, rocuronium is about 6 and 10 times less potent than vecuronium and pancuronium, respectively. [102] [103] [104] Replacement of the acetyl ester attached to the A ring by a hydroxy group has made it possible to present rocuronium as a stable solution. At room temperature, rocuronium is stable for only 60 days, whereas 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 Chlorofumarates

Gantacurium ( Fig. 29-10 ) represents a new class of nondepolarizing neuromuscular blockers called asymmetric mixed-onium chlorofumarates. The presence of three methyl groups between the quaternary nitrogen and oxygen atom at each end of the carbon chain suggests that similar to mivacurium, this compound will not undergo Hofmann elimination.[105] Gantacurium has an ultrashort duration of action in human volunteers and in different animal species. A study in anesthetized human volunteers using an earlier formulation of gantacurium estimated the ED95 to be 0.19 mg/kg.[106] The pattern of blockade resembled that of succinylcholine. The time to onset of 90% blockade ranged from 1.3 to 2.1 minutes, depending on the dose. Clinical durations ranged from 4.7 to 10.1 minutes and increased with increasing dose. Spontaneous recovery to a TOF of 0.9 develops in the thumb within about 12 to 15 minutes after the administration of doses as large as 0.54 mg/kg (or three times the ED95). Recovery is accelerated by edrophonium. Transient cardiovascular side effects were observed at doses beginning at three times the ED95 and were suggestive of histamine release.[106]

Figure 29-10 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 46:2502-2515, 2003.)

Phenolic Ether Derivative

Gallamine is a trisquaternary compound ( Fig. 29-11 ). Its potent vagolytic activity is due to the

presence of three positively charged nitrogen atoms. Gallamine was originally synthesized by Bovet[27] as part of an extensive structure-activity study that helped evolve the concepts of pachycurares and leptocurares. Succinylcholine also evolved from this work, for which Bovet received the Nobel Prize.

Figure 29-11 Chemical structure of gallamine, a trisquaternary ether of gallic acid. Gallamine is the only trisquaternary compound available. Its strong vagolytic property is probably due to its trisquaternary structure. Diallyl Derivative of Toxiferine

Introduced in 1964, alcuronium is a long-acting agent that is the semisynthetic diallyl derivative of toxiferine ( Fig. 29-12 ). The latter is purified from Strychnos toxifera. The advantage of alcuronium at the time of its introduction was a relative lack of side effects. It is mildly vagolytic and is excreted unchanged by the kidney with a minor secondary biliary pathway.

Figure 29-12 Chemical structure of alcuronium, the semisynthetic diallyl derivative of toxiferine. The quaternizing allyl groups actually reduce its potency by a factor of 3 to 5. Potency of Nondepolarizing Neuromuscular Blockers

Drug potency is commonly expressed by the dose-response relationship. The dose of a neuromuscular blocking drug required to produce an effect (e.g., 50%, 90%, or 95% depression of twitch height, commonly expressed as ED50, ED90, and ED95, respectively) is taken as a measure of its potency. [9] [11] [103] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] The neuromuscular blocking drugs have different potencies, as illustrated in Table 29-4 and Figure 29-13 . For factors affecting the potency of neuromuscular blockers, see the section on drug interactions later in this chapter. The dose-response relationship for nondepolarizing neuromuscular blockers is sigmoidal in shape (see Fig. 29-13 ) 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 can be subjected to nonlinear regression using the sigmoid Emax model of the formThis can be applied to the raw data.[119] More complex models relating the concentration of neuromuscular blockers at the

neuromuscular junction to their pharmacologic effect have been developed, as discussed later. [120] [121] Table 29-4 -- Dose-response relationships of nondepolarizing neuromuscular blocking drugs in human subjects ED50 (mg/kg) LongActing Pancuroniu 0.036 (0.022m 0.042) d0.23 (0.16Tubocurari 0.26) ne Intermedia te-Acting Rocuroniu 0.147 (0.069m 0.220) Vecuroniu 0.027 (0.015m 0.031) Atracurium 0.12 (0.080.15) Cisatracuri 0.026 (0.015um 0.031) ShortActing Mivacuriu 0.039 (0.027m 0.052) Ultrashort -Acting Gantacuriu 0.09 m 0.19 106 0.067 (0.0450.081) 9, 113-115 [9] [113] [114] [115] 0.268 (0.2000.419) 0.042 (0.0230.055) 0.18 (0.190.24) 0.305 (0.2570.521) 0.043 (0.0370.059) 0.21 (0.130.28) 0.04 (0.0320.05) 103, 108-110 [103] [108] [109] [110] 107 107 11, 111, 112, 118 [11] [111] [112] [118] 0.056 (0.0440.070) 0.41 (0.270.45) 0.067 (0.0590.080) 0.48 (0.340.56) 103, 107 [103] [107] 107 ED90 (mg/kg) ED95 (mg/kg) Reference(s)

Data are medians and ranges of reported values. ED50, ED90, and ED95 are the doses of each drug that produce, respectively, a 50%, 90%, and 95% decrease in the force of contraction or amplitude of the electromyogram of the adductor pollicis muscle after ulnar nerve stimulation.

Figure 29-13 Schematic representation of a semilogarithmic plot of a muscle relaxant dose versus neuromuscular blockade. A drug of high potency is doxacurium; one of medium potency, atracurium; and one of low potency, gallamine. The graph illustrates that the relative potencies of muscle relaxants span a range of approximately 2 orders of magnitude. Pharmacokinetics and Pharmacodynamics

As defined by Wright,[122] pharmacokinetics and pharmacodynamics are empirical mathematical model[s] that [describe] drug effect time course after administration. In pharmacokinetic modeling, the concept of compartments represents different organs or tissues (or both) grouped together on the basis of their degree of blood perfusion (high or low). After a neuromuscular blocker is injected into the circulation, its concentration in plasma decreases rapidly at first and then more slowly ( Fig. 2914 ). The shape of this curve is determined by the processes of distribution and elimination. Classically,

this curve is divided into an initial (distribution) phase and a terminal (elimination) phase. This curve can be represented mathematically by biexponential or triexponential equations in the formThese multiexponential equations express the concept of drug distribution between two or three theoretical compartments.

Figure 29-14 Disappearance of vecuronium from plasma after a single bolus dose of 0.2 mg/kg as shown in a semilogarithmic plot of mean concentration versus time for patients with normal hepatic function (yellow circles) and cirrhotic patients (blue circles). Error bars are the standard deviation for that value. (From Lebrault C, Berger JL, DHollander AA, et al: Pharmacokinetics and pharmacodynamics of vecuronium (ORG NC 45) in patients with cirrhosis. Anesthesiology

62:601-605, 1985.)

Figure 29-15 illustrates the classic model, in which the drug is administered intravenously into a central compartment with volume V1 and is distributed and eliminated from this compartment only. The drug is distributed very rapidly throughout this central compartment, which includes the plasma volume and the organs of elimination; in the case of neuromuscular blockers, the organs of elimination are the kidneys and liver. The k terms are the rate constants for movement of drug between compartments in the direction of the arrows. The peripheral compartments (usually one or two, here represented by V2 and V3) can be thought of as the tissues. The effect compartment, which will be discussed later, is the neuromuscular junction. For computational purposes, it has infinitesimal volume and therefore does not influence overall drug distribution. Drug administration and elimination are unidirectional; distribution is bidirectional.

Figure 29-15 Schematic representation of drug disposition into different compartments. These compartments are mathematical concepts only and do not represent real physiologic spaces. The effect compartment in this case would be the neuromuscular junction; for computational purposes, it has infinitesimal volume. The terms knm are the rate constants for drug movement, in

the direction of the arrow, between these theoretical compartments. See text for further discussion.

Initially, the drug concentration in the central compartment (i.e., the plasma concentration) will exceed that in the peripheral compartment (i.e., the tissue concentration), and the drug will move from plasma to tissues. Later, as the plasma concentration decreases, it becomes less than the tissue concentration, and the net direction of drug movement is now from tissues to plasma. In general, this conceptual model is appropriate for all the neuromuscular blockers, with the exception of atracurium and cisatracurium, which also undergo elimination (by degradation) from tissues.[123] For simplicity, the following discussion assumes the presence of only one peripheral compartment.

The volume of distribution is the volume to which the drug has distributed when the processes of distribution and elimination are in equilibrium. Elimination is represented by the variable plasma clearance, that is, the volume of plasma from which the drug is irreversibly and completely eliminated per unit time. For most nondepolarizing neuromuscular blockers, the process of distribution is more rapid than the process of elimination, and the initial rapid decline in plasma concentration is due primarily to distribution of the drug to tissues. An exception to this rule is mivacurium, which has such rapid clearance, because of metabolism by butyrylcholinesterase, that elimination is the principal determinant of the initial decline in plasma concentration.

After the initial process of drug distribution to tissues, the plasma concentration falls more slowly (the terminal phase). The rate of decrease in plasma concentration during this terminal phase is often expressed in terms of elimination half-life, which equals the natural logarithm of 2 divided by the rate constant of decline (i.e., the slope of the terminal phase). During this terminal phase, the concentration of drug in the tissue exceeds that in plasma, and the rate of decrease in plasma concentration is determined by two factors: the rate at which drug can move from tissues back into plasma and clearance of drug from plasma. In classic theory for neuromuscular blockers, the drug can move rapidly from tissues into plasma, and its elimination from plasma (i.e., clearance) is the rate-limiting step. For this reason, the terminal portion of the curve is often termed the elimination phase, even though the distribution of drug from tissues into plasma occurs continually throughout. The volume of distribution can also influence the terminal portion of the curve: the greater the volume of distribution, the slower the decline in plasma concentration.

The neuromuscular blockers are polar drugs, and their volume of distribution is classically thought to be limited to a volume roughly equivalent to a portion of the extracellular fluid space, namely, 150 to 450 mL/kg (see Tables 29-13 and 29-14 [0130] [0140]).[124] With this model of drug distribution, the potential rate of drug movement from tissues to plasma exceeds the rate of elimination, and plasma clearance is the process that limits the rate of decline in plasma drug concentration. However, there is evidence that neuromuscular blockers are distributed more widely into tissues with low blood flow (e.g., connective tissue),[125] and the true volume of distribution of dTc has been estimated to be as high as 3.4 L/kg and its elimination half-life as long as 40 hours (compare with values in Tables 29-13 and 29-14 [0130] [0140]).[126] Because the rate of drug movement from such tissues is less than that of plasma clearance, this becomes the limiting step in the rate of decline in plasma drug concentration.

This phase becomes obvious only when drug is administered for many days or when sampling is continued for 24 to 96 hours after drug administration. In normal operating room use of neuromuscular blockers, the amount of drug that is distributed to this compartment does not affect clinical response to the drug. In conditions in which clearance of the neuromuscular blocker is reduced, such as renal or hepatic disease, the terminal portion of the plasma concentration-versus-time curve is most affected (see Fig. 29-14 ).[127] The rate of decline in plasma concentration is slowed, and recovery from paralysis is potentially delayed.[127] In conditions associated with an increased volume of distribution, such as renal or hepatic disease, early plasma concentrations of drug may be less than those observed when organ function is normal: with a greater volume of distribution, the plasma concentration should be less, whereas the total amount of a drug would be greater ( Fig. 29-16 ). Decreased protein binding of a drug results in a larger distribution volume, but because the degree of protein binding of neuromuscular blockers is small, changes in protein binding will have minimal effect on their distribution.[128]

Figure 29-16 Average plasma concentration (Cp) versus time after a dose of 0.6 mg/kg rocuronium in patients with normal renal function (blue line) or patients undergoing renal transplantation (yellow line). (From Szenohradszky J, Fisher DM, Segredo V, et al: Pharmacokinetics of rocuronium bromide (ORG 9426) in patients with normal renal function or patients undergoing cadaver renal transplantation. Anesthesiology 77:899-904, 1992.)

Recovery of neuromuscular function takes place as plasma concentrations decline, and the greater part of this decrease occurs primarily because of distribution. Thus, processes that primarily affect elimination of the drug, such as renal failure, may not be associated with prolonged duration of blockade. [129] [130] However, as recovery comes to rely more on drug elimination than on distribution (i.e., from 25% to 75% or greater) or after the administration of larger or repeated doses, the duration of action may be prolonged. [123] [131]

After the injection of a neuromuscular blocker, the plasma drug concentration immediately starts to decrease. The effect (neuromuscular blockade) takes approximately 1 minute to begin, increases initially, and does not start to recover for many more minutes despite the continually decreasing plasma concentration of drug. This discrepancy between plasma concentration and drug effect occurs because the action of neuromuscular blockers is not in plasma but at the neuromuscular junction. To produce paralysis, the drug must diffuse from plasma into the neuromuscular junction, and the effect is terminated later by diffusion of drug back into plasma (see Fig. 29-15 ). Thus, concentrations at the neuromuscular junction lag behind those in plasma, and they are lower during the onset of blockade and greater during recovery. The plasma concentration-effect relationship exhibits hysteresis; that is, for a given level of blockade, plasma concentrations are greater during onset than during recovery. For this reason, a concentration-effect relationship cannot be obtained simply by directly relating the plasma concentration to the level of neuromuscular blockade.

To overcome this problem, pharmacodynamic models have been developed to incorporate a factor for the delay caused by diffusion of drug to and from the neuromuscular junction. [84] [120] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] This factor, ke0, is the rate constant for equilibration of drug between plasma and the neuromuscular junction. By measuring plasma drug concentrations and neuromuscular blockade during both the onset and recovery phases and using the technique of simultaneous pharmacokinetic/pharmacodynamic modeling, it is possible to collapse the hysteresis in the plasma concentration-effect curve, estimate actual drug concentrations at the neuromuscular junction, and derive true concentration-effect relationships (Ce50 and ke0) for the neuromuscular blockers ( Table 29-5 ).[120] Table 29-5 -- Pharmacodynamic parameters derived by simultaneous pharmacokinetic/pharmacodynamic modeling Study Group Adducto r Pollicis Ce50 * ke0[] (ng/mL) (min-1) Mivacurium Refer ence

Central link Peripheral link Rocuronium Adult female: Propofol-remifentanil anesthesia, standard model Recirculatory model Volunteers: Propofol-fentanyl anesthesia Infants Children Cisatracurium, 0.075- Adults: Propofol-fentanyl anesthesia 3.0 mg/kg Atracurium Infants Children Young adults Elderly adults Standard model Threshold model Young adults Burn patients No succinylcholine After succinylcholine Vecuronium Young adults Young adults Elderly adults d-Tubocurarine Normal renal function Renal failure Halothane, 0.5%-0.7% Halothane, 1.0%-1.2% Narcotic anesthesia

57 130 684 876 3510 1190 1650

0.169 0.101 0.329 0.129 0.405 0.25 0.32

132 132 133 133 134 135 135

126-158 0.07-0.09 135 363 444 449 436 359 357 669[] 2270[] 454[] 305[] 94 92 106 370 380 360[] 220[] 600[] 0.19 0.16 0.13 0.12 0.12 0.12 0.07 0.10 0.07 0.09 0.17 0.17 0.13 0.16 0.09 0.12 0.15 137 137 138 138 139 139 140 140 84 84 141 142 143 120 120 143 [] 143 [] 143 []

Pancuronium

Young adults

88

141

Ce50 is the concentration of each drug at the neuromuscular junction that produces a 50% decrease in the force of contraction or amplitude of the electromyogram of the adductor pollicis muscle after ulnar nerve stimulation. ke0 is the rate constant for equilibration of drug between plasma and the neuromuscular junction. All groups different from each other. ke0 values calculated as 0.693/ ke0.

Clinical Management

Neuromuscular blockers are used mainly to facilitate tracheal intubation and provide surgical relaxation. The intensity of neuromuscular blockade required varies with the surgical procedure. Important safety issues arise with the use of neuromuscular blockers: cardiovascular and respiratory side effects and the adequacy of recovery to normal neuromuscular function.

Several clinical alternatives to neuromuscular blockers are available that provide adequate surgical relaxation. It is important to keep them all in mind to avoid relying only on neuromuscular blockade to achieve a desired degree of relaxation. Such options include adjustment of the depth of general anesthesia, the use of regional anesthesia, proper positioning of the patient on the operating table, and proper adjustment of 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. Dosage General Dosage Guidelines

It is important to select the proper dosage of a nondepolarizing neuromuscular blocker to ensure that the desired effect is achieved without overdosage (Tables 29-6 and 29-7 [0060] [0070]). In addition to general knowledge of the guidelines, precise practice requires the use of a peripheral nerve stimulator to adjust the relaxant dosage for the individual patient. Overdosage must be avoided for two reasons: to limit the duration of drug effect to match the anticipated length of surgery and to avoid unwanted cardiovascular side effects. Table 29-6 -- Guide to nondepolarizing relaxant dosage (mg/kg) with different anesthetic techniques *

ED95 under N2O/O2

Dose for Intubation

Supplemental Dose after Intubation

Dosage for Relaxation N2O Anesthetic Vapors[]

Long-Acting Pancuronium 0.07 d0.5 Tubocurarine Intermediate -Acting Vecuronium 0.05 Atracurium 0.23 0.1-0.2 0.5-0.6 0.15-0.2 0.6-1.0 0.02 0.1 0.02 0.1 0.05 0.3 0.05 0.3 0.03 0.15 0.04 0.15 0.08-0.12 0.5-0.6 0.02 0.1 0.05 0.3 0.03 0.15

Cisatracurium 0.05 Rocuronium 0.3 Short-Acting Mivacurium Continuous Infusion Dosage (g/kg/min) Required to Maintain 90%-95% Twitch Inhibition under N2O/O2 with Intravenous Agents Mivacurium Atracurium Cisatracurium Vecuronium Rocuronium 3-15 4-12 1-2 0.8-1.0 9-12 0.08

0.2-0.25

0.05

0.1

0.08

The suggested dosages provide good intubating conditions under light anesthesia. Satisfactory abdominal relaxation may be achieved at the dosages listed after intubation without a relaxant

or with succinylcholine. This table is intended as a general guide to dosage. Individual relaxant requirements should be confirmed with a peripheral nerve stimulator.

The potentiation of nondepolarizing relaxants by different anesthetic vapors has been reported to vary 20% to 50%. Recent data suggest, however, that this variation may be much less, particularly in the case of 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.

Table 29-7 -- Pharmacodynamic effects of succinylcholine and nondepolarizing neuromuscular blockers Anesthesia Intubating Approximate Maximu Time to Dose ED95 m Block Maximum (mg/kg) Multiples (%) Block (min) Succiny Narcotic or 0.5 lcholine halothane Succiny Desflurane 0.6 lcholine Succiny Narcotic or 1.0 lcholine halothane Succiny Desflurane 1.0 lcholine Succiny Narcotic lcholine Succiny Narcotic lcholine 1.0 1.0 1.7 2 2 3 3 3 3 100 100 100 100 100 1.4 1.2 1.1 1.1 0.8 Clinical Refe Duration * renc (min) e 6.7 7.6 11.3 9.3 8 9 9 144 145 144 145 146 147 148

Succiny Isoflurane 1.0 lcholine Steroid al Compo unds Rocuron Narcotic ium 0.6

2 2 3 4

100 100 100 100

1.7 1.5 1.3 0.9

36 37 53 73

149 148 148 148

Rocuron Isoflurane 0.6 ium Rocuron Isoflurane 0.9 ium Rocuron Isoflurane 1.2

ium Vecuron Isoflurane 0.1 ium Vecuron Narcotic ium Pancuro Narcotic nium Pancuro Narcotic nium Benzyli soquino linium Compo unds Mivacur Narcotic ium Mivacur Narcotic ium 0.15 0.15 2 2 2 2.6 3.3 3.3 2 2 2 4 8 100 100 100 100 100 100 99 100 100 100 3.3 3 2.8 2.5 2.3 2.1 3.2 7.7 5.2 2.7 1.9 16.8 14.5 18.6 19.7 20.3 21 46 46 45 68 91 9 149 153 9 9 147 11 154 11 11 11 0.1 0.08 0.1 2 2 1.3 1.7 100 100 100 99 2.4 2.4 2.9 4 41 44 86 100 148 150 151 152

Mivacur Halothane 0.15 ium Mivacur Narcotic ium Mivacur Narcotic ium Mivacur Narcotic ium Atracuri Narcotic um Cisatrac Narcotic urium Cisatrac Narcotic urium Cisatrac Narcotic urium Cisatrac Narcotic urium 0.2 0.25 0.25 0.5 0.1 0.1 0.2 0.4

dNarcotic Tubocur arine

0.6

1.2

97

5.7

81

152

For atracurium and mivacurium, slower injection (30 seconds) is recommended to minimize circulatory effects.

Time from injection of the intubating dose to recovery of twitch to 25% of control.

Initial and Maintenance Dosage

The initial dose is determined by the purpose of administration. Traditionally, doses used to facilitate tracheal intubation are twice the ED95 (this also approximates four times the ED50) (see Table 29-6 ). If the trachea has already been intubated without the use of a nondepolarizing blocker or with succinylcholine and the purpose is simply to produce surgical relaxation, a dose slightly less than the ED95 (see Table 29-7 ) should be given, with adjustment upward as indicated by responses evoked by peripheral nerve stimulation. Downward adjustment of the initial dose is necessary in the presence of any of the potent inhaled anesthetics (see the subsection later on drug interactions).

To avoid prolonged residual paralysis, inadequate antagonism of residual blockade, or both, the main goal should be to use the lowest possible dose that will provide adequate relaxation for surgery. Management of individual patients should always be guided by monitoring with a peripheral nerve stimulator. In an adequately anesthetized and monitored patient, there is little reason to completely abolish twitch or TOF responses to peripheral nerve stimulation during maintenance of relaxation. Supplemental (maintenance) doses of neuromuscular blockers should be about one-fourth (in the case of intermediate- and short-acting neuromuscular blockers) to one-tenth (in the case of long-acting neuromuscular blockers) the initial dose and should not be given until there is clear evidence of beginning of recovery from the previous dose.

Maintenance of relaxation by continuous infusion of intermediate- and short-acting drugs can be performed and is useful to keep the relaxation smooth and to rapidly adjust the depth of relaxation according to surgical needs. The depth of blockade in each patient is kept moderate, if possible, to ensure prompt spontaneous recovery or easy reversal at the end of the procedure. Table 29-6 lists the approximate dose ranges that are usually required during infusion to maintain 90% to 95% blockade of the twitch (one twitch visible on TOF stimulation) under nitrous oxideoxygen anesthesia supplemented with intravenous anesthetics. The infusion dosage is usually decreased by 30% to 50% in the presence of potent inhaled anesthetics. Neuromuscular Blockers and Tracheal Intubation

The speed of onset of neuromuscular blockade is one of the requirements for rapidly securing the airway, and it is affected by several factors, including the rate of delivery of drug to the neuromuscular junction, receptor affinity, plasma clearance, and the mechanism of neuromuscular blockade (depolarizing versus nondepolarizing). [101] [155] [156] The speed of onset is inversely proportional to the potency of nondepolarizing neuromuscular blockers. [101] [155] A high ED95 (i.e., low potency) is predictive of rapid onset of effect and vice versa ( Fig. 29-17 ; Table 29-7 ). Except for atracurium,[157] the molar potency (the ED50 or ED95 expressed as M/kg) is highly predictive of a drug's initial rate of onset of effect (at the adductor pollicis).[155] A drug's measured molar potency is the end result of many contributing factors: the drug's intrinsic potency (Ce50the biophase concentration resulting in 50% twitch depression), the rate of equilibration between plasma and the biophase (ke0), the initial rate of plasma clearance, and probably other factors as well.[158] Rocuronium has a molar potency (ED95) of 0.54 M/kg, which is about 13% that of vecuronium and only 9% that of cisatracurium. Thus, rapid onset of rocuronium's effect (at the adductor pollicis) is not unexpected.

Figure 29-17 Linear regression of the onset of neuromuscular blockade (ordinate) versus potency of a series of steroidal relaxants studied in the cat model by Bowman and colleagues.[101] The data show that onset may be increased in compounds of low potency and encouraged the eventual development of rocuronium and rapacuronium (ORG 9487). A, pipecuronium; C, pancuronium; D, vecuronium.

Donati and Meistelman[156] proposed a model to explain this inverse potency-onset relationship. Nondepolarizing neuromuscular blockers 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,[156] a process that occurs with more potent drugs. Buffered diffusion causes repetitive binding and unbinding to receptors, which keeps potent drugs in the neighborhood of the effector sites and potentially lengthens the duration of effect.

The times to 95% blockade at the adductor pollicis after administration of the ED95 dose of succinylcholine, rocuronium, vecuronium, atracurium, mivacurium, and cisatracurium are shown in Figure 29-18 . [117] [155] [157] This illustration shows that the most potent compound, cisatracurium, has the slowest onset and that the least potent compound, rocuronium, has the most rapid onset. [117] [155] [157] Bevan[159] 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.

Figure 29-18 Percentages of peak effect after an ED95 of succinylcholine, rocuronium,

rapacuronium, vecuronium, atracurium, mivacurium, and cisatracurium at the adductor pollicis muscle. Times (mean SD) in seconds to 95% of peak effect are shown in parentheses. (Data from Kopman AF, Klewicka MM, Ghori K, et al: Dose-response and onset/offset characteristics of rapacuronium. Anesthesiology 93:1017-1021, 2000; Kopman AF, Klewicka MM, Kopman DJ, Neuman GG: Molar potency is predictive of the speed of onset of neuromuscular block for agents of intermediate, short, and ultrashort duration. Anesthesiology 90:425-431, 1999; and Kopman AF, Klewicka MM, Neuman GG: Molar potency is not predictive of the speed of onset of atracurium. Anesth Analg 89:1046-1049, 1999.)

The onset of neuromuscular blockade is much more rapid 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) (see Fig. 29-4 ).[160] Thus, neuromuscular blockade develops faster, lasts a shorter time, and recovers more quickly in these muscles ( Table 29-8 ). [26] [160] [161] [162] [163] These observations may seem contradictory because there is also convincing evidence that the median effective concentration (EC50) for almost all drugs studied is between 50% and 100% higher at the diaphragm or larynx than it is at the adductor pollicis. Fisher and coworkers[164] explain this apparent contradiction by postulating more rapid equilibration (shorter ke0) between plasma and the effect compartment at these central muscles. This accelerated rate of equilibrium probably represents little more than differences in regional blood flow. Therefore, muscle blood flow rather than the drug's intrinsic potency may be more important in determining the onset and offset time of nondepolarizing neuromuscular blockers. More luxuriant blood flow (greater blood flow per gram of muscle) at the diaphragm or larynx would result in delivery of a higher peak plasma concentration of drug to the central muscle in the brief period before rapid redistribution is well under way. Table 29-8 -- Time course of action and peak effect at the laryngeal adductors and adductor pollicis Dose Anesthesi Laryn (mg/kg) a geal Adduc tors Adduc tor Pollici s Refe renc e

Onset Maximum Clinical Onset Maximum Clinical Time Block (% Duration Time Block (% Duration (sec) Depression) (min) (sec) Depression) (min) Succinylc Propofol- 34 holine, 1.0 fentanyl 12 100 0 4.3 1.6 56 15 180 18 155 40 100 0 69 8 99 3 82 24 7 161 160 161

Rocuroniu Propofol- 96 6 37 8 m, 0.25 fentanyl Rocuroniu Propofol- 92 m, 0.4 fentanyl 29 70 15

Rocuroniu Propofol- 84 6 77 5 m, 0.5 fentanyl Vecuroniu Propofol- 198 m, 0.04 fentanyl 6 Vecuroniu Propofol- 198 m, 0.07 fentanyl 12 Mivacuriu Propofol- 137 m, 0.14 alfentanil 20 Mivacuriu Propofol- 89 m, 0.2 mg alfentanil 26 55 8 88 4 90 7 99 4

83 92 5.7 2.1

144 12 342 12 342 18 201 59

98 1 89 3 98 1 99 1 99 2

22 3 11 2 22 2

160 26 26

16.2 4.6 162 20.5 3.9 163

10.4 1.5 202 45

Clinical duration is the time until T1 recovers to 25% of its control value. Values are means SD [161] [162] [163] or SEM. [26] [160]

Onset of blockade occurs 1 to 2 minutes earlier in the larynx than at the adductor pollicis after the administration of nondepolarizing neuromuscular blocking agents. The pattern of blockade (onset, depth, and speed of recovery) in the orbicularis oculi is similar to that in the larynx.[165] By monitoring the onset of neuromuscular blockade at the orbicularis oculi, one can predict the quality of intubating conditions. The onset of maximal blockade in the larynx also corresponds to the point at which the adductor pollicis begins to show palpable evidence of weakening. Furthermore, the return of thumb responses to normal suggests that the efferent muscular arc of the protective airway reflexes is intact. Rapid Tracheal Intubation

Succinylcholine remains the drug of choice when rapid tracheal intubation is needed because it consistently provides muscle relaxation within 60 to 90 seconds. When succinylcholine is considered undesirable or contraindicated, the onset of action of nondepolarizing neuromuscular blocking drugs can be accelerated by preceding the intubating dose with a priming dose of neuromuscular blocker,[166] by using high doses of an individual agent,[148] or by using combinations of neuromuscular blockers.[149] Although some combinations of mivacurium and rocuronium can achieve rapid onset without undue prolongation of action and without undesirable side effects,[149] combination therapy may not consistently result in rapid onset of effect. THE PRIMING TECHNIQUE.

Since the introduction of rocuronium, the use of priming has decreased considerably. Several groups of investigators have recommended that a small subparalyzing dose of the nondepolarizer (about 20% of the ED95 or about 10% of the intubating dose) be given 2 to 4 minutes before a large second dose for tracheal intubation.[166] This procedure, termed priming, has been shown to accelerate the onset of blockade for most nondepolarizing neuromuscular blockers by 30 to 60 seconds, which means that intubation can be performed within approximately 90 seconds of the second dose. However, the intubating conditions that occur after priming do not match those that occur after succinylcholine. Moreover, priming carries the risks of aspiration and difficulty swallowing, and the visual disturbances associated with subtle degrees of blockade are uncomfortable for the patient.[167] THE HIGH-DOSE REGIMEN FOR RAPID TRACHEAL INTUBATION.

Larger doses of neuromuscular blockers are usually recommended when intubation must be accomplished in less than 90 seconds. High-dose regimens, however, are associated with a considerably prolonged duration of action and potentially increased cardiovascular side effects (see Table 29-7 ). [148] [168] Increasing the dosage of rocuronium from 0.6 mg/kg (twice the ED95) to 1.2 mg/kg (four times the ED95) shortened the onset time of complete neuromuscular blockade from 89 33 seconds (mean SD) to 55 14 seconds but significantly prolonged the clinical duration (i.e., recovery of the first twitch of TOF [T1] to 25% of baseline) from 37 15 minutes to 73 32 minutes.[148]

Whatever technique of rapid-sequence induction of anesthesia and intubation is elected, the following four principles are important: (1) preoxygenation must be performed, (2) sufficient doses of intravenous drugs must be administered to ensure that the patient is adequately anesthetized, (3) intubation within 60 to 90 seconds must be considered acceptable, and (4) cricoid pressure should be applied subsequent to injection of the induction agent. Low-Dose Relaxants for Tracheal Intubation

The low-dose technique is not suitable for rapid-sequence induction, but several studies have demonstrated that low doses of neuromuscular blocking drugs can be used for routine tracheal intubation. The use of low doses of neuromuscular blockers has 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 neuromuscular blocking agents currently available. [160] [161] The maximal effect of either 0.25 or 0.5 mg/kg of rocuronium at the laryngeal muscles occurs after 1.5 minutes.[160] This interval is shorter than the 3.3 minutes reported after the administration of equipotent doses of vecuronium (0.04 or 0.07 mg/kg)[26] and only slightly more than the 0.9 minute reported after 0.25 or 0.5 mg/kg of succinylcholine (see Table 29-8 ).[169]

With a better understanding of the multiple factors that contribute to satisfactory conditions for intubation, it is now possible to take full advantage of the onset profile for rocuronium. 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. Figure 29-19 demonstrates this principle.[158] Complete blockade at the larynx, diaphragm, or both may not be a

prerequisite for satisfactory tracheal intubating conditions.

Figure 29-19 Computer simulation based on Sheiner's model[120] and data reported by Wierda and colleagues.[170] The ED95 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 (such as 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 a 50% block (EC50) of muscle X is 2.5 times that of the adductor pollicis, but the half-life of transport between plasma and the effect compartment ( ke0) of muscle X is only half as long. The rapid equilibration between plasma concentrations of rocuronium and muscle X results in more rapid onset of blockade of muscle X than the adductor pollicis. The greater EC50 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. (From Naguib M, Kopman AF: Low dose rocuronium for tracheal intubation. Middle East J Anesthesiol 17:193-204, 2003.)

Kopman and associates[171] noted that 0.5 mg/kg of rocuronium (1.5 times the ED95) provided very satisfactory conditions for intubation (25 intubations were rated excellent and 5 were rated good) in patients anesthetized with 12.5 g/kg of alfentanil and 2.0 mg/kg of propofol if laryngoscopy were delayed for 75 seconds after drug administration. They estimated that 1.5 times the ED95 of rocuronium will produce at least 95% blockade in 98% of the population.[171] A similar or lower multiple of rocuronium's ED95 was shown to have a more rapid onset and shorter duration of action than atracurium[172] or cisatracurium.[112] The onset of cisatracurium's effect is too slow to provide good conditions for intubation in less than 2 minutes, even after a dose twice the ED95.

In the vast majority of patients receiving 15 g/kg of alfentanil followed by 2.0 mg/kg of propofol and 0.45 mg/kg of rocuronium, good to excellent conditions for intubation will be present 75 to 90 seconds after the completion of drug administration. Metabolism and Elimination

The specific pathways of the metabolism (biotransformation) and elimination of neuromuscular blocking drugs are summarized in Table 29-9 . Of the nondepolarizing neuromuscular blockers listed, pancuronium, pipecuronium, vecuronium, atracurium, cisatracurium, and mivacurium are the only ones that are metabolized or degraded. Nearly all nondepolarizing neuromuscular blocker 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 urine by glomerular filtration, with no tubular resorption or secretion. Therefore, all nondepolarizing neuromuscular blockers show elimination of the parent molecule in 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 to 2 mL/kg/min). Table 29-9 -- Metabolism and elimination of neuromuscular blocking drugs Dru Du Metabolism (%) Elimina g rati tion on Kidney Liver (%) (%) Succ Ultr Butyrylcholinester <2% inylc ash ase (98%-99%) holi ort Metabolites

None Monoester (succinyl monocholine) and choline; monoester metabolized much more slowly than succinylcholine

ne Gant Ultr Cysteine (fast) and ? acuri ash ester hydrolysis um ort (slow) Miv Sho Butyrylcholinester <5% acuri rt ase (95%-99%) um (Metabo lites eliminat ed in urine and bile) Atra Inte Hofmann 10%curi rme elimination and 40% um diat nonspecific ester e hydrolysis (60%90%) (Metabo lites eliminat ed in urine and bile) Cisa Inte Hofmann tracu rme elimination rium diat (77%?) e Renal clearanc e 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 to 10 times lower than in the case of atracurium, thus making this not an issue in practice. 50%- The 3-OH metabolite accumulates, particularly in 60% renal failure. It has about 80% the potency of vecuronium and may be responsible for delayed recovery in ICU patients. None Laudanosine, acrylates, alcohols, and acids. Although laudanosine has CNS-stimulating properties, the clinical relevance of this effect is negligible. ? Inactive cysteine adduction product, chloroformate monoester, and alcohol

None Monoester and quaternary alcohol. The metabolites are inactive. They are most likely not themselves metabolized any further.

Vec Inte Liver (30%-40%) 40%uron rme 50% ium diat e (Metabo lites excreted in urine and bile,

40%) Roc Inte None uron rme ium diat e 10%25% >70% None

Panc Lon Liver (10%-20%) 85% uron g ium d- Lon None Tub g ocur arine

15% The 3-OH metabolite may accumulate, particularly in renal failure. It is about two thirds as potent as the parent compound.

80% (?) 20% None

CNS, central nervous system; ICU, intensive care unit.

Steroidal Compounds LONG-ACTING NEUROMUSCULAR BLOCKERS.

Pancuronium is cleared largely by the kidney.[173] Its hepatic uptake is limited. A small amount (15% to 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 that it is clinically irrelevant. The three known metabolites have been studied individually in anesthetized humans.[151] 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 plasma. This metabolite has pharmacokinetics and a duration of action similar to those of pancuronium.[151] In addition, the 3-OH metabolite is most likely excreted largely by the kidney.[151] The parent compound and the 3-OH metabolite are also cleared in small amounts via a minor liver pathway. Total clearance is delayed, and the duration of action is significantly lengthened by severe disorders of renal or hepatic function. [129] [174]
[175]

INTERMEDIATE-ACTING NEUROMUSCULAR BLOCKERS.

Vecuronium, the 2-desmethyl derivative of pancuronium, is more lipid soluble than pancuronium because of absence of the quaternizing methyl group at the 2-position. It undergoes two to three times more metabolism than pancuronium does. Vecuronium is taken up into the liver by a carrier-mediated transport system[176] and then deacetylated at the 3-position by liver microsomes. About 12% of

clearance of vecuronium occurs by conversion to 3-desacetylvecuronium,[177] and 30% to 40% is cleared in bile as parent compound.[127] 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. [177] [178]

The principal metabolite of vecuronium, 3-desacetylvecuronium, is a potent (80% of vecuronium) neuromuscular blocking drug in its own right. The metabolite, though, has slower plasma clearance and a longer duration of action than vecuronium does.[177] 3-Desacetylvecuronium has a clearance rate of 3.5 mL/kg/min, and renal clearance accounts for approximately a sixth of its elimination.[177] In patients in the ICU with renal failure, 3-desacetylvecuronium can accumulate and produce prolonged neuromuscular blockade.[179] Other putative metabolites are 17-desacetylvecuronium and 3,17bisdesacetylvecuronium, neither of which occurs in clinically significant amounts.

Rocuronium is eliminated primarily by the liver, with a small fraction (10%) eliminated in urine.[180] It is taken up into the liver by a carrier-mediated active transport system.[181] The putative metabolite, 17-desacetylrocuronium, has not been detected in significant quantities. Benzylisoquinolinium Compounds SHORT-ACTING NEUROMUSCULAR BLOCKERS.

Mivacurium is hydrolyzed in plasma by butyrylcholinesterase to a monoester and an amino alcohol,[9] which are excreted in urine and bile. The metabolites are positively charged, thus making their entry into the central nervous system (CNS) unlikely. They show less than 1% of the neuromuscular blocking activity of the parent compound and do not affect the autonomic nervous system. Less than 5% is excreted in urine as the parent compound.

Mivacurium consists of three stereoisomers, and clearance rates for the two most pharmacologically active isomers, cis-trans and trans-trans, are approximately 100 and 50 to 70 mL/kg/min, respectively. [99] [182] [183] These two isomers show elimination half-lives of 2 to 3 minutes.[99] The third stereoisomer, 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.[99] 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.[99] This rapid enzymatic clearance of mivacurium accounts for its short duration of action, [9] [99] which is much shorter than that of vecuronium and atracurium but about twice that of succinylcholine.[184] When butyrylcholinesterase activity is severely deficient, however, such as in the rare patients (1/3000) who are homozygous for genetically atypical enzymes, the duration of action of mivacurium is prolonged for up to several hours. [185] [186] [187] [188] INTERMEDIATE-ACTING NEUROMUSCULAR BLOCKERS.

Theoretically, atracurium is metabolized by two pathways: Hofmann elimination and ester hydrolysis by nonspecific esterases. 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 were thought to have no neuromuscular and little or no cardiovascular activity of clinical relevance.[189] Under the proper chemical conditions, however, these breakdown products may actually be used to synthesize the parent compound.

Because it undergoes Hofmann elimination, atracurium is relatively stable at pH 3.0 and 4C and becomes unstable when injected into the bloodstream. Early observations of breakdown of the drug in buffer and plasma showed faster degradation in plasma, thus suggesting possible enzymatic hydrolysis of the ester groups. Further evidence suggested that this second pathway, ester hydrolysis, may be more important than originally realized in the breakdown of atracurium.[190] By pharmacokinetic analysis, Fisher and colleagues[191] concluded that a significant amount of clearance of atracurium may be accomplished by routes other than ester hydrolysis and Hofmann elimination. Hence, it appears that atracurium's metabolism is complicated and may not be completely understood.[191]

Laudanosine, a metabolite of atracurium, has CNS-stimulating properties. Unlike atracurium, laudanosine is dependent on the liver and kidney for its elimination and has a long elimination half-life. [192] Laudanosine concentrations are elevated in patients with liver disease[193] and those who have received atracurium for many hours in an ICU.[194] Laudanosine freely crosses the blood-brain barrier. [192] Beemer and coworkers[195] found that patients awakened at a 20% higher arterial concentration of thiopental when atracurium had been given; this was attributed to the CNS-stimulatory effect of laudanosine. These relatively low concentrations of laudanosine, however, did not influence an animal model of epilepsy[196] or lidocaine-induced seizures.[197] In the ICU, blood levels of laudanosine can be as high as 5.0 to 6.0 g/mL.[186] Though not known in humans, the seizure threshold in animals ranges from 5.0 g/mL in rabbits[198] to 17 g/mL in dogs.[199] Thus, adverse effects are unlikely to occur with the use of atracurium in the operating room or ICU.

Laudanosine also has cardiovascular effects. In dogs, hypotension occurs at a blood concentration of about 6 g/mL,[199] a level higher than that usually found in patients in the ICU. However, there is one case report of a patient who experienced severe hypotension and bradycardia while receiving atracurium, which resolved only when vecuronium was substituted.[200] Laudanosine enhances the stimulation-evoked release of norepinephrine,[201] a finding that may also partly account for its CNSstimulating effect.

Atracurium is a mixture of 10 optical isomers. Cisatracurium is the 1R cis1R cis isomer of atracurium.[95] Like atracurium, cisatracurium is metabolized by Hofmann elimination to laudanosine and a monoquaternary acrylate. [202] [203] In contrast, however, there is no ester hydrolysis of the parent molecule. Hofmann elimination accounts for 77% of the total clearance of 5 to 6 mL/kg/min. Twentythree percent of the drug is cleared through organ-dependent means, with renal elimination accounting for 16% of this figure.[203] Because cisatracurium is about four or five times as potent as atracurium, about five times less laudanosine is produced, and accumulation of this metabolite is not thought to be of any consequence in clinical practice.

LONG-ACTING NEUROMUSCULAR BLOCKERS.

With these agents, there is no active metabolism of dTc. The kidney is the major pathway of elimination, with approximately 50% of a dose being eliminated through renal pathways. The liver is probably a secondary route of elimination. Therefore and because more suitable agents are available, these drugs are not indicated for use in patients with either renal[130] or hepatic failure. Asymmetric Mixed-Onium Chlorofumarates (Gantacurium)

Gantacurium appears to be degraded by two chemical mechanisms, 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, presumably to inactive hydrolysis products (see Fig. 29-10 ).[105]

In summary, the only short-acting neuromuscular blocker currently available for clinical use, mivacurium, is cleared rapidly and almost exclusively via metabolism by butyrylcholinesterase, which results in much greater plasma clearance than with any other nondepolarizing neuromuscular blocker.[9] Neuromuscular blockers 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 elimination. Atracurium is cleared two to three times more rapidly than the long-acting drugs. [123] [193] [204] [205] Similar clearance values have been obtained for rocuronium [206] [207] [208] [209] [210] and cisatracurium. [202] [203] [211] Finally, the long-acting neuromuscular blockers 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 Blockers

Neuromuscular blocking agents 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 neuromuscular blocking drugs.[212] Autonomic Effects

Neuromuscular blocking agents may interact with nicotinic and muscarinic cholinergic receptors within the sympathetic and parasympathetic nervous systems and with nicotinic receptors at the neuromuscular junction.

Dose-response ratios to compare the neuromuscular blocking potencies of these agents (the ED95) with their potencies in blocking vagal (parasympathetic) or sympathetic ganglionic transmission (the ED50) can be constructed ( Table 29-10 ). These ratios are termed the autonomic margin of safety of the

relaxant in question. The higher the dose ratio, the lower 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. Table 29-10 -- Approximate autonomic margins of safety of nondepolarizing neuromuscular blockers * Drug Benzylisoquinolini um Compounds Mivacurium Atracurium Cisatracurium d-Tubocurarine Steroidal Compounds Vecuronium Rocuronium Pancuronium 20 3.0-5.0 3.0 >250 >10 >250 None None None >50 16 >50 0.6 >100 40 >50 2.0 3.0 2.5 None 0.6 Vagus[] Sympathetic Ganglia[] Histamine Release[]

Number of multiples of the ED95 for neuromuscular blockade required to produce the autonomic side effect (ED50). In the cat. In human subjects.

These autonomic responses are not reduced by slower injection of the 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; that is, 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 neuromuscular blocking drugs are summarized in Table 29-11 . Table 29-11 -- Clinical autonomic effects of neuromuscular blocking drugs Drug Autonomic Ganglia Cardiac Muscarinic Receptors Histamine Release

Depolarizing Substance Succinylcholine Benzylisoquinoli nium Compounds Mivacurium Atracurium Cisatracurium d-Tubocurarine Steroidal Compounds Vecuronium Rocuronium Pancuronium None None None None Blocks weakly Blocks moderately None None None None None None Blocks None None None None Slight Slight None Moderate Stimulates Stimulates Slight

HISTAMINE RELEASE.

Quaternary ammonium compounds such as neuromuscular blockers are generally weaker histaminereleasing substances than tertiary amines such as morphine are. Nevertheless, when large doses of certain neuromuscular blockers are administered rapidly, erythema of the face, neck, and upper part of the 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 to 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.[213] The serosal mast cell, located in the skin and connective tissue and near blood vessels and nerves, is principally involved in the degranulation process.[213]

The side effect of histamine release is most often noted after administration of the benzylisoquinolinium class of muscle relaxants, although it has also been noted with steroidal relaxants of low potency. The effect is usually of short duration (1 to 5 minutes), is dose related, and is clinically insignificant in healthy patients. Hatano and associates[214] showed that the hypotensive cardiovascular response to 0.6 mg/kg of dTc in humans is prevented not only by antihistamines but also by nonsteroidal anti-inflammatory drugs (e.g., aspirin). These investigators concluded that the final step in dTc-induced hypotension is modulated by prostaglandins that are vasodilators.[214] This side effect can

be reduced considerably by using a slower injection rate. It is also prevented by prophylaxis with combinations of histamine1 and histamine2 blockers.[215] If a minor degree of histamine release such as just described occurs after an initial dose of a neuromuscular blocker, 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 anaphylactic or anaphylactoid reactions; these reactions are very rare. Clinical Cardiovascular Manifestations of Autonomic Mechanisms HYPOTENSION.

The hypotension seen with the use of atracurium and mivacurium is due to release of histamine, whereas dTc causes hypotension via histamine release and ganglion blockade. [216] [217] The effects of dTc occur closer to the dose required to achieve neuromuscular blockade.[116] The safety margin for histamine release is about three times greater for atracurium and mivacurium than it is for dTc. [213] [214] [217] Rapid administration of atracurium in doses greater than 0.4 mg/kg and mivacurium in doses greater than 0.15 mg/kg has been associated with transient hypotension as a result of release of histamine ( Fig. 29-20 ).

Figure 29-20 Dose response to mivacurium in patients under nitrous oxideoxygenopioid 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 ED95 (0.20 to 0.25 mg/kg). B, The changes were less than 10% with a slower injection (30 seconds). (From Savarese JJ, Ali HH, Basta SJ, et al: The cardiovascular effects of mivacurium chloride [BW B1090U] in patients receiving nitrous oxideopiatebarbiturate anesthesia. Anesthesiology 70:386-394, 1989.)

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.[218] Pancuronium-induced tachycardia has been attributed to (1) vagolytic action,[218] probably secondary to inhibition of M2 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.[219] In studies in humans, Roizen and colleagues[220] surprisingly found decreases in plasma norepinephrine levels after the administration of either pancuronium or atropine. They postulated that the increase in heart rate or rate-pressure product occurs because pancuronium (or atropine) acts through baroreceptors to reduce sympathetic outflow.[220] More specifically, the vagolytic effect of pancuronium increases the heart rate and, hence, blood pressure and cardiac output, which in turn influences the baroreceptors to decrease sympathetic tone. Support for this concept is provided by the fact that prior administration of atropine will attenuate or eliminate the cardiovascular effects of pancuronium.[218] However, a positive chronotropic effect that places emphasis on the vagolytic mechanism has not been found in humans.[221] The tachycardia seen with benzylisoquinolinium compounds is due to release of histamine. DYSRHYTHMIAS.

Succinylcholine and dTc actually reduce the incidence of epinephrine-induced dysrhythmias.[222] Possibly because of enhanced atrioventricular conduction,[223] the incidence of dysrhythmias caused by pancuronium appears to increase during halothane anesthesia.[218] Edwards and associates[224] observed a rapid tachycardia (more than 150 beats/min) that progressed to atrioventricular dissociation in two patients anesthetized with halothane who also received pancuronium. The only other factor common to these two patients was that both were taking tricyclic antidepressant agents. BRADYCARDIA.

Several case reports [225] [226] have described the occurrence of severe bradycardia and even asystole after the administration of vecuronium or atracurium. All of these cases were also associated with opioid administration. Subsequent studies indicated that administration of vecuronium or atracurium alone does not cause bradycardia.[227] 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,[228] three of whichM1 to M3exist in the airways.[229] M1 receptors are under sympathetic control, and they mediate bronchodilation.[230] M2 receptors are located presynaptically ( Fig. 29-21 ) at the postganglionic parasympathetic nerve endings, and they function in a negative-feedback mechanism to limit the release of acetylcholine. M3 receptors, which are located postsynaptically ( Fig. 29-21 ), mediate contraction of the airway smooth muscles (i.e., bronchoconstriction).[230] Nondepolarizing neuromuscular blockers have different antagonistic activities

at both the M2 and M3 receptors.[231] For example, blockage of M3 muscarinic receptors on airway smooth muscle inhibits vagally induced bronchoconstriction (i.e., causes bronchodilation), whereas blockage of M2 receptors results in increased release of acetylcholine, which will act on M3 receptors and cause bronchoconstriction.

Figure 29-21 The muscarinic M3 receptors are located postsynaptically on airway smooth muscle. Acetylcholine (ACh) stimulates M3 receptors to cause contraction. M2 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 M2 receptors is 15 times higher than its affinity to block M3 receptors.[231] This explains the high incidence (>9%) of severe bronchospasm [232] [233] [234] that was seen with this drug and resulted in its withdrawal from the market.

The administration of benzylisoquinolinium neuromuscular blocking drugs (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. Allergic Reactions

The frequency of life-threatening anaphylactic (immune-mediated) or anaphylactoid reactions occurring during anesthesia has been estimated to be between 1 in 1000 and 1 in 25,000 anesthetizations, with about a 5% mortality rate. [235] [236] In France, the most common causes of anaphylaxis in patients who experienced allergic reactions were reported to be neuromuscular blocking drugs (58.2%), latex (16.7%), and antibiotics (15.1%).[237] Anaphylactic reactions are mediated through immune responses involving immunoglobulin E antibodies fixed to mast cells. Anaphylactoid reactions are not immune mediated and represent exaggerated pharmacologic responses in very rare and very sensitive individuals.

Neuromuscular blocking drugs contain two quaternary ammonium ions, which are the epitopes commonly recognized by specific immunoglobulin E.[238] Cross-reactivity has been reported between neuromuscular blocking drugs and food, cosmetics, disinfectants, and industrial materials.[238] Crossreactivity is seen in 70% of patients with a history of anaphylaxis to a neuromuscular blocking drug.[237]

Steroidal compounds (e.g., rocuronium, vecuronium, pancuronium) result in no significant histamine release.[217] For example, four times the ED95 of rocuronium (1.2 mg/kg) causes no significant release of histamine.[239] Nevertheless, rocuronium and succinylcholine are reportedly associated with a 43.1% and 22.6% incidence of anaphylaxis in France.[237] Rose and Fisher[240] classified rocuronium and atracurium as having intermediate levels of risk for causing allergic reactions. They also noted that the increased number of reports of anaphylaxis with rocuronium is in line with the market share of that drug's use. Watkins[241] 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 antibodymediated response as an explanation of all anaphylactoid reaction presentations. There are currently no standards against which diagnostic tests (skin prick test, interdermal test, or immunoglobulin E testing) are performed, and new recommendations are still only in the proposal stage.[242] For instance, Laxenaire and Mertes[243] used a 1:10 dilution of rocuronium for interdermal skin testing, whereas Rose and Fisher[240] used a 1:1000 dilution. Levy and colleagues[244] showed that rocuronium in a 1:10 dilution can produce false-positive results on intradermal testing and suggested that rocuronium be diluted at least 100-fold to prevent such results. These authors also reported that high concentrations (10-4 M) of both rocuronium and cisatracurium are 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.[244]

All neuromuscular blocking drugs can cause noncompetitive inhibition of histamine-Nmethyltransferase, but the concentrations required for such inhibition far exceed those that would be used clinically, except in the case of vecuronium, with which the effect becomes manifested at 0.1 to 0.2 mg/kg.[245] This could explain the occurrence of occasional severe bronchospasm in patients after receiving vecuronium.[246]

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.[247]

Many drugs have been shown to interact with neuromuscular blockers or their antagonists, or both, and it is beyond the scope of this chapter to review them all. [247] [248] Some of the more important drug interactions with neuromuscular blockers and their antagonists are discussed in the following sections. Interactions Among Nondepolarizing Neuromuscular Blockers

Mixtures of two nondepolarizing neuromuscular blockers 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 the administration of chemically related agents, such as atracurium and mivacurium,[249] or after the coadministration of various pairs of steroidal neuromuscular blockers.[103] On the other hand, combinations of structurally dissimilar (e.g., a steroidal with a benzylisoquinolinium) neuromuscular blockers, such as pancuronium and dTc,[250] pancuronium and metocurine,[250] rocuronium and mivacurium,[149] or rocuronium and cisatracurium,[112] produce a synergistic response.

The administration of two neuromuscular blockers in combination was first introduced by Lebowitz and coworkers[250] in an attempt to reduce the cardiovascular side effects of neuromuscular blockers by giving smaller doses of each drug as a combination. An additional advantage (rapid onset and short duration) is noted for mivacurium-rocuronium combinations.[149] 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)[251] and the nonequivalence of binding affinities of the two -subunits (H and L). Furthermore, inhibition of butyrylcholinesterase by pancuronium results in decreased plasma clearance of mivacurium and marked potentiation of the neuromuscular blockade.[252]

It should be noted that the pharmacodynamic response to the use of two different nondepolarizing blockers during the course of anesthesia depends not only on the specific drugs used but also on the sequence of their administration. [253] [254] Approximately three half-lives will be 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.[253] Similarly, Naguib and coauthors[249] 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[249] and the prolongation reported with vecuronium after pancuronium [253] [254] are not related to synergism. Combinations of atracurium and mivacurium[249] and vecuronium and pancuronium[103] are simply additive. However, this prolongation of 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 are occupied by that drug, and its clinical profile becomes evident. Interactions between Succinylcholine and Nondepolarizing Neuromuscular Blockers

The interaction between succinylcholine and nondepolarizing neuromuscular blockers depends on the order of administration and the doses used. [86] [255] [256] Small doses of different nondepolarizing neuromuscular blockers administered before succinylcholine to prevent fasciculations have an antagonistic effect on the development of a subsequent depolarizing block produced by succinylcholine. [28] [86] Therefore, it is recommended that the dose of succinylcholine be increased after the administration of a defasciculating dose of a nondepolarizing neuromuscular blocker.[28]

Studies on the effects of administration of succinylcholine before nondepolarizing neuromuscular blockers have produced conflicting results. Several investigators reported potentiation of the effects of pancuronium,[255] vecuronium, and atracurium[256] by prior administration of succinylcholine. In contrast, others found no significant influence of succinylcholine on the subsequent administration of pancuronium, rocuronium, or mivacurium. [86] [257] [258] Interactions with Inhaled Anesthetics

Deep anesthesia induced with potent volatile anesthetics (in the absence of neuromuscular blockade) may cause a slight reduction in neuromuscular transmission, as measured by depression of sensitive indicators of clinical neuromuscular function, such as tetanus and TOF.[259] Inhaled anesthetics also enhance the neuromuscular blocking effects of nondepolarizing neuromuscular blockers. Inhaled anesthetics will decrease the dose of neuromuscular blockers needed, as well as prolong both the duration of action of the blocker and recovery from neuromuscular blockade,[260] depending on the duration of anesthesia, [259] [261] [262] the specific inhaled anesthetic,[263] and the concentration (dose) given. [264] The rank order of potentiation is desflurane > sevoflurane > isoflurane > halothane > nitrous oxide barbiturateopioid or propofol anesthesia ( Fig. 29-22 ). [265] [266] [267]

Figure 29-22 Cumulative dose-response curves for rocuronium-induced neuromuscular blockade during 1.5 minimum alveolar concentration (MAC) 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 45:526-532, 1998, with permission from the Canadian Journal of Anaesthesia.)

The greater clinical muscle-relaxing effect produced by less potent anesthetics is mainly due to their larger aqueous concentrations.[268] 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 neuromuscular blockers is one of pharmacodynamics, not pharmacokinetics.[143] The proposed mechanisms behind this interaction include (1) a central effect on motoneurons and interneuronal synapses,[269] (2) inhibition of postsynaptic nAChRs,[270] and (3) augmentation of the antagonist's affinity at the receptor site.[268] Interactions with Antibiotics

Most antibiotics can cause neuromuscular blockade in the absence of neuromuscular blocking agents. 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, on the other hand, exhibit postjunctional activity only. When combined with neuromuscular blockers, the aforementioned antibiotics can potentiate neuromuscular blockade.[271] The cephalosporins and penicillins have not been reported to potentiate neuromuscular blockade. Because antagonism of neuromuscular blockade has been reported to be more difficult after the administration of aminoglycosides,[272] ventilation should be controlled until the neuromuscular blockade terminates spontaneously. Calcium should not be used to hasten the recovery of neuromuscular function for two reasons: the antagonism that it produces is not sustained, and it may prevent the antibacterial effect of the antibiotics. Temperature

Hypothermia prolongs the duration of action of nondepolarizing neuromuscular blockers. [273] [274] [275] The force of contraction of the adductor pollicis decreases by 10% to 16% per degree Celsius decline in muscle temperature below 35.2C. [276] [277] To maintain muscle temperature at or above 35.2C, central temperature must be maintained at 36.0C.[273] Recovery to 10% twitch height with 0.1 mg/kg of vecuronium increases from 28 minutes at a mean central temperature of 36.4C to 64 minutes at 34.4C.[273] The mechanism or mechanisms underlying this prolongation may be pharmacodynamic, pharmacokinetic, or both.[275] 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. [273] [278] Hypothermia decreases the plasma clearance and prolongs the duration of action of rocuronium and vecuronium.[275] Temperature-related differences in the pharmacodynamics of vecuronium have also been reported: ke0 decreases (0.023/min/C) with lower temperature, suggesting slightly delayed equilibration of drug between the circulation and the neuromuscular junction during hypothermia.[275] The Hofmann elimination process of atracurium is slowed by a decrease in pH and especially by a decrease in temperature.[279] In fact, atracurium's duration of action is markedly prolonged by hypothermia.[274] For instance, the duration of action of a 0.5-mg/kg dose of atracurium is 44 minutes at 37C but 68 minutes at 34.0C.

Changes in temperature will also affect 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 27C is prolonged, and monitoring by post-tetanic count in that arm is unreliable.[280] In the same patient, TOF responses are different if the arms are at different temperatures, and correlation of responses in the two arms becomes progressively poorer as the temperature difference between the arms increases.[281]

The efficacy of neostigmine is not altered by mild hypothermia. [282] [283] [284] Hypothermia does not change the clearance, maximum effect, or duration of action of neostigmine in volunteers.[284] Interactions with Magnesium and Calcium

Magnesium sulfate, given for the treatment of preeclampsia and eclamptic toxemia, potentiates the neuromuscular blockade induced by nondepolarizing neuromuscular blockers (see Chapter 69 ). [285] [286] After a dose of 40 mg/kg of magnesium sulfate, the ED50 of vecuronium was reduced by 25%, the onset time was nearly halved, and the recovery time nearly doubled.[286] Neostigmine-induced recovery is also attenuated in patients treated with magnesium.[285] The mechanisms underlying the enhancement of nondepolarizing blockade by magnesium probably involve both prejunctional and postjunctional effects. High magnesium concentrations inhibit calcium channels at the presynaptic nerve terminals that trigger the release of acetylcholine.[14] Furthermore, 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 neuromuscular blocker must be reduced and carefully titrated with a nerve stimulator to ensure adequate recovery of neuromuscular function at the end of surgery.

The interaction between magnesium and succinylcholine is controversial. However, more recent results suggest that magnesium antagonizes the block produced by succinylcholine.[287]

Calcium triggers the release of acetylcholine from the motor nerve terminal and enhances excitationcontraction coupling in muscle.[14] Increasing calcium concentrations decreased the sensitivity to dTc and pancuronium in a muscle-nerve model.[288] In hyperparathyroidism, hypercalcemia is associated with decreased sensitivity to atracurium and thus a shortened time course of neuromuscular blockade.
[289]

Interactions with Lithium

Lithium remains the drug of choice for the treatment of bipolar affective disorder (manic-depressive illness). The lithium ion resembles sodium, potassium, magnesium, and calcium ions and may therefore affect the distribution and kinetics of all of these electrolytes.[290] Lithium enters cells via sodium channels and tends to accumulate within the cells.

By its activation of potassium channels, lithium inhibits neuromuscular transmission presynaptically and muscular contraction postsynaptically.[291] 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.[291] Prolongation of neuromuscular blockade was reported in patients taking lithium carbonate and both depolarizing[282] and nondepolarizing neuromuscular blockers.[292] Only one report did not demonstrate prolongation of recovery from succinylcholine in patients receiving lithium.[293] In patients who are stabilized on lithium therapy and undergoing surgery, neuromuscular blockers 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, postsynaptic, and muscle membranes. In large intravenous

doses, most local anesthetics block neuromuscular transmission; in smaller doses, they enhance the neuromuscular blockade produced by both nondepolarizing and depolarizing neuromuscular blockers. [294] The ability of neostigmine to antagonize a combined local anestheticneuromuscular 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 post-tetanic potentiation, and this is thought to be a neural prejunctional effect.[295] In larger doses, local anesthetics block acetylcholine-induced muscular contractions, which suggests that local anesthetics have a stabilizing effect on the postjunctional membrane.[296] Procaine displaces calcium from the sarcolemma and thus inhibits caffeine-induced contracture of skeletal muscle.[297] Most of these mechanisms of action probably apply to all of the local anesthetics.

Several drugs used for the treatment of dysrhythmias augment the blockade induced by neuromuscular blockers. Single-fiber electromyography has disclosed that verapamil and amlodipine impair neuromuscular transmission in subjects without neuromuscular disease.[298] Clinical reports have suggested potentiation of neuromuscular block with verapamil[299] and impaired reversal of vecuronium in a patient receiving disopyramide.[300] However, the clinical significance of these interactions is probably minor. Interactions with Antiepileptic Drugs

Anticonvulsants have a depressant action on release of acetylcholine at the neuromuscular junction.[301] Patients receiving chronic anticonvulsant therapy demonstrated resistance to nondepolarizing muscle blockers (except mivacurium[302] and probably atracurium as well),[301] as evidenced by accelerated recovery from neuromuscular blockade and the need for increased doses to achieve complete neuromuscular blockade. Clearance of vecuronium is increased twofold in patients receiving chronic carbamazepine therapy.[303] Some investigators, however, attribute this resistance to increased binding (i.e., decreased free fraction) of the neuromuscular blockers to 1-acid glycoproteins or to upregulation of neuromuscular acetylcholine receptors (or to both mechanisms).[204] The latter could also explain the hypersensitivity seen with succinylcholine.[205] The slight prolongation of succinylcholine's action in patients taking anticonvulsants has few clinical implications. On the other hand, the potential hyperkalemic response to succinylcholine in the presence of receptor upregulation is of concern. Interactions with Diuretics

In patients undergoing renal transplantation, the intensity and duration of dTc neuromuscular blockade is increased after a dose of furosemide (1 mg/kg intravenously).[306] 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.[307] Furosemide appears to inhibit the production of cyclic adenosine monophosphate. In addition, the breakdown of adenosine triphosphate is inhibited, which results in reduced output of acetylcholine. Acetazolamide antagonizes the effects of anticholinesterases in the rat phrenic-diaphragm preparation.

[308]

However, in one report, 1 mg/kg of furosemide facilitated recovery of the evoked twitch response after pancuronium.[309] Chronic furosemide treatment had no effect on either dTc- or pancuroniuminduced neuromuscular blockade.[310]

In contrast, mannitol appears to have no effect on nondepolarizing neuromuscular blockade. Moreover, 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 neuromuscular blockers are eliminated in urine. [126] However, this lack of effect on the excretion of dTc should not be surprising. Urinary excretion of all neuromuscular blockers that are long acting depends primarily on glomerular filtration. Mannitol is an osmotic diuretic that exerts its effects by altering the osmotic gradient within the proximal tubules so that water is retained within them. An increase in urine volume in patients with adequate glomerular filtration, therefore, would not be expected to increase the excretion of neuromuscular blockers. Interactions with Other Drugs

Dantrolene (see Chapter 37 ), a drug used for the treatment of malignant hyperthermia, prevents release of calcium from the sarcoplasmic reticulum and blocks excitation-contraction coupling. Although it does not block neuromuscular transmission, the mechanical response to stimulation will be depressed, with subsequent potentiation of the nondepolarizing neuromuscular blockade.[88]

Azathioprine, an immunodepressant drug used in patients undergoing renal transplantation, has a minor antagonistic action on muscle relaxantinduced neuromuscular blockade.[311]

Steroids antagonize the effects of nondepolarizing neuromuscular blockers in both humans[312] and animals.[313] Possible mechanisms for this interaction include facilitation of acetylcholine release because of the effect of steroids on the presynaptic motor nerve terminal[314] and channel blockade of the nAChR.[315] Endogenous steroids act noncompetitively on nAChRs.[316] Prolonged treatment with a combination of corticosteroids and neuromuscular blocking drugs can result in prolonged weakness in critical care patients (see the later section Neuromuscular Blockers and Weakness Syndromes in the Critically Ill).

Antiestrogenic drugs such as tamoxifen appear to potentiate the effects of nondepolarizing neuromuscular blockers.[317] Recovery From Neuromuscular Blockade

In the 1970s, Ali and colleagues[318] described a TOF ratio of 0.60 as indicating adequate recovery of neuromuscular strength. Nonetheless, in 1997 a TOF ratio of 0.70 in unanesthetized volunteers was associated with difficulty speaking and swallowing, weakness of the facial musculature, visual disturbances, and inability to sit up without assistance.[319] Also in human volunteers, TOF ratios of 0.6 to 0.7 were associated with decreased upper esophageal tone and decreased coordination of the

esophageal musculature during swallowing. [320] [321] Fluoroscopic examination of these individuals demonstrated significant pharyngeal dysfunction resulting in a fourfold to fivefold increase in the risk for aspiration. With recovery of the TOF ratio to 0.9, esophageal tone and pharyngeal coordination returned toward baseline. [320] [321]

Residual paralysis also decreases the hypoxic ventilatory drive ( Fig. 29-23 ), [322] [323] which is due to inhibition of the carotid body's neural response to hypoxia.[324] Vecuronium decreases carotid sinus nerve activity in response to hypoxia in a dose-related fashion, presumably through its interaction with nicotinic chemotransduction of the carotid body.

Figure 29-23 Hypoxic ventilatory response (HVR) before (control); during steady-state infusion (train-of-four [TOF] = 0.07) of atracurium, pancuronium, and vecuronium; and after recovery (TOF > 0.90). Data are presented as means SD. *P < .01. (From Eriksson LI: Reduced hypoxic chemosensitivity in partially paralysed man. A new property of muscle relaxants? Acta Anaesthesiol Scand 40:520-523, 1996.)

After the administration of nondepolarizing neuromuscular blocking drugs, adequate return of normal neuromuscular function must be present. Whether that degree of recovery is a TOF ratio of 0.7, 0.8, or 0.9 has been an area of debate, and in a recent international guideline a TOF ratio of 0.9 was

recommended as an end point for recovery from a nondepolarizing neuromuscular block. Certainly, the clinician's ability to quantify the degree of residual neuromuscular block is limited. Kopman and colleagues[319] work in volunteers demonstrated that when they could oppose their incisors to retain a tongue depressor, their TOF ratio was, on average, 0.8 and at least 0.68. This test of muscle strength, though, would have limited usefulness in tracheally intubated patients.

Recommendations for detection and prevention of residual neuromuscular blockade are summarized in Chapter 47 .

Recovery from muscle relaxation caused by nondepolarizing neuromuscular blockers depends on several factors. Primarily, it depends on an increase in the acetylcholine concentration relative to that of the relaxant to overcome the competitive neuromuscular blockade. Although neostigmine will increase the acetylcholine concentration, ultimately, the muscle relaxant needs to be eliminated. The relative increase in acetylcholine concentration depends first on the ongoing movement of relaxant from the motor end plate into the central circulation and then on its elimination from the circulating blood volume so that it is not free to move into the synaptic cleft. Ultimately, recovery depends on elimination of the neuromuscular blocker from the body. Neuromuscular blockers may be eliminated through a host of mechanisms, including excretion as unchanged drug in urine, metabolism in the liver, enzymatic hydrolysis, and chemical breakdown. Although it has never been specifically examined, several groups of investigators have, through their ranges of recovery parameters, described wide interpatient variation in the spontaneous recovery of neuromuscular function. [325] [326] [327]

Several factors in addition to coexisting disease will affect the speed of spontaneous recovery of neuromuscular function. The presence of volatile anesthetics will potentiate any existing neuromuscular block and, presumably, cause recovery to be more prolonged.[328] If the anesthesiologist observes no or only minimal recovery of neuromuscular function in the presence of a volatile anesthetic, discontinuing or decreasing the concentration of that anesthetic should augment the recovery of neuromuscular function.

As will be discussed later in this section, acidosis, hypokalemia, hypothermia, and concomitant medications all potentiate residual neuromuscular blockade and render pharmacologic antagonism more difficult. Antagonism of Residual Neuromuscular Blockade

Anticholinesterases act by inhibiting acetylcholinesterase (enzyme classification 3.1.1.7), which is a type B carboxylesterase. At the neuromuscular junction, acetylcholinesterase occurs in the asymmetric or A12 form and consists of three tetramers of catalytic subunits covalently linked to a collagen-like tail. Acetylcholinesterase has a powerful catalytic capacity: it can catalyze 4000 molecules of acetylcholine per active site per second. The active site lies deep inside the enzyme protein. Nearly half of the acetylcholine released is hydrolyzed across the synaptic cleft before reaching the nAChRs. For a detailed account of this enzyme, see the article by Soreq and Seidman.[329]

The active surface of acetylcholinesterase is best viewed as having two sites: the anionic site, which is concerned with binding and orienting the substrate molecule, and the esteratic site, which is responsible for the hydrolytic process. The existence of a second anionic site, known as the peripheral anionic site, has also been proposed. This topic has been reviewed by Silman and Sussman.[330]

Three anticholinesterasesneostigmine, pyridostigmine, and edrophoniumare used to antagonize residual neuromuscular blockade. They exert their effect primarily by inhibiting acetylcholinesterase and thus increasing the concentration of acetylcholine at the motor end plate. Neostigmine and pyridostigmine are oxydiaphoretic (acid-transferring) inhibitors of acetylcholinesterase. They transfer a carbamate group to acetylcholinesterase and form a covalent bond at the esteratic site. Edrophonium is a prosthetic inhibitor that binds to the anionic site on the acetylcholinesterase by electrostatic attraction and to the esteratic site by hydrogen bonding. In addition, anticholinesterases may increase the release of acetylcholine from presynaptic nerve terminals, block neural potassium channels, and have a direct agonistic effect. For more details, see Bevan and colleagues.[331] Major Determinants of the Speed and Adequacy of Recovery

Antagonism of nondepolarizing neuromuscular blockade is time dependent. Recovery occurs at a rate that depends primarily on five factors: (1) depth of the blockade when the antagonist is administered, (2) which anticholinesterase is administered, (3) dose of the anticholinesterase, (4) rate of spontaneous recovery from the neuromuscular blocker, and (5) concentration of inhaled anesthetic agent present during reversal. Depth of the Blockade

Generally, more time is required to antagonize profound levels than lesser levels of blockade.[332] It is interesting that in a study by Bevan and coworkers,[333] antagonism of the blockade induced by doses of vecuronium or rocuronium that were 1.5 times the ED95 occurred at the same rate regardless of the timing of administration of 70 g/kg of neostigmine. Neostigmine shortened the recovery time by approximately 40%, whether it was administered at the time of 1%, 10%, or 25% of spontaneous recovery. However, as shown in Figure 29-24 , the time from administration of the neuromuscular blocker to TOF ratios of 0.7 and 0.9 did not decrease as the extent of spontaneous recovery at the time of neostigmine administration increased. Recovery to TOF ratios of 0.7 and 0.9 required, on average, 25 and 30 minutes, respectively. More specifically, should neostigmine be given during a profound (i.e., little or no response to peripheral nerve stimulation) neuromuscular block? Unfortunately, the answer is not clear. Thus, recommendations about the timing of administration of anticholinesterase are equivocal. Instinctively, many experts recommend not administering the anticholinesterase at the earliest degrees of recovery. Kirkegaard and associates[334] recently demonstrated that to recover to a TOF ratio of 0.7 within 10 minutes of administering neostigmine, three or four responses to TOF stimulation had to be present at the time of neostigmine administration. If only one response to TOF stimulation was present, recovery to a TOF ratio of 0.7 required up to 23 minutes.

Figure 29-24 Recovery times (mean SD) after the administration of a single dose of 0.45 mg/kg (1.5 times the ED95) rocuronium. In one group (Spont), spontaneous recovery was allowed. In the remaining groups, 70 g/kg of neostigmine was administered 5 minutes after rocuronium or at 1%, 10%, and 25% recovery of the first twitch (T1) from its control value. *P < .01 versus spontaneous recovery. Note that the times to attain a train-of-four (TOF) ratio of 0.9 are significantly shorter when neostigmine was administered at T1 = 10% or 25% of control tension. (From Bevan JC, Collins L, Fowler C, et al: Early and late reversal of rocuronium and vecuronium with neostigmine in adults and children. Anesth Analg 89:333-339, 1999.)

The maximum antagonistic effect of neostigmine occurs in 10 minutes or less. If adequate recovery does not occur within this time, subsequent recovery is slow and requires ongoing elimination of the neuromuscular blocker from plasma. For profound vecuronium-induced blockade in which no twitch recovery has occurred, administration of 70 g/kg of neostigmine produces an initial reversal that falls far short of adequate recovery.[327] Subsequent recovery occurs at the same rate as spontaneous recovery and is caused by the decrease in plasma concentration of vecuronium as the drug is eliminated. [327] [335]

Administration of a second dose of neostigmine has no further effect on recovery[327] because acetylcholinesterase is already maximally inhibited.

If the blockade at the time of neostigmine administration is sufficiently deep that adequate recovery does not occur within 10 minutes, the time at which full recovery of neuromuscular function will occur depends on the inherent duration of action of the neuromuscular blocker.[332] With drugs that have a long duration of action, this period of inadequate neuromuscular function can be 30 to 60 minutes or even longer, whereas with drugs that have an intermediate duration of action, it will be much shorter (e.g., 15 to 30 minutes).[336] The Anticholinesterase Administered

Under the conditions of a moderate depth of blockade (such as two to three twitches palpable by TOF monitoring), the order of rapidity of antagonism of residual blockade by anticholinesterases is edrophonium > neostigmine > pyridostigmine. [337] [338] For this reason and because of its lesser atropine requirement, edrophonium regained popularity as an antagonist during the 1980s.[327] However, Rupp and coworkers[339] found that edrophonium is not as effective as neostigmine in antagonizing profound blockade of more than 90% twitch depression (only one twitch palpable by TOF) whereas increasing the edrophonium dose from 0.5 to 1.0 mg/kg increased its efficacy. Neostigmine remains capable of more complete antagonism.[340] To be equivalent to 40 g/kg of neostigmine as an antagonist of profound vecuronium blockade, 1.5 mg/kg of edrophonium must be administered.[330]

The relative potencies of edrophonium and neostigmine differ at various intensities of blockade ( Fig. 29-25 .).[341] Edrophonium becomes less potent relative to neostigmine as the depth of blockade becomes more intense. In other words, the dose-response curves are not parallel and become increasingly divergent as the depth of blockade intensifies. This difference indicates that edrophonium may be less effective than neostigmine when antagonizing very deep levels of blockade.

Figure 29-25 First twitch height (logit scale) versus dose (log scale) 10 minutes after the administration of neostigmine and edrophonium given at either 1% (99% block) or 10% (90% block) first twitch recovery. (From Donati F, Smith CE, Bevan DR: Dose-response relationships for edrophonium and neostigmine as antagonists of moderate and profound atracurium blockade. Anesth Analg 68:13-19, 1989.)

The Dose of Anticholinesterase

Larger doses of anticholinesterases should antagonize neuromuscular blockade more rapidly and more completely than smaller doses do. This relationship is true up to the point of the maximum effective dose, beyond which additional amounts of anticholinesterase will not produce any further antagonism.

For neostigmine, this maximum effective dose is in the 60- to 80-g/kg range,[327] and for edrophonium, it is in the 1.0- to 1.5-mg/kg range. [339] [340]

Mixing or combining antagonists is not advisable. Neostigmine and edrophonium do not potentiate each other; in fact, their effects in combination may not even be additive.[342] Therefore, when inadequate reversal occurs, one should not be tempted to add a different anticholinesterase but should ensure only that the maximum dose of the original drug has been administered. Ventilation should then be supported until adequate neuromuscular function is achieved. Rate of Spontaneous Recovery from the Neuromuscular Blocker

After administration of an anticholinesterase, two processes contribute to recovery of neuromuscular function. The first is the antagonism induced by the effect of the anticholinesterase at the neuromuscular junction; the second is the natural process of decrease in plasma concentration of the neuromuscular blocker (and hence its effect at the neuromuscular junction). [332] [335] Therefore, the more rapid the elimination of the neuromuscular blocker, the faster the recovery of adequate neuromuscular function after the administration of an antagonist ( Fig. 29-26 ).[343] A clear illustration of this principle is the difference in antagonism of the blockade induced by neuromuscular blockers with an intermediate duration of action versus those with a long duration. Plasma concentrations of drugs with an intermediate duration of action decrease more rapidly than those with a long duration of action,[141] and consequently, recovery of neuromuscular function is more rapid. Thus, the incidence of inadequate neuromuscular function in the postoperative period is less with intermediate-acting than with longacting neuromuscular blockers. [336] [344] This difference in speed of reversal between intermediate- and long-acting drugs is due to the effect of different rates of spontaneous recovery and not to a difference in response to neostigmine.[345] When neostigmine is administered to antagonize a stable level of blockade maintained by continuous infusion of either vecuronium or pancuronium, the rate and degree of recovery are similar to those achieved in the case of administration of each neuromuscular blocker alone.[345]

Figure 29-26 Comparative mean speed of antagonism by neostigmine of neuromuscular blockade induced by long-acting agents (doxacurium, pancuronium, pipecuronium), intermediate-acting drugs (atracurium and others), and the short-acting agent mivacurium. Antagonism is more rapid as processes of clearance increase (see text). (From Savarese JJ: Reversal of nondepolarizing blocks: More controversial than ever? In Review Course Lectures, 67th Congress. Cleveland, OH, International Anesthesia Research Society, 1993.)

Even though mivacurium is no longer available in the United States, its pharmacology allows better understanding of basic pharmacology. The interaction between spontaneous recovery from and anticholinesterase-induced reversal of mivacurium's effect is more complex. The rate of spontaneous recovery from mivacurium-induced bockade is more rapid than that from any other nondepolarizing neuromuscular blocker. This is a result of its rapid hydrolysis by butyrylcholinesterase. Neostigmineinduced reversal of mivacurium is similar to or faster than that of atracurium. [184] [346] During profound (<3% twitch recovery) mivacurium-induced blockade, the administration of neostigmine may prolong recovery.[347] Neostigmine has two major effects relevant to mivacurium. First, it inhibits

acetylcholinesterase at the neuromuscular junction, thereby effectively increasing the acetylcholine concentration and facilitating recovery. Second, it inhibits butyrylcholinesterase, the enzyme responsible for metabolism of mivacurium, and slows the normally rapid decrease in the plasma concentration of mivacurium.[348] In contrast, edrophonium is a less potent inhibitor of butyrylcholinesterase[348] and should have little effect on the metabolism of mivacurium. Provided that there is 10% recovery of twitch response (one twitch in the TOF), either 20 to 40 g/kg of neostigmine or 0.3 to 0.5 mg/kg of edrophonium will accelerate recovery from mivacurium.[346]

It has been suggested that routine administration of an anticholinesterase may often be omitted because spontaneous recovery from mivacurium's effect is so rapid. However, this strategy may lead to inadequate recovery and postoperative weakness unless at least 20 minutes is allowed for spontaneous recovery before the anticholinesterase is administered.[346]

Because mivacurium is metabolized by butyrylcholinesterase, administration of exogenous human butyrylcholinesterase can theoretically hasten recovery from mivacurium's effects. Administration of purified human cholinesterase does produce some antagonism of mivacurium-induced blockade,[349] but it is ineffective in profound blockade[348] and no better than edrophonium alone.[350] Administration of purified butyrylcholinesterase to patients who are genetically homozygous for atypical butyrylcholinesterase and have a prolonged blockade may be justified,[188] but this therapy is expensive and has not yet been tested adequately. Concentration of Inhaled Anesthetic

Several studies have documented that antagonism of residual blockade is actually retarded by anesthetizing concentrations of anesthetic vapors. [351] [352] For example, reversal of rocuronium by neostigmine under sevoflurane (and to a lesser extent, isoflurane) anesthesia occurred more slowly than under propofol anesthesia.[352] Sevoflurane may impede neostigmine-induced antagonism more than isoflurane does.[351] When compared with recovery from isoflurane anesthesia, recovery from that produced by desflurane or sevoflurane is prolonged.[343] Withdrawal of the anesthetic vapor at the end of surgery, with subsequent reduction of its enhancement of neuromuscular blockade, will speed pharmacologic reversal.[328] Clinical Recommendations

When antagonizing deep levels of neuromuscular blockade (about 10% recovery or one twitch in response to TOF stimulation), larger doses of anticholinesterases (e.g., neostigmine, 35 g/kg) should be administered and adequate time allowed for recovery of neuromuscular function. The time required for recovery to a TOF ratio of 0.7 will be approximately 60 minutes for the long-acting neuromuscular blocking drugs (pancuronium) and 30 minutes for the intermediate-acting ones (rocuronium). To antagonize lesser degrees of blockade, smaller doses of anticholinesterases may be administered, with additional anticholinesterase given if adequate recovery has not occurred in 10 minutes.

It is not advisable to administer additional anticholinesterase if maximal doses of edrophonium (1.5 mg/kg), neostigmine (70 g/kg), or pyridostigmine (350 g/kg) fail to antagonize the residual blockade.[340] Giving too much anticholinesterase to antagonize residual neuromuscular blockade may actually render patients weaker. [326] [354] [355] These doses inhibit acetylcholinesterase completely, and if they fail to fully antagonize the residual blockade, another likely cause of the inadequate antagonism should be sought. Some of these additional potential causes of inadequate antagonism of neuromuscular blockade are described in the following sections. Acid-Base State

Both metabolic and respiratory acidosis may augment the blockade induced by a nondepolarizing neuromuscular blocker, but only respiratory acidosis prevents adequate antagonism. [338] [356] The probability of achieving adequate antagonism of nondepolarizing neuromuscular blockade in the presence of significant respiratory acidosis (partial pressure of carbon dioxide in arterial gas >50 mm Hg) is low. Therefore, attempts to antagonize residual blockade may fail if a patient hypoventilates. Administration of narcotics to relieve pain may, by producing hypoventilation, increase the likelihood of this adverse event. Although metabolic acidosis might also be predicted to prevent antagonism by neostigmine, this hypothesis has not been substantiated. [338] [356] Metabolic alkalosis, but not metabolic acidosis, prevents neostigmine's antagonism of dTc and pancuronium. [338] [356] [357] These results suggest that extracellular pH is not as important as changes in electrolyte concentrations and intracellular pH. Electrolyte Imbalance

Few data are available on the effect of electrolyte imbalance on antagonism of a nondepolarizing neuromuscular blockade induced by neostigmine. Low extracellular concentrations of potassium enhance the blockade from nondepolarizing neuromuscular blockers and diminish the ability of neostigmine to antagonize the blockade. This effect is caused by the increase in end-plate transmembrane potential that results from a higher ratio of intracellular to extracellular potassium. Thus, a decrease in extracellular potassium causes hyperpolarization and produces resistance to depolarization. Patients with an imbalance in potassium may have other diseases or injuries that alter their response to neuromuscular blockers (e.g., patients with burns). In addition, severe dehydration will concentrate the neuromuscular blocker present in plasma, in effect decreasing the volume of distribution and increasing muscle relaxant activity. In an animal model of chronic hypokalemia, cats were given a diuretic without potassium supplementation for 15 days. Less pancuronium was required for neuromuscular blockade and more neostigmine was required for antagonism.[358] Even though the differences were small, the blockade was always antagonized completely. If we assume that this animal model approximates the clinical situation, changes in potassium appear to be of relatively minor consequence with respect to the clinical question of adequacy of reversal. Other Factors

The calcium channel blocker verapamil will potentiate nondepolarizing neuromuscular blocking drugs and may render achieving adequate reversal difficult. [359] [360] When attempting reversal of neuromuscular blockade in patients receiving verapamil, edrophonium may be more effective than neostigmine. [359] [360] Other factors that may interfere with antagonism are hypothermia and the

administration of antibiotics, particularly those of the aminoglycoside or polypeptide classes (see the section on drug interactions).[271] In the case of antibiotics, administration of an anticholinesterase may in fact deepen the blockade. Side Effects of Anticholinesterases Cardiovascular Effects

Because only the nicotinic effects of edrophonium, neostigmine, and pyridostigmine are desired, the muscarinic effects must be blocked by atropine or glycopyrrolate. Atropine induces its vagolytic effect much more rapidly than glycopyrrolate does. To minimize cardiovascular changes, atropine is better suited for administration with the rapid-acting edrophonium, and glycopyrrolate is better suited for administration with the slower-acting neostigmine and pyridostigmine.[361] In general, 7 to 10 g/kg of atropine should be given with 0.5 to 1.0 mg/kg of edrophonium.[337] When cardiac dysrhythmias are a concern, glycopyrrolate may be preferable to atropine,[362] and the anticholinesterases and anticholinergics should be administered more slowly (e.g., 2 to 5 minutes) to reduce the incidence and severity of disordered rhythm. Nausea and Vomiting

Reports on the effect of anticholinesterase administration on postoperative nausea and vomiting are conflicting. Neostigmine has been implicated as a cause of postoperative nausea and vomiting,[363] but it has also been described as having antiemetic properties[364] and as having no effect on the incidence of postoperative nausea and vomiting.[365] A meta-analysis by Tramer and Fuchs-Bader[366] looked at the results of anticholinesterase administration in more than 1100 patients. They found a dose-response relationship for the incidence of nausea and vomiting after the administration of neostigmine: the highest incidence of vomiting after the administration of 1.5 mg of neostigmine was lower than the lowest incidence of vomiting after the administration of 2.5 mg of neostigmine. Discrepancies between the results of other studies may have been at least partly attributable to the use of different dosing regimens. Although vomiting occurs in 17% to 33% of patients after the administration of neostigmine, the authors did not recommend that all patients be allowed to recover spontaneously because of the risk for postoperative residual paralysis.[366] A more recent study demonstrated the hazards of not antagonizing residual neuromuscular blockade at least 2 hours after the administration of a dose twice the ED95 of vecuronium, rocuronium, or atracurium.[367] Pharmacokinetics of Neostigmine, Pyridostigmine, and Edrophonium

The pharmacokinetics of edrophonium, neostigmine, and pyridostigmine is summarized in Table 29-12 . [368] [369] [370] [371] The data indicate several relevant clinical conclusions: 1. Pyridostigmine has a longer elimination half-life than that of the other anticholinesterases, which probably accounts for its longer duration of action. [368] [369] 2. Comparison data on the elimination half-lives in patients with and without renal failure showed that renal excretion accounts for about 50% of the excretion of neostigmine and about 75% of the excretion of pyridostigmine and edrophonium. Renal failure decreases the

plasma clearance of neostigmine, pyridostigmine, and edrophonium as much as, if not more than that of the long-acting neuromuscular blockers. Therefore, if proper doses of anticholinesterase drugs are given and overdoses of neuromuscular blockers are avoided, renal failure should not be associated with recurarization. [368] [369] This remote possibility is further diminished if the clinician restricts the relaxants used to the intermediate- or short-acting drugs in patients with renal failure. 3. Edrophonium was once thought to be an unsuitable antagonist in clinical practice because its duration of action was believed to be too short. However, when larger doses (e.g., 0.5 to 1.0 mg/kg) are given, sustained antagonism of nondepolarizing neuromuscularinduced blockade results.[372] In fact, the elimination half-life of edrophonium is similar to that of neostigmine and pyridostigmine (see Table 29-12 ).[370] Table 29-12 -- Pharmacokinetics of neostigmine (N), pyridostigmine (P), and edrophonium (E) in patients without and with renal failure Withou t Renal Failure N Distribution half-life ( , min) Elimination half-life ( , min) Volume of central compartment (L/kg) Total plasma clearance (mL/kg/min) 3.4 77 0.2 9.1 6.7 113 0.3 8.6 P 7.2 110 0.3 9.5 E With Renal Failur e N 2.5 181 0.3 4.8 P 3.9 379 0.4 3.1 E 7.0 304 0.3 3.9

Data from Cronnelly et al. [368] [369] and Morris et al. [370] [371]

Mild hypothermia (i.e., 34C to 35C), which commonly occurs intraoperatively, affects the pharmacokinetics of neostigmine. Its clearance is decreased from 16.2 mL/kg/min at 36.5C to 13.5 mL/kg/min at 34.5C.[284] In addition, onset of the peak effect of neostigmine is delayed by mild hypothermia from 4.2 to 5.5 minutes.[284] If hypothermia has any influence on the efficacy of neostigmine-induced reversal, it is more likely to be due to the effect of temperature on the neuromuscular blocker (e.g., prolonged duration of action[273]) than to the pharmacology of neostigmine.

The pharmacokinetics of the anticholinesterases depends on several factors, including distribution, metabolism, and elimination. In the case of neostigmine, a carbamylated complex with acetylcholinesterase is formed, and it is the rate of dissociation of neostigmine from this complex (i.e., its metabolism) that is probably the major determinant of its duration of action. The decrease in the

plasma concentration of neostigmine (i.e., its distribution and elimination) may not be as pertinent a determinant of its duration of action. Other Antagonists of Nondepolarizing Neuromuscular Blockade Sugammadex

Sugammadex may be the most exciting drug in clinical neuromuscular pharmacology in the last 50 years. The combination of rocuronium and sugammadex could replace succinylcholine for rapidsequence induction of anesthesia and completely eliminate residual paralysis in the postanesthetic recovery room.[373]

Sugammadex (ORG 25969) is the first selective relaxant binding agent (su refers to sugar, and gammadex refers to the structural molecule gamma-cyclodextrin). A modified -cyclodextrin, sugammadex ( Fig. 29-27 ) is a new type of reversal agent.[374] The three natural unmodified cyclodextrins consist of six, seven, and eight cyclic oligosaccharides (i.e., dextrose units joined through one to four glycosyl bonds) and are called -, -, and -cyclodextrin, respectively. Their threedimensional structure resembles a hollow truncated cone or a doughnut. The structure has a hydrophobic cavity and a hydrophilic exterior because of the presence of polar hydroxyl groups. Hydrophobic interactions trap the drug in the cyclodextrin cavity (the doughnut hole), thereby resulting in the formation of a water-soluble guest-host complex. Although unmodified -cyclodextrin possesses a larger lipophilic cavity (7.5 to 8.3 ) than any other cyclodextrin does, it is still not deep enough to accommodate the larger rigid structure of the rocuronium molecule. Therefore, the cavity was modified by adding eight side chains to extend it to 11 for better accommodation of the four hydrophobic steroidal rings of rocuronium and by adding negatively charged carboxyl groups at the end of the side chains to enhance electrostatic binding to the positively charged quaternary nitrogen of rocuronium ( Fig. 29-28 ). [374] [375] The stability of the rocuronium-sugammadex complex is the end result of an interplay of intermolecular forces (van der Waals forces), including thermodynamic (hydrogen bonds) and hydrophobic interactions.[376]

Figure 29-27 Structure of the synthetic -cyclodextrin sugammadex (ORG 25969).

Figure 29-28 The sugammadex-rocuronium complex. (From Bom A, Bradley M, Cameron K, et al: A novel concept of reversing neuromuscular block: Chemical encapsulation of rocuronium bromide by a cyclodextrin-based synthetic host. Angew Chem 41:266-270, 2002.)

Sugammadex exerts its effect by forming very tight complexes in a 1:1 ratio with steroidal neuromuscular blocking agents (rocuronium > vecuronium pancuronium).[374] The guest-host complex exists in an equilibrium with a very high association rate and very low dissociation rate, so the complex is tight.[374] During rocuronium-induced neuromuscular blockade, intravenous administration

of sugammadex results in rapid removal of free rocuronium molecules from plasma. This creates a concentration gradient favoring movement of the remaining rocuronium molecules from the neuromuscular junction back into plasma, where they are encapsulated by free sugammadex molecules. These molecules also enter tissues and form a complex with rocuronium. Therefore, the neuromuscular blockade of rocuronium is terminated rapidly by the diffusion of rocuronium away from the neuromuscular junction back into plasma. This results in an increase in the total plasma concentration of rocuronium (free and that bound to sugammadex).[377] Sugammadex therefore acts as a binding agent and has no effect on acetylcholinesterase or any receptor system in the body, thus eliminating the need for anticholinergic drugs and their undesirable side effects. PHARMACOKINETICS.

During an infusion of rocuronium to maintain a stable depth of neuromuscular blockade, administration of sugammadex increases the measured plasma concentration of rocuronium; the relaxant is redistributed from the effect compartment to the central compartment as it is encapsulated by sugammadex.[377] Recovery of muscle strength can occur despite increasing plasma concentrations of relaxant because the efficacy of sugammadex does not rely on renal excretion of the cyclodextrinrelaxant complex.[378]

When administered by itself to volunteers who had not received a neuromuscular blocking agent, 0.1 to 8.0 mg/kg of sugammadex had a clearance rate of 120 mL/min, an elimination half-life of 100 minutes, and a volume of distribution of 18 L.[379] Approximately 75% of a dose was eliminated in urine. The kinetics of sugammadex appears to be dose dependent in that clearance increases and the elimination half-life decreases as the dose of sugammadex increases from 0.15 to 1.0 mg/kg.[379]

In the absence of sugammadex, rocuronium is eliminated mainly by biliary excretion (>75%) and to a lesser degree by renal excretion (10% to 25%). Plasma clearance of sugammadex alone is approximately three times lower than that of rocuronium alone.[380] In volunteers, plasma clearance of rocuronium was decreased by a factor of greater than 2 after the administration of a 2.0-mg/kg or greater dose of sugammadex.[379] This decreased clearance occurs because the biliary route of excretion becomes unavailable for the rocuronium-sugammadex complex, and rocuronium clearance decreases to a value approaching the glomerular filtration rate (120 mL/min). Because of the soluble nature of the rocuronium-cyclodextrin complex, urinary excretion of the complex is the major route of elimination of rocuronium. Renal excretion of rocuronium is increased by more than 100% after the administration of 4 to 8 mg/kg of sugammadex.[380]

As noted earlier, after the administration of sugammadex, the plasma concentration of free rocuronium decreases rapidly, but the total plasma concentration of rocuronium (both free and that bound to sugammadex) increases.[377] PHARMACODYNAMICS.

In male volunteers, administration of 8 mg/kg of sugammadex 3 minutes after the administration of 0.6 mg/kg of rocuronium resulted in recovery of the TOF ratio to 0.9 within 2 minutes.[379] Decreasing the dose of sugammadex to 4 mg/kg resulted in recovery of the TOF ratio to 0.9 in less than 4 minutes.[379] Additionally, in surgical patients who were anesthetized with total intravenous anesthetic agents and had received 0.6 mg/kg of rocuronium, different doses of sugammadex or placebo were administered at reappearance of the second twitch of the TOF response.[381] Sugammadex decreased the median recovery time in a dose-dependent manner from 21.0 minutes in the placebo group to 1.1 minutes in the group given 4.0 mg/kg of sugammadex.[381]

Administration of sugammadex when the TOF count had returned to two detectable responses resulted in a dose-dependent recovery from the neuromuscular blockade induced by either rocuronium (0.60 mg/kg) or vecuronium (0.10 mg/kg).[382] After a dose of 4.0 mg/kg of sugammadex, the mean time to recovery of the TOF ratio to 0.9 was 1.1 minutes and 1.5 minutes after rocuronium and vecuronium, respectively. A sugammadex dose of 0.5 mg/kg is considered to be grossly inadequate for antagonism.
[382] [383] [384]

One of the features that make sugammadex so different pharmacodynamically from the available anticholinesterases is that it takes effect more quickly and reliably than either neostigmine or edrophonium.[385] In a trial by Sacan and colleagues,[385] patients received 0.6 mg/kg of rocuronium, and neuromuscular blockade was maintained with supplemental doses of rocuronium given at reappearance of the second twitch in the TOF. The reversal agent70 g/kg of neostigmine, 1 mg/kg of edrophonium, or 4 mg/kg of sugammadexwas administered at least 15 minutes after the last dose of rocuronium. A 4-mg/kg dose of sugammadex reversed the rocuronium-induced neuromuscular blockade more rapidly than neostigmine or edrophonium did. The average time to achieve a TOF ratio of 0.9 was 10 times longer after the administration of neostigmine than it was after sugammadex (1044 versus 107 seconds) and three times longer after the administration of edrophonium (331 seconds) than after sugammadex. Although 5 of 20 patients in the neostigmine group and 2 of 20 patients in the edrophonium group achieved a TOF ratio of 0.9, all 20 in the sugammadex group achieved this degree of recovery. Furthermore, 5 minutes after the administration of edrophonium, none of the patients who had received edrophonium and 5% of those who had received neostigmine had recovered to a TOF ratio of 0.9, but all the patients in the sugammadex group had.[385] Hence, sugammadex appears to allow more complete recovery of neuromuscular function than the anticholinesterases do, and it does so more quickly than the more conventional agents. Unlike the case with neostigmine or edrophonium, [328] [351] [353] the choice of anesthetic agent (e.g., propofol versus sevoflurane) does not appear to influence the ability of sugammadex to antagonize rocuronium-induced neuromuscular blockade.[386]

Whereas there is a ceiling effect to what anticholinesterases can do[332] in that they cannot effectively antagonize profound levels of neuromuscular blockade, sugammadex has been shown to do so in trials. [384] [387] Deep neuromuscular blockade (post-tetanic count of <10) was maintained for at least 2 hours in patients anesthetized with propofolnitrous oxideopioid anesthesia.[387] After spontaneous recovery of the second twitch of the TOF, different doses of sugammadex were administered; increasing the sugammadex dose from 0.5 to 4.0 mg/kg shortened the average recovery time to a TOF of 0.9 from 6.8 minutes (range, 4.8 to 11.4 minutes) to 1.4 minutes (range, 0.95 to 2.3 minutes), respectively.[387] Unexpectedly, the recovery time was longer (2.6 minutes[388]) with a 6.0-mg/kg dose.[387] The reason for

this deviation is unclear.

Sugammadex produces rapid and effective reversal of even more profound rocuronium-induced neuromuscular blockade. In one study, sugammadex or placebo was administered 5 minutes after the administration of 1.2 mg/kg of rocuronium.[389] Increasing the dose of sugammadex to 16 mg/kg decreased the mean recovery time to a TOF ratio of 0.9 from 122.1 minutes (spontaneous recovery) to less than 2 minutes.[389]

In another study, patients were randomized to receive an intubating dose of 1.2 mg/kg of rocuronium followed 3 minutes later by 16 mg/kg of sugammadex or an intubating dose of 1.0 mg/kg of succinylcholine.[390] The mean time to 90% recovery of first twitch was significantly faster in the rocuronium-sugammadex group than it was in the succinylcholine group. The mean ( SD) time to 90% recovery of first twitch from the start of sugammadex administration was 2.9 minutes (1.7 minutes).[390] Therefore, the use of rapid-sequence induction with rocuronium can be facilitated by the presence of sugammadex. Administration of 1.2 mg/kg of rocuronium followed 3 minutes later by 16 mg/kg of sugammadex seems to provide a faster onset-offset profile than that seen with 1.0 mg/kg of succinylcholine ( Fig. 29-29 ).[391]

Figure 29-29 A, Recovery of twitch height and the train-of-four (TOF) ratio after the administration of 1.2 mg/kg of rocuronium, followed 3 minutes later by 16 mg/kg of sugammadex, both given intravenously. Recovery to a first twitch height (T1) of 90% and a TOF ratio of 0.94 occurred 110 seconds later. The onset-offset time with this sequence (i.e., time from the end of the injection of rocuronium until T1 recovery to 90%) was 4 minutes, 47 seconds. B, Effects of administering 1.0 mg/kg of succinylcholine (Sch) with spontaneous recovery to a T1 of 90% occurring after 9 minutes, 23 seconds. (From Naguib M: Sugammadex: Another milestone in clinical neuromuscular pharmacology. Anesth Analg 104:575-581, 2007.)

Sugammadex is ineffective against succinylcholine and benzylisoquinolinium neuromuscular blockers such as mivacurium, atracurium, and cisatracurium[392] because it cannot form inclusion complexes with these drugs. Therefore, if neuromuscular blockade must be reestablished after using sugammadex, one of the benzylisoquinolinium neuromuscular blockers should be considered. SIDE EFFECTS.

The ability of sugammadex to form complexes with steroidal and nonsteroidal compounds such as cortisone, atropine, and verapamil is probably clinically insignificant and is 120 to 700 times less than that of rocuronium.[393] In phase I and II studies, the most frequently reported side effects have been hypotension, coughing, movement, nausea, vomiting, dry mouth, parosmia (an abnormal sense of smell), a sensation of a changed temperature, and abnormal levels of N-acetyl-glucosaminidase in urine. [379] [381] [387] Patient movement with the administration of sugammadex may have been due to the unmasking of inadequate anesthesia rather than an adverse response to the reversal agent. In one study, prolongation of the corrected QT interval was noted in five subjects who received placebo and in three who received sugammadex.[379] Cysteine

Gantacurium undergoes rapid degradation in plasma by chemical hydrolysis and inactivation by cysteine adduction (see Fig. 29-10 ),[105] which is a novel chemical mechanism of inactivation. Exogenous administration of cysteine can accelerate the antagonism of gantacurium-induced neuromuscular blockade. As shown in Figure 29-30 , after administration of a second 0.2-mg/kg dose of gantacurium, followed less than 1 minute later by 10 mg/kg of cysteine, complete recovery from neuromuscular blockade occurred within 4 minutes.

Figure 29-30 Twitch recording from a single monkey demonstrating complete spontaneous recovery from 3.2 times the ED95 of gantacurium, 0.2 mg/kg. Complete spontaneous recovery occurred within 10 minutes. Six minutes after complete recovery, a second dose of gantacurium, 0.2 mg/kg, was administered to this animal. Less than 1 minute later, 10 mg/kg of cysteine was administered. With cysteine administration, complete recovery occurred within 4 minutes of administering gantacurium. (Courtresy of John J. Savarese.)