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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 ofthe transmitter acetylcholine and are the principal reason for the attraction of these drugs to muscle-and neuronal-type nAChRs at the neuromuscular junction. These receptors are also located at otherphysiologic sites of acetylcholine in the body, such as the neuronal-type nicotinic receptors inautonomic ganglia and as many as five different muscarinic receptors on both the parasympathetic andsympathetic sides of the autonomic nervous system. In addition, populations of neuronal nicotinic andmuscarinic receptors are located prejunctionally at the neuromuscular junction.

The depolarizing neuromuscular blocker succinylcholine is composed of two molecules ofacetylcholine linked back to back through the acetate methyl groups ( Fig. 29-5 ). As described byBovet,[27] succinylcholine is a long, thin, flexible molecule. Like acetylcholine, succinylcholinestimulates cholinergic receptors at the neuromuscular junction and at nicotinic (ganglionic) andmuscarinic autonomic sites, thereby opening the ionic channel in the acetylcholine receptor.

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


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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-responsetechniques, Kopman and coworkers[29] estimated that its potency is far greater, with an ED95 of less than0.3 mg/kg.

Administration of 1 mg/kg of succinylcholine results in complete suppression of response toneuromuscular stimulation in approximately 60 seconds.[30] In patients with genotypically normalbutyrylcholinesterase (also known as plasma cholinesterase or pseudocholinesterase) activity, recoveryto 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 tosuccinylmonocholine and choline. Butyrylcholinesterase has an enormous capacity to hydrolyzesuccinylcholine, and only 10% of the administered drug reaches the neuromuscular junction.[32] Theinitial metabolite, succinylmonocholine, is a much weaker neuromuscular blocking agent thansuccinylcholine and is metabolized much more slowly to succinic acid and choline. The eliminationhalf-life of succinylcholine is estimated to be 47 seconds.[33]

Because there is little or no butyrylcholinesterase at the neuromuscular junction, the neuromuscularblockade of succinylcholine is terminated by its diffusion away from the neuromuscular junction backinto the circulation. Butyrylcholinesterase, therefore, influences the onset and duration of action ofsuccinylcholine by controlling the rate at which the drug is hydrolyzed before it reaches and after itleaves the neuromuscular junction.

Dibucaine Number and Butyrylcholinesterase Activity

Butyrylcholinesterase is synthesized by the liver and found in plasma. The neuromuscular blockadeinduced by succinylcholine is prolonged by a decreased concentration or activity of the enzyme. Theactivity 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 quitelarge[31]; significant decreases in butyrylcholinesterase activity result in modest increases in the timerequired to return to 100% twitch recovery ( Fig. 29-6 ).


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Figure 29-6 Correlation between the duration of succinylcholine neuromuscular blockade andbutyrylcholinesterase activity. The normal range of activity lies between the arrows. (FromViby-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 onbutyrylcholinesterase activity or the duration of succinylcholine's effect.[39] Bambuterol, a prodrug ofterbutaline, produces marked inhibition of butyrylcholinesterase activity and causes prolongation ofsuccinylcholine-induced blockade.[40] The -blocker esmolol inhibits butyrylcholinesterase but causesonly minor prolongation of succinylcholine blockade.[41]

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


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enzyme activity may be low, this has not been a major concern in clinical practice because even largedecreases in butyrylcholinesterase activity result in only moderate increases in the duration of action ofsuccinylcholine. When butyrylcholinesterase activity is reduced to 20% of normal by severe liverdisease, the duration of apnea after the administration of succinylcholine increases from a normalduration of 3 minutes to just 9 minutes. Even when treatment of glaucoma with echothiophatedecreased 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 ofneuromuscular blockade exceed 23 minutes.[42]

Dibucaine Number and Atypical Butyrylcholinesterase Activity

Succinylcholine-induced neuromuscular blockade can be significantly prolonged if the patient has anabnormal genetic variant of butyrylcholinesterase. The variant was found by Kalow and Genest[43] torespond to dibucaine differently than normal butyrylcholinesterase does. Dibucaine inhibits normalbutyrylcholinesterase to a far greater extent than it inhibits the abnormal enzyme. This observation ledto 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 thedibucaine-resistant variants are the most important. The review by Jensen and Viby-Mogensen[44] canbe consulted for more detailed information on this topic.

Table 29-1-- Relationship between dibucaine number and duration of succinylcholine ormivacurium neuromuscular blockade

Type of

Butyrylcholinesterase

Genot

ype

Inciden

ce

Dibucaine

Number *

Response to Succinylcholine or

Mivacurium

Homozygous typical E1u

E1u

Normal 70-80 Normal

Heterozygous atypical E1uE1a 1/480 50-60 Lengthened by 50%-100%

Homozygous atypical E1aE1a 1/3200 20-30 Prolonged to 4-8 hr

* 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 itindicate 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 beinfluenced by genotype.

The molecular biology of butyrylcholinesterase is well understood. The amino acid sequence of theenzyme is known, and the coding errors responsible for most genetic variations have been identified.[44]


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Most variants are due to a single amino acid substitution error or sequencing error at or near the activesite of the enzyme. For example, in the case of the atypical dibucaine-resistant (A) gene, a mutationoccurs at nucleotide 209, where guanine is substituted for adenine. The resultant change in this codoncauses substitution of glycine for aspartic acid at position 70 in the enzyme. In the case of the fluoride-resistant (F) gene, two amino acid substitutions are possible, namely, methionine for threonine atposition 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 cholinergicautonomic receptors: nicotinic receptors on both sympathetic and parasympathetic ganglia[46] andmuscarinic receptors in the sinus node of the heart. At low doses, both negative inotropic andchronotropic responses may occur. These responses can be attenuated by prior administration ofatropine. With large doses of succinylcholine, these effects may become positive[47] and result intachycardia. A prominent clinical manifestation of generalized autonomic stimulation is thedevelopment of cardiac dysrhythmias, principally manifested as sinus bradycardia, junctional rhythms,and ventricular dysrhythmias. Clinical studies have described these dysrhythmias under variousconditions in the presence of the intense autonomic stimulus of tracheal intubation. It is not entirelyclear whether the cardiac irregularities are due to the action of succinylcholine alone or to the addedpresence of extraneous autonomic stimulation. An in vitro study using the ganglionic acetylcholinereceptor subtype 34 expressed inXenopus laevis oocytes suggested that at clinically relevantconcentrations, succinylcholine had no effect on the expressed receptors.[48] Only at high doses ofsuccinylcholine was inhibition of ganglionic acetylcholine receptors noted.[48] The significance of thesefindings is difficult to extrapolate into clinical practice because the method used (Xenopus laevis oocyteexpression model) does not match clinical reality.

SINUS BRADYCARDIA.

The autonomic mechanism involved in sinus bradycardia is stimulation of cardiac muscarinic receptorsin the sinus node. This is particularly problematic in individuals with predominantly vagal tone, such aschildren who have not received atropine. Sinus bradycardia has also been noted in adults and appearsmore commonly after a second dose of the drug is given approximately 5 minutes after the first. [49] Thebradycardia may be prevented by the administration of thiopental, atropine, ganglion-blocking drugs,and nondepolarizing neuromuscular blockers.[50] The implication of this information is that directmyocardial effects, increased muscarinic stimulation, and ganglionic stimulation may all be involved inthe bradycardia response. The higher incidence of bradycardia after a second dose of succinylcholinesuggests that the hydrolysis products of succinylcholine (succinylmonocholine and choline) maysensitize the heart to a subsequent dose.

NODAL (JUNCTIONAL) RHYTHMS.


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Nodal rhythms commonly occur after the administration of succinylcholine. The mechanism probablyinvolves relatively greater stimulation of muscarinic receptors in the sinus node, which suppresses thesinus mechanism and allows emergence of the atrioventricular node as the pacemaker. The incidence ofjunctional rhythm is greater after a second dose of succinylcholine but is prevented by prioradministration of dTc.[50]

VENTRICULAR DYSRHYTHMIAS.

Under stable anesthetic conditions, succinylcholine lowers the threshold of the ventricle tocatecholamine-induced dysrhythmias in the monkey and dog. Circulating catecholamine concentrationsincrease fourfold and potassium concentrations increase by a third after administration ofsuccinylcholine to dogs.[51] Similar increases in catecholamine levels after administration ofsuccinylcholine to humans are also observed.[52] Other autonomic stimuli, such as endotrachealintubation, hypoxia, hypercapnia, and surgery, may be additive to the effect of succinylcholine. Thepossible 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 ofcatecholamines, must also be considered. Ventricular escape beats may also occur as a result of severesinus and atrioventricular nodal slowing secondary to succinylcholine administration. The developmentof ventricular dysrhythmias is further encouraged by the release of potassium from skeletal muscle as aconsequence of the depolarizing action of the drug.

Hyperkalemia

Administration of succinylcholine to an otherwise well individual for an elective surgical procedureincreases 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 ofsodium into the cells is accompanied by movement of potassium out of the cells. This slight increase inpotassium 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 hyperkalemicresponse to succinylcholine.[53] Nevertheless, more controlled studies have shown that such patients areno more susceptible to an exaggerated response to succinylcholine than those with normal renalfunction are.[54] One might postulate that patients who have uremic neuropathy may be susceptible tosuccinylcholine-induced hyperkalemia, although the evidence supporting this view is scarce. [53] [54]

However, severe hyperkalemia may follow the administration of succinylcholine to patients withsevere metabolic acidosis and hypovolemia.[55] In rabbits, the combination of metabolic acidosis andhypovolemia results in a high resting potassium level and an exaggerated hyperkalemic response tosuccinylcholine.[56] In this situation, the potassium originates from the gastrointestinal tract, not frommuscle 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 beattempted before administration of succinylcholine. Should severe hyperkalemia occur, it can be treated


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with immediate hyperventilation, 1.0 to 2.0 mg of calcium chloride intravenously, 1 mEq/kg of sodiumbicarbonate, and 10 units of regular insulin in 50 mL of 50% glucose for adults or, for children, 0.15units 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 ofsuccinylcholine. These investigators found that in patients with intra-abdominal infections persistingfor longer than 1 week, the possibility of a hyperkalemic response to succinylcholine should beconsidered.

Stevenson and Birch[59] described a single, well-documented case of a marked hyperkalemic responseto 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]

foundthat a significant increase in serum potassium did not occur in 59 patients until about 1 week after theinjury, at which time a progressive increase in the serum potassium level was noted after the infusion ofsuccinylcholine. Three weeks after injury, three of these patients with especially severe trauma showedmarked hyperkalemia with an increase in serum potassium of greater than 3.6 mEq/L, sufficient tocause cardiac arrest. Birch and coworkers[60] found that prior administration of 6 mg of dTc preventedthe hyperkalemic response to succinylcholine. In the absence of infection or persistent degeneration oftissue, a patient is susceptible to the hyperkalemic response for probably at least 60 days after massivetrauma or until adequate healing of damaged muscle has occurred.

In addition, patients with any number of conditions that result in the proliferation of extrajunctionalacetylcholine receptors, such as neuromuscular disease, are likely to have an exaggerated hyperkalemicresponse after the administration of succinylcholine. The response of these patients to neuromuscularblocking agents is reviewed in detail later in this chapter. These disease states include cerebrovascularaccident with resultant hemiplegia or paraplegia, muscular dystrophies, and Guillain-Barr syndrome(see also Chapter 37 ). The hyperkalemia occurring after the administration of succinylcholine may beof such an extent that cardiac arrest ensues. For a recent review on succinylcholine-inducedhyperkalemia 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 ismanifested within 1 minute after injection, peaks at 2 to 4 minutes, and subsides by 6 minutes.[62] Themechanism by which succinylcholine increases IOP has not been clearly defined, but it is known toinvolve 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 fromsuccinylcholine, thus suggesting a circulatory mechanism.[63] Despite this increase in IOP, the use ofsuccinylcholine for eye operations is not contraindicated unless the anterior chamber is open. AlthoughMeyers and associates[64] were unable to confirm the efficacy of precurarization in attenuating increases


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in IOP after the administration of succinylcholine, numerous other investigators have found that prioradministration of a small dose of nondepolarizing neuromuscular blocker (such as 3 mg of dTc or 1 mgof pancuronium) will prevent a succinylcholine-induced increase in IOP.[65] Furthermore, Libonati andcoauthors[66] described the anesthetic management of 73 patients with penetrating eye injuries whoreceived succinylcholine; no loss of global contents resulted. Thus, despite the potential concerns ofMeyers 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 andwith 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 thetube, that may elevate IOP.[64] Of prime importance is ensuring that the patient is well anesthetized andnot straining or coughing. Because nondepolarizing neuromuscular blockers with shorter times to onsetof effect are now available, providing an anesthetic that allows the trachea to be intubated rapidlywithout administering succinylcholine is now an option. Finally, should a patient's anesthesia becometoo light over the course of intraocular surgery, succinylcholine should not be given to immobilize thepatient. Rather, the surgeon should be asked to pause while the anesthesia is deepened. If necessary, thedepth 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 bysuccinylcholine is quite variable. The increase in IGP from succinylcholine is presumed to be due tofasciculations of abdominal skeletal muscle. This is not surprising because more coordinatedabdominal skeletal muscle activity (e.g., straight-leg raising) may increase IGP to values as high as 120cm H2O. In addition to skeletal muscle fasciculations, the acetylcholine-like effect of succinylcholinemay be partly responsible for the observed increases in IGP. Greenan[67] noted consistent increases inIGP 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 theadministration 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 abdominalskeletal muscle fasciculations. Accordingly, when fasciculations were prevented by prioradministration of a nondepolarizing neuromuscular blocker, no increase in IGP was observed.

Are the increases in IGP after succinylcholine administration enough to cause incompetence of thegastroesophageal junction? Generally, an IGP of greater than 28 cm H2O is required to overcome thecompetence of the gastroesophageal junction. However, when the normal oblique angle of entry of theesophagus 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 gastroesophagealjunction is frequently less than 15 cm H2O.[68] In these circumstances, regurgitation of stomach contentsafter the administration of succinylcholine is a distinct possibility, and precautionary measures shouldbe taken to prevent fasciculation. Endotracheal intubation may be facilitated by administration of eithera nondepolarizing neuromuscular blocker or a defasciculating dose of a nondepolarizing relaxantbefore the succinylcholine.


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Apparently, succinylcholine does not increase IGP appreciably in infants and children, which may berelated 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 clinicalsignificance of this transient increase are unknown, but the rise in intracranial pressure does not occurafter pretreatment with nondepolarizing neuromuscular blockers.[70]

Myalgias

The incidence of muscle pain after the administration of succinylcholine varies from 0.2% to 89%.[71] Itoccurs more frequently after minor surgery, especially in women and in ambulatory rather thanbedridden patients.[72] Waters and Mapleson[72] postulated that the pain is secondary to damageproduced 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 andincreases in serum creatine kinase after succinylcholine administration.[73] Prior administration of asmall dose of a nondepolarizing neuromuscular blocker clearly prevents succinylcholine-relatedfasciculations.[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 nondepolarizingneuromuscular blocker has no effect,[71] many believe that the pain from succinylcholine is at leastattenuated.[73] Pretreatment with a prostaglandin inhibitor (e.g., lysine acetyl salicylate) has been shownto be effective in decreasing the incidence of muscle pain after succinylcholine. [74] This suggests apossible role for prostaglandins and cyclooxygenases in succinylcholine-induced myalgias. Otherinvestigators have found that myalgias after outpatient surgery occur even in the absence ofsuccinylcholine.[75]

Masseter Spasm

An increase in tone of the masseter muscle is a frequent response to succinylcholine in adults[76] andchildren.[77] Meakin and coworkers[77] suggested that the high incidence of spasm in children may bedue to an inadequate dosage of succinylcholine. In all likelihood, this increase in tone is an exaggeratedcontractile response at the neuromuscular junction and cannot be used to establish a diagnosis ofmalignant hyperthermia. Although an increase in tone of the masseter muscle may be an early indicatorof malignant hyperthermia, it is not consistently associated with that syndrome.[78] There is currently noindication 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 probablydue to its rapid onset of effect, the profound depth of neuromuscular blockade that it produces, and itsshort duration of action. Although it may be less commonly used than in the past for routineendotracheal intubation, it is the neuromuscular blocker of choice for rapid-sequence induction ofanesthesia. In a study comparing intubating conditions after the administration of 1 mg/kg of


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succinylcholine with those after the administration of 0.1 mg/kg of vecuronium or 0.1 mg/kg ofpancuronium 30 seconds after administration of the relaxant and at 30-second intervals after that up for120 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 upto 90 seconds, intubating conditions were better after the administration of succinylcholine than aftereither 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 0.6mg/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 ofhemoglobin saturation from 85% to 65% but did not shorten the time to spontaneous diaphragmaticmovement.[82] However, a significant fraction of patients would be at risk if there were failure tointubate and ventilate regardless of whether succinylcholine is administered or the dose ofsuccinylcholine administered.[82]

A small dose of nondepolarizing neuromuscular blocker is commonly given 2 minutes before theintubating dose of succinylcholine. This defasciculating dose of nondepolarizing neuromuscular

blocker will attenuate any increases in IGP and intracranial pressure and minimize the incidence offasciculations in response to succinylcholine. Prior administration of a nondepolarizing agent willrender the muscle relatively resistant to succinylcholine, however, so the succinylcholine dose shouldbe increased by 50%.[83] The use of a defasciculating dose of a nondepolarizing neuromuscular blockermay also slow the onset of succinylcholine and produce less favorable conditions for trachealintubation.[73]

Typically after administration of succinylcholine for intubation, a nondepolarizing neuromuscularblocker is given to maintain neuromuscular blockade. Succinylcholine given first may enhance thedepth 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 ofaction of pancuronium, pipecuronium, or mivacurium [86] [87] but increases that of atracurium androcuronium. [84] [85] The reasons for these differences are not clear.

The changing characteristics of succinylcholine neuromuscular blockade over the course of prolongedadministration have been reviewed by Lee and Katz[88] and are summarized in Table 29-2. TOFstimulation is a very safe and useful guide for detecting the transition from a phase 1 to a phase 2block. A phase 1 block has all the characteristics of a depolarizing block as described previously in themonitoring 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 aneuromuscular blockade monitor, changes from that of a depolarizing agent to that of anondepolarizing agent. Clearly, both the dose and the duration of administration of succinylcholine areimportant variables, although the relative contribution of each has not been established. In practicalterms, if administration of the drug is terminated shortly after TOF fading is clearly evident, rapidreturn of normal neuromuscular function should ensue. In addition, the decision whether to attemptantagonism of a phase 2 block has always been controversial. However, if the TOF ratio is less than0.4, administration of edrophonium or neostigmine should result in prompt antagonism. Ramsey andassociates[89] recommended that antagonism of a succinylcholine-induced phase 2 block with


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edrophonium or neostigmine be attempted after spontaneous recovery of the twitch has been observedfor 20 to 30 minutes and has reached a plateau phase with further recovery proceeding slowly. Theseresearchers stated that in this situation, edrophonium and neostigmine invariably produce dramaticacceleration of the return of the TOF ratio toward normal. [89] In any event, monitoring neuromuscularfunction via TOF stimuli will help avoid succinylcholine overdose, detect the development of phase 2blockade, 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 duringsuccinylcholine infusion

Characteristic Phase 1 Transition Phase 2

Tetanic stimulation No fade Slight fade Fade

Post-tetanic facilitation None Slight Yes

Train-of-four fade No Moderate fade Marked fade

Train-of-four ratio >0.7 0.4-0.7 6

Tachyphylaxis No Yes 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 ofpotent anesthetic vapors, such as isoflurane.

A recent study showed that post-tetanic potentiation and fade in response to TOF and tetanic stimuli arecharacteristics of neuromuscular blockade after bolus administration of different doses ofsuccinylcholine.[25] It seems that some characteristics of phase 2 blockade are evident after an initialdose 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, afterdTc has been used for intra-abdominal surgery of long duration and the neuromuscular blockade hasbeen reversed by neostigmine, the surgeon announces that another 15 minutes is needed to retrieve amissing sponge. Succinylcholine should not be administered to reestablish neuromuscular blockadebecause it produces relaxation that will last up to 60 minutes when given soon after the administration


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of neostigmine. Sunew and Hicks[36] found that the effect of succinylcholine (1 mg/kg) was prolongedfrom 11 to 35 minutes when given 5 minutes after the administration of neostigmine (5 mg). This canbe partly explained by the inhibition of butyrylcholinesterase by neostigmine and, to a lesser extent, bypyridostigmine. Ninety minutes after the administration of neostigmine, butyrylcholinesterase activitywill 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 Indiansarrow poisons or curare. Several nondepolarizing neuromuscular blockers are still purified fromnaturally occurring sources. For example, although dTc can be synthesized, it is still less expensive toisolate from the Amazonian vine Chondodendron tomentosum. Similarly, intermediates for theproduction of metocurine and alcuronium, which are semisynthetic, are obtained from Chondodendronand Strychnos toxifera. Malouetine, the first steroidal neuromuscular blocking drug, was originallyisolated fromMalouetia bequaertiana, which grows in the jungles of the Democratic Republic ofCongo in central Africa. The agents pancuronium, vecuronium, pipecuronium, rocuronium,rapacuronium, atracurium, doxacurium, mivacurium, cisatracurium, gantacurium, and gallamine areentirely synthetic.

The available nondepolarizing neuromuscular blockers can be classified according to chemical class(steroidal, benzylisoquinolinium, or other compounds) or, alternatively, according to onset or durationof action (long-, intermediate-, and short-acting drugs) of equipotent doses ( Table 29-3 ).

Table 29-3-- Classification of nondepolarizing neuromuscular blockers according to duration ofaction (time to T1 = 25% of control) after twice the ED95

Class of Blocker Clinical

Duration

Long-

Acting (>50

min)

Intermediate-

Acting (20-50

min)

Short-Acting

(15-20 min)

Ultrashort-acting

(


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Phenolic ether Gallamine

Diallyl derivative oftoxiferine

Alcuronium

A majority of nondepolarizing neuromuscular blockers are bisquaternary ammoniumcompounds. d-Tubocurarine, vecuronium, rocuronium, and rapacuronium are monoquaternarycompounds, 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 extensivelystudied chemical series of synthetic nondepolarizing neuromuscular blockers are the aminosteroids(steroidal), in which the interonium distance is maintained by an androstane skeleton, and thebenzylisoquinolinium 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, seeLee.[90]

Benzylisoquinolinium Compounds

dTc is a neuromuscular blocker in which the amines are present in the form of two benzyl-substitutedtetrahydroisoquinoline structures ( Fig. 29-7 ). The quaternary or tertiary nature of the two amines wasinitially questioned; however, with the use of nuclear magnetic resonance spectroscopy andmethylation-demethylation studies, Everett and coworkers[91] demonstrated that dTc contains only threeN-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 ofthe bis-benzylisoquinolines (see Fig. 29-7 ) have been described by Waser[92] and by Hill andassociates[93] as follows:

1. The nitrogen atoms are incorporated into isoquinoline ring systems. This bulky moleculefavors 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 dueto the presence of the tertiary amine function.

4. When dTc is methylated at the tertiary amine and at the hydroxyl groups, the result ismetocurine, a compound with greater potency (by a factor of 2 in humans) but much


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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 tertiarynitrogen of dTc; the other two form methyl ethers at the phenolic hydroxyl groups.

5. Bisquaternary compounds are more potent than their monoquaternary analogs. Thebisquaternary 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.


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Figure 29-7 Chemical structures ofd-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-carbonseparations between quaternary nitrogen and ester carbonyl provides the basis for a Hofmannelimination reaction.[94] Furthermore, it can undergo ester hydrolysis. In a Hofmann eliminationreaction, a quaternary ammonium group is converted to a tertiary amine by cleavage of a carbon-nitrogen bond. This is a pH- and temperature-dependent reaction in which higher pH and temperaturefavor elimination. The actual structure of the quaternary centers is the laudanosinium moiety, as inmetocurine. 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 geometricisomer groups that are designated cis-cis, cis-trans, and trans-trans according to their configurationabout the tetrahydroisoquinoline ring system.[94] The ratio of the cis-cis, cis-trans, and trans-transisomers 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. Theasterisks indicate chiral centers; arrows show cleavage sites for Hofmann elimination.

Cisatracurium is the 1Rcis1Rcis isomer of atracurium and represents about 15% of the marketedatracurium mixture by weight but more than 50% in terms of potency or neuromuscular blocking


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activity (see Fig. 29-8 ). R designates the absolute stereochemistry of the benzyl tetrahydroisoquinolinerings 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 approximatelyfour times as potent as atracurium, but unlike atracurium, it does not cause release of histamine in theclinical dose range. [95] [97] This indicates that the phenomenon of histamine release may bestereospecific. [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 (seeFig. 29-8 ). When compared with other isoquinolinium neuromuscular blockers, the interonium chainof mivacurium is longer (16 atoms).[93] Mivacurium consists of a mixture of three stereoisomers.[99] Thetwo most active are the trans-trans and cis-trans isomers (57% and 37% wt/wt, respectively), whichare equipotent; the cis-cis isomer (6% wt/wt) has only a 10th the activity of the others in cats andmonkeys.[99] Mivacurium is metabolized by butyrylcholinesterase at 70% to 88% the rate ofsuccinylcholine to a monoester, a dicarboxylic acid.[9]

Doxacurium is a bisquaternary benzylisoquinolinium diester of succinic acid (see Fig. 29-8 ). Theinteronium chain is shorter than that of either atracurium or mivacurium. Lee[90] pointed out that thenumber 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 anda 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 bequaternized. The presence of acetyl ester (acetylcholine-like moiety) is thought to facilitate itsinteraction 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 thesteroidal molecule. Pancuronium is a potent neuromuscular blocking drug with both vagolytic andbutyrylcholinesterase-inhibiting properties ( Fig. 29-9 ).[100] Deacetylation of the 3-OH or 17-OHgroups decreases its potency.[101]


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

Vecuronium is theN-demethylated derivative of pancuronium in which the 2-piperidine substituent isnot methylated (i.e., vecuronium lacks theN-methyl group at position 2) (see Fig. 29-9 ). [7] Atphysiologic pH, the tertiary amine is largely protonated, as it is in dTc. The minor molecularmodification relative to pancuronium results in (1) a slight change in potency; (2) a marked reductionin vagolytic properties; (3) molecular instability in solution, which explains in part the shorter durationof action of vecuronium than pancuronium; and (4) increased lipid solubility, which results in greaterbiliary elimination of vecuronium than pancuronium.[93]

Pancuronium and vecuronium are very similar in structure, yet vecuronium is prepared as a lyophilizedpowder. Vecuronium is degraded by the hydrolysis of acetyl esters at either or both the C3 and C17positions. Hydrolysis at the C3 position is the primary degradation product. The acetate at position 3 ismore susceptible to hydrolysis in aqueous solutions. Vecuronium is less stable in solution because ofthe group effect of the adjacent basic piperidine at position 2, which facilitates hydrolysis of the 3-


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acetate. Therefore, vecuronium cannot be prepared as a ready-to-use solution with a sufficient shelflife, even as a buffered solution. In pancuronium, the 2-piperidine is quaternized and no longeralkaline. 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 (seeFig. 29-9 ).[93] Pipecuronium is a nonvagolytic substitute for pancuronium. Changes in the quaternarygroups 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 vagolyticthan pancuronium.

Rocuronium lacks the acetyl ester that is found in the steroid nucleus of pancuronium and vecuroniumin the A ring (see Fig. 29-9 ). The introduction of cyclic substituents other than piperidine at the 2- and16-positions results in a fast-onset compound.[102] The methyl group attached to the quaternary nitrogenof vecuronium and pancuronium is replaced by an allyl group in rocuronium. As a result, rocuronium isabout 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 topresent 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 thefact that rocuronium is terminally sterilized in manufacturing and pancuronium is not. Terminalsterilization causes some degree of degradation.

Asymmetric Mixed-Onium Chlorofumarates

Gantacurium ( Fig. 29-10 ) represents a new class of nondepolarizing neuromuscular blockers calledasymmetric mixed-onium chlorofumarates. The presence of three methyl groups between thequaternary nitrogen and oxygen atom at each end of the carbon chain suggests that similar tomivacurium, this compound will not undergo Hofmann elimination.[105] Gantacurium has an ultrashortduration of action in human volunteers and in different animal species. A study in anesthetized humanvolunteers using an earlier formulation of gantacurium estimated the ED95 to be 0.19 mg/kg.[106] Thepattern of blockade resembled that of succinylcholine. The time to onset of 90% blockade ranged from1.3 to 2.1 minutes, depending on the dose. Clinical durations ranged from 4.7 to 10.1 minutes andincreased with increasing dose. Spontaneous recovery to a TOF of 0.9 develops in the thumb withinabout 12 to 15 minutes after the administration of doses as large as 0.54 mg/kg (or three times theED95). Recovery is accelerated by edrophonium. Transient cardiovascular side effects were observed atdoses beginning at three times the ED95 and were suggestive of histamine release.[106]


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Figure 29-10 Chemical structure of gantacurium (a mixed-onium chlorofumarate). In wholehuman blood, two pathways of deactivation occur, neither of which is enzymatic: (1) rapidformation of an apparently inactive cysteine adduction product, with cysteine replacing chlorine,and (2) slower hydrolysis of the ester bond adjacent to the chlorine substitution tochlorofumarate 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


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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 andleptocurares. 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 isthe 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 oftoxiferine ( Fig. 29-12 ). The latter is purified from Strychnos toxifera. The advantage of alcuronium atthe time of its introduction was a relative lack of side effects. It is mildly vagolytic and is excretedunchanged by the kidney with a minor secondary biliary pathway.


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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 neuromuscularblocking 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 neuromuscularblockers, see the section on drug interactions later in this chapter. The dose-response relationship fornondepolarizing neuromuscular blockers is sigmoidal in shape (see Fig. 29-13 ) and has been derived invarious ways. The simplest method is to perform linear regression over the approximately linearportion of a semilogarithmic plot between 25% and 75% neuromuscular blockade. Alternatively, thecurve can be subjected to probit or logit transformation to linearize it over its whole length or can besubjected to nonlinear regression using the sigmoid Emax model of the formThis can be applied to theraw data.[119] More complex models relating the concentration of neuromuscular blockers at the


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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 inhuman subjects

ED50 (mg/kg) ED90 (mg/kg) ED95 (mg/kg) Reference(s)

Long-

Acting

Pancuronium

0.036 (0.022-0.042)

0.056 (0.044-0.070)

0.067 (0.059-0.080)

103, 107 [103] [107]

d-Tubocurarine

0.23 (0.16-0.26)

0.41 (0.27-0.45)

0.48 (0.34-0.56)

107

Intermedia

te-Acting

Rocuronium

0.147 (0.069-0.220)

0.268 (0.200-0.419)

0.305 (0.257-0.521)

103, 108-110 [103] [108] [109][110]

Vecuronium

0.027 (0.015-0.031)

0.042 (0.023-0.055)

0.043 (0.037-0.059)

107

Atracurium 0.12 (0.08-0.15)

0.18 (0.19-0.24)

0.21 (0.13-0.28)

107

Cisatracuri

um

0.026 (0.015-

0.031)

0.04 (0.032-

0.05)

11, 111, 112, 118 [11] [111]

[112] [118]

Short-

Acting

Mivacurium

0.039 (0.027-0.052)

0.067 (0.045-0.081)

9, 113-115 [9] [113] [114] [115]

Ultrashort

-Acting

Gantacuriu

m

0.09 0.19 106

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


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Figure 29-13 Schematic representation of a semilogarithmic plot of a muscle relaxant doseversus 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 potenciesof muscle relaxants span a range of approximately 2 orders of magnitude.

Pharmacokinetics and Pharmacodynamics

As defined by Wright,[122] pharmacokinetics and pharmacodynamics are empirical mathematicalmodel[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 thebasis of their degree of blood perfusion (high or low). After a neuromuscular blocker is injected intothe circulation, its concentration in plasma decreases rapidly at first and then more slowly ( Fig. 29-14 ). The shape of this curve is determined by the processes of distribution and elimination. Classically,


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

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


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62:601-605, 1985.)

Figure 29-15 illustrates the classic model, in which the drug is administered intravenously into a centralcompartment with volume V1 and is distributed and eliminated from this compartment only. The drugis distributed very rapidly throughout this central compartment, which includes the plasma volume andthe organs of elimination; in the case of neuromuscular blockers, the organs of elimination are thekidneys and liver. The k terms are the rate constants for movement of drug between compartments inthe direction of the arrows. The peripheral compartments (usually one or two, here represented by V2and V3) can be thought of as the tissues. The effect compartment, which will be discussed later, isthe neuromuscular junction. For computational purposes, it has infinitesimal volume and therefore doesnot influence overall drug distribution. Drug administration and elimination are unidirectional;distribution is bidirectional.

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


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

Initially, the drug concentration in the central compartment (i.e., the plasma concentration) will exceedthat in the peripheral compartment (i.e., the tissue concentration), and the drug will move from plasmato 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 conceptualmodel is appropriate for all the neuromuscular blockers, with the exception of atracurium andcisatracurium, which also undergo elimination (by degradation) from tissues.[123] For simplicity, thefollowing 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 ofdistribution and elimination are in equilibrium. Elimination is represented by the variable plasmaclearance, 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 morerapid than the process of elimination, and the initial rapid decline in plasma concentration is dueprimarily to distribution of the drug to tissues. An exception to this rule is mivacurium, which has suchrapid clearance, because of metabolism by butyrylcholinesterase, that elimination is the principaldeterminant of the initial decline in plasma concentration.

After the initial process of drug distribution to tissues, the plasma concentration falls more slowly (theterminal phase). The rate of decrease in plasma concentration during this terminal phase is oftenexpressed in terms of elimination half-life, which equals the natural logarithm of 2 divided by the rateconstant 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 isdetermined by two factors: the rate at which drug can move from tissues back into plasma andclearance of drug from plasma. In classic theory for neuromuscular blockers, the drug can move rapidlyfrom tissues into plasma, and its elimination from plasma (i.e., clearance) is the rate-limiting step. Forthis reason, the terminal portion of the curve is often termed the elimination phase, even though thedistribution of drug from tissues into plasma occurs continually throughout. The volume of distributioncan also influence the terminal portion of the curve: the greater the volume of distribution, the slowerthe decline in plasma concentration.

The neuromuscular blockers are polar drugs, and their volume of distribution is classically thought tobe limited to a volume roughly equivalent to a portion of the extracellular fluid space, namely, 150 to450 mL/kg (see Tables 29-13 and 29-14 [0130] [0140]).[124] With this model of drug distribution, thepotential rate of drug movement from tissues to plasma exceeds the rate of elimination, and plasmaclearance is the process that limits the rate of decline in plasma drug concentration. However, there isevidence 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 highas 3.4 L/kg and its elimination half-life as long as 40 hours (compare with values in Tables 29-13 and29-14 [0130] [0140]).[126] Because the rate of drug movement from such tissues is less than that ofplasma clearance, this becomes the limiting step in the rate of decline in plasma drug concentration.


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This phase becomes obvious only when drug is administered for many days or when sampling iscontinued for 24 to 96 hours after drug administration. In normal operating room use of neuromuscularblockers, the amount of drug that is distributed to this compartment does not affect clinical response tothe drug. In conditions in which clearance of the neuromuscular blocker is reduced, such as renal orhepatic 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 asrenal or hepatic disease, early plasma concentrations of drug may be less than those observed whenorgan function is normal: with a greater volume of distribution, the plasma concentration should beless, whereas the total amount of a drug would be greater ( Fig. 29-16 ). Decreased protein binding of adrug results in a larger distribution volume, but because the degree of protein binding of neuromuscularblockers 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/kgrocuronium in patients with normal renal function (blue line) or patients undergoing renaltransplantation (yellow line). (From Szenohradszky J, Fisher DM, Segredo V, et al:Pharmacokinetics of rocuronium bromide (ORG 9426) in patients with normal renal function orpatients undergoing cadaver renal transplantation. Anesthesiology 77:899-904, 1992.)


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Recovery of neuromuscular function takes place as plasma concentrations decline, and the greater partof 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 ofblockade. [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 ofaction may be prolonged. [123] [131]

After the injection of a neuromuscular blocker, the plasma drug concentration immediately starts todecrease. The effect (neuromuscular blockade) takes approximately 1 minute to begin, increasesinitially, and does not start to recover for many more minutes despite the continually decreasing plasmaconcentration of drug. This discrepancy between plasma concentration and drug effect occurs becausethe action of neuromuscular blockers is not in plasma but at the neuromuscular junction. To produceparalysis, the drug must diffuse from plasma into the neuromuscular junction, and the effect isterminated later by diffusion of drug back into plasma (see Fig. 29-15 ). Thus, concentrations at theneuromuscular junction lag behind those in plasma, and they are lower during the onset of blockadeand 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. Forthis reason, a concentration-effect relationship cannot be obtained simply by directly relating theplasma 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 plasmaand the neuromuscular junction. By measuring plasma drug concentrations and neuromuscularblockade during both the onset and recovery phases and using the technique of simultaneouspharmacokinetic/pharmacodynamic modeling, it is possible to collapse the hysteresis in the plasmaconcentration-effect curve, estimate actual drug concentrations at the neuromuscular junction, andderive true concentration-effect relationships (Ce50 and ke0) for the neuromuscular blockers ( Table 29-5).[120]

Table 29-5-- Pharmacodynamic parameters derived by simultaneouspharmacokinetic/pharmacodynamic modeling

Study Group Adducto

r Pollicis

Refer

ence

Ce50 *

(ng/mL)

ke0[]

(min-1)

Mivacurium


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Central link 57 0.169 132

Peripheral link 130 0.101 132

Rocuronium Adult female: Propofol-remifentanilanesthesia, standard model

684 0.329 133

Recirculatory model 876 0.129 133

Volunteers: Propofol-fentanyl anesthesia 3510 0.405 134

Infants 1190 0.25 135

Children 1650 0.32 135

Cisatracurium, 0.075-3.0 mg/kg

Adults: Propofol-fentanyl anesthesia 126-158 0.07-0.09 135

Atracurium Infants 363 0.19 137

Children 444 0.16 137

Young adults 449 0.13 138

Elderly adults 436 0.12 138

Standard model 359 0.12 139

Threshold model 357 0.12 139

Young adults 669[] 0.07 140

Burn patients 2270[] 0.10 140

No succinylcholine 454[] 0.07 84

After succinylcholine 305[] 0.09 84

Vecuronium Young adults 94 141

Young adults 92 0.17 142

Elderly adults 106 0.17 143

d-Tubocurarine Normal renal function 370 0.13 120Renal failure 380 0.16 120

Halothane, 0.5%-0.7% 360[] 0.09 143 []

Halothane, 1.0%-1.2% 220[] 0.12 143 []

Narcotic anesthesia 600[] 0.15 143 []


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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 pollicismuscle after ulnar nerve stimulation.

ke0 is the rate constant for equilibration of drug between plasma and the neuromuscularjunction.

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 surgicalrelaxation. The intensity of neuromuscular blockade required varies with the surgical procedure.Important safety issues arise with the use of neuromuscular blockers: cardiovascular and respiratoryside effects and the adequacy of recovery to normal neuromuscular function.

Several clinical alternatives to neuromuscular blockers are available that provide adequate surgicalrelaxation. It is important to keep them all in mind to avoid relying only on neuromuscular blockade toachieve a desired degree of relaxation. Such options include adjustment of the depth of generalanesthesia, the use of regional anesthesia, proper positioning of the patient on the operating table, andproper 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 thesurgical maneuver required.

Dosage

General Dosage Guidelines

It is important to select the proper dosage of a nondepolarizing neuromuscular blocker to ensure thatthe desired effect is achieved without overdosage (Tables 29-6 and 29-7 [0060] [0070]). In addition togeneral 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: tolimit the duration of drug effect to match the anticipated length of surgery and to avoid unwantedcardiovascular side effects.

Table 29-6-- Guide to nondepolarizing relaxant dosage (mg/kg) with different anesthetictechniques *


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ED95 under

N2O/O2

Dose for

Intubation

Supplemental Dose

after Intubation

Dosage for

Relaxation

N2O Anesthetic

Vapors[]

Long-Acting

Pancuronium 0.07 0.08-0.12 0.02 0.05 0.03

d-Tubocurarine

0.5 0.5-0.6 0.1 0.3 0.15

Intermediate

-Acting

Vecuronium 0.05 0.1-0.2 0.02 0.05 0.03

Atracurium 0.23 0.5-0.6 0.1 0.3 0.15

Cisatracurium 0.05 0.15-0.2 0.02 0.05 0.04

Rocuronium 0.3 0.6-1.0 0.1 0.3 0.15

Short-Acting

Mivacurium 0.08 0.2-0.25 0.05 0.1 0.08

Continuous

Infusion

Dosage

(g/kg/min)Required to

Maintain

90%-95%

Twitch

Inhibition

under

N2O/O2 with

Intravenous

Agents

MivacuriumAtracuriumCisatracuriumVecuroniumRocuronium

3-154-121-20.8-1.09-12

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


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

The potentiation of nondepolarizing relaxants by different anesthetic vapors has been reportedto 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 neuromuscularblockers

Anesthesia Intubating

Dose

(mg/kg)

Approximate

ED95Multiples

Maximu

m Block

(%)

Time to

Maximum

Block (min)

Clinical

Duration *

(min)

Refe

renc

e

Succinylcholine

Narcotic orhalothane

0.5 1.7 100 6.7 144

Succinylcholine

Desflurane 0.6 2 100 1.4 7.6 145

Succinylcholine

Narcotic orhalothane

1.0 2 100 11.3 144

Succinylcholine

Desflurane 1.0 3 100 1.2 9.3 145

Succinylcholine

Narcotic 1.0 3 1.1 8 146

Succinylcholine

Narcotic 1.0 3 1.1 9 147

Succinylcholine

Isoflurane 1.0 3 100 0.8 9 148

Steroid

al

Compo

unds

Rocuronium Narcotic 0.6 2 100 1.7 36 149

Rocuronium

Isoflurane 0.6 2 100 1.5 37 148

Rocuronium

Isoflurane 0.9 3 100 1.3 53 148

Rocuron Isoflurane 1.2 4 100 0.9 73 148


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ium

Vecuronium

Isoflurane 0.1 2 100 2.4 41 148

Vecuronium

Narcotic 0.1 2 100 2.4 44 150

Pancuronium

Narcotic 0.08 1.3 100 2.9 86 151

Pancuronium

Narcotic 0.1 1.7 99 4 100 152

Benzyli

soquino

linium

Compo

unds

Mivacurium

Narcotic 0.15 2 100 3.3 16.8 9

Mivacurium

Narcotic 0.15 2 100 3 14.5 149

Mivacurium

Halothane 0.15 2 100 2.8 18.6 153

Mivacur

ium

Narcotic 0.2 2.6 100 2.5 19.7 9

Mivacurium

Narcotic 0.25 3.3 100 2.3 20.3 9

Mivacurium

Narcotic 0.25 3.3 2.1 21 147

Atracurium

Narcotic 0.5 2 100 3.2 46 11

Cisatrac

urium

Narcotic 0.1 2 99 7.7 46 154

Cisatracurium

Narcotic 0.1 2 100 5.2 45 11

Cisatracurium

Narcotic 0.2 4 100 2.7 68 11

Cisatracurium

Narcotic 0.4 8 100 1.9 91 11


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d-Tubocurarine

Narcotic 0.6 1.2 97 5.7 81 152

For atracurium and mivacurium, slower injection (30 seconds) is recommended to minimizecirculatory 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 facilitatetracheal intubation are twice the ED95 (this also approximates four times the ED50) (see Table 29-6 ). Ifthe trachea has already been intubated without the use of a nondepolarizing blocker or withsuccinylcholine and the purpose is simply to produce surgical relaxation, a dose slightly less than theED95 (see Table 29-7 ) should be given, with adjustment upward as indicated by responses evoked byperipheral nerve stimulation. Downward adjustment of the initial dose is necessary in the presence ofany 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 maingoal 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 nervestimulator. In an adequately anesthetized and monitored patient, there is little reason to completelyabolish 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 caseof intermediate- and short-acting neuromuscular blockers) to one-tenth (in the case of long-actingneuromuscular blockers) the initial dose and should not be given until there is clear evidence ofbeginning of recovery from the previous dose.

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

Neuromuscular Blockers and Tracheal Intubation


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The speed of onset of neuromuscular blockade is one of the requirements for rapidly securing theairway, and it is affected by several factors, including the rate of delivery of drug to the neuromuscularjunction, receptor affinity, plasma clearance, and the mechanism of neuromuscular blockade(depolarizing versus nondepolarizing). [101] [155] [156] The speed of onset is inversely proportional to thepotency 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 ofonset of effect (at the adductor pollicis).[155] A drug's measured molar potency is the end result of manycontributing 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 ofplasma clearance, and probably other factors as well.[158] Rocuronium has a molar potency (ED95) of0.54 M/kg, which is about 13% that of vecuronium and only 9% that of cisatracurium. Thus, rapidonset of rocuronium's effect (at the adductor pollicis) is not unexpected.

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


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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 todiffuse from the central compartment into the effect compartment. Once in the effect compartment, allmolecules act promptly. Weaker binding of the low-potency drugs to receptors prevents buffereddiffusion,[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 andpotentially lengthens the duration of effect.

The times to 95% blockade at the adductor pollicis after administration of the ED95 dose ofsuccinylcholine, rocuronium, vecuronium, atracurium, mivacurium, and cisatracurium are shown inFigure 29-18 . [117] [155] [157] This illustration shows that the most potent compound, cisatracurium, has theslowest 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 fastonset 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,


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rapacuronium, vecuronium, atracurium, mivacurium, and cisatracurium at the adductor pollicismuscle. Times (mean SD) in seconds to 95% of peak effect are shown in parentheses. (Datafrom Kopman AF, Klewicka MM, Ghori K, et al: Dose-response and onset/offset characteristicsof 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 onsetof atracurium. Anesth Analg 89:1046-1049, 1999.)

The onset of neuromuscular blockade is much more rapid in the muscles that are relevant to obtainingoptimal intubating conditions (laryngeal adductors, diaphragm, and masseter) than in the muscle that istypically monitored (adductor pollicis) (see Fig. 29-4 ).[160] Thus, neuromuscular blockade developsfaster, 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 medianeffective concentration (EC50) for almost all drugs studied is between 50% and 100% higher at thediaphragm or larynx than it is at the adductor pollicis. Fisher and coworkers[164] explain this apparentcontradiction by postulating more rapid equilibration (shorter ke0) between plasma and the effectcompartment at these central muscles. This accelerated rate of equilibrium probably represents littlemore than differences in regional blood flow. Therefore, muscle blood flow rather than the drug'sintrinsic potency may be more important in determining the onset and offset time of nondepolarizingneuromuscular blockers. More luxuriant blood flow (greater blood flow per gram of muscle) at thediaphragm or larynx would result in delivery of a higher peak plasma concentration of drug to thecentral 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 adductorpollicis

Dose

(mg/kg)

Anesthesi

a

Laryn

geal

Adduc

tors

Adduc

tor

Pollici

s

Refe

renc

e

Onset

Time

(sec)

Maximum

Block (%

Depression)

Clinical

Duration

(min)

Onset

Time

(sec)

Maximum

Block (%

Depression)

Clinical

Duration

(min)

Succinylcholine, 1.0

Propofol-fentanyl

34 12

100 0 4.3 1.6 56 15

100 0 8 2 161

Rocuronium, 0.25

Propofol-fentanyl

96 6 37 8 180 18

69 8 160

Rocuronium, 0.4

Propofol-fentanyl

92 29

70 15 155 40

99 3 24 7 161


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Rocuronium, 0.5

Propofol-fentanyl

84 6 77 5 8 3 144 12

98 1 22 3 160

Vecuronium, 0.04

Propofol-fentanyl

198 6

55 8 342 12

89 3 11 2 26

Vecuronium, 0.07

Propofol-fentanyl

198 12

88 4 9 2 342 18

98 1 22 2 26

Mivacurium, 0.14

Propofol-alfentanil

137 20

90 7 5.7 2.1 201 59

99 1 16.2 4.6 162

Mivacurium, 0.2 mg

Propofol-alfentanil

89 26

99 4 10.4 1.5 202 45

99 2 20.5 3.9 163

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 theadministration 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 intubatingconditions. The onset of maximal blockade in the larynx also corresponds to the point at which theadductor pollicis begins to show palpable evidence of weakening. Furthermore, the return of thumbresponses 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 itconsistently provides muscle relaxation within 60 to 90 seconds. When succinylcholine is consideredundesirable 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 undueprolongation of action and without undesirable side effects,[149] combination therapy may notconsistently result in rapid onset of effect.

THE PRIMING TECHNIQUE.


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Since the introduction of rocuronium, the use of priming has decreased considerably. Several groups ofinvestigators have recommended that a small subparalyzing dose of the nondepolarizer (about 20% ofthe ED95 or about 10% of the intubating dose) be given 2 to 4 minutes before a large second dose fortracheal intubation.[166] This procedure, termed priming, has been shown to accelerate the onset ofblockade for most nondepolarizing neuromuscular blockers by 30 to 60 seconds, which means thatintubation 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 disturbancesassociated 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 beaccomplished in less than 90 seconds. High-dose regimens, however, are associated with aconsiderably prolonged duration of action and potentially increased cardiovascular side effects (seeTable 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 33seconds (mean SD) to 55 14 seconds but significantly prolonged the clinical duration (i.e., recoveryof 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 followingfour principles are important: (1) preoxygenation must be performed, (2) sufficient doses ofintravenous 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 beapplied 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 havedemonstrated that low doses of neuromuscular blocking drugs can be used for routine trachealintubation. The use of low doses of neuromuscular blockers has advantages: (1) it shortens the time torecovery from neuromuscular blockade and (2) it reduces the requirement for anticholinesterase drugs.Rocuronium has the shortest onset time of all the nondepolarizing neuromuscular blocking agentscurrently available. [160] [161] The maximal effect of either 0.25 or 0.5 mg/kg of rocuronium at thelaryngeal muscles occurs after 1.5 minutes.[160] This interval is shorter than the 3.3 minutes reportedafter 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 forintubation, it is now possible to take full advantage of the onset profile for rocuronium. Intubatingconditions are related more closely to the degree of neuromuscular blockade of the laryngeal adductormuscles than to the degree of blockade typically monitored at the adductor pollicis. Figure 29-19demonstrates this principle.[158] Complete blockade at the larynx, diaphragm, or both may not be a


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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 asthe diaphragm or the laryngeal adductors) that is less sensitive to the effects of nondepolarizingrelaxants than the adductor pollicis but has greater blood flow. In this example, the concentrationof rocuronium producing a 50% block (EC50) of muscle X is 2.5 times that of the adductorpollicis, but the half-life of transport between plasma and the effect compartment ( ke0) of muscleX is only half as long. The rapid equilibration between plasma concentrations of rocuronium andmuscle X results in more rapid onset of blockade of muscle X than the adductor pollicis. Thegreater EC50 at muscle X explains the faster recovery of this muscle than of the adductor pollicis


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from neuromuscular blockade. Lower blood concentrations of rocuronium must be achieved atthe 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 verysatisfactory conditions for intubation (25 intubations were rated excellent and 5 were rated good) inpatients anesthetized with 12.5 g/kg of alfentanil and 2.0 mg/kg of propofol if laryngoscopy weredelayed for 75 seconds after drug administration. They estimated that 1.5 times the ED95 of rocuroniumwill produce at least 95% blockade in 98% of the population.[171] A similar or lower multiple ofrocuronium's ED95 was shown to have a more rapid onset and shorter duration of action thanatracurium[172] or cisatracurium.[112] The onset of cisatracurium's effect is too slow to provide goodconditions 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 and0.45 mg/kg of rocuronium, good to excellent conditions for intubation will be present 75 to 90 secondsafter the completion of drug administration.

Metabolism and Elimination

The specific pathways of the metabolism (biotransformation) and elimination of neuromuscularblocking drugs are summarized in Table 29-9 . Of the nondepolarizing neuromuscular blockers listed,

pancuronium, pipecuronium, vecuronium, atracurium, cisatracurium, and mivacurium are the only onesthat are metabolized or degraded. Nearly all nondepolarizing neuromuscular blocker molecules containester linkages, acetyl ester groups, and hydroxy or methoxy groups. These substitutions, especially thequaternary 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 showelimination of the parent molecule in urine as the basic route of elimination; those with a long durationof 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

Drug

Durati

on

Metabolism (%) Elimination

Metabolites

Kidney

(%)

Liver

(%)

Succinylcholi

Ultrashort

Butyrylcholinesterase (98%-99%)


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ne

Gantacurium

Ultrashort

Cysteine (fast) andester hydrolysis(slow)

? ? Inactive cysteine adduction product,chloroformate monoester, and alcohol

Mivacurium

Short

Butyrylcholinesterase (95%-99%)


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40%)

Rocuronium

Intermediate

None 10%-25%

>70% None

Pancuronium

Long

Liver (10%-20%) 85% 15% The 3-OH metabolite may accumulate,particularly in renal failure. It is about two thirdsas potent as the parent compound.

d-Tubocurarine

Long

None 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% to20%) is deacetylated at the 3-position in the liver, but this makes a minimal contribution to the totalclearance. Deacetylation also occurs at the 17-position, but to such a small extent that it is clinicallyirrelevant. The three known metabolites have been studied individually in anesthetized humans.[151] The3-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 haspharmacokinetics and a duration of action similar to those of pancuronium.[151] In addition, the 3-OHmetabolite is most likely excreted largely by the kidney. [151] The parent compound and the 3-OHmetabolite are also

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