continuing the dissection of remi's clan............courtesy NEJM
Neuromuscular blocking drugs are routinely used during the administration of anesthesia to allow surgical access to body cavities, in particular the abdomen and thorax, without hindrance from voluntary or reflex muscle movement. The introduction of these agents in 1942 marked a major advance in anesthesia and surgery, allowing the anesthesiologist to maintain respiratory function during prolonged and complex surgery. Neuromuscular blocking drugs are also used in the care of critically ill patients undergoing intensive therapy, to facilitate compliance with mechanical ventilation when sedation and analgesia alone have proved inadequate. In this review, I describe the pharmacology and uses of neuromuscular blocking drugs, as well as their side effects and disadvantages, with particular reference to conditions in which the drugs have an altered effect.
Neuromuscular Transmission and Blockade
The neuromuscular junction contains three types of nicotinic receptors: two on the muscle surface, one junctional and the other extrajunctional, and a presynaptic receptor on the parasympathetic-nerve ending.1 On the arrival of a nerve impulse, a burst of molecules of the neurotransmitter acetylcholine is released from the presynaptic nerve ending. Acetylcholine crosses the junctional cleft and stimulates the postsynaptic junctional receptors, allowing ions to flow through them and depolarize the end plate. Acetylcholine is then rapidly broken down by the enzyme acetylcholinesterase, which is present in the junctional cleft. This neurotransmitter also stimulates the presynaptic receptors to mobilize more acetylcholine for subsequent release from the nerve ending. The extrajunctional receptors are not involved in normal neuromuscular transmission but may proliferate if the muscle is diseased or damaged, altering the effect of neuromuscular blocking drugs.
The postsynaptic receptors are concentrated on the junctional folds, immediately opposite the sites on the nerve ending where acetylcholine is released. They are proteins consisting of five subunits, designated , , , and , which are arranged concentrically; each receptor has two subunits. One acetylcholine molecule binds to one subunit. When two acetylcholine molecules bind simultaneously to the two subunits of a receptor, a channel opens through the center of the receptor, allowing sodium and calcium ions to move into the muscle and potassium to move out. Each neuromuscular junction contains several million junctional receptors. After a burst of acetylcholine has been released from the nerve ending, at least 400,000 receptors open and allow sufficient current through them to depolarize the end plate and create the potential that triggers muscle contraction.
Depolarizing neuromuscular blocking drugs bind to the subunit in the same way that acetylcholine does. If these drugs bind to a pair of subunits, they stimulate an initial opening of the ion channel, producing a contraction known as a fasciculation. But since these drugs are not broken down by acetylcholinesterase, they bind for a much longer period than acetylcholine does, causing persistent depolarization of the end plate and a neuromuscular block.
Nondepolarizing neuromuscular blocking drugs compete with acetylcholine to bind to an subunit. If they are attached to at least one subunit, the ion channel through the center of the receptor will not open and no current will flow through it. The membrane will not depolarize, and the muscle will become flaccid. The physiology and pharmacology of neuromuscular transmission have been reviewed by Bowman.2
Depolarizing Neuromuscular Blocking Drugs
Succinylcholine (suxamethonium) is the only depolarizing neuromuscular blocking drug currently available. It has a structure similar to that of two molecules of acetylcholine (Figure 1). The onset of the neuromuscular block is rapid (one minute), and its duration is short (seven to eight minutes).3 Because of these characteristics, succinylcholine is used to facilitate rapid tracheal intubation during the induction of anesthesia, which is essential if aspiration of gastric contents is to be avoided. The drug is metabolized by plasma cholinesterase, which is synthesized in the liver. The side effects of succinylcholine, however, are formidable. Postoperative muscle pain is common, and hyperkalemia and increased intraocular and intragastric pressure may occur.4 The drug may also trigger malignant hyperthermia, a rare but potentially fatal muscle disorder
Nondepolarizing Neuromuscular Blocking Drugs
The nondepolarizing neuromuscular blocking drugs — tubocurarine, gallamine, metocurine, alcuronium, pancuronium, atracurium, and vecuronium — were introduced between 1942 and 1982. These drugs are quaternary ammonium compounds that have at least one positively charged nitrogen atom to bind to the subunit of the postsynaptic receptor (Figure 1). They are either benzylisoquinolinium compounds (tubocurarine, metocurine, alcuronium, and atracurium), quaternary amines (gallamine), or aminosteroid compounds (pancuronium and vecuronium).
Although the nondepolarizing neuromuscular blocking drugs do not have the same adverse effects as succinylcholine, their onset of action is slower (Table 1). They also have a longer duration of action, making them more suitable for maintaining neuromuscular relaxation during major surgical procedures
In the past three years, two new aminosteroid compounds, pipecuronium and rocuronium, and two new benzylisoquinolinium compounds, doxacurium and mivacurium, have become available. Other compounds, such as cisatracurium, the 1R cis–1'R cis isomer of atracurium, are being evaluated in clinical trials. These new compounds have been developed in an attempt to speed up the onset of action and diminish the side effects associated with the older drugs.
One drug will probably never satisfy all the requirements, however, because different uses call for different properties. Three types of drug have been proposed: a drug with a rapid onset of action (within 1 minute) but a short duration of action (5 to 10 minutes) that can be given by continuous infusion, a drug with a rapid onset of action and an intermediate duration of action (20 to 30 minutes), and for major surgery, a long-acting drug without cardiovascular effects.20
There is actually little need for a long-acting drug. Anesthesiologists require a nondepolarizing drug with a rapid onset of action (within 1 minute) and a short duration of action (about 10 to 12 minutes) that has no adverse cardiovascular effects. Such a drug could be given by continuous infusion during major surgery, thereby prolonging the duration of action.
The effect of nondepolarizing neuromuscular blocking drugs can be reversed, once recovery from the blockade has commenced, by the administration of an anticholinesterase drug, such as neostigmine or edrophonium, that inhibits the action of acetylcholinesterase at the neuromuscular junction. Acetylcholine thus accumulates, competing with the diminishing concentration of the neuromuscular blocking drug at the postsynaptic membrane and potentiating recovery from residual neuromuscular blockade.
Anticholinesterase drugs, especially neostigmine, also inhibit plasma cholinesterase activity and may therefore potentiate and lengthen the blockade produced by succinylcholine.21 But neostigmine antagonizes the blockade produced by mivacurium, the new short-acting nondepolarizing agent that is also broken down by plasma cholinesterase.22
The clinical pharmacodynamics of neuromuscular blocking drugs are determined by measuring the speed of onset of the neuromuscular blockade and its duration. A peripheral muscle that is easily accessible during surgery, such as the adductor pollicis muscle in the hand, is monitored by electrical stimulation of its motor nerve (the ulnar nerve) to determine the duration of action. Such monitoring does not accurately reflect the behavior of certain other muscle groups, such as the respiratory or laryngeal muscles, because of variations in sensitivity and the duration of the response to neuromuscular blocking drugs.23 The diaphragm is more resistant than the adductor pollicis and may remain paralyzed for a shorter period. The varying duration of the response to a neuromuscular blocking drug in different muscle groups is probably due to more rapid equilibration of the drug in muscles with greater blood flow.24 Nevertheless, monitoring of the response to electrical stimulation provides more information than clinical evaluation and can detect a degree of residual blockade not otherwise apparent at the end of surgery.
During the monitoring procedure, supramaximal stimuli are applied to the nerve and the response is assessed by visual or tactile means. The mechanical response can be recorded by a strain-gauge transducer, or the evoked compound muscle action potential can be measured by electromyography. Various patterns of nerve stimulation are used to assess the degree of the blockade — for example, a tetanic burst (50 to 100 Hz) or single-twitch stimuli (up to 1 Hz). The train-of-four stimulus is popular; in this procedure four twitch stimuli (2 Hz) are applied at intervals of at least 10 seconds.25 After the administration of a nondepolarizing drug, the height of the successive responses decreases, but no such decrease occurs when succinylcholine is given (Figure 2). The ratios of the first response in the train to the control response (T1:Tc) and of the fourth response to the first response (T4:T1) are used as measures of the blockade. Although the recovery of the T1 response and that of the single-twitch response are similar, use of the T4:T1 ratio has the advantage of not requiring a base-line measurement. The return of full muscle power can be relied on only if the anticholinesterase is not given until the second twitch of the train-of-four response is detectable (20 to 25 percent recovery of T1
To compare neuromuscular blocking drugs, it is necessary to use comparably effective doses, since these drugs differ widely in potency. The dose required to produce a 95 percent reduction in twitch height (ED95) is measured for this purpose. A doubling of this dose is usually suitable to facilitate tracheal intubation (Table 1). The depth and duration of neuromuscular blockade are potentiated by volatile anesthetic agents, particularly enflurane and isoflurane and, to a lesser extent, halothane,26 and the effect is more marked with the longer-acting drugs. The duration of the blockade produced by nondepolarizing drugs is also increased by prior administration of succinylcholine.27
The plasma clearance, volume of distribution, and terminal half-life of neuromuscular blocking drugs have been determined in healthy subjects, patients with impaired renal or hepatic function, young and old subjects, and patients anesthetized with different volatile agents. The clearance and volume of distribution of neuromuscular blocking drugs in healthy subjects are shown in Table 2. (The values for the terminal half-life are not included because they are poorly correlated with the duration of action of a neuromuscular blocking drug administered in a bolus dose.) These drugs are highly ionized, water-soluble compounds; they have volumes of distribution not much greater than the extracellular-fluid volume (200 ml per kilogram of body weight).
Atracurium is a mixture of 10 geometric isomers with different clearance rates and terminal half-lives.39 Mivacurium chloride is a mixture of three stereoisomers — one with a cis–trans configuration (57 percent), one with a trans–trans configuration (37 percent), and one with a cis–cis configuration (6 percent) — all of which are metabolized by plasma cholinesterase.40 The two more abundant isomers are 10 to 15 times more potent than cis–cis mivacurium, have very short half-lives,41 and are responsible for the duration of action of a bolus dose. The cis–cis isomer is cleared at a rate closer to that of other nondepolarizing neuromuscular blocking drugs of intermediate duration (Table 2).
Elimination by Organs
Before the development of atracurium in 1982, all the available nondepolarizing neuromuscular blocking drugs were excreted by glomerular filtration (Table 3), and their action was prolonged in patients with renal dysfunction. Atracurium is degraded spontaneously in the plasma at body temperature and pH (Hofmann elimination) and by ester hydrolysis.51 It is therefore the only nondepolarizing neuromuscular blocking drug with sufficient alternative pathways of disposition that the dose need not be reduced in patients with renal failure. Vecuronium, doxacurium, pipecuronium, and rocuronium are all excreted in the urine (Table 3). Since the aminosteroid drugs are deacetylated in the liver, their clearance and effect may be prolonged in patients with hepatic disease. These drugs are also excreted unchanged in the bile (Table 3); their clearance is decreased in the presence of extrahepatic biliary obstruction
Deacetylation of some of the aminosteroid compounds produces metabolites with neuromuscular blocking activity. Such an effect has been demonstrated with 3-desacetylpancuronium47 and 3-desacetylvecuronium. These water-soluble metabolites are half as potent as the parent compound and are excreted in the bile and urine. 3-Desacetylvecuronium may contribute to the cumulative effect of repeated doses of vecuronium.52
Laudanosine, the metabolite of Hofmann degradation of atracurium, does not have neuromuscular blocking properties but is epileptogenic at very high doses in animals.53 It is excreted in part in the urine.45 A plasma laudanosine concentration of 17 µg per milliliter causes convulsions in dogs.54 After a bolus dose of 0.5 mg of atracurium per kilogram in patients with renal failure, the peak plasma laudanosine concentration is 0.3 µg per milliliter55; after continuous infusions of atracurium (at least 0.6 mg per kilogram per hour) for 30 hours in patients with multiple organ failure who are undergoing intensive therapy, the plasma laudanosine concentration may reach 4.3 µg per milliliter.56 In no instance, however, has any adverse effect been attributed to the accumulation of laudanosine.
Since cisatracurium is a more potent drug than atracurium57 (ED95, 0.05 and 0.23 mg per kilogram, respectively), a smaller mass of laudanosine should be produced when an equipotent dose is given, presumably with even less possibility of an effect within the central nervous system.
Specific Indications for Neuromuscular Blocking Drugs
Succinylcholine has a rapid onset of action, but its use to facilitate intubation is essential only in the presence of residual gastric contents. Otherwise, nondepolarizing drugs can be used, although their slower onset of action makes it necessary for the anesthesiologist to take gradual control of ventilation until the blockade is maximal (Table 1). The conditions for intubation will then be optimal, and there will be no need for succinylcholine. Rocuronium, one of the new nondepolarizing neuromuscular blocking drugs, has an onset of action that may be similar to that of succinylcholine, although the duration of its action is similar to that of vecuronium (Table 1).19
Short Surgical Procedures
Before atracurium and vecuronium became available, procedures of less than 30 minutes' duration that required muscle relaxation were difficult for the anesthesiologist to manage. The dose of a nondepolarizing drug such as tubocurarine had to be reduced; otherwise, the duration of action was too long. Administration of a lower dose had the disadvantage of delaying the onset of action and reducing the degree of neuromuscular blockade. The alternative was to administer bolus doses of succinylcholine repeatedly, which had the disadvantage of resulting in a widely variable degree of blockade and an increased risk of side effects. The shorter duration of action of atracurium and vecuronium makes them more suitable for brief procedures,58 although if the operation lasts less than 15 minutes, even these agents are too long-acting (Table 1). The introduction of mivacurium has proved useful in this respect. The speed of its onset of action is similar to that of atracurium, but recovery is two to three times more rapid.40
Long Surgical Procedures
Longer-acting nondepolarizing drugs, such as tubocurarine, pancuronium, and now doxacurium and pipecuronium, may be more suitable for procedures lasting more than 90 minutes, although even with these drugs, repeated doses will be needed if the operation lasts many hours. Induced recovery from residual blockade after the administration of an anticholinesterase drug will take longer and may be less complete with long-acting drugs than with intermediate-acting drugs.59
A more satisfactory alternative may be the administration of shorter-acting drugs, such as atracurium, by continuous infusion.60 An anticholinesterase drug is given after the infusion has been stopped, when recovery from the neuromuscular blockade has commenced. Neuromuscular function should be monitored throughout the procedure.
Neuromuscular blocking drugs are occasionally used, in addition to analgesic and sedative drugs, to maintain adequate oxygenation in patients who are receiving mechanical ventilation in an intensive care unit. These drugs are particularly useful in patients with the adult respiratory distress syndrome, in whom the respiratory drive is substantial. Other indications are given in Table 4. For many years, the older agents, especially pancuronium, were given in repeated bolus doses. The cost of the drug itself was low, but in patients with organ dysfunction, the recovery from neuromuscular blockade could be slow, resulting in delayed weaning from the ventilator.61 A similar effect can occur with vecuronium, in part because of the accumulation of 3-desacetylvecuronium, the active metabolite.
Atracurium has proved useful in the care of critically ill patients. No evidence of delayed recovery from neuromuscular blockade was found when the drug was administered as a continuous infusion for many days.63 Concern has been expressed, however, about the higher cost of this technique, as compared with the cost of bolus doses of pancuronium, in addition to the potential side effects of laudanosine. Early studies of cisatracurium in critically ill patients suggest that the speed of recovery is nearly identical to that of atracurium64 but that plasma laudanosine concentrations are lower with cisatracurium (unpublished data).
Adverse Effects of Nondepolarizing Neuromuscular Blocking Drugs
Cardiovascular Side Effects
Neuromuscular blocking drugs have the potential to produce adverse effects at muscarinic receptors and nicotinic receptors other than those at the neuromuscular junction. These effects, which are common with the older drugs, include hypertension and tachycardia due to muscarinic blockade. Ganglionic blockade occurs with large doses of tubocurarine (Table 5). Atracurium and vecuronium have no direct cardiovascular effects.58 The newer agents have been developed with the aim of avoiding these side effects, but rocuronium may have a slight vagolytic effect.19 Although the absence of cardiovascular effects is considered advantageous, it may allow the effects of other anesthetic agents to become manifest (e.g., bradycardia with opioid analgesic drugs).
The release of histamine may lead to vasodilatation, hypotension, and compensatory tachycardia (Table 5). These effects are more pronounced with the older benzylisoquinolinium compounds, especially tubocurarine, than with atracurium and do not occur with the aminosteroid compounds.65,66 Mivacurium stimulates the release of histamine to the same degree that atracurium does, but doxacurium and cisatracurium do not have such an effect.57,65,67
A small fraction of patients with multiple-organ failure who receive mechanical ventilation for many days have severe muscle weakness on recovery. Some of these patients have received nondepolarizing neuromuscular blocking drugs.68 Recovery from the myopathy may take several weeks. The condition is thought to be more common when an aminosteroid compound is used in conjunction with corticosteroid therapy,69 but this impression may be influenced by the more frequent use of aminosteroid compounds than of atracurium in critically ill patients in North America. Two cases of persistent weakness after high doses of atracurium and a corticosteroid agent were recently reported.70 Such myopathy is probably caused by several factors, such as immobility, metabolic disturbances, and multiple-drug therapy. It is unlikely that the effect is due solely to the use of neuromuscular blocking drugs.
Neuromuscular Blocking Drugs in Particular Groups of Patients
Neonates may have a resistance to the action of depolarizing drugs,71 but the results of electromyographic studies suggest that they do not differ from adults in their response to nondepolarizing neuromuscular blocking drugs.72 A given plasma concentration of tubocurarine has a greater effect in neonates than in adults.73 Because the volume of distribution of the drug is larger in neonates, however, an equivalent dose per unit of body weight will result in a lower plasma concentration. The two factors tend to balance one another, so that the required dose per unit of body weight does not differ greatly according to age.
Infants and Young Children
The physiologic factors influencing the distribution and effect of neuromuscular blocking drugs in infants and young children are intermediate between those in neonates and adults. For example, the plasma concentration of tubocurarine at which a 50 percent depression of the T1 response occurs is higher in infants than in neonates, but not as high as in adults.73 Cardiac output in relation to body weight is higher in infants and children than in adults, and the onset of the neuromuscular blockade may therefore be more rapid.
The action of neuromuscular blocking drugs may be prolonged in elderly patients, since renal function and hepatic function decline with advancing age. The plasma clearance of tubocurarine,74 metocurine,74 vecuronium,75 and rocuronium76 is reduced in elderly patients. The clearance of mivacurium is slightly decreased,77 possibly reflecting a small reduction in plasma cholinesterase concentrations with increasing age. The plasma clearance of atracurium is not affected.78 Cardiac output may be reduced in elderly patients, prolonging the delivery of the drug to the neuromuscular junction and slowing the onset of its action.
Patients with Renal Disease
Prolonged neuromuscular blockade was reported in 1963 in a patient with chronic renal failure who had received 120 mg of gallamine.79 Despite repeated doses of anticholinesterase, recovery took five days. Prolonged blockade has subsequently been reported not only in other patients with renal failure who received gallamine, but also in similar patients who received pancuronium,80 tubocurarine,80 or vecuronium,81 although in the latter patients the neuromuscular blockade did not last as long. Decreased renal clearance, together with an increased volume of distribution in patients with edema, accounts for the delayed recovery.
Atracurium has improved the anesthetic care of patients with chronic renal failure, because its pharmacodynamics and pharmacokinetics are not altered in these patients.82 There are multiple pathways for the elimination of atracurium, and only about 10 percent of a dose of the drug is excreted in the urine in 24 hours.45 Therefore, the risk of residual neuromuscular blockade is low.
Pipecuronium and doxacurium should not be given to patients with renal failure, because the clearance of these drugs is markedly reduced.34,83 Plasma cholinesterase activity may be reduced in patients with chronic renal failure, so that the duration of action of mivacurium is increased.84 The plasma clearance of rocuronium is not affected by renal dysfunction, but patients with renal failure have a larger volume of distribution of the drug, and the terminal half-life is therefore longer.38
Patients with Hepatic Disease
Since patients with hepatic disease retain fluid, they may have a resistance to the effect of neuromuscular blocking drugs because of a larger volume of distribution.85 When adequate neuromuscular blockade has been achieved, the action of the drugs metabolized or excreted by the liver will be prolonged.86,87 The pharmacodynamics88 and pharmacokinetics32 of atracurium in patients with cirrhosis are similar to those in healthy subjects. Doxacurium may be given during prolonged procedures, such as liver transplantation (if renal function is normal),34 but mivacurium may have a prolonged effect, since plasma cholinesterase activity is frequently reduced.14 In patients with extrahepatic biliary obstruction, atracurium or doxacurium may be preferable. All the other nondepolarizing drugs except gallamine42 are excreted in the bile (Table 3).
Patients with Cardiovascular Disease
Vecuronium is most suitable for patients with cardiovascular disease, because the drug has no cardiovascular effect. For major surgery, such as cardiac bypass procedures, doxacurium or pipecuronium can be used, especially if controlled ventilation is continued after surgery.
Patients with Neuromuscular Disorders
Succinylcholine should not be given to patients with any of the muscular dystrophies because of the risk of severe hyperkalemia or a malignant-hyperthermia–type syndrome.89 Patients with myotonic dystrophy may have severe contractures after the administration of succinylcholine, preventing tracheal intubation. Reduced doses of nondepolarizing drugs with an intermediate or short duration of action should be given to such patients, and neuromuscular monitoring should be used.89,90
Patients with myasthenia gravis may have a resistance to succinylcholine, but their sensitivity to nondepolarizing drugs is increased.91 Atracurium92 and vecuronium93 can be given in small doses, with recovery induced rapidly by an anticholinesterase drug.
Succinylcholine and possibly tubocurarine94 and gallamine may trigger malignant hyperthermia. Pancuronium, atracurium, vecuronium, doxacurium,95 mivacurium,95 and rocuronium96 are less likely to have such an effect.
Patients with Thermal Injury
Within 48 hours after a burn, extrajunctional nicotinic receptors develop on the membranes of damaged muscles. Administration of succinylcholine may then cause a massive efflux of potassium from the muscle cells. Plasma potassium concentrations as high as 13 mmol per liter have been reported, with cardiac arrhythmias and arrest.97 Succinylcholine should therefore not be given to patients who have been burned. A marked resistance to nondepolarizing drugs has been reported in patients with severe burns, probably also as a result of the increased number of extrajunctional receptors.98
Patients with Reduced Cholinesterase Activity
An abnormally low plasma cholinesterase level can affect the rate at which succinylcholine or mivacurium is broken down. Several abnormal autosomal genotypes are recognized.99 In patients who are heterozygous for the most common abnormality, the atypical gene, the duration of action of 1 mg of succinylcholine per kilogram is 30 minutes, as compared with 7 to 10 minutes in normal subjects. In patients who are homozygous for this defect, the blockade can last up to 3 hours, and 25 percent recovery of the T1 response after a small dose of mivacurium (0.03 mg per kilogram) takes up to 80 minutes.100 In heterozygotes, 25 percent recovery of the T1 response after 0.2 mg of mivacurium per kilogram takes 32 minutes, as compared with 20 minutes in phenotypically normal patients.100
Plasma cholinesterase activity may also be reduced in pregnant women and patients with hepatic disease, renal disease, cancer, collagen disease, or hypothyroidism.99
The new nondepolarizing neuromuscular blocking drugs have specific advantages over succinylcholine. Rocuronium has an onset of action that is almost as rapid as that of succinylcholine and may be useful in patients with residual gastric contents. This drug may replace vecuronium, since the two agents are otherwise similar. The onset of action of mivacurium is similar to that of atracurium, but recovery from the blockade is more rapid (if the plasma cholinesterase level is normal), making mivacurium useful for short procedures. Although pipecuronium and doxacurium have minimal effects on the cardiovascular system, their long and variable onset and duration of action limit their usefulness. The need for either drug is questionable. There is still a need, however, for a nondepolarizing drug that has an onset of action as rapid as that of succinylcholine but a duration of action similar to that of mivacurium, with no adverse cardiovascular effects and clearance from the body that is independent of organ function.