Inherited Factors: The exact structure of plasma cholinesterase is determined genetically, by autosomal genes, and this has been completely defined. Several abnormalities in the amino acid sequence of the normal enzyme, usually designated , are recognized. The most common is produced by the atypical gene, , which occurs in about 4% of the Caucasian population. Thus a patient who is a heterozygote for the atypical gene demonstrates a longer effect from a standard dose of succinylcholine (about 30 min). If the individual is a homozygote for the atypical gene , the duration of action of succinylcholine may exceed 2 h. Other, rarer, abnormalities in the structure of plasma cholinesterase are also recognized, e.g. the fluoride and silent genes. The latter has very little capacity to metabolize succinylcholine and thus neuromuscular block in the homozygous state lasts for at least 3 h. In such patients, non-specific esterases gradually clear the drug from plasma.

It has been suggested that a source of cholinesterase, such as fresh frozen plasma, should be administered in such cases, or an anticholinesterase such as neostigmine be used to reverse what has usually developed into a dual block (see below). However, it is wiser to:

This condition is not life-threatening, but the risk of awareness is considerable, especially after the end of surgery, when the anaesthetist, who may not yet have made the diagnosis, is attempting to waken the patient. Anaesthesia must be continued until full recovery from neuromuscular block is demonstrable.

As plasma cholinesterase activity is reduced by the presence of succinylcholine, a plasma sample to measure the patient’s cholinesterase activity should not be taken for several days after prolonged block has been experienced, by which time new enzyme has been synthesized. A patient who is found to have reduced enzyme activity and structurally abnormal enzyme should be given a warning card or alarm bracelet, detailing his or her genetic status. Examining the genetic status of the patient’s immediate relatives should be considered.

In 1957, Kalow & Genest first described a method for detecting structurally abnormal cholinesterase. If plasma from a patient of normal genotype is added to a water bath containing a substrate such as benzoylcholine, a chemical reaction occurs with plasma cholinesterase, emitting light of a given wavelength, which may be detected spectrophotometrically. If dibucaine is also added to the water bath, this reaction is inhibited; no light is produced. The percentage inhibition is referred to as the dibucaine number. A patient with normal plasma cholinesterase has a high dibucaine number of 77–83. A heterozygote for the atypical gene has a dibucaine number of 45–68; in a homozygote, the dibucaine number is less than 30.

If fluoride is added to the solution instead of dibucaine, the fluoride gene may be detected. If there is no reaction in the presence of the substrate only, the silent gene is present.

Acquired Factors: In these instances, the structure of plasma cholinesterase is normal but its activity is reduced. Thus, neuromuscular block is prolonged by only minutes rather than hours. Causes of reduced plasma cholinesterase activity include:

Muscle Pains: These occur especially in the patient who is ambulant soon after surgery, such as the day-case patient. The pains, thought possibly to be caused by the initial fasciculations, are more common in young, healthy patients with a large muscle mass. They occur in unusual sites, such as the diaphragm and between the scapulae, and are not relieved easily by conventional analgesics. The incidence and severity may be reduced by the use of a small dose of a non-depolarizing muscle relaxant given immediately before administration of succinylcholine, e.g. gallamine 10 mg (which is thought to be most efficacious in this respect) or atracurium 2.5 mg. However, this technique, termed pre-curarization or pretreatment, reduces the potency of succinylcholine, necessitating administration of a larger dose to produce the same effect. Many other drugs have been used in an attempt to reduce the muscle pains, including lidocaine, calcium, magnesium and repeated doses of thiopental, but none is completely reliable.

Increased Intraocular Pressure: This is thought to be caused partly by the initial contraction of the external ocular muscles and contracture of the internal ocular muscles after administration of succinylcholine. It is not reduced by pre-curarization. The effect lasts for as long as the neuromuscular block and concern has been expressed that it may be sufficient to cause expulsion of the vitreal contents in the patient with an open eye injury. This is unlikely. Protection of the airway from gastric contents must take priority in the patient with a full stomach in addition to an eye injury, as inhalation of gastric contents may threaten life.

It is also possible that succinylcholine may increase intracranial pressure, although this is less certain.

Increased Intragastric Pressure: In the presence of a normal lower oesophageal sphincter, the increase in intragastric pressure produced by succinylcholine should be insufficient to produce regurgitation of gastric contents. However, in the patient with incompetence of this sphincter from, for example, hiatus hernia, regurgitation may occur.

Hyperkalaemia: It has long been recognized that administration of succinylcholine during halothane anaesthesia increases the serum potassium concentration by 0.5 mmol L^–1. This effect is thought to be caused by muscle fasciculation. It is probable that the effect is less marked with the newer potent inhalational agents, e.g. isoflurane, sevoflurane. A similar increase occurs in patients with renal failure, but as these patients may already have an elevated serum potassium concentration, such an increase may precipitate cardiac irregularities and even cardiac arrest.

In some conditions in which the muscle cells are swollen or damaged, or in which there is proliferation of extrajunctional receptors, this release of potassium may be exaggerated. This is most marked in the burned patient, in whom potassium concentrations up to 13 mmol L^–1 have been reported. In such patients, pre-curarization is of no benefit. Succinylcholine should be avoided in this condition. In diseases of the muscle cell, or its nerve supply, hyperkalaemia after succinylcholine may also be exaggerated. These include the muscular dystrophies, dystrophia myotonica and paraplegia. Hyperkalaemia has been reported to cause death in such patients. Succinylcholine may also precipitate prolonged contracture of the masseter muscles in patients with these disorders, making tracheal intubation impossible. The drug should be avoided in any patient with a neuromuscular disorder, including the patient with malignant hyperthermia, in whom the drug is a recognized trigger factor (see p. 879).

Hyperkalaemia after succinylcholine has also been reported, albeit rarely, in patients with widespread intra-abdominal infection, severe trauma and closed head injury.

Cardiovascular Effects: Succinylcholine has muscarinic in addition to nicotinic effects, as does acetylcholine. The direct vagal effect (muscarinic) produces sinus bradycardia, especially in patients with high vagal tone, such as children and the physically fit. It is also more common in the patient who has not received an anticholinergic agent (such as glycopyrrolate) or who is given repeated increments of succinylcholine. It is advisable to use an anticholinergic routinely if it is planned to administer more than one dose of succinylcholine. Nodal or ventricular escape beats may develop in extreme circumstances.

Anaphylactic Reactions: Anaphylactic reactions to succinylcholine are rare, but may occur, especially after repeated exposure to the drug. They are more common after succinylcholine than any other neuromuscular blocking agent.

 a decreased response to a single, low-voltage (1 Hz) twitch stimulus applied to a peripheral nerve is detected. Tetanic stimulation (e.g. at 50 Hz) produces a small, but sustained, response.

 if four twitch stimuli are applied at 2 Hz over 2 s (train-of-four stimulus), followed by a 10-s interval before the next train-of-four, no decrease in the height of successive stimuli is noted (Fig. 6.5).

 the application of a 5-s burst of tetanic stimulation after the application of single twitch stimuli, followed 3 s later by a further run of twitch stimuli, produces no potentiation of the twitch height; there is no post-tetanic potentiation (sometimes termed facilitation).

 neuromuscular block is potentiated by the administration of an anticholinesterase such as neostigmine or edrophonium.

 if repeated doses of succinylcholine are given, the characteristics of this depolarizing block alter; signs typical of a non-depolarizing block develop (see below). Initially, such changes are demonstrable only at fast rates of stimulation, but with further increments of succinylcholine they may occur at slower rates. This phenomenon is termed ‘dual block’.

 muscle fasciculation is typical of a depolarizing block.

Tubocurarine Chloride: This is the only naturally occurring muscle relaxant. It is derived from the bark of the South American plant Chondrodendron tomentosum which has been used for centuries by South American Indians as an arrow poison. It was the first non-depolarizing neuromuscular blocking agent to be used in humans, by Griffith and Johnson in Montreal, in 1942. The intubating dose is 0.5–0.6 mg kg^–1. It has a slow onset of action and a prolonged duration of effect (Table 6.1), and its effects are potentiated by inhalational agents and prior administration of succinylcholine. It has a marked propensity to produce histamine release and thus hypotension, with possibly a compensatory tachycardia. In large doses, it may also produce ganglion blockade, which potentiates these cardiovascular effects. It is excreted unchanged through the kidneys, with some biliary excretion. It is no longer available in the UK.

Alcuronium Chloride: This drug is a semi-synthetic derivative of toxiferin, an alkaloid of calabash curare. It has less histamine-releasing properties, and therefore cardiovascular effect, than tubocurarine, although it may have some vagolytic effect, producing a mild tachycardia. It also has a slow onset time and nearly as long a duration of effect as tubocurarine (Table 6.1). It is almost entirely excreted unchanged through the kidneys. The intubating dose is 0.2–0.25 mg kg^–1. Before the advent of atracurium and vecuronium, this inexpensive agent was used widely, but now its popularity has declined and it is no longer available commercially in the UK.

Gallamine Triethiodide: This synthetic substance is a trisquaternary amine. It was first used in France in 1948. The intubating dose in adults is of the order of 160 mg. It has a similar onset to, but slightly shorter duration of action than, tubocurarine, and is excreted almost entirely by the kidneys. Consequently, it should not be used in patients with renal impairment. Being more lipid-soluble than bisquaternary amines, it crosses the placenta to a significant degree and should not be used in obstetric practice. Gallamine has potent vagolytic properties and produces some direct sympathomimetic stimulation. Thus, it increases pulse rate and arterial pressure.

The only recent use of gallamine in the UK has been as a small pretreatment dose (10 mg) prior to succinylcholine, when it seems to be more efficacious than any other non-depolarizing muscle relaxant in minimizing muscle pains.

Atracurium Besylate: This drug, introduced into clinical practice in 1982, was developed by Stenlake at Strathclyde University. Quaternary ammonium compounds break down spontaneously at varying temperature and pH, a phenomenon recognized for over 100 years and known as Hofmann degradation. Many such substances also have neuromuscular blocking properties, and atracurium was developed in the search for such an agent which broke down at body temperature and pH. Hofmann degradation may be considered as a ‘safety net’ in the sick patient with impaired liver or renal function, because atracurium is still cleared from the body. Some renal excretion occurs in the healthy patient (10%), as does ester hydrolysis in the plasma; probably only about 45% of the drug is eliminated by Hofmann degradation in the normal patient.

Atracurium (and vecuronium) was developed in an attempt to obtain a non-depolarizing agent which had a more rapid onset, was shorter-acting and had fewer cardiovascular effects than the older agents. Atracurium 0.5 mg kg^–1 does not produce neuromuscular block as rapidly as succinylcholine; the onset time is 2.0–2.5 min, depending on the dose used (Table 6.1). However, recovery occurs more rapidly from it than after use of the older non-depolarizing agents and atracurium may be reversed easily 20–25 min after administration of a dose of 2 × ED₉₅ (0.45 mg kg^–1). The drug does not have any direct cardiovascular effect, but may release histamine (about a third of that released by tubocurarine) and may therefore produce a local wheal and flare around the injection site, especially if a small vein is used. This may be accompanied by a slight reduction in arterial pressure. It can produce anaphylaxis, but to a lesser degree than succinylcholine.

A metabolite of Hofmann degradation, laudanosine, has epileptogenic properties, although fits have never been reported in humans. The plasma concentrations of laudanosine required to make animals convulse are much higher than those occurring during general anaesthesia, even if large doses of atracurium are given during a prolonged procedure, and there is little cause for concern about this metabolite in clinical practice. In patients in the ITU with multiple organ failure, who may receive atracurium for several days, laudanosine concentrations are higher, but as yet no reports of cerebral toxicity have occurred.

Cisatracurium: This is the most recently introduced benzylisoquinolinium neuromuscular blocker. It is of particular interest because it is an example of the development of a specific isomer of a drug to produce a ‘clean’ substance with the desired clinical actions but with reduced side-effects. Cisatracurium is the 1R-cis 1’R-cis isomer of atracurium, and one of 10 isomers of the parent compound. It is three to four times more potent than atracurium (ED₉₅ = 0.05 mg kg^–1) and has a slightly slower onset and longer duration of action. Its main advantage is that it does not release histamine and therefore is associated with greater cardiovascular stability. It undergoes even more Hofmann degradation than atracurium. Because a lower dose of this more potent drug is given, it produces less laudanosine than an equipotent dose of atracurium. It is therefore particularly useful in the critically ill patient requiring prolonged infusion of a neuromuscular blocking drug.

Doxacurium Chloride: This bisquaternary ammonium compound is only available in the USA. It undergoes a small amount of metabolism in the plasma by cholinesterase (6%), but is excreted mainly through the kidneys. It is the most potent non-depolarizing neuromuscular blocking agent available; an intubating dose is only 0.05 mg kg^–1. It has a very slow onset of action (Table 6.1) and a prolonged and unpredictable duration of effect. However, it has no cardiovascular effects and may therefore be of use during long surgical procedures in which cardiovascular stability is required, e.g. cardiac surgery.

Mivacurium Chloride: This drug is metabolized by plasma cholinesterase at 88% of the rate of succinylcholine. An intubating dose (2 × ED₉₅ = 0.15 mg kg^–1) has a similar onset of action to an equipotent dose of atracurium, but in the presence of normal plasma cholinesterase, recovery after mivacurium is much faster (Table 6.1) and administration of an anticholinesterase may not be necessary (if neuromuscular function is being monitored and good recovery can be demonstrated). Full recovery in such circumstances takes about 20–25 min, but the drug may be antagonized easily within 15 min. Mivacurium is useful particularly for surgical procedures requiring muscle relaxation in which even atracurium and vecuronium seem too long-acting, and when it is desirable to avoid the side-effects of succinylcholine, e.g. for bronchoscopy, oesophagoscopy, laparoscopy or tonsillectomy. The drug produces a similar amount of histamine release to atracurium.

In the presence of reduced plasma cholinesterase activity, because of either inherited or acquired factors, the duration of action of mivacurium may be increased. In patients heterozygous for the atypical cholinesterase gene, the duration of action of mivacurium is comparable to that of atracurium, negating its advantages. The action of the drug may also be prolonged in patients with hepatic or renal disease, in whom plasma cholinesterase activity may be reduced.

Pancuronium Bromide: This bisquaternary amine, the first steroid muscle relaxant used clinically, was developed by Savege and Hewitt and marketed in 1964. The intubating dose is 0.1 mg kg^–1, which takes 3–4 min to reach its maximum effect (Table 6.1). The clinical duration of action of the drug is long, especially in the presence of potent inhalational agents or renal dysfunction, as 60% of a dose of the drug is excreted unchanged through the kidneys. It is also deacetylated in the liver; some of the metabolites have neuromuscular blocking properties.

Pancuronium does not stimulate histamine release and is therefore useful in patients with a history of allergy. However, it has direct vagolytic and sympathomimetic effects which may cause tachycardia and hypertension. It slightly inhibits plasma cholinesterase and therefore potentiates any drug metabolized by this enzyme, e.g. succinylcholine and mivacurium.

Vecuronium Bromide: This steroidal agent was developed in an attempt to reduce the cardiovascular effects of pancuronium. It is similar in structure to the older drug, differing only in the loss of a methyl group from one quaternary ammonium radical. Thus it is a monoquaternary amine. An intubating dose of 0.1 mg kg^–1 produces profound neuromuscular block within 3 min, which is slightly longer than the onset time of atracurium, but shorter than those of tubocurarine and pancuronium. This dose produces clinical block for about 30 min. Vecuronium rarely produces histamine release, nor does it have any direct cardiovascular effects, although it allows the cardiac effects of other anaesthetic agents, such as bradycardia produced by the opioids, to go unchallenged. Vecuronium is excreted through the kidneys (30%), although to a lesser extent than pancuronium, and undergoes hepatic deacetylation; the deacetylated metabolites have neuromuscular blocking properties. Repeated doses should be used with care in patients with renal or hepatic disease because they accumulate.

Pipecuronium Bromide: This analogue of pancuronium was developed in Hungary in 1980 and is marketed in Eastern Europe and the USA. The intubating dose is 0.07 mg kg^–1. The onset time and time to recovery from block are similar to those of pancuronium (Table 6.1), and excretion of the drug through the kidneys is significant (66%). In contrast to pancuronium, pipecuronium possesses marked cardiovascular stability, having no vagolytic or sympathomimetic effects. It may therefore be useful during major surgery in patients with cardiac disease.

Rocuronium Bromide: This monoquaternary amine has a very rapid onset of action for a non-depolarizing muscle relaxant. It is six to eight times less potent than vecuronium but has approximately the same molecular weight; consequently, a greater number of drug molecules may reach the postjunctional receptors within the first few circulations, enabling faster development of neuromuscular block. In a dose of 0.6 mg kg^–1, good or excellent intubating conditions are achieved within 60–90 s; this is only slightly slower than the onset time of succinylcholine. The clinical duration is 30–45 min. At higher doses, such as 0.9 mg kg^–1, rocuronium has an onset time similar to succinylcholine, albeit with a greater range of effect. In such doses, however, rocuronium is a very long-acting drug, lasting about 90 min.

In most other respects, rocuronium resembles vecuronium. The drug stimulates little histamine release or cardiovascular disturbance, although in high doses it has a mild vagolytic property which sometimes results in an increase in heart rate. The drug is excreted unchanged in the urine and in the bile, and thus the duration of action may be increased by severe renal or hepatic dysfunction. Rocuronium has no metabolites with significant neuromuscular blocking activity.

Anaphylactic reactions are more common after rocuronium than after any other aminosteroid neuromuscular blocking drug. They occur at a similar rate to anaphylactic reactions to atracurium and mivacurium.

Rapacuronium Bromide: This was the last aminosteroid to become available. It is less potent than rocuronium (2 × ED₉₀ = 1.15 mg kg^–1) and in equipotent doses has an even more rapid onset of action (< 75 s). It is cleared rapidly from the plasma by hepatic uptake and deacetylation and thus has a shorter duration of effect than rocuronium, 12–15 min (Table 6.1). As with the deacetylation of pancuronium and vecuronium, a metabolite of rapacuronium has neuromuscular blocking properties (Org 9488). This may prolong the effect of incremental doses of the drug.

Rapacuronium has similar cardiovascular effects to rocuronium but it may also produce bronchospasm, possibly because of the release of histamine or leukotrienes. After several reports to the US Food and Drug Administration of bronchospasm and hypoxaemia following administration of rapacuronium, especially in small children, the manufacturers voluntarily withdrew the drug from release in the USA in 2002. It has never been commercially available in the UK.

 decreased response to a low-voltage twitch stimulus (e.g. 1 Hz) which, if repeated, decreases further in amplitude. This effect, which is in contrast to that produced by a depolarizing drug, also occurs to a greater degree when the train-of-four (TOF) twitch response is applied, and even more so with higher, tetanic rates of stimulation. It is referred to as ‘fade’ or decrement.

 post-tetanic potentiation (PTP) or facilitation (PTF) of the twitch response may be demonstrated (Fig. 6.6).

 neuromuscular block is reversed by administration of an anticholinesterase.

 no muscle fasciculation is visible.

Neostigmine: This drug combines reversibly with acetylcholinesterase by formation of an ester linkage. Neostigmine is excreted largely unchanged through the kidneys and has a half-life of about 45 min. It is presented in brown vials because it breaks down on exposure to light. Neostigmine potentiates the action of acetylcholine wherever it is a neurotransmitter, including all cholinergic nerve endings; thus, it produces bradycardia, salivation, sweating, bronchospasm, increased intestinal motility and blurred vision. These cholinergic effects may be reduced by simultaneous administration of an anticholinergic agent such as atropine or glycopyrrolate. The usual dose of neostigmine is of the order of 0.035 mg kg^–1, in combination with either atropine 0.015 mg kg^–1 or glycopyrrolate 0.01 mg kg^–1. Neostigmine takes at least 2 min to have an initial effect, and recovery from neuromuscular block is maximally enhanced by 10 min.

Edrophonium: This anticholinesterase forms an ionic bond with the enzyme but does not undergo a chemical reaction with it. The effect is therefore more short-lived than with neostigmine, of the order of only a few minutes. Edrophonium has a quicker onset of action than neostigmine, producing signs of recovery within 1 min. However, its effects are more evanescent; when edrophonium is given in the presence of profound neuromuscular block, the degree of neuromuscular block may increase after an initial period of recovery. The dose of edrophonium is 0.5–1.0 mg kg^–1.

Pyridostigmine: This drug has a slower onset time than neostigmine or edrophonium, and also a longer duration of action. It is used more frequently as oral therapy in patients with myasthenia gravis than in anaesthesia.

Physostigmine: This anticholinesterase, also known as eserine, is a tertiary amine and is more lipid-soluble than the other carbamate esters. It is therefore absorbed more easily from the gastrointestinal tract, and also crosses the blood–brain barrier.

Organophosphorus Compounds: These substances are irreversible inhibitors of acetylcholinesterase; by phosphorylation of the enzyme, they produce a very stable complex which is resistant to reactivation or hydrolysis. Synthesis of new enzyme must occur before recovery. These agents, which include di-isopropylfluorophosphonate (DFP) and tetraethylpyrophosphate (TEPP), are used as insecticides and chemical warfare agents. They are absorbed readily through the lungs and skin. Poisoning is not uncommon among farm workers. Muscarinic effects such as salivation, sweating and bronchospasm are combined with nicotinic effects, such as muscle weakness. Central nervous effects such as tremor and convulsions may occur, as may unconsciousness and respiratory failure. Reactivators of acetylcholinesterase are used to treat this form of poisoning: they include pralidoxime and obidoxime. Atropine, anticonvulsants and artificial ventilation may be necessary. Chronic exposure may produce polyneuritis. Carbamates such as pyridostigmine are used prophylactically in those threatened by chemical warfare with these compounds.

Ecothiopate is an organophosphorus compound with a quaternary amine group; it was used as an eye drop preparation in ophthalmology to produce miosis in narrow-angle glaucoma. It inhibits cholinesterase by phosphorylation and thus potentiates all esters metabolized by this enzyme. It has now been withdrawn from the UK market.

A new generation of organophosphorus compounds may be beneficial in Alzheimer’s disease, and clinical trials are in progress. Neuromuscular blockers must be used with caution if such patients require anaesthesia.