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Concurrent medication and the neuromuscular junction

Haywood, P. T.; Divekar, N.; Karalliedde, L. D.

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European Journal of Anaesthesiology: February 1999 - Volume 16 - Issue 2 - p 77-91


Many patients present for anaesthesia with disease processes that may be associated with or unrelated to the surgical condition. Epilepsy, bronchial asthma, peptic ulcer, manic and depressive illness, angina pectoris and essential hypertension are common in any population group. Such patients are often on medications for prolonged periods. Furthermore, antibiotics, diuretics, corticosteroids and immuno-suppressants are in frequent use and are often required as a part of the surgical procedure.

The administration of anaesthesia may require the use of muscle relaxants. Concurrent medication has the potential to interfere with neuromuscular function and thus create an unexpected response to muscle relaxants.

The effects of long-term medications on the neuromuscular junction and the possible effects on the action of muscle relaxants are discussed in this review according to their site of action (see Table 1). We have not considered the effects of drugs administered to produce the anaesthetic state (e.g. inhalational anaesthetics or local anaesthetic agents) or medications used for acute interventions during anaesthesia or surgery (e.g. sympathomimetic amines or ion exchange resins), which may also produce effects at the neuromuscular junction.

Table 1
Table 1:
Sites of alteration of neuromuscular function by to concurrent medication

Prejunctional effects, cAMP production


Large doses of pancuronium (5 mg h−1) were required to stop spontaneous respiratory efforts and terminate restlessness in a 17-year-old male with bronchial asthma receiving large doses of aminophylline and corticosteroids. The authors speculated that aminophylline, which is a known inhibitor of phosphodiesterase, raised the level of cAMP, which in turn raised the amount of ACh at the neuromuscular junction, thus antagonizing the blocking effect of pancuronium [1].

Evidence for a prejunctional role of cyclic nucleotides in neuromuscular transmission was suggested by Dretchen and colleagues in 1976 [2]. It is likely that patients receiving prolonged aminophylline therapy in the upper therapeutic range may show an impaired response to non-depolarizing muscle relaxants. This abnormal response has not been quantified, however, with respect to doses or durations of therapy for these agents.


In concentrations ranging from 10 to 1000 μg kg−1, administered intra-arterially in the in vivo cat soleus muscle preparation, azathioprine caused motor axons to fire repetitively and produced a dose-related increase in the force of contraction. Azathioprine reversed a neuromuscular block produced by tubocurarine and potentiated a neuromuscular block produced by suxamethonium. It was concluded that the effects of azathioprine on neuromuscular transmission result from inhibition of phosphodiesterase in the motor nerve terminal [3].


Diuretics, in particular frusemide, have differing effects on non-depolarizing muscle relaxants. At low doses(0.1-10 μg kg−1), frusemide had a depressant effect, reducing the force of muscle contraction and intensifying the neuromuscular block produced by tubocurarine and suxamethonium in an in vitro rat phrenic nerve-diaphragm preparation and an in vivo soleus nerve muscle preparation [4]. In contrast, higher doses(1-4 mg kg−1) antagonized a tubocurarine and suxamethonium block. High doses of frusemide inhibit non-competitively both the high- and the low-affinity forms of phosphodiesterase in both soluble and particulate fractions of cat sciatic nerve. This leads to an increase in the amount of ACh at the neuromuscular junction.

Loss of potassium induced by thiazide diuretics may be important. Hypokalaemia produces increased sensitivity to non-depolarizing muscle relaxants, although it is the ratio of intra- to extracellular potassium that is important and not the absolute value of either. The cell membrane becomes hyperpolarized, and there is resistance to the action of ACh. Nondepolarizing muscle relaxants are potentiated, and depolarizers may be antagonized [5].

Low doses of frusemide and thiazide diuretics are likely to potentiate the block produced by non-depolarizing muscle relaxants, whereas high doses of frusemide may antagonize a non-depolarizing block.

Aminoglycoside antibiotics

The anaesthetist frequently encounters patients on prophylactic antibiotics and often administers antibiotics in the perioperative period [6].

Several antibiotics have been shown to enhance the neuromuscular block produced by non-depolarizing neuromuscular blocking agents [7]. Prominent among these are the aminoglycosides. All the aminoglycosides are capable of causing neuromuscular block and alone result in paralysis. The mechanism appears to involve inhibition of calcium uptake, which results in both reduction in presynaptic ACh release and block of post-synaptic ACh receptors [8]. The aminoglycosides differ in their presynaptic and postsynaptic effects [9, 10].

The effects of seven antibiotics (streptomycin, amikacin, polymyxin B, lincomycin, clindamycin, tetracycline and oxytetracycline) were compared with those of Mg2+, tubocurarine and lignocaine in the frog sciatic nerve-sartorius muscle preparation [11]. All except tubocurarine decreased end-plate potential quantal content. Neomycin is capable of producing respiratory arrest by blocking neuromuscular transmission by a presynaptic mechanism [12]. Aminoglycosides have prejunctional effects, similar to magnesium, resulting in decreased release of ACh [13]. Dibekacin and sisomycin block the neuromuscular junction and are associated with the disappearance of action potentials and a decrease in the frequency of miniature end-plate potentials. These effects were augmented by the use of MgCl2. Factors known to enhance neuromuscular block in the presence of aminoglycosides include the curare-like drugs, magnesium and botulinum toxin. Patients who have received large doses of aminoglycoside administered into the peritoneal or pleural space, which can lead to high peak serum concentrations following absorption from these spaces, are also susceptible. The neuromuscular paralysis can be prevented or reversed by providing additional calcium intravenously [8]. Critically ill patients requiring prolonged ventilatory care and coincident treatment with aminoglycoside antibiotics and steroids are at particular risk. Pancuronium and vecuronium are reported to have caused a myopathy [14], although neither the mechanism nor the validity of the association with steroidal relaxants is known at present. Muscle dysfunction is a common feature of critical illness, and it is possible that neuromuscular blocking drugs may interfere with muscle repair and that these effects are compounded by aminoglycoside antibiotics and large doses of corticosteroids. Hasfurther and Bailey [15] reported failure of reversal after rocuronium in a patient who had received oral neomycin in anticipation of open bowel resection.

It is well established that the administration of aminoglycoside antibiotics will cause a prolongation of the action of non-depolarizing muscle relaxants, owing to both pre- and post-synaptic effects of the antibiotics at the neuromuscular junction.

Calcium channel-blocking drugs

Calcium channel-blocking drugs are widely used in the treatment and prevention of cardiovascular and cerebrovascular disease, bronchospasm associated with exercise-induced asthma and the treatment of oesophageal spasms [16].

A patient known to have hypertrophic obstructive cardiomyopathy on long-term verapamil, 40 mg three times a day, was given pancuronium 2 mg and tubocurarine 5 mg for muscle relaxation for an elective cholecystectomy. Approximately 2.5 h after initial administration, there was a profound degree of muscle paralysis with no third twitch in the train-of-four. Antagonism of the block was attempted with neostigmine 2.5 mg and atropine 1.2 mg. After 6 min, there was no change in the degree of residual block with no return of the third or fourth twitch and no significant alteration of the height in the first or second twitch [17]. Similar reports of prolonged duration of action of non-depolarizing muscle relaxants have appeared in the literature [18,19].

The effects of four organic calcium channel antagonists (nicardipine, nifedipine, diltiazem and verapamil) on the neuromuscular blocking activities of tubocurarine, suxamethonium, decamethonium and neomycin were studied in isolated mouse phrenic nerve-diaphragm preparations [20]. The effective concentration of suxamethonium for 50% inhibition of single indirect twitch responses was reduced threefold when the preparations were pretreated with calcium channel antagonists at 10 μmol. The neuromuscular blocking effect of decamethonium was also enhanced to a similar degree. In a similar study with nicardipine, verapamil and diltiazem, each of which caused a concentration-related depression in muscle response, nicardipine had the most and diltiazem the least effect [21].

It has been suggested that calcium channel antagonists are endowed with the unique capability to affect the post-synaptic nicotinic ACh receptor allosterically, thus promoting its desensitization [20]. This view supported the work of Adam and Henderson in 1986 [22] who found that certain calcium channel antagonists significantly potentiated the block of endplate currents produced by suxamethonium at concentrations at which the calcium channel antagonists themselves had no effect on end-plate currents. Rooke et al. in 1994 [23] found that patients receiving chronic calcium channel antagonist therapy are at no greater risk of hyperkalaemia after suxamethonium than those not taking such medication.

Intravenous verapamil (0.2 mg kg−1) reduced by 25% and 30%, respectively, the dose of atracurium required to produce a 50% or 95% neuromuscular block. In contrast, diltiazem (1 mg kg−1) failed to produce significant changes [24].

Nicardipine decreased significantly the vecuronium requirement in a dose-dependent manner at doses of 1, 2 and 3 μmol kg−1 min−1. Nicardipine also reduced both the plasma concentration of vecuronium to maintain 90% depression and the total plasma clearance of vecuronium. The results of Kawabata et al.[25] indicate that vecuronium infusion dose requirements are reduced by as much as 53% after a clinical dose of nicardipine. However, Bell et al.[26] found that neither the time to onset of maximum block nor the duration of clinical relaxation differed significantly between patients receiving chronic nifedipine therapy when given atracurium and vecuronium. Neostigmine 10−6 mol L−1 did not produce any significant changes in the maximal recovery of twitch depression induced with calcium channel blockers and muscle relaxants in combination, and neostigmine also had no effect on maximal recovery time of twitch depression [27].

Although there have been contradictory reports, vigilance is advised regarding potential problems resulting from the interaction of both depolarizing and non-depolarizing neuromuscular blocking agents with concurrent calcium channel blocker therapy.


Lithium and sodium are in the same group of the Periodic Table and share similar physical properties. Lithium is transported into the cell with sodium during cellular depolarization. Lithium influx is about 70% of that of sodium, and extrusion from the cell occurs at only 10% of the rate of sodium. Intracellular accumulation of lithium may reduce resting membrane potential (more positive), which could in turn reduce the height of the action potentials and reduce the effectiveness of the Na+:K+ pump. At concentrations above 2 mmol L−1, lithium produces somnolence, lethargy, muscle weakness, stupor and coma.

When animals were chronically pretreated with lithium, there was a slight reduction in the dosage requirement for tubocurarine. At concentrations well above therapeutic serum levels, indirect and direct twitch responses were depressed [28]. In a study on the isolated rat phrenic nerve-hemidiaphragm preparation, lithium led to significant enhancement of the myoneural blocking effects of suxamethonium, pancuronium and vecuronium [29]. Prolonged treatment of rats with lithium inhibited the increase in the number of extra junctional ACh receptors that occurred in denervated skeletal muscle. In normal muscle, lithium reduces the number of ACh receptors at the neuromuscular junction. These changes appear to be relatively specific for lithium [30].

In the 1970s, two case reports described prolonged neuromuscular block; in patients receiving lithium therapy, one after suxamethonium and the other after pancuronium [31,32]. There had been a previous report of abnormal recovery following an anaesthetic with methohexitone and suxamethonium (30 mg) in a patient with a serum lithium concentration of 3.4 mmol L−1[33]. It was suggested that lithium should be discontinued for at least 24 h before anaesthesia. The effects of lithium on transmitter release are not clear. The primary mechanism of block by lithium may result from decreased transmitter release and reduced excitability of the presynaptic terminals [34]. However, there have been reports showing that lithium stimulated the secretion of ACh [35,36]. Even though the presynaptic effects of lithium, particularly on ACh release, are not clearly defined, it seems very likely, from the available evidence, that the effects of muscle relaxants are likely to be enhanced during chronic lithium therapy. At therapeutic levels, there appears to be only a minimal interaction with competitive neuromuscular blocking agents. The reduction in post-synaptic nicotinic receptor turnover and density during chronic lithium therapy, along with the reduction in the efficacy of the Na+:K+ pump, are important factors in increasing the sensitivity to muscle relaxants.

Lithium has a narrow therapeutic range, and high plasma levels cause muscle weakness. Patients on lithium therapy are required to maintain adequate sodium and fluid intake. Alterations in lithium levels may occur during disease, particularly of the gastrointestinal tract. The British National Formulary suggests that lithium should be stopped for 2 days before major surgery, but the normal dose can be continued for minor surgery [37]. It is recommended that there is close monitoring of fluids and electrolytes and that lithium levels be measured before the administration of muscle relaxants to patients on lithium.


Magnesium is a physiological calcium antagonist, and there is a correlation between the depression of neuromuscular transmission and serum magnesium concentration. The depression of neuromuscular transmission actually has a better correlation with the serum Mg2+:Ca2+ ratio than with the serum magnesium concentration itself. Magnesium sulphate is used increasingly in the treatment of pre-eclampsia, endocrine crises (e.g. phaeochromocytoma) and in cardiac surgery. This has significant implications for anaesthesia because of its interaction with neuromuscular blockers [38,39].

Magnesium sulphate causes a dose-related depression of ACh release by competition with Ca2+ at the presynaptic membrane and in the sarcoplasm of the muscle. There is a significant correlation between the Ca2+:Mg2+ ratio and the effect produced at the neuromuscular junction [40,41]. There is a reduction in twitch response that will potentiate the non-depolarizing neuromuscular blocking drugs. Unlike non-depolarizing blocking drugs, however, magnesium decreases twitch response without tetanic or TOF fade.

The effect of magnesium sulphate is only partially reversed by Ca2+, suggesting that alternative mechanisms of action may exist. In the presence of suxamethonium, magnesium hastens the development of phase 2 block [42]. After treatment with magnesium sulphate, an increase in the degree of block and a prolonged duration of action of vecuronium has been noted.

Kwan et al. in 1996 [43] reported a case in which 1 mg of vecuronium lasted 4 h in a patient treated with magnesium sulphate for severe pre-eclampsia, whose serum Mg2+ level was in the therapeutic range. Magnesium sulphate in 60 mg kg−1 doses administered at recovery from vecuronium block, at a train-of-four ratio of 0.7, caused rapid and profound recurarization [44].

In a pregnant patient with an open eye injury, who was receiving i.v. magnesium 2 g hourly during preterm labour, rocuronium produced a fourfold increase in the duration of neuromuscular block [45].

Where suxamethonium is concerned, the situation is less clear. There was no significant increase in serum K+ concentration after pretreatment with magnesium sulphate before suxamethonium administration [46]. In one study, in the cat, antagonism between suxamethonium and Mg2+ was demonstrated [47]. A bolus of magnesium sulphate may reduce the hypertensive response to laryngoscopy and intubation [48].

Patients receiving magnesium therapy are likely to have a prolonged response to non-depolarizing muscle relaxants; the increase in duration of paralysis may be as much as fourfold.


Patients chronically receiving anticonvulsants are resistant to competitive neuromuscular blockers [49]. Acutely administered phenytoin enhances a pre-existing non-depolarizing block [50]. In this group, phenytoin was administered intravenously in a dose of 10 mg kg−1 to a group of patients in whom steady-state neuromuscular block had been established with an infusion of vecuronium. There was an increase in block at 30 and 45 min after the start of the phenytoin infusion. This observation agrees with previous animal work, which had shown a direct neuromuscular blocking action of phenytoin [51]. In a study with patients chronically receiving anticonvulsants, those receiving phenytoin recovered more quickly from a vecuronium-induced block. The recovery index in the phenytoin group was 7.9±2.2 min compared with 17.8±5.1 min in the control group. The total duration of vecuronium-induced neuromuscular block was significantly shorter in the phenytoin group (31.9±6 min compared with 69.7 ± 12.9 min in the control group). However, the time to maximum block and recovery from atracurium was unaffected by phenytoin therapy.

The mechanism of action of phenytoin on the neuromuscular junction appears to be complex. There have been reports showing a post-junctional effect, a pre-junctional effect and a reduction in synthesis of ACh [52]. Phenytoin also has a stabilizing effect on neuronal membranes related to its action on the transcellular flux of sodium, potassium and calcium ions [53]. Decreased sensitivity to metocurine during long-term phenytoin therapy may also be attributable to altered protein binding and ACh receptor changes [54]. Gray et al.[50] suggested that, as vecuronium is 90% protein bound and phenytoin is 80% protein bound, an increased concentration of free active drug after displacement of vecuronium from protein binding sites may be a factor in the increased neuromuscular block after acute phenytoin therapy.

The explanation for the resistance to neuromuscular block observed after chronic phenytoin therapy is not clear. Norris et al.[51] reported muscle weakness, which improved after chronic phenytoin therapy was stopped. In 1997, Hans et al.[55] showed that anticonvulsant therapy increased plasma alpha 1 acid glycoprotein (AAG) levels independent of the plasma anticonvulsant level. However, duration and recovery of vecuronium-induced block did not correlate with plasma AAG levels, and it was concluded that elevated AAG did not contribute to the resistance to vecuronium-induced block by anticonvulsants.

There have been reports of prolonged onset time and accelerated recovery from pipecuronium in patients treated with chronic anticonvulsant therapy [56,57]. Chronic treatment with anticonvulsants also resulted in more rapid recovery from a neuromuscular block produced by doxacurium and metocurine [58].

Even though there is resistance to pancuronium in patients receiving carbamazepine [59], prior chronic carbamazepine therapy did not influence mivacurium-induced neuromuscular block [60]. However, resistance to rocuronium in an epileptic patient on long-term carbamazepine therapy has been reported [61].

In patients receiving long-term treatment with phenytoin or carbamazepine, three possible mechanisms for resistance to non-depolarizers are reported: (1) increased hepatic metabolism and clearance by enzyme induction; (2) an increase in protein binding resulting in a decreased free fraction of the drug; and (3) decreased ACh receptor sensitivity with subsequent upregulation of the ACh receptor [62-64].

A decreased duration of action of rocuronium in a patient with renal failure on chronic phenytoin therapy has also been reported [65]. Loan and colleagues [66] found a reduction in the duration of action of rocuronium in patients receiving carbamazepine alone or in combination with other anticonvulsants. The actions of atracurium and mivacurium are not affected by co-medication with phenytoin or carbamazepine [67].

In a study of the in vitro neuromuscular effects of valproic acid on the rat neuromuscular junction [68], significant block did not occur. The partial block that was produced was caused predominantly by a direct inhibitory effect of valproic acid on the muscle itself. However, it has been suggested that valproic acid may cause upregulation of the ACh receptor, as acute administration in animals causes partial neuromuscular block and potentiates the effects of neuromuscular blocking drugs [63]. Driessen et al.[69] reported accelerated recovery from rocuronium in an end-stage renal failure patient on chronic anticonvulsant therapy with sodium valproate and primidone.

After suxamethonium, there have been observations of prolonged duration of action (14.3±2.3 min in anticonvulsant-treated patients compared with 10.0±1.6 min in a control group), which was attributed to anticonvulsant-induced upregulation of post-synaptic ACh receptors [70]. It has also been shown that phenytoin reduces suxamethonium-induced myalgia [71].

Resistance or decreased sensitivity to non-depolarizing muscle relaxants in patients receiving chronic phenytoin therapy is reasonably well established. A similar response may occur in patients on chronic carbamazepine therapy. In contrast, acute administration of phenytoin is likely to enhance a non-depolarizing block. The effect of valproic acid is uncertain, but it is known to have a direct inhibitory effect on muscle.

Effect on ACh release

Botulinum toxin

Botulinum toxin is known to block ACh release at the neuromuscular junction [72]. Botulinum neurotoxin type A, a di-chain protein produced by Clostridium botulinum, blocks ACh release from peripheral nerves by binding to the terminals, undergoing internalization and proteolysing a protein essential for exocytosis [73]. Perie et al.[74] concluded that the intracellular target of botulinum neurotoxin A is a protein of the ACh vesicle membrane. The toxin has been used for periocular injections in patients with blepharospasm [75]. When used for focal dystonias, botulinum toxin may cause a transient impairment of neuromuscular transmission in muscles distant from those injected. Fiacchino et al.[76] described a patient who underwent general anaesthesia twice during treatment with botulinum toxin. The patient's sensitivity to vecuronium was low 90 days after the seventh treatment with toxin and normal 8 days after the ninth treatment. It is possible that repeated treatments with the toxin may cause continuous remodelling of neuromuscular junctions and may cause the patient to develop some tolerance to the action of neuromuscular blockers.


Chloroquine has a non-depolarizing neuromuscular blocking action and can have an additive effect on non-depolarizing muscle relaxants used during anaesthesia.

Chloroquine has been shown to generate ACh receptor antibodies [77]. Chloroquine also has a local anaesthetic-like effect on the membranes of axons and muscle fibres, which results in a reduction in transmitter output and a decrease in the amplitude of the action potentials of the muscle fibres [78].

Chloroquine induced myasthenic syndrome [79], in a patient taking the drug for presumed reticular erythematous mucinosis, was probably caused by a direct effect of chloroquine on the neuromuscular junction. The generalized myasthenic syndrome was responsive to i.v. edrophonium. The syndrome was rapidly reversible, as clinical and electrophysiological recovery was documented 4 days after discontinuation of chloroquine therapy, and recovery was complete in 11 days.

From the available evidence, it is likely that chronic chloroquine therapy will prolong the effect of non-depolarizing block.

Quinidine and procainamide

Quinidine, a potent antiarrhythmic drug, is used to treat both ventricular and supraventricular arrhythmias. Quinidine potentiates both depolarizing and non-depolarizing muscle relaxants. Kambam et al.[80] observed desensitization block and prolongation of a suxamethonium block in a patient receiving quinidine preoperatively. It was concluded that the principal mechanism for this was depression of plasma cholinesterase activity. Miller et al.[81] studied the interaction between quinidine and neuromuscular blockers in the cat anterior tibialis and the rat phrenic nerve-diaphragm preparations. The neuromuscular block produced by tubocurarine, suxamethonium and gallamine was doubled in intensity and duration after quinidine. Edrophonium was not completely effective in antagonizing a block produced by quinidine. Posttetanic facilitation with non-depolarizing blockers is decreased after quinidine.

Procainamide and quinidine also possess local anaesthetic properties. These anti-arrhythmics may potentiate neuromuscular block by interfering with the release of ACh [82] and by impairing transmission at nerve terminals. Local anaesthetics are also known to displace muscle relaxants, which are bound to plasma proteins, thus providing increased concentrations of the muscle relaxant at the myoneural junction. Harrah et al.[83] reported that procainamide, lignocaine and propranolol increased the intensity and duration of a tubocurarine block. It has been suggested that procainamide and quinidine cause clinically significant potentiation of non-depolarizing drugs because of their AChR channel-blocking activity [84].

Effect in the synaptic cleft


Bambuterol is an inactive prodrug that is slowly converted in the body to its active form terbutaline. The carbonate groups that are split off can selectively inhibit plasma cholinesterase. Oral administration of bambuterol has been reported to augment a suxamethonium block [85,86]. A mivacurium block may be similarly augmented, especially in patients with a heterozygous abnormality of plasma cholinesterase [87].


Administration of the alpha 2 agonist clonidine has the ability to reduce the anaesthetic requirements of traditional agents by as much as 50% [88]. Conflicting reports have appeared regarding the effects of clonidine on a vecuronium-induced neuromuscular block [89,90]. The clinical duration of a bolus of vecuronium 0.1 mg kg−1 was measured in a group of patients who received clonidine, 4.0-5.5 mm kg−1 orally 90 min before arriving in the operating room and compared with a control group receiving no premedication. The time to recovery to 25% of the control (first twitch in the train-of-four sequence) after vecuronium was significantly longer in the clonidine group (51.2±7.5 min compared with 40.5±5.1 min in the control group) and was probably caused by a pharmacokinetic interaction [89]. Substance B, a chemical isolated from brain, reverses presynaptically modulated inhibition of evoked ACh release. Inhibitory modulating agents whose activity is reversed by substance B included clonidine [91]. No difference between clonidine-treated and control patients in onset time, duration or recovery index of neuromuscular block from vecuronium has been reported [90].

Although clonidine interferes with ACh release, its effect at the neuromuscular junction has not been quantified, and its effect on the action of muscle relaxants remains uncertain.


In 1995, Vigouroux and Voltaire [92] reported a case of prolonged neuromuscular block after mivacurium for laparoscopic cholecystectomy in a 45-year-old patient treated with cyclophosphamide for Wegener's granulomatosis. The duration of action of an intubating dose of 0.2 mg kg−1 of mivacurium was 75 min. Additional bolus doses of 1 mg (25% of the maintenance dose) every 10-15 min were sufficient for maintaining relaxation. Plasma butyrylcholinesterase activity was reduced by 50%. Cholinesterase inhibition from cyclophosphamide could be a significant factor.


Ecothiopate is a potent long-acting cholinesterase inhibitor used in the treatment of glaucoma. In addition to its local effect in the eye, systemic absorption is sufficient to produce a decrease in plasma cholinesterase activity. The fall in activity of plasma cholinesterase is rapid in the first 2 weeks, and levels of less than 5% of normal have been reported in patients receiving ecothiopate eye drops for a prolonged period of time. After the cessation of therapy, it takes 4 weeks for the plasma cholinesterase levels to return to normal. Pantuck [93] reported an extended response to suxamethonium in a patient receiving ecothiopate eye drops. Prolonged apnoea after suxamethonium was reported by Gesztes [94]. Muscle relaxation can be achieved safely with suxamethonium in patients with decreased plasma cholinesterase activity if neuromuscular function is monitored closely [95].

In a study performed by Kraunak et al.[96], ecothiopate had no significant effect on the potentiation of suxamethonium caused by anaesthetic drugs.

The manufacturers of mivacurium advise that this drug should not be used in the presence of ecothiopate because of the unpredictable duration of action after the suppression of plasma cholinesterase activity.

H2 receptor antagonists

H2 receptor antagonists are used extensively for the treatment and prevention of oesophageal and gastroduodenal ulcer disease. An extensive range of proprietary medicines are available over the counter.

Both cimetidine (5 mmol L−1) and ranitidine (1 mmol L−1) have been shown to potentiate the effect of ACh on the toad rectus abdominis muscle 4 and 2.6 times, respectively, when compared with saline [97]. Increasing doses of the drugs did not produce muscle contracture as did suxamethonium, but there was a concentration-dependent and non-parallel shift of the ACh response curve together with a reduction in maximal response, suggesting a non-depolarizing mechanism of action, possibly resulting from ion channel block.

Cimetidine and ranitidine both produce an immediate and prolonged effect on the neuromuscular block in rats receiving suxamethonium infusions [98]. The degree of non-competitive block produced by H2 receptor antagonists has been the subject of several studies [99,100]. Anticholinesterase activity has been attributed to cimetidine and ranitidine, although there is no clinical relevance in the parturient [101] or in patients presenting for elective surgery [102].

Ulsamer [103] found that the time from injection of vecuronium to neuromuscular recovery was significantly prolonged after 5 mg kg−1 cimetidine. It has also been suggested that interaction between cimetidine and non-depolarizing muscle relaxants occurs at the presynaptic level, because experimental investigation has shown calcium to reverse the effects of cimetidine [104].

The neuromuscular blocking action of tubocurarine was potentiated at high concentrations of nizatidine and ranitidine, while it was antagonized at lower doses [105]. However, McCarthy et al.[106] found no differences in non-depolarizing block after pretreatment with ranitidine or cimetidine.

Chronic exposure to cimetidine or ranitidine at human therapeutic concentrations in rats does not affect the neuromuscular pharmacodynamics of suxamethonium or atracurium [107]. Intravenous famotidine at human therapeutic doses fails to alter neuromuscular function in vivo[108]. Exposure to cimetidine has no effect on neuromuscular block from rocuronium [109].

These conflicting reports do not permit a clear conclusion on the effect of H2 receptor antagonists on the neuromuscular junction. The anticholinesterase effect of H2 antagonists in the doses used in clinical practice is unlikely to have an effect on muscle relaxants. With non-depolarizing muscle relaxants, potentiation occurs only at very high concentrations, much above therapeutic levels. However, individual variations may occur during the use of muscle relaxants in patients on long-term treatment with H2 receptor antagonists.


Anticholinesterase therapy is the mainstay of treatment for patients suffering from myasthenia gravis. The use of suxamethonium in these patients may have variable effects [110]. There is a documented resistance to onset of depolarizing block in patients who are maintained on their anticholinesterase therapy preoperatively [111]. Reduced metabolism of the depolarizing drugs results in a propensity for prolonged recovery and the development of phase 2 block [112]. There does, however, seem to be little correlation between plasma cholinesterase activity and the duration of block [113].

Mivacurium has been used successfully in myasthenic patients in a dose that was half the recommended ED95. This resulted in a 93% block of T1 with a prolonged recovery index (25-75% T1) of 20.5 min, and subsequent antagonism with neostigmine was uncomplicated [114]. However, Fleming and Lewis [115] showed no increase in duration of action with mivacurium when used in rats treated with pyridostigmine and suggested that increased competition at the neuromuscular junction, following pretreatment with anticholinesterase agents, has a more marked effect on duration of action than inhibition of plasma cholinesterase.

Preoperative use of pyridostigmine has also been shown to reduce the neuromuscular block produced by vecuronium [116].


Tacrine is a powerful anticholinesterase inhibitor that prolongs the duration of action of suxamethonium-induced neuromuscular block and may lead to phase 2 block [117,118]. This interaction was used clinically before the introduction of short-acting non-depolarizing agents [119]. Tacrine is currently being investigated for use in patients with Alzheimer's disease [120], and this important interaction may be encountered more frequently.

Post-synaptic effect

β-Receptor blocking drugs

There have been reports of prolonged response to non-depolarizing neuromuscular blocking drugs in patients receiving atenolol or propranolol [83,121,122]. It is difficult to explain this interaction in terms of neuromuscular conduction and block, although it is known that propranolol possesses local anaesthetic properties and may interfere with the propagation of the nerve action potential. It is also possible that a pharmokinetic effect is involved.


There have been conflicting reports on the interactions of benzodiazepines with muscle relaxants. In 1970, Feldman and Crawley [123] suggested that diazepam interacted with muscle relaxant drugs. Diazepam alone has no effect on the response of the tibialis anterior muscle to indirect stimulation in dogs and, in a bolus dose of 5 mg, does not influence a pre-existing partial block by tubocurarine, gallamine or pancuronium [124]. The degree and duration of block by tubocurarine was not affected significantly by simultaneous administration of diazepam in man.

In a review of the literature by Martins [125] in 1975, it was concluded that diazepam exerts a possible sparing effect on the dose of muscle relaxants of between 8% and 30%. It was concluded that diazepam in therapeutic doses did not affect neuromuscular transmission and that this sparing effect did not result from a direct pharmacological interaction nor an effect on skeletal muscle fibres. This sparing effect of diazepam was thought most probably to be caused by a summation of muscle relaxant actions exerted at different levels of the nervous system (spinal and brainstem levels), resulting in inhibition of polysynaptic reflex activity, enhancement of presynaptic inhibition and depression of gamma motor neurone activity.

Experimental work has shown that, at low concentrations (1-100 μg mL−1), diazepam increased the twitch contractions in response to motor nerve stimulation in the chick and rat in a dose-dependent manner [126]. Higher concentrations decreased twitch tension and greatly reduced the contractions produced by ACh and tetraethylammonium in chick skeletal muscle. However, in a dose of 0.15 mg kg−1, diazepam had no significant effect on the neuromuscular block produced by either tubocurarine or suxamethonium. It was concluded that diazepam may either increase or decrease the twitch tension in rat and chick skeletal muscle, the effect being dependent on the concentrations used. Similar results were obtained by Driessen et al.[127].

At present, the consensus is that benzodiazepines, in concentrations achieved during normal therapy, do not influence a neuromuscular block.


The pre- and post-junctional effects of the lincosamide antibiotics clindamycin and lincomycin have been studied in animals [128]. Lincomycin and clindamycin appeared to produce muscle paralysis by different mechanisms. Clindamycin exerts a direct depressant action on muscle contractility, whereas lincomycin primarily depresses neuromuscular transmission [129]. Wright and Collier [130] demonstrated that the direct depressant action on muscle contractility by clindamycin was fivefold more potent than that of lincomycin. Rubbo and colleagues [131] observed that lincomycin decreased ACh release, while clindamycin increased it. The antagonism by neostigmine and calcium of a clindamycin-augmented non-depolarizing blockade in man may be incomplete [132]. The latter results suggested that the neuromuscular blocking effects of clindamycin involve primarily a post-junctional mechanism, whereas the effects of lincomycin are both pre- and post-junctional. In 1993, de Gouw et al.[133] concluded that the administration of colistin and clindamycin may cause a significant prolongation of an already long-acting neuromuscular block.

Unknown site of action


The neuroexcitatory and depressant effects of penicillin at the animal soleus neuromuscular junction was studied by Raines and Dretchen [134]. Post-tetanic potentiation in this system, which is mediated by repetitive discharges originating in nerve terminals after high-frequency stimulation, is augmented by penicillin. Larger doses depressed post-tetanic stimulation, and still larger doses produced varying degrees of neuromuscular block.

Only extremely large doses of penicillin will produce any effect on neuromuscular block, and this is unlikely to be encountered in clinical practice.


Metronidazole has been reported to facilitate neuromuscular transmission and to antagonize tubocurarine-induced neuromuscular block partially in isolated rat diaphragm [135]. However, in cats, metronidazole was observed to potentiate the effects of vecuronium after 1 h of administration. The potentiating action of metronidazole seen with vecuronium was not reproducible when pancuronium was used, suggesting that it was not an effect of metronidazole on neuromuscular transmission. It may be secondary to an effect of metronidazole on the distribution or metabolism of vecuronium. The slow onset of the effect of metronidazole on the neuromuscular junction suggests that the effect may be brought about by a metabolite rather than by metronidazole itself. Caution may be necessary when vecuronium is administered to patients treated with metronidazole [136].


The effect of corticosteroids (hydrocortisone, methyl prednisolone) on the recovery time from vecuronium-induced neuromuscular block was studied using evoked potential measurements following stimulation of the ulnar nerve [137]. Recovery time was prolonged by corticosteroids and, in the case of hydrocortisone, this effect was significant. It was speculated that corticosteroids reduced the clearance of vecuronium. Prolongation of recovery time from vecuronium-induced block after the administration of corticosteroids may be explained not only by the direct effects of hydrocortisone on the neuromuscular junction but also by the effect of hydrocortisone on the elimination of vecuronium from plasma. In the cat, hydrocortisone in 7-15 mg kg−1 doses significantly enhanced the 50% depression of the indirectly elicited twitch tension of the tibialis anterior muscle produced by an i.v. infusion of pancuronium [138]. It is uncertain as to the doses of corticosteroids that may affect neuromuscular function. It is likely that chronic high-dose corticosteroid therapy may prolong the duration of action of vecuronium and pancuronium.


Tamoxifen has been reported to prolong block after the administration of atracurium, but the mechanism is not known [139].


Medications in use for disease states commonly encountered in any population group may have the potential to alter function at the neuromuscular junction. We have reviewed the possible effects of drugs that are in common usage, often chronically, on neuromuscular junctional activity.

Much of the evidence for the effects of drugs on the neuromuscular junction comes from animal experiments, often with doses not used in clinical practice. It is noteworthy that, despite the extremely wide use of these drugs, the incidence in the literature of prolonged or adverse interactions with neuromuscular blocking agents is sparse. This could result from either difficulty in establishing the diagnosis or the rarity of clinically important events. The determination of the role of concurrent medication in producing an unpredicted neuromuscular block usually follows a process of elimination, often after the problem has resolved. Thus, knowledge of the possibilities provides awareness of potential problems during clinical practice.


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