DRUG EXPERIE CE

Drug Safety 10 (6): 420-438, 1994 0114-5916/94/0006-0420/$9,50/0 © Adis International Lintited, All rights reserved,

Adverse Effects of Nondepolarising Neuromuscular Blocking Agents Incidence, Prevention and Management

Mark Abel, W. Jeffrey Book and James B. Eisenkraft

Department of Anesthesiology, The Mount Sinai Medical Center, New York, New York, USA

Contents

420 Summary 421 1. Cardiovascular Effects 421 1.1 Autonomic Mechanisms 422 1.2 Histamine Release 423 1.3 Bradyarrhythmias 423 1.4 Individual Nondepolarising Muscle Relaxants 426 2. Anaphylactic and Anaphylactoid Reactions 428 3. Drug Interactions 428 3.1 Antibiotics 429 3.2 Inhaled Anaesthetic Agents 429 3.3 Local Anaesthetics 430 3.4 Cardiovascular Drugs 430 3.5 Magnesium and Lithium 430 3.6 Other Muscle Relaxants 431 3.7 Other Drugs 431 4. Increased Sensitivity 433 5. Resistance 434 6. Miscellaneous 434 7. Conclusion

Summary Nondepolarising muscle relaxants block neuromuscular transmission, acting as antagonists of the nicotinic receptors at the neuromuscular junction. Their undesired effects are frequently caused by interaction with acetylcholine receptors outside this junction, and autonomic cardiovascular effects may result. Other adverse effects include anaphylactic or anaphylactoid reactions, and histamine release. Various disease states may present specific considerations in the use of nonde­polarising muscle relaxants. Although many complications of these drugs (such as prolonged block or resistance) are easily treated, others may necessitate immediate intervention and vigorous therapy. Careful selection of an appropriate relaxant for a particular patient will usually prevent the occurrence of complications.

Complications of Nondepolarising Muscle Relaxants

Neuromuscular blocking drugs are designed to structurally resemble acetylcholine. This allows them to interact with the cholinergic site on the nicotinic receptors at the neuromuscular junction. The bulky nature of nondepolarising muscle relax­ants (NDMR) molecules, compared with that of acetylcholine, causes these drugs to interact with the receptors as antagonists, rather than agonists.

NDMRs are divided according to basic molecu­lar structure into steroidal and nonsteroidal agents. Nonsteroidal agents include benzylisoquinolinium and nonbenzylisoquinolinium compounds. Each class is associated with its own particular complic­ations, and some complications are common to more than one class. For example, Benzylisoquino­linium agents are associated with histamine rel­ease, whereas steroidal muscle relaxants are not. Autonomic adverse effects, anaphylactic and ana­phylactoid reactions are common to all classes of muscle relaxants. Adverse effects may affect neur­omuscular sites or other organ systems. This rev­iew discusses complications associated with NDMRs. For a review of adverse effects associated with depolarising neuromuscular blocking agents, see Book et al. (1994).

One property of an ideal muscle relaxant is spe­cificity for the nicotinic receptor of the neuromus­cular junction. These agents may, however, also bind with autonomic cholinergic receptor sites, causing haemodynamic adverse effects. Some neu­romuscular blockers exert such effects at clinically relevant concentrations, while others require con­centrations in excess ofthose usually achieved cli­nically in order to cause autonomic adverse effects. The ratio of the dose required to cause an adverse effect to that required to block the neuromuscular junction is referred to as the safety ratio. Safety ratios have been extensively measured for the vag­olytic effects of neuromuscular blocking drugs. Over time, molecular chemists have altered the str­uctural characteristics of NDMRs and increased the safety ratios of these drugs.

1. Cardiovascular Effects

NDMRs exert cardiovascular adverse effects

421

via the autonomic nervous system or via histamine release. Autonomic mechanisms may be further su­bdivided into muscarinic and nicotinic effects. Structure-activity relationships exist in determin­ing adverse effects of muscle relaxants. Benzyl­isoquinolinium relaxants may cause histamine re­lease, whereas steroidal relaxants are rarely associated with histamine release. Autonomic me­chanisms are common to both steroidal and benzyl­isoquinolinium nondepolarising relaxants.

Most cardiovascular adverse effects are well tolerated by most patients. Caution should be taken in administering some muscle relaxants to certain patients. For example, drugs which cause tachycar­dia may not be appropriate for a patient with coro­nary artery disease. Adverse effects may also be used to advantage. Thus, vagotonic drugs (i.e. sufe­ntanil) may be combined with drugs which cause tachycardia.

1.1 Autonomic Mechanisms

Cholinergic receptor sites exist throughout both the sympathetic and parasympathetic autonomic nervous system, and are classified into muscarinic and nicotinic subtypes. All muscarinic receptors are stimulated by muscarine and inhibited by atrop­ine (Weiner & Tayler 1985). Muscarinic receptors are, nevertheless, heterogeneous and are classified into 3 subtypes called MI, M2 and M3 (Scott 1992; Vizi et al. 1989) [fig. I]. They exist both presynapti­cally and postsynaptically. Presynaptic muscarinic receptors mediate the release of neurotransmitters, including noradrenaline. They also inhibit the re­lease of noradrenaline from sympathetic nerve ter­minals (Vizi et al. 1989).

Postsynaptic muscarinic receptors exist on eff­ector cells, including atrial and nodal cells of the heart, smooth muscle of arterioles and gastrointest­inal tract, the eye, and neuronal cell bodies (Vizi et al 1989). Because muscarinic receptors are hetero­geneous, NDMRs with low muscarinic safety ra­tios do not manifest muscarinically-mediated adv­erse effects uniformly at all muscarinic sites. Block of muscarinic sites by NDMRs may cause tachy­cardia via a vagolytic effect, by release of nor-

422

Dopamlnergic Intemeuron

~. ~sympatheticneuron L ( /l---+ NE

N ~ M1

Sympathetic ganglion

Parasympathetic ganglion

Parasympathetic neuron

Effector cellM2

Fig. 1. Schematic representation of the peripheral autonomic nerv­ous system. Some sites of action of neuromuscular blocking drugs, including the heart, are represented. Stimulation of musca­rinic M I receptors causes release of norepinephrine (NE; nor­adrenaline). This effect is not blocked by relaxants. Stimulation of the M2 receptor, an inhibitory receptor on a dopaminergic in­terneuron, inhibits presynaptic release ofNE. Another class ofM2 receptors in presynaptic sympathetic terminals promotes uptake of NE by the terminal. Blockade of these M2 receptors results in decreased NE reuptake. Abbreviation: N == nicotinic acetylcholine receptor.

adrenaline from sympathetic nerve terminals (dis­inhibition), or by a combination of the two (Vizi et al. 1989).

As previously discussed the neuromuscular jun­ction contains nicotinic acetylcholine receptors. Both sympathetic and parasympathetic ganglia are stimulated via nicotinic acetylcholine receptors. Neuromuscular blocking drugs may exert cardio­vascular effects by blocking these ganglionic re­ceptors (Weiner & Taylor 1985). Quaternary ammonium drugs with ganglionic blocking prop­erties, such as muscle relaxants, block ion channels rather than by blocking cholinergic recognition sites (Bowman 1990).

1.2 Histamine Release

Cardiovascular adverse effects of NDMRs may also be mediated via histamine release. Basic com­pounds such as muscle relaxants may cause mast

Drug Safety 10 (6) 1994

cells and basophils to release histamine via a non­immunologically (non-IgE) mediated mechanism. Instead, histamine release occurs as a result of di­rect contact between the muscle relaxant and the membrane of the basophil or mast cell (Bowman 1990). In contrast to immunologically mediated anaphylactic reactions or anaphylactoid reactions (non-IgE-mediated reactions resembling true ana­phylaxis), histamine release is common. It is usual­ly transient and self limited, rarely requiring ag­gressive therapy (Basta 1992). Histamine release may sometimes manifest as signs of shock requir­ing aggressi ve treatment, particularly if the muscle relaxant is given in combination with a second hist­amine-releasing drug. Benzylisoquinolinium re­laxants may cause histamine release whereas steroid relaxants do not (Basta 1992).

Normal plasma histamine levels vary through­out the day, ranging between 100 to 300 ng/L. Cut­aneous manifestations of histamirie release, inclu­ding flushing, pruritus and urticaria, occur consistently at plasma histamine level greater than 1000 ng/L (Lorenz et al. 1982). Infusion of his tam­ine to awake volunteers results in concentration­dependent hypotension and tachycardia at plasma histamine levels between 770 and 1970 ng/L (Ind et al. 1982). No volunteers in this study demonst­rated wheezing. It has been suggested that histam­ine alone is insufficient to trigger bronchospasm, requiring the presence of co-mediators to do so, such as prostaglandins and leukotrienes (Basta 1992).

Several strategies have been proposed to limit the effects of histamine release by NDMRs. Since histamine release depends upon the concentration of drug at basophils and mast cells (Stellato et al. 1991), decreasing the rate of administration may attenuate the effects of histamine release (Savarese et al. 1989; Scott et al. 1985). Pretreatment of pat­ients with a combination of histamine HI- and H2-receptor antagonists 15 to 30 minutes before admi­nistration of atracurium ablated the haemodynamic effects of known histamine-releasing doses of atra­curium (Hosking et al. 1988; Scott et al. 1985). Pretreatment was effective despite a 10- to 19-fold

Complications of Nondepolarising Muscle Relaxants

increase in plasma histamine levels. Simultaneous use of both Hl- and H2-antagonists was required to attenuate the effects of histamine release, either class of agent being ineffective alone. With the availability of newer agents, it is possible to select NDMRs which do not release histamine. Histam­ine release, when it occurs, is usually transient and self-limited. Treatment, if necessary, usually con­sists of fluid administration and a small dose of a vasopressor.

1.3 Bradyarrhythrnias

High doses of fentanyl or sufentanil combined with vecuronium may result in bradyarrhythmias. This is most commonly seen in patients receiving

~-blockers, either alone or in combination with cal­cium antagonists (Schmeling 1990; Starr et al. 1986). Either fentanyl or sufentanil may cause brady arrhythmias when administered with vecuro­nium (Gravlee et al. 1988). In one study, 18% of all patients who received high dose fentanyl comb­ined with vecuronium developed bradyarrhythrnias requiring pharmacological intervention (Pauliss­ian et al. 1991). These patients were receiving long term ~-blocker and calcium antagonist therapy. These bradycardias occurred despite the fact that scopolamine (hyoscine) was used for premedica­tion. Conversely, others have demonstrated that scopolamine premedication decreases the inci­dence of brady arrhythmias during induction of an­aesthesia with vecuronium and sufentanil (Thom­son et al. 1992).

Doxacurium has also been associated with bradyarrhythmias. These were seen in patients maintained with halothane-nitrous oxide anaesthe­sia (Scott & Norman 1989). Pipecuronium may similarly be associated with bradycardia (Dubois et al. 1991), as well as decreased cardiac output, even in the absence of bradycardia (Wierda et al. 1990a).

Bradyarrhythmias seen with particular muscle relaxants are probably due to their lack of vagolytic and/or sympathomimetic properties. They are therefore unable to offset brady arrhythmias indu­ced by other drugs. Treatment of brady arrhythmias

423

depends upon the associated ECG rhythm and the degree of haemodynamic instability. It may inc­lude intravenous administration of atropine, ephe­drine, adrenaline and isoprenaline (isoproterenol). Pacemakers are rarely required.

1.4 Individual Nondepolarising Muscle Relaxants (See Table I)

1.4.1 Gallamine Gallamine is now primarily of historic interest.

It lacks antimuscarinic adverse effects at a wide array of muscarinic sites, but is a potent blocker of cardiac vagal postganglionic muscarinic receptors. It has a muscarinic safety ratio of less than 1. The triquaternary structure of gallamine is thought to contribute to this effect (Hughes & Chapple 1976a; Riker & Wescoe 1951; Vizi et al. 1989). Gallamine also blocks adrenergic presynaptic muscarinic rec­eptors causing increased noradrenaline release (Brown & Crout 1970; Vercruysse et al. 1979). Block of noradrenaline reuptake is also thought to playa role (Vercruysse et al. 1979). Overall, gallamine causes profound tachycardia, even following small 'defasciculating' doses, and reaches a ceiling effect at doses of 100mg in adults (Eisele et al. 1971). Usual clinical doses of gallamine may also result in a slight increase in mean arterial pressure and a slight decrease in systemic vascular resistance (SVR), with a marked increase in cardiac index (Richardson & Agoston 1988). While muscarinic blocking effects account for the predominant ad­verse effects of gallamine (tachycardia), histamine release may be associated with gallamine admin­istration (Richardson & Agoston 1988).

1.4.2 Pancuronium Pancuronium, a steroidal compound containing

2 acetylcholine moieties, is also vagolytic, block­ing cardiac post junctional muscarinic receptors in clinically useful doses (Saxena & Bonta 1970). Its safety ratio for blocking the cardiac vagus is 2.86 (Scott & Savarese 1985). Pancuronium also blocks presynaptic muscarinic receptors of the sympathetic system, causing noradrenaline release from sym­pathetic nerve terminals (Vercruysse et al. 1979). In animal studies, pancuronium blocks norepinep-

424 Drug Safety 10 (6) 1994

Table I. Mechanisms(s) and propensity for cardiovascular effects of nondepolarising muscle relaxants

Drug Cardiovascular effect Mechanism(s) Propensity

Gallamine Tachycardia Vagal muscarinic blockade. Increased noradrenaline (norepinephrine) release. Decreased noradrenaline reuptake. ?Histamine release

+t+

Pancuronium Tachycardia, hypertension, increased cardiac output

Vagal muscarinic blockade. Increased noradrenaline release

+t+

Fazadinium Tachycardia, hypertension or hypotension, decreased SVR

Vagal muscarinic blockade. Decreased noradrenaline reuptake. Ganglionic blockade

+t+

Tubocurarine Tachycardia, hypotension, Histamine release. Ganglionic blockade ++ decreased SVR

Metocurine Tachycardia, hypotension, Histamine release. Ganglionic blockade + decreased SVR

Alcuronium Tachycardia, hypotension, Vagal muscarinic blockade. Histamine release ++ decreased SVR

Atracurium Tachycardia, hypotension, Histamine release + decreased SVR

Mivacurium Hypotension, tachycardia Histamine release +

Doxacurium Hypotension (rare)

Rocuronium Tachycardia

Histamine release (rare)

Vagal muscarinic blockade

±

+

Pipecuronium None

Vecuronium None

Abbreviations and symbols: SVR = systemic vascular resistance; +t+ = high propensity; ++ = moderate/medium propensity; + = low

propensity; ± = questionable propensity.

hrine reuptake into sympathetic nerve terminals (Salt et al. 1980). Like other steroidal muscle rel­axants, it does not release histamine in clinically significant doses. Overall, pancuronium causes a mild dose-dependent tachycardia with accompany­ing increases in cardiac output and blood pressure (Coleman et al. 1972). Tachycardia induced by pa­ncuronium may produce myocardial ischaemia in patients with coronary artery disease (Thomson & Putnins 1985).

1.4.3 Fazadinium Fazadinium blocks cardiac postsynaptic musca­

rinic receptors in clinical doses. Its vagolytic safety ratio is 1.0, equivalent to that of gallamine. Like pancuronium, fazadinium is a potent blocker of no­radrenaline reuptake into sympathetic nerve termi­nals (Marshall & Ojewole 1979). Fazadinium also has some ganglionic blocking properties (Hughes

& Chapple 1976a). The combination of vagolysis, ganglionic blockade and decreased noradrenaline uptake is responsible for the profound dose-depen­dent tachycardia seen following administration of fazadinium. Heart rate may increase by as much as 100%. A decrease in SVR may occur as well. Hyper­tension or hypotension may accompany the use of fazadinium, while tachycardia is predictable. Not surprisingly, fazadinium is unpopular because of these varied and profound cardiovascular adverse effects (Richardson & Agoston 1988). Histamine release is not usually associated with fazadinium (Richardson & Agoston 1988).

1.4.4 Tubocurarine Tubocurarine is a benzylisoquinolinium comp­

ound and a potent releaser of histamine, an effect which occurs within the clinical dose range. Tubo­curarine has a histamine release safety ratio of 1

Complications of Nondepo\arising Muscle Relaxants

(Scott & Savarese 1985). Tubocurarine has 2 free hydroxyl groups which contribute to its propensity to release histamine (Buckett & Frisk-Holmberg 1970). Tubocurarine produces some ganglionic blockade in a dose range similar to that required to produce neuromuscular blockade. Its effect may be slightly greater on sympathetic than on parasympa­thetic ganglia (Bowman 1982). It is devoid of clini­cally relevant muscarinically-mediated vagolytic adverse effects (safety ratio 8 to 16) [Hughes & Chapple 1976a]. Tubocurarine commonly causes mild to moderate hypotension, slight tachycardia and decreased SVR. Ganglionic blockade contrib­utes to the decrease in SVR, however, the drug's histamine releasing property is the predominant cause of its cardiovascular adverse effects (Stoelt­ing 1972).

1.4.5 Metocurine Metocurine is a structural analogue of tubocura­

rine, and is bisquaternary rather than monoquatern­ary because of a methyl substitution at an amino group. It also contains 2 methyl substitutions at the 2 phenols of tubocurarine. These su]Jstitutions make metocurine a weaker releaser of histamine than tubocurarine (Basta et al. 1983; Buckette & Fisk-Holmberg 1970; McCullough et al. 1972). Metocurine also lacks the 2 free hydroxy groups of tubocurarine, having O-methyl substitutions ins­tead. This results in a lower propensity to block autonomic ganglia compared with tubocurarine (Hughes & Chapple 1976a, 1976b). Mild tachycar­dia and hypotension follow metocurine adminis­tration when doses larger than 0.4 mg/kg are admi­nistered rapidly. The effect is probably a result of histamine release (Savarese et al. 1977).

1.4.6 Alcuronium Alcuronium in clinically relevant doses blocks

muscarinic receptors but has very low ganglion blocking potential. It releases histamine in doses comparable to those required to produce neuromu­scular blockade. Low doses of alcuronium cause mild tachycardia, hypotension and a fall in SVR, whereas doses exceeding 0.2 mg/kg cause more extreme cardiovascular effects. The cardiovascular

425

profile of alcuronium is due to a combination of cardiac muscarinic block and histamine release (Hughes & Chapple 1976a; Richardson & Agoston 1988).

1.4.7 Atracurium Atracurium causes histamine release when ad­

ministered rapidly in doses of 3 x ED95 (the aver­age dose that produces a 95% depression of twitch response) over 5 to 10 seconds, while smaller doses do not (Scott et al. 1985). As the bolus dose of atracurium is increased, so is the likelihood ofhist­amine release (Basta et al. 1981). The haemodyna­mic response to histamine release is usually trans­ient and self-limited, but may be more significant in patients with underlying cardiovascular disease. Doses of 0.6 mg/kg given intravenously over 75 seconds do not result in increased plasma levels of histamine, and are associated with stable haemody­namics (Scott et al. 1985).

1.4.8 Mivacurium Mivacurium is a new benzylisoquinolinium es­

ter. It has a histamine releasing and cardiovascular profile similar to atracurium. It causes minimal cardiovascular adverse effects at doses up to 0.15 mg/kg (2 x ED95). When higher doses are adminis­tered rapidly, transient hypotension associated with facial erythema occurs in 18 to 32% of patie­nts. As with atracurium, slow administration (over 30 to 60 seconds) of doses up to 4 X ED95 usually avoids the release of histamine and hence cardio­vascular adverse effects (Savarese et al. 1989). In patients undergoing coronary artery bypass sur­gery or valve replacement, even the slow adminis­tration of large doses (> 0.20 mg/kg) may be asso­ciated with profound hypotension secondary to histamine release (Stoops et al. 1989).

1.4.9 Doxacurium Doxacurium is also a benzylisoquinolinium co­

mpound which, despite its structure, does not usually cause histamine release when administered in doses of up to 0.8 mg/kg (2 to 3 x ED95) [Basta et al. 1988]. One of the main features of doxacurium is extreme cardiovascular stability. Two of 81 pat-

426

ients had an increase in serum histamine level of greater than 200%, however, there were no con­comitant haemodynamic changes in either patient (Basta et al. 1988). One case of transient signific­ant hypotension following doxacurium 0.05 mglkg has been reported (Reich 1989). This was probably caused by simple histamine release, although an anaphylactoid reaction may have been responsible. Bradycardia has been reported with the use of dox­acurium (Scott & Norman 1989).

1.4.10 Rocuronium Rocuronium is a new steroidal nondepolarising

drug which is 6 to 8 times less potent than vecuron­ium (Wierda et al. 1990b). Its main feature is rapid onset of action, and doses exceeding ED95 may be used to accelerate the onset of neuromuscular block (Powers et al. 1992a; Wierda et al. 1990b). One study in male patients reported a lack of cardi­ovascular adverse effects even at high doses (Booij & Knape 1991), however, a vagolytic response to such doses has been noted in animals (Muir et al. 1989). Further studies in humans are needed to cla­rify the potential of rocuronium to cause tachycar­dia. Like other steroid-based molecules, rocuronium does not usually cause histamine release.

1.4.11 Pipecuronium and Vecuronium Pipecuronium is a new steroid NDMR which is

a close structural analogue of pancuronium and ve­curonium. They both lack any cardiovascular adverse effects. They do not release histamine nor do they produce autonomic adverse effects when given in clinically relevant doses. Bradyarrhythmias have been associated with vecuronium or pipecuronium use (see section 1.3).

2. Anaphylactic and Anaphylactoid Reactions

Most reactions seen in the operating room are nonimmunologically-mediated histamine reactions, and are self-limited (Basta 1992). More serious reac­tions are either nonimmunologically-mediated anaphylactoid reactions or IgE-mediated type I hy­persensitivity reactions, also termed anaphylactic reactions (Bowman 1990). Anaphylactoid reactions

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are clinically indistinguishable from anaphylactic re­actions, but involve non immunological release of histamine and other substances from mast cells and basophils. Life-threatening hypersensitivity is gener­ally IgE-mediated, although nonantibody comple­ment-mediated reactions may account for some se­vere reactions to neuromuscular blocking drugs (Moneret-Vautrin et al. 1988). Life-threatening ana­phylactic and anaphylactoid reactions are charac­terised by cardiovascular collapse, broncho­spasm,and angioneurotic oedema (Fisher & Munro 1983). Bronchospasm occurs less frequently than cardiovascular collapse. Only 20 to 40% of pa­tients with cardiovascular collapse will manifest bronchospasm (Moneret-Vautrin et al. 1988).

The overall incidence of anaphylactoid or anap­hylactic reactions is 1 in 1750 general anaesthetic procedures (Galletly & Treuren 1985). True IgE-me­diated anaphylaxis is responsible for 66% of these events (Laxenaire et al. 1990). Approximately 80% of anaphylactic reactions occur secondary to mus­cle relaxants (Laxenaire et al. 1990).

The gender ratio in anaphylactic reactions stro­ngly favours females by a ratio of 4 to 1 (Fisher & More 1981). Prior uneventful exposure to relaxants is seen in only 15% of life-threatening reactions (Fisher & Munro 1983). There is a higher incidence of allergy, atopy and asthma in patients with hyper­sensitivity reactions to muscle relaxants compared with nonreacting patients (Fisher & Munro 1983). It has been demonstrated that substituted ammo­nium ions are allergenic determinants in muscle relaxant allergy (Baldo & Fisher 1983). The high frequency with which anaphylaxis occurs in the absence of prior exposure to muscle relaxants has been explained on the basis of prior sensitisation by foods, cosmetics, household materials and drug additives which contain quaternary ammonium compounds (Fisher & More 1981).

Cross-reactivity between individual muscle re­laxants also occurs. It is evident by intradermal skin testing in 66% of patients with a history of anaphylaxis secondary to a muscle relaxant. The highest concordance rates occur between pancuro­nium and vecuronium. Suxamethonium and galla-

Complications of Nondepolarising Muscle Relaxants

mine have a high concordance rate as well. Alcuro­nium may interact with either pair. The inclusion of ammonium groups within a ring structure may ex­plain the cross-reactivity between pancuronium and vecuronium, whereas the choline-like side chains of both gallamine and suxamethonium may explain their cross reactivity. Alcuronium has both of these features (Leynadier & Dry 1991).

The diagnosis of anaphylaxis depends primarily upon intradermal testing and IgE antibody detect­ion. IgE antibodies against muscle relaxants may be detected by radioimmunoassay (RIA) when mo­lecules resembling muscle relaxants are chemical­ly linked to a carrier molecule (sepharose). New techniques to improve the sensitivity of RIAs in detecting specific IgE antibodies against muscle relaxants are under investigation (Fisher & Baldo 1992; Laxenaire & Moneret-Vautrin 1992). Intra­dermal testing is positive when 2 molecules of IgE are bridged by divalent or multivalent antigens (Moneret-Vautrin et al. 1988). Gallamine is a tri­valent compound, tubocurarine has a 1 quaternary and 1 tertiary structure using nitrogen atoms. AI­curonium, pancuronium, suxamethonium, mivacu­rium, doxacurium and pipecuronium are all diva­lent, having bisquaternary structures. Vecuronium contains 1 quaternary and 1 tertiary ammonium and acts as a divalent molecule. Multimolecular complexes in solution may provide the required multivalent structure. In order for a divalent comp­ound to cross-link, 2 IgE molecules and a minim­um distance of 4.5A is required; the optimum dist­ance varies from 8 to 13A (Moneret-Vautrin et al. 1988). Both suxamethonium and NDMRs have charged nitrogen atoms that are separated within this optimal distance range (Moneret-Vautrin et al. 1988).

The incidence of anaphylactic and anaphylac­toid reactions varies. This is partially due to usage pattern - the more commonly used a particular rel­axant is, the higher the likelihood of a reaction occ­urring. Alcuronium has been reported by some to cause reactions in Australia, but much more rarely in other countries (Bowman 1990). When the ratio of reactions to total clinical usage is considered,

427

most studies demonstrate that suxamethonium and gallamine are most likely to cause anaphylactic and anaphylactoid reactions while pancuronium is least likely to cause such reactions. Alcuronium and tubocurarine are intermediate (Fisher & Munro 1983; Galletly & Treuren 1985; Laxenaire et al. 1985). Vecuronium and atracurium were re­ported to be more likely than pancuronium but less likely than tubocurarine, alcuronium, gallamine and suxamethonium to cause serious adverse reac­tions (anaphylactic or anaphylactoid) [Bowman 1990]. Recently, it has been suggested that vecuronium accounts for 24% of reactions to mus­cle relaxants, which is far more than previously suggested (Laxenaire & Moneret-Vautrin 1990).

Anaphylactic or anaphylactoid episodes may be characterised by skin manifestations, tachycardia, hypotension with massive extravasation of fluid, cardiac arrhythmias or bronchospasm. Episodes involving many of the above features are typical anaphylactic/anaphylactoid reactions and should be treated with generous fluid administration via a large­bore intravenous catheter, adrenaline (epinephrine) should be given for hypotension and/or bronchospasm (when present), and appropriate cardiopulmonary re­suscitation protocols should be carried out for man­agement of arrhythmias. A severe reaction under an­aesthesia with some or all of the above features should be investigated with postoperative skin and RIA testing (Fisher & Baldo 1992). While results of skin testing and RIA may be discordant, avoid­ing all drugs positive by either test is safe and prac­tical.

Of all commonly used anaesthetic agents, muscle relaxants account for a majority (80%) of true IgE­mediated allergic reactions (Laxenaire et al. 1990). The combination of propofol and atracurium may be associated with an increased incidence of seri­ous adverse reactions (Kumar et al 1993; Naquib 1989). Skin testing is valid for IgE-mediated ana­phylaxis but is of no value for non-lgE-mediated anaphylactoid reactions. Skin testing is highly spe­cific but lacks sensitivity. Positive results reliably determine the causative agent but negative results do not.

428

Readministration of the causative agent clearly should be avoided in patients with a history of anaphylaxis. In patients where no clear cause has been determined, attempts should be made to avoid readministration of possible causative agents. Fin­ally, patients with a history of anaphylactic or ana­phylactoid reactions to anaesthetic drugs, includ­ing muscle relaxants, should be premedicated with HI-antagonists (e.g. intravenous diphenhydramine 0.1 mg/kg) and H2-antagonists (e.g. intravenous ci­metidine 4 mg/kg). Although the prevention of an IgE-mediated anaphylactic reaction with premedi­cation is not possible, preventing the effects of sim­ple, nonspecific histamine release, using a combin­ation of HI- and H2-antagonists, is possible (Scott et al. 1985; Hosking et al. 1988).

3. Drug Interactions 3.1 Antibiotics

Aminoglycoside antibiotics may produce neu­romuscular blockade in their own right (Viby­Mogensen 1985), and they enhance the neuromus­cular blockade produced by depolarising muscle relaxants (Bevan & Donati 1992). The mechanism is primarily presynaptic, producing an effect simi­lar to high concentrations of magnesium (Singh et al. 1982), resulting in decreased acetylcholine rel­ease from motor nerve terminals. A smaller but sig­nificant effect is a decrease in post junctional receptor sensitivity to acetylcholine (Paradelis et al. 1988). Calcium chloride readily reverses the neuromuscular block produced by aminoglycosides (Bevan & Donati 1992; Paradelis et al. 1988), whereas mag­nesium salts exacerbate it (Bevan & Donati 1992). Acetylcholinesterase inhibitors only partially and inconsistently reverse aminoglycoside-induced neuromuscular blockade (Bevan & Donati 1992; Paradelis et al. 1988).

The polymyxins are very potent neuromuscular blockers and exert a pronounced facilitatory effect on neuromuscular block produced by nondepolar­ising muscle relaxants. They exert their actions via several mechanisms at both pre- and post junctional sites (Viby-Mogensen 1985). Polymyxin B red­uces quantal release of acetylcholine, suggestive of

Drug Safety 10 (6) 1994

prejunctional competition with calcium (Singh et al. 1982). The effect is less pronounced than simil­ar effects from magnesium or the aminoglycosides, implying that other mechanisms are more import­ant. The polymyxins also decrease post junctional sensitivity to acetylcholine, at least partially by blocking end plate conductance in acetylcholine­activated ion channels (Durant & Lambert 1981). At high concentrations, polymyxin B also depresses muscle action potentials (Wright & Collier 1976a). Some local anaesthetic-like activity has been dem­onstrated (Wright & Collier 1976b). Reversal of the block with calcium salts or acetylcholi­nesterase inhibitors is difficult and inconsistent (Bevan & Donati 1992).

The lincosamide antibiotics, lincomycin and clindamycin, are slightly different in structure from aminoglycosides, but both augment nondepolarising neuromuscular block. They act by different mecha­nisms from the aminoglycosides. Lincomycin and clindamycin both exert prejunctional effects that are not strongly affected by external calcium levels, indicating a non-magnesium-like mechanism (Singh et al. 1982). Clindamycin, but not lincomycin, has a local anaesthetic-like effect on nerve conduction, whereas both depress the response of muscles to direct stimulation, indicating an active site beyond the neuromuscular junction (Wright & Collier 1976b). Since the direct effect on the muscle predominates, it is not surprising that neither calcium salts nor acetylcholinesterase inhibitors are effective antag­onists of lincomycin- and clindamycin-induced block (0stergaard et al. 1989a; Wright & Collier 1976b).

The tetracyclines are weak neuromuscular blockers, however, they may augment the block caused by NDMRs (Sokol & Gergis 1981). They act by a combination of prejunctional and postjun­ctional mechanisms. Oxytetracycline has a greater magnesium-like prejunctional effect than tetracyc­line. Both depress muscle contractility directly (Singh et al. 1982). Rolitetracycline has been rep­orted to cause paralysis in patients with myasthenia gravis (Pittinger et al. 1970). In vivo, calcium is partially effective in reversing nondepolarising

Complications of Nondepolarising Muscle Relaxants

block enhanced by the tetracyclines, whereas acetylcholinesterase inhibitors are ineffective (0stergaard et al. 1989a). Aminopyridine has been used to improve neuromuscular transmission. It prolongs the open state of voltage-activated calcium channels in motor nerve terminals, en­hancing the release of acetylcholine. Its use has been limited by CNS adverse effects, including sei­zures. 3,4-Diaminopyridine is a related compound with a more limited ability to cross the blood brain barrier (Palace et al. 1991). It has been shown in vitro that 4-aminopyridine antagonises the neuro­muscular depressant effects of aminoglycosides and, to a lesser extent, of polymyxin B (Foldes & Bikhazi 1989).

3.2 Inhaled Anaesthetic Agents

Potent inhaled anaesthetics, particularly enflur­ane and isoflurane, potentiate nondepolarising neuromuscular blockade. Several mechanisms contribute to this effect. CNS depression, pre­junctional depression of neuromuscular transmis­sion, desensitisation of the post junctional muscle membrane and direct depression of excitation-con­traction coupling all contribute (0stergaard et al. 1989a). The greater effect on tetanic and train-of­four responses than on single twitch response imp­lies the importance of prejunctional mechanisms (Bevan & Donati 1992).

Halothane is less potent than enflurane or iso­flurane in potentiating the effects of NDMRs (Bevan & Donati 1992; 0stergaard et al. 1989a). The durations of action of the intermediate acting agents, atracurium and vecuronium, are prolonged to a lesser extent than the long acting NDMRs (e.g. pipecuronium and pancuronium) [Swen et al. 1989]. The intermediate acting agents are pro­longed to a greater extent by enflurane than isoflurane or halothane (Bevan & Donati 1992). When NDMRs are administered immediately after the start of inhalationa1 anaesthesia, prior to equil­ibration of the potent inhaled agent, halothane does not increase the duration of neuromuscular block­ade produced by pipecuronium, pancuronium, atracurium or vecuronium, whereas enflurane pro-

429

longs the duration of action of pipecuronium and pancuronium, but not atracurium or vecuronium, to a clinically significant extent (Swen et al. 1989). The infusion rate of mivacurium required is de­creased by 30% in the presence of isoflurane, however, recovery rate is unaltered (Powers et al. 1992b).

Desflurane, a new potent inhaled anaesthetic, affects nondepolarising neuromuscular and depol­arising neuromuscular blockade to an extent very similar to isoflurane. The ED so of pancuronium and suxamethonium are similar during anaesthesia with equipotent alveolar concentrations of desflur­ane or isoflurane (Caldwell et al. 1991). The potency, onset and duration of vecuronium action are affected to a similar extent by desflurane and isoflurane (Ghouri & White 1992).

3.3 Local Anaesthetics

Intravenous local anaesthetics may potentiate the effects ofNDMRs (Matsuo et al. 1978; Katz & Gissen 1969). Presynaptic and postsynaptic mech­anisms contribute to the effect. Local anaesthetics are fast (sodium) channel blockers (0stergaard et al. 1989a). Presynaptically, local anaesthetics block propagation of axonal action potentials, decreasing acetylcholine released at the motor nerve terminals (Matthews & Quilliam 1964). Postsynaptically, lo­cal anaesthetics bind to the acetylcholine receptor of the motor end plate at nonacetylcholine recog­nition sites, thereby desensitising the end plate to the effects of acetylcholine (Sine & Taylor 1982). Local anaesthetics may also produce channel block at open acetylcholine receptors, further desensitis­ing the end plate to the effects of acetylcholine (Neher & Steinback 1978). Local anaesthetics may also directly depress excitability of the muscle cell membrane (0stergaard et al. 1989a; Viby-Mogensen 1985). Intensification of neuromuscular block by intravenously injected local anaesthetics is well documented. It has been recently shown that epi­dural bupivacaine prolongs the clinical duration of atracurium-induced neuromuscular block (Toft et al. 1990).

430

3.4 Cardiovascular Drugs

Several cardiovascular drugs have been reported to affect NDMRs. Low doses of furosemide (frus­emide) intensify pancuronium-induced neuro­muscular block in cats (Scappaticci et al. 1982) while higher doses (1 to 4 mg/kg) have been shown to antagonise both tubocurarine- and pancuronium­induced neuromuscular block (Azar et al. 1980). Facilitation of neuromuscular block by low doses of furosemide may be explained by protein kinase inhibition; antagonism of neuromuscular block by higher doses is attributable to phosphodiesterase inhibition. Hypokalaemia associated with diuretic use may increase sensitivity to nondepolarising neuromuscular block secondary to membrane hyperpolarisation.

Calcium channel blockers have been shown to potentiate neuromuscular blockade in vitro (Paradelis et al. 1988) and in animal studies (Du­rant et al 1984a). Cases of difficulty in reversing neuromuscular blockade secondary to potentiation of nondepolarising relaxation by calcium channel blockers have been reported (Jones et al. 1985; Van Poorten et al. 1984), however, there is no direct evidence in humans for potentiation of muscle rel­axants by calcium channel blockers. It has been shown that long term nifedipine therapy does not significantly alter the onset or the clinical duration of either atracurium or vecuronium (Bell et al. 1989). The mechanism by which calcium channel blockers potentiate nondepolarising neuromuscul­ar blockade is probably both prejunctional and pos­tjunctional (0stergaard et al. 1989a). Edrophonium may be a more effective reversal agent than neostig­mine in the presence of calcium channel blockers (Jones et al. 1985).

~-Adrenergic receptor blockers have been rep­orted to exacerbate myasthenia gravis; however, there is inconclusive evidence that neuromuscular blockade is potentiated by these drugs (Vi by­Mogensen 1985).

Quinidine augments the block caused by NDMRs. It exerts both pre- and post junctional effects. Recurarisation in patients receiving quinidine has

Drug Safety 10 (6) 1994

been reported. The block is not reversible by edrophonium (Viby-Mogensen 1985).

3.5 Magnesium and Lithium

Magnesium enhances the block from NDMRs. Magnesium decreases presynaptic release of acetyl­choline by interfering with calcium entry into the nerve terminal. It also decreases excitability of the muscle fibre membrane (0stergaard et al. 1989a).

Lithium has been reported to potentiate pancu­ronium-induced neuromuscular block (Borden et al. 1974). Others have suggested a negligible effect of lithium on nondepolarising neuromuscular block (Waud et al. 1982).

3.6 Other Muscle Relaxants

Simultaneous administration of different NDMRs may cause either an additive or synergist­ic interaction. In general, combinations of structur­ally similar drugs tend to interact additively e.g. vecuronium and pancuronium. The classic synerg­istic combination is between metocurine and pan­curonium, two structurally dissimilar agents. Other synergistic combinations include atracurium with vecuronium, tubocurarine, metocurine or pancuro­nium, and tubocurarine with alcuronium or vecuro­nium. Possible causes of synergism include com­bining drugs producing predominantly presynaptic acetylcholine receptor block with drugs causing predominantly postsynaptic block. Alternatively, 2 different drugs may stimulate postsynaptic acetyl­choline receptors asymmetrically (Bevan & Donati 1992).

Suxamethonium is frequently given to facilitate tracheal intubation, then followed with administra­tion of an NDMR. Results of studies of the effects of subsequent administration of NDMRs have been conflicting. Some studies have found poten­tiation of pancuronium (Katz 1971) by prior suxa­methonium administration while others have demon­strated no effect (Walts & Rusin 1987). Potentiation of small doses of atracurium (0.15 mglkg) follow­ing suxamethonium has been demonstrated (Stirt et al. 1983) while large doses (0.24 mglkg) of doxacur­ium are not potentiated by prior suxamethonium ad-

Complications of Nondepolarising Muscle Relaxants

ministration (Katz et al. 1988). A recent study failed to demonstrate significant potentiation of large (> ED95) doses of pancuronium or pipecuron­ium following suxamethonium (Dubois et al. 1991). Other studies have demonstrated increased block intensity following pancuronium 0.02 mg/kg or tubocurarine 0.1 mg/kg. Most data indicate that prior administration of suxamethonium has little or no effect on subsequent large doses ofNDMRs ap­proximating ED95, whereas smaller doses are po­tentiated by prior suxamethonium administration (Dubois et al. 1991; Katz 1971; Katz et al. 1969, 1988; Stirt et al. 1983).

3.7 Other Drugs

Cyclosporin has been shown to potentiate nond­epolarising neuromuscular block in cats. Vecuroni­urn is particularly affected, but atracurium is poten­tiated also. The solvent of cyclosporin, cremophor, has some potentiating effect alone which is enh­anced by cyclosporin (Crosby & Robblee 1988). Several cases of potentiation ofNDMRs in humans have been reported (Crosby & Robblee 1988; Dubois et al. 1991). The occurrence of cyclospo­rin-induced potentiation is controversial. One pro­posed mechanism is decreased entry of calcium into motor nerve terminals (Crosby & Robblee 1988). Doxapram, a CNS stimulant, is occasional­ly used as a respiratory stimulant. It prolongs re­covery from vecuronium but not atracurium (Coo­per et al. 1992). The reason for the interaction remains unclear.

A single oral dose of cimetidine but not ranitid­ine prolongs the duration of action of vecuronium but has no effect upon atracurium (McCarthy et al. 1991). Ion channel blockade has been suggested as a cause of this phenomenon (Chea et al. 1985). In vitro but not in vivo studies suggest an anticholine­sterase action by intravenous ranitidine, antagonis­ing the action of atracurium (Law et al. 1989).

When muscle relaxants are administered toget­her with agents that potentiate them, neuromuscul­ar function should be monitored. Careful titration of reduced doses of neuromuscular blocking drugs to train of four response will prevent overdose of

431

muscle relaxants. Prior to tracheal extubation, ade­quate recovery should be documented both by ab­sence of fade on train-of-four monitoring, sus­tained tetanus at 50Hz stimulation, as well as clinical parameters of recovery.

4. Increased Sensitivity

Prolonged neuromuscular block may complic­ate the administration of NDMRs. The increased duration is generally predictable, occurring as a re­sult of impairment of metabolic pathways for the drug. Mivacurium is metabolised by plasma chol­inesterase. In patients who are heterozygous for the atypical plasma cholinesterase gene, recovery times are prolonged by 50% following mivacurium 0.2 mg/kg (0stergaard et al. 1989b) whereas in ho­mozygotes, the block was very prolonged (26 to 128 min) and the patients were very sensitive to small doses (0.03 mg/kg) [0stergaard et al. 1991]. Prolonged block may occur in patients who are pre­viously undiagnosed homozygotes for atypical pseu­docholinesterase (Peterson et al. 1993). The duration of action of mivacurium is prolonged in hepatic cirrhosis as a result of decreased plasma cholines­terase levels. This diagnosis should be suspected whenever mivacurium induces a deep and long lasting block.

Between 50 and 70% of an intravenous dose of pancuronium is excreted unchanged in the urine. The remainder is metabolised by the liver, with subsequent renal and biliary elimination of hepatic metabolites. The elimination half-life (tYz) of pan­curonium is doubled in chronic renal failure from 133 to 257 minutes (Collins 1993). Hepatic cirrho­sis increases the volume of distribution (V d) for muscle relaxants, including pancuronium, which has a 50% increased Vd as well as a 22% decrease in plasma clearance. Consequently, the elimination tl/2 of pancuronium increases by 82% in hepatic cir­rhosis (114 vs 208 min) [Duvaldestin et al. 1978].

Pipecuronium, like pancuronium, is a steroidal molecule. Between 37 and 39% of a pipecuronium dose is excreted unchanged in the urine (Wierda et al. 1991). The elimination tv, is consequently in­creased in renal failure compared with otherwise

432

normal patients (137 vs 263 min) [Caldwell et al. 1989]. Hepatic cholestasis increases the elimina­tion tt/2 of pipecuronium by 79% (101 vs 179 min) [Wierda et al. 1991].

30% of an intravenous dose of doxacurium is excreted unchanged in the urine (Cook et al. 1991). Biliary excretion and enzymatic hydrolysis have been suggested as alternative routes of elimination (Dressner et al. 1990). Renal failure prolongs the elimination tt/2 of doxacurium (99 vs 221 min) as does hepatic cirrhosis to a smaller extent (99 vs 115 min) [Cook et al. 1991]. The Vd of doxacurium increases markedly in the presence of hepatic dis­ease (220 vs 290 ml/kg) resulting in an increased ED95 in patients with hepatic cirrhosis (Cook et al. 1991).

Rocuronium is a new steroidal relaxant which has an increased elimination tI/2 in the presence of renal failure (71 vs 97 min) [Szenohradszky et al. 1992]. This occurs as a result of an increased Vd, since renal clearance is unchanged.

Atracurium is metabolised in both tissue and plasma by nonplasma cholinesterase-dependent ester hydrolysis and Hofmann elimination. Its eli­mination tJ/2 is not significantly affected in renal (Vandenbrom et al. 1990) or hepatic (Parker & Hunter 1989) disease.

Vecuronium, like atracurium, is intermediate in duration of action. It is eliminated via biliary routes (40%) and to a lesser extent via the kidney (20%) [Bencini et al. 1986a,b]. Renal failure has very lit­tle effect on clinical recovery from vecuronium-in­duced neuromuscular blockade, only slightly pro­longing its elimination t\l2 (Bencini et al. 1986b).

38% of an intravenous dose of tubocurarine in eliminated unchanged in the kidneys of normal pat­ients' and its duration is increased by renal failure (Miller et al. 1977). Hepatic disease necessitates the use of 2 to 3 times the usual dose of tubocurar­ine owing to the increased V d. Recovery times are not affected.

Metocurine is primarily dependent upon the kidney for its elimination and its t\l2 is prolonged in renal failure (Brotherton & Matteo 1981). Alcuron­ium and gallamine are also eliminated predomi-

Drug Safety 10 (6) 1994

nantly by the kidney (Collins 1993), both having dramatically prolonged t\l2 in the presence of renal failure (Agoston et al. 1992).

The administration of NDMRs to patients with impairment of metabolic pathways should general­ly be avoided. Patients with renal failure, for exam­ple, should be given atracurium or vecuronium to produce relaxation. Patients who are homozygotes for atypical plasma cholinesterase should not rec­eive mivacurium. Responses to most NDMRs that are prolonged by renal failure are highly variable from individual to individual. Therefore, if these agents are administered to patients in renal failure, careful titration of the drug must be accompanied by neuromuscular transmission monitoring.

Prolonged paralysis may be predictable, as in the instances described above. Persistent paralysis following prolonged infusion ofNDMRs to trache­ally-intubated patients in intensive care units has also been described (Benzing et al. 1990; Segredo et al. 1992; Smith et al. 1987). The causes vary, but may occur as a result of neuromuscular or metabo­lic factors. No single aetiology in this phenomenon can be found. The cases all involve administration of steroidal relaxants. Most cases involved cofac­tors which may have contributed to the prolonged paralysis. In addition to prolonged infusion of mu­scle relaxants, patients who exhibited prolonged paralysis were often being treated with antibiotics such as aminoglycosides, which adversely affect neuromuscular transmission, or with corticoster­oids which may also produce deterioration in neuro­muscular function. Renal failure and high plasma concentrations of 3-deacetyl-vecuronium, an active metabolite of vecuronium (Segredo et al. 1991), con­stituted a clear risk factor for prolonged paralysis fol­lowing vecuronium infusion (Segredo et al. 1992). Neuromuscular function should be monitored in pa­tients receiving prolonged infusions of muscle relax­ants.

Many neuromuscular diseases may cause incr­eased sensitivity to muscle relaxants. Myasthenia gravis is characterised by a decreased number of acetylcholine receptors at the neuromuscular junc­tion. Patients with myasthenia gravis behave as if

Complications of Nondepolarising Muscle Relaxants

partially curarised and are extremely sensitive to nondepolarising muscle relaxants (Eisenkraft et al. 1990; Miller & Lee 1990). Often, muscle relaxants may be avoided entirely in patients with myasthe­nia gravis. If NDMRs are administered, careful titration of small doses should be accompanied by careful monitoring of neuromuscular transmis­sion. Intermediate acting agents such as vecuron­ium and atracurium or a short acting agent such as mivacurium are preferable, because in the event of inadvertent overdosage, the drug will be metabo­lised sooner.

Myasthenic (Eaton-Lambert) syndrome is char­acterised by weakness, usually in proximal limb muscles. It is caused by decreased presynaptic rele­ase of acetylcholine. Unlike myasthenia gravis, symptoms of myasthenic syndrome improve with exercise. Like true myasthenia gravis, myasthenic syndrome is characterised by increased sensitivity to NDMRs. 3,4-Diaminopyridine has been shown to improve neuromuscular function in myasthenic syndrome (McEnvoy et al. 1989). It has also been successfully used as adjunct to acetylcholinesterase inhibitors in the reversal of deep vecuronium-in­duced block in a patient with the myasthenic syn­drome (Telford & Hollway 1990).

A comprehensive review of neuromuscular dis­orders is beyond the scope of this review, however, when NDMRs are used in patients with neuromus­cular disease, titration of muscle relaxants accomp­anied by monitoring of neuromuscular transmis­sion is required.

5. Resistance

Several conditions may cause resistance to NDMRs. Bum victims have an increased require­ment for these agents (Martyn 1986; Martyn et al. 1986). Patients with upper motor neuron disease such as spinal cord lesions or cerebrovascular acci­dents should be monitored on an unaffected limb when NDMRs are administered. The affected limb of such patients will be resistant to the effects of these drugs. Monitoring of the affected limb will, there­fore, underestimate the degree of neuromuscular

433

blockade (Graham 1980; Moorthy & Hilgenberg 1980).

Short term administration of corticosteroids has been reported to enhance the neuromuscular block­ing effect of pancuronium in animal models, whereas long term corticosteroid administration was without effect (Durant et al. 1984b). This is consistent with the fact that exacerbations of myas­thenia gravis may occur early during the course of corticosteroid therapy (Jenkins 1972).

Long term treatment with corticosteroids may result in improvement of myasthenic symptoms. This is consistent with studies which demonstrate that glucocorticoids increase motor nerve excit­ability, (Riker et al. 1975) release of acetylcholine from nerve terminals (Arts & Oosterhuis 1975) and choline transport (Leuwin & Walters 1977). Case reports in humans conflict, some reporting antago­nism of nondepolarising block (Laflin 1977) by corticosteroids and others reporting no effect (Schwartz et al. 1986). One case report describes resistance to vecuronium in a transsexual patient who was receiving testosterone (androgenic ste­roids) as part of a sexual reassignment procedure (Reddy et al. 1989).

Cases of methylxanthines antagonising pancu­ronium neuromuscular block have been reported (Azar et al. 1982; Doll & Rosenberg 1979). Inhib­ition of phosphodiesterase activity in the motor nerve terminal may lead to increased acetylcholine stores (Viby-Mogensen 1985). A recent report des­cribes antagonism of pancuronium-induced neuro­muscular block by aminophylline, while no effect was noted with vecuronium (Daller et al. 1991). The difference may be due to the different affinities of vecuronium and pancuronium for post junctional acetylcholine receptors.

Studies have demonstrated that patients receiv­ing anticonvulsants have higher requirements for many anaesthetic drugs, including muscle relax­ants (Tempelhoff et al. 1990a,b). Resistance and accelerated recovery have been described for NDMRs including pancuronium, (Chen et al. 1983; Messick et al. 1982) metocurine (Ornstein et al. 1985), vecuronium (Ornstein et al. 1986),

434

doxacurium (Ornstein et al. 1991). Resistance has been demonstrated following long term adminis­tration of both phenytoin and carbamazepine (Ornstein et al. 1991). Approximately twice as much NDMR is required per hour in patients re­ceiving phenytoin therapy (Chen et al. 1983; Or­nstein et al. 1985). The potency of metocurine de­creased by 15% in patients receiving phenytoin therapy (Ornstein et al 1985). While onset times are not affected (Ornstein et al. 1986; Templehoff et al. 1990b), recovery of neuromuscular function is accelerated in patients receiving anticonvulsant therapy (Chen et al. 1983; Messick et al. 1982; Or­nstein et al. 1985, 1986, 1991; Templehoff et al. 1990b). Recovery is accelerated to a greater extent in patients being treated with more than 1 anticon­vulsant compared with patients receiving a single anticonvulsant (Templehoff et al. 1990b).

Several studies failed to demonstrate that phen­ytoin or carbamazepine induced resistance or acc­elerated recovery during atracurium administrat­ion (Ebrahim et al. 1988; Ornstein et al. 1987). These studies included some patients on short term therapy. A recent study exclusively of patients rec­eiving long term (years) anticonvulsant therapy de­monstrated resistance to atracurium with carbama­zepine. The effect was augmented when patients received carbamazepine plus another anticonvul­sant (Templehoff et al. 1990a). Proposed mechan­isms for anticonvulsant-induced resistance to NDMRs include increased metabolism by enzyme induction, decreased sensitivity at the receptor site and increased numbers of acetylcholine receptors. Pharmacodynamic and pharmacokinetic factors playa role (Ornstein et al. 1991). The occurrence of the effect with atracurium demonstrates that he­patic enzyme induction is not exclusively respons­ible for anticonvulsant-induced resistance to NDMRs.

The effects of the above medications must be recognised when administering NDMRs to pati­ents receiving one or more anticonvu1sants. Care­ful monitoring of neuromuscular transmission is essential. Titration ofNDMRs to patients receiving

Drug Safety 10 (6) 1994

drugs which interfere with neuromuscular trans­mission is advisable.

6. Miscellaneous

Atracurium is degraded by ester hydrolysis and Hofmann elimination. Laudanosine is a metabolic byproduct of Hofmann elimination which can cross the blood brain barrier (Eddleston et al. 1989; Gwinnutt et al. 1990). High plasma concentrations of laudanosine produce seizure activity in dogs (Hennis et al. 1986), however, clinical doses of atracurium are unlikely to result in important cen­tral effects in humans (Eddleston et al. 1989; Gwinnutt et al. 1990; Tabardel et al. 1990). Highly active acrylate metabolites of Hofmann eliminat­ions are being investigated for potential toxicity. They may cause cellular damage by a1kylating nuc­leophiles present on cell membranes (Nigrovic et al. 1989).

Transient inability to see has been reported fol­lowing a 'defasciculating' dose of atracurium. Microsaccadic eye movements, which normally prevent retinal fatigue by shifting the image, may be prevented by 'defasciculating' doses of muscle relaxants, resulting in transient blindness (Peacock & Padfield 1988).

7. Conclusion

Neuromuscular blocking drugs have greatly fa­cilitated the safe conduct of anaesthesia and surg­ery. The ideal muscle relaxant would likely be a nondepolarising agent. It would act specifically at the nicotinic receptor of the motor endplate and lack effects on all other organ systems. Rapid, rel­iable onset as well as rapid, reliable elimination and predictable duration of action in all patients, regardless of other medical conditions, are additi­onal features of the ideal relaxant. Reversal of neu­romuscular blockade would not be required. No currently available drug has reached this ideal standard.

Complications of Nondepolarising Muscle Relaxants

Acknowledgements

The authors are grateful to Colette Bradford for her research assistance and Joanne Delenne for her secretarial assistance in preparing the manuscript.

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Correspondence and reprints: Dr Mark Abel, Department of

Anesthesiology, Box 10 I 0, The Mount Sinai Medical Center, One

Gustave L. Levy Place, New York, NY 10029, USA.