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Review

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

Introduction

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

Aminophylline

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.

Azathioprine

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

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

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

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.

Anticonvulsants

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

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

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].

Clonidine

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.

Cyclophosphamide

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

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.

Pyridostigmine

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

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.

Benzodiazepines

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.

Lincosamides

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

Penicillin

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

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].

Corticosteroids

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

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

Conclusion

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.

References

1 Azar I, Kumar D, Betcher AM. Resistance to pancuronium in an asthmatic patient treated with aminophylline and steroids. Can Anaesth Soc J 1982; 29: 280-282.
2 Dretchen KL, Standaert FG, Skirboll LR, Morgenroth VH, III. Evidence for a prejunctional role of cyclic nucleotides in neuromuscular transmission. Nature 1976; 264: 79-81.
3 Dretchen KL, Morgenroth VH, III, Standaert FG, Walts LF. Azathioprine: effects on neuromuscular transmission. Anesthesiology 1976; 45: 604-609.
4 Scappaticci KA, Ham JA, Sohn YJ et al. Effects of frusemide on the neuromuscular junction. Anesthesiology 1982; 57: 381-388.
5 Atkinson RS, Rushman GB, Lee JA, (eds). A Synopsis of Anaesthesia. Bristol: Wright, 1987.
6 Cheng EY, Nimphius N, Hennen CR. Antibiotic therapy and the anesthesiologist. J Clin Anesth 1995; 7: 425-439.
7 Sokoll MD, Gergis SD. Antibiotics and neuromuscular function. Anesthesiology 1981; 55: 148-159.
8 Barclay ML, Begg EJ. Aminoglycoside toxicity and relation to dose regimen. Adverse Drug Reactions Toxicol Rev 1994; 13: 207-234.
9 Lee C, De Silva JC. Acute and subchronic neuromuscular blocking characteristics of streptomycin: a comparison with neomycin. Br J Anaesth 1979; 51: 431.
10 Caputy AJ, Kim YI, Sanders DB. The neuromuscular blocking effects of therapeutic concentrations of various antibiotics on normal rat skeletal muscle: a quantitative comparison. J Pharmacol Exp Ther 1981; 217: 369.
11 Singh YN, Marshall IG, Harvey AL. Pre- and post-junctional blocking effects of aminoglycoside, polymyxin, tetracycline and lincosamide antibiotics. Br J Anaesth 1982; 54: 1295-1306.
12 Sobek V. The effect of calcium, neostigmine and 4-aminopyridine upon respiratory arrest and depression of cardiovascular functions after aminoglycoside antibiotics. Arzneimittel-Forschung 1982; 32: 222-224.
13 Yamada S, Kuno Y, Iwanaga H. Effects of aminoglycoside antibiotics on the neuromuscular junction. Part 1. Int J Clin Pharmacol Ther 1986; 24: 130-138.
14 Elliot JM, Bion JF. The use of neuromuscular blocking drugs in intensive care practice. Acta Anaesthesiol Scand 1995; 106: 70-82.
15 Hasfurther DL, Bailey PL. Failure of neuromuscular blockade reversal after rocuronium in a patient who received oral neomycin. Can J Anaesth 1996; 43: 617-620.
16 Stoelting RK. Pharmacology and Physiology in Anaesthetic Practice. Philadelphia: JB Lippincott, 1991; 354.
17 Jones RM, Cashman JN, Casson WR, Broadbent MP. Verapamil potentiation of neuromuscular blockade: failure of reversal with neostigmine but prompt reversal with edrophonium. Anesth Analg 1985; 65: 1021.
18 van Poorten JF, Dhasmana KM, Kuypers RS, Erdmann W. Verapamil and the reversal of vecuronium neuromuscular blockade. Anesth Analg 1984; 63: 155.
19 Durant NN, Nguyen N, Katz RL. Potentiation of neuromuscular blockade by verapamil. Anesthesiology 1984; 60: 298.
20 Chang CC, Chiou LC, Hwang LL, Huang CY. Mechanisms of the synergistic interactions between organic calcium channel antagonists and various neuromuscular blocking agents. Jpn J Pharmacol 1990; 53: 285-292.
21 Salvador A, del Pozo E, Carlos R, Baeyens JM. Differential effects of calcium channel blocking agents on pancuronium and suxamethonium induced neuromuscular blockade. Br J Anaesth 1988; 60: 459-459.
22 Adam LP, Henderson EG. Augmentation of succinylcholine-induced neuromuscular blockade by calcium channel antagonists. Neurosci Lett 1986; 70: 148-153.8.
23 Rooke GA, Freund PR, Tomlin J. Calcium channel blockers do not enhance increases in plasma potassium after succinylcholine in humans. J Clin Anesth 1994; 6: 114-118.
24 Gomez Iglesias E, Garcia Pascual E, Aguirre Gomez C et al. Influence of verapamil and diltiazem on the muscle-relaxing effect of atracurium in vivo. Rev Esp Anesthesiol Reanim 1991; 38: 297-300.
25 Kawabata K, Sumikawa K, Kamibayashi T et al. Decrease in vecuronium infusion dose requirements by nicardipine in humans. Anesth Analg 1994; 79: 1159-1164.
26 Bell PF, Mirakhur RK, Elliott P. Onset and duration of clinical relaxation of atracurium and vecuronium in patients on chronic nifedipine therapy. Eur J Anaesthesiol 1989; 6: 343-346.
27 Sekerci S, Tulunay M. Interaction of calcium channel blockers with non-depolarising muscle relaxants in vitro. Anaesthesia 1996; 51: 140-144.
28 Waud BE, Farell L, Waud DR. Lithium and neuromuscular transmission. Anesth Analg 1982; 61: 399-402.
29 Saarnivaara L, Ertama P. Interactions between lithium/rubidium and six muscle relaxants. A study on the rat phrenic nerve-hemidiaphragm preparation. Anaesthesist 1992; 41: 760-764.
30 Pestronk A, Drachman DB. Lithium reduces the number of acetylcholine receptors in skeletal muscle. Science 1980; 210: 342-343.
31 Hill GE, Wong KC, Hodges MR. Potentiation of succinylcholine neuromuscular blockade by lithium carbonate. Anesthesiology 1976; 44: 439-442.
32 Reimherr FW, Hodges MR, Hill GE, Wong KC. Prolongation of muscle relaxant effects by lithium carbonate. Am J Psychiat 1977; 134: 205-206.
33 Jephcott G, Kerry RJ. Lithium: an anaesthetic risk. Br J Anaesth 1974; 46: 389-390.
34 Ortiz CL, Junge D. Depressant action of lithium at the crayfish neuromuscular junction: pre- and postsynaptic effects. J Exp Biol 1978; 75: 171-187.
35 Carmody JJ, Gage PW. Lithium stimulates secretion of acetylcholine in the absence of extracellular calcium. Brain Res 1973; 50: 476-479.
36 Branisteanu DD, Volle RL. Modification by lithium of transmitter release at the neuromuscular junction of the frog. J Pharmacol Exp Ther 1975; 194: 362-372.
37 Joint Formulary Committee. Drugs used in anaesthesia. In: The British Medical Association and the Royal Pharmaceutical Society of Great Britain, eds. British National Formulary. Bath: The Bath Press, 1997; 34: 526.
38 Lee C, Zhang X, Kwan WF. Neuromuscular refractoriness prejunctional block by MgSO4 in the pig. Anesth Analg 1995; 80: 5270.
39 James MF. Clinical use of magnesium infusions in anaesthesia. Anesth Analg 1992; 74: 129-136.
40 del Castillo J, Engback L. The nature of the neuromuscular block produced by magnesium. J Physiol 1954; 124: 370-384.
41 Ramanthan J, Sibai BM, Pillai R, Angel JJ. Neuromuscular transmission studies in pre-eclamptic women receiving magnesium sulphate. Am J Obstet Gynecol 1988; 158: 40-46.
42 Crul JF, Long GJ, Brunner EA, Coolen JM. The changing pattern of neuromuscular blockade caused by succinylcholine in man. Anesthesiology 1966; 27: 729-735.
43 Kwan WF, Lee C, Chen BJA. non-invasive method in the differential diagnosis of vecuronium-induced and magnesium-induced protracted neuromuscular block in a severely pre-eclamptic patient. J Clin Anesth 1996; 8: 392-397.
44 Fuchs-Buder T, Tassonyi E. Magnesium sulphate enhances residual block induced by vecuronium. Br J Anaesth 1996; 76: 565-566.
45 Gaiser RR, Seem EH. Use of rocuronium in a pregnant patient with an open eye injury, receiving magnesium medication, for preterm labour. Br J Anaesth 1996; 77: 669-671.
46 Stacey MR, Barclay K, Asai T, Vaughan RS. Effects of magnesium sulphate on suxamethonium-induced complications during rapid-sequence induction of anaesthesia. Anaesthesia 1995; 50: 933-936.
47 Tsai SK, Huang SW, Lee TY. Neuromuscular interactions between suxamethonium and magnesium sulphate in the cat. Br J Anaesth 1994; 72: 674-678.
48 Yap LC, Ho RT, Jawan B, Lee JH. Effects of magnesium sulphate pretreatment on succinylcholine-facilitated tracheal intubation. Acta Anaesthesiol Sin 1994; 32: 45-50.
49 Ornstein E, Matteo RS, Schwartz AE et al. The effect of phenytoin on the magnitude and duration of neuromuscular block following atracurium or vecuronium. Anesthesiology 1997; 67: 191-196.
50 Gray HS, Slater RM, Pollard BJ. The effect of acutely administered phenytoin on vecuronium-induced neuromuscular blockade. Anaesthesia 1989; 44: 379-381.
51 Norris FH, Colella J, McFarlin D. Effect of diphenylhydantoin on neuromuscular synapse. Neurology 1964; 14: 896-876.
52 Ghandi IC, Jindal MN, Patel VK. Mechanism of neuromuscular blockade with some antiepileptic drugs. Arzneimittel-Forschung 1976; 26: 258-261.
53 Raines A, Standaert FG. Effects of anticonvulsant drugs on nerve terminals. Epilepsia 1969; 10: 211-227.
54 Kim CS, Arnold FJ, Itani MS, Martyn JA. Decreased sensitivity to metocurine during long-term phenytoin therapy may be attributable to protein binding and acetylcholine receptor changes. Anesthesiology 1992; 77: 500-506.
55 Hans P, Brichant JF, Pieron F et al. Elevated plasma alpha 1 acid glycoprotein levels: lack of connection to resistance to vecuronium blockade induced by anticonvulsant therapy. J Neurosurg Anesthesiol 1997; 9: 3-7.
56 Jellish WS, Modica PA, Tempelhoff R. Accelerated recovery from pipercuronium in patients treated with chronic anticonvulsant therapy. J Clin Anesth 1993; 5: 105-108.
57 Hans P, Ledoux D, Bonhomme V. Effect of plasma anticonvulsant level on pipecuronium-induced neuromuscular blockade: preliminary results. J Neurosurg Anesthesiol 1995; 7: 254-258.
58 Ornstein E, Matteo RS, Weinstein JA et al. Accelerated recovery from doxacurium-induced neuromuscular blockade in patients receiving chronic anticonvulsant therapy. J Clin Anesth 1991; 3: 8-11.
59 Roth S, Ebrahim ZY. Resistance to pancuronium in patients receiving carbamazepine. Anesthesiology 1987; 66: 691-693.
60 Spacek A, Neiger FX, Spiss CK, Kress HG. Chronic carbamazepine therapy does not influence mivacurium-induced neuromuscular block. Br J Anaesth 1996; 77: 500-502.
61 Baraka A, Idriss N. Resistance to rocuronium in an epileptic on long-term carbamazepine therapy - a case report. Middle East J Anesthesiol 1996; 13: 561-564.
62 Alloul K, Whalley DG, Shutway F, Ebrahim Z, Varin F. Pharmacokinetic origin of carbamazepine-induced resistance to vecuronium neuromuscular blockade in anaesthetized patients. Anesthesiology 1996; 84: 330-339.
63 Pollard BJ. Drug interactions. In: Harper NJN, Pollard BJ, eds. Muscle Relaxants in Anaesthesia. London: Edward Arnold, 1995; 177-197.
64 Martyn JA, White DA, Gronert GA et al. Up- and down regulation of skeletal acetylcholine receptors. Effects on neuromuscular blockers. Anesthesiology 1992; 76: 822-843.
65 Szenohradsky J, Caldwell JE, Sharma ML et al. Interaction of rocuronium (ORG 9426) and phenytoin in a patient undergoing cadaver renal transplantation: a possible pharmacokinetic mechanism? Anesthesiology 1994; 80: 1167-1170.
66 Loan PB, Connoly FM, Mirakhur RK et al. Neuromuscular effects of rocuronium in patients receiving beta-adrenoceptor blocking, calcium entry blocking and anticonvulsant drugs. Br J Anaesth 1997; 78: 90-91.
67 Ornstein E, Matteo RS, Weinstein JA et al. Accelerated recovery from doxacurium-induced neuromuscular blockade in patients receiving chronic anticonvulsant therapy. J Clin Anesth 1991; 3: 108-111.
68 Nguyen A, Ramzan I. In vitro neuromuscular effects of valproic acid. Br J Anaesth 1997 78: 197-200.
69 Driessen JJ, Robertson EN, Booij LHDJ, Vree TB. Accelerated recovery and disposition from rocuronium in an end-stage renal failure patient on chronic anticonvulsant therapy with sodium valproate and primidone. Br J Anaesth 1998; 80: 386-388.
70 Melton AT, Antognini JF, Gronert GA. Prolonged duration of succinylcholine in patients receiving anticonvulsants: evidence for mild up-regulation of acetylcholine receptors? Can J Anaesth 1993; 40: 939-942.
71 Hatta V, Saxena A, Kaul HL. Phenytoin reduces suxamethonium-induced myalgia. Anaesthesia 1992; 47: 664-667.
72 Stanley EF, Drachman DB. Botulinum toxin blocks quantal but not non-quantal release of ACh at the neuromuscular junction. Brain Res 1983; 261: 172-175.
73 Daniels-Holgate PU, Dolly JO. Productive and non-productive binding of botulinum neurotoxin A to motor nerve endings are distinguished by its heavy chain. J Neurosci Res 1996; 44: 263-271.
74 Perie S, Lacau St-Guily J. Mode of action and effects of botulinum toxin A. Ann Otolaryngol Chir Cervicofac 1996; 113: 73-78.
75 Sanders DB, Massey EW, Buckley EG. Botulinum toxin for blepharospasm:single-fiber EMG studies. Neurology 1986; 36: 545-547.
76 Fiacchino F, Grandi L, Soliveri P et al. Sensitivity to vecuronium after botulinum toxin administration. J Neurosurg Anesthesiol 1997; 9: 149-153.
77 Sghirlanzoni A, Mantegazza R, Mora M et al. Chloroquine myopathy and myasthenia like syndrome. Muscle Nerve 1988; 11: 114-119.
78 Tseng J. Clinical and experimental studies on mechanism of neuromuscular blockade by chloroquine diorotate. Jpn J Anaesthesiol 1971; 20: 491-503.
79 Robberecht W, Bednarik J, Bourgeois P et al. Myasthenic syndrome caused by direct effect of chloroquine on neuromuscular junction. Arch Neurol 1989; 46: 464-468.
80 Kambam JR, Franks JJ, Naukam R, Sastry BV. Effect of quinidine on plasma cholinesterase activity and succinyl choline neuromuscular blockade. Anesthesiology 1987; 67: 858-860.
81 Miller RD, Way WL, Katzung BG. The potentiation of neuromuscular blocking agents by quinidine. Anesthesiology 1967; 28: 1036-1041.
82 Cuthbert MF. The effect of quinidine and procainamide on the neuromuscular blocking action of suxamethonium. Br J Anaesth 1966; 38: 775-779.
83 Harrah MD, Way WL, Katzung BG. The interaction of d-tubocurarine with antiarrhythmic drugs. Anesthesiology 1970; 33: 406-410.
84 Feldman S, Karalliedde L. Drug interactions with neuromuscular blockers. Drug Safety 1996; 15: 261-273.
85 Staun P, Lenmarken C, Eriksson LI, Wiren JE. The influence of 10 mg and 20 mg of bambuterol on the duration of succinylcholine-induced neuromuscular blockade. Acta Anaesthesiol Scand 1990; 34: 498-500.
86 Fisher DM, Caldwell JE, Sharma M, Wiren JE. The influence of bambuterol (carbamylated terbutaline) on the duration of action of succinylcholine-induced paralysis in humans. Anesthesiology 1988; 69: 757-759.
87 Bang V, Viby-Mogensen J, Wiren JE. The effect of bambuterol on plasma cholinesterase activity and suxamethonium-induced neuromuscular blockade in subjects heterozygous for abnormal plasma cholinesterase. Acta Anaesthesiol Scand 1990; 34: 600-604.
88 Waugaman WR, Foster SD. New advances in anaesthesia. Nurs Clin North Am 1991; 26: 451-461.
89 Nakahara T, Akazawa T, Kinoshita Y, Nozaki J. The effect of clonidine on the duration of vecuronium-induced neuromuscular blockade in humans. Jpn J Anesthesiol 1995; 44: 1458-1463.
90 Takahashi H, Nishikawa T. Oral clonidine does not alter vecuronium neuromuscular blockade in anaesthetized patients. Can J Anaesth 1995; 42: 511-515.
91 Cooper JR, Pearce LB, Benishin CG. Isolation of a factor that reverses presynaptic inhibition of acetylcholine release. J Physiol 1986; 81: 266-269.
92 Vigoroux D, Voltaire L. Prolonged neuromuscular block induced by mivacurium in a patient treated with cyclophosphamide. Ann Fr Anesth Reanim 1995; 14: 508-510.
93 Pantuck EJ. Ecothiopate iodide eye drops and prolonged response to suxamethonium. Br J Anaesth 1966; 38: 406-407.
94 Gesztes T. Prolonged apnoea after suxamethonium injection associated with eyedrops containing an anticholinesterase agent. Br J Anaesth 1966; 38: 408-409.
95 Donati F, Bevan DR. Controlled succinyl choline infusion in a patient receiving ecothiopate eye drops. Can Anaesth Soc J 1981; 28: 488-490.
96 Kraunak P, Pleurvy BJ, Rees JM. In vitro study of interactions between i.v. anaesthetics and neuromuscular blocking agents. Br J Anaesth 1977; 49: 765-70.
97 Cheah LS, Lee HS, Gwee MCE. Anticholinesterase activity of and possible ion channel block by cimetidine, ranitidine and oxmetridine in the toad isolated rectus abdominis muscle. Clin Exp Pharmacol Physiol 1985; 12: 353-357.
98 Mishra Y, Ramzan I. Interaction between succinylcholine and cimetidine in rats. Can J Anaesth 1992; 39: 370-374.
99 Sato Y, Tsuchida H, Harada Y, Namiki A. Effect of cimetidine on neuromuscular blockade by succinylcholine and pancuronium. Jpn J Anesthesiol 1990; 39: 168-173.
100 Gwee MC, Cheah LS. Actions of cimetidine and ranitidine at some cholinergic sites: implications in toxicology and anaesthesia. Life Sci 1986; 39: 383-388.
101 Bogod DG, Oh TE. The effect of H2 antagonists on duration of action of suxamethonium in the parturient. Anaesthesia 1989; 44: 591-593.
102 Turner DR, Kao YJ, Bivona C. Neuromuscular block by suxamethonium following treatment with histamine type 2 antagonists or metoclopramide. Br J Anaesth 1989; 63: 348-350.
103 Ulsamer B. Vecuronium bromide: modification of its pharmacodynamics by etomidate, cimetidine and ranitidine. Anaesthesist 1988; 37: 504-509.
104 Tryba M, Wruck G. Interactions of H2 antagonists and non-depolarizing muscle relaxants. Anaesthesist 1989; 38: 251-254.
105 Kounenis G, Koutsoviti-Papadopoulou M, Elezoglou V. Effect of nizatidine and ranitidine on the D-tubocurarine neuromuscular blockade in the toad rectus abdominis muscle. Pharmacol Res 1994; 29: 155-161.
106 McCarthy G, Mirakhur RK, Elliott P, Wright J. Effect of H2 receptor antagonist pretreatment on vecuronium- and atracurium-induced neuromuscular block. Br J Anaesth 1991; 66: 713-715.
107 Rana J, Ramzan I. Neuromuscular blocking drug pharmacodynamics after chronic exposure to H2 antagonists. In Vivo 1995; 9: 163-166.
108 Mishra Y, Ramzan I. Interaction between famotidine and neuromuscular blockers: an in vivo study in rats. Anesth Analg 1993; 77: 780-783.
109 Latorre F, de Almeida MC, Stanek A et al. The effect of cimetidine on the pharmacodynamics of rocuronium. Anaesthesist 1996; 45: 900-902.
110 Ransom ES, Mueller RA. Safety considerations in the use of drug combinations during general anaesthesia. Drug Safety 1997; 16: 88-103.
111 Vanlinthout LE, Robertson EN, Booij LH. Response to suxamethonium during propofol-fentanyl-N2O/O2 anaesthesia in a patient with active myasthenia gravis receiving long-term anticholinesterase therapy. Anaesthesia 1994; 49: 509-511.
112 Valdrighi JB, Fleming NW, Smith BK et al. Effects of cholinesterase inhibitors on the neuromuscular blocking action of suxamethonium. Br J Anaesth 1994; 72: 237-239.
113 Fleming NW, Macres S, Antognini JF, Vengco J. Neuromuscular blocking action of suxamethonium after antagonism of vecuronium by edrophonium, pyridostigmine or neostigmine. Br J Anaesth 1996; 77: 492-495.
114 Seigne RD, Scott RP. Mivacurium and myasthenia gravis. Br J Anaesth 1994; 72: 468-469.
115 Fleming NW, Lewis BK. Cholinesterase inhibitors do not prolong neuromuscular block produced by mivacurium. Br J Anaesth 1994; 73: 241-243.
116 Baraka A, Taha S, Yazbeck V, Rizkallah P. Vecuronium block in the myasthenic patient. Influence of anticholinesterase therapy. Anaesthesia 1993; 48: 588-590.
117 Norman J, Morgan M. The effect of tacrine on the neuromuscular block produced by suxamethonium in man. Br J Anaesth 1975; 47: 1027.
118 Karis JH, Nastuk WL, Katz RL. The action of tacrine on neuromuscular transmission: a comparison with hexafluorenium. Br J Anaesth 1966; 38: 762-774.
119 Lindsay PA, Lumley J. Suxamethonium apnoea masked by tetrahydraminacrine. Anaesthesia 1978; 33: 620-622.
120 Davis KL, Powchik P. Tacrine. Lancet 1995; 345: 625-630.
121 Glynne GL. Drug interaction? Anaesthesia 1984; 39: 293.
122 Rozen MS, Whan FM. Prolonged curarization associated with propranolol. Med J Aust 1972; 1: 467-468.
123 Feldman SA, Crawley BE. Interaction of diazepam with the muscle-relaxant drugs. Br Med J 1970; 1: 336-338.
124 Jain PD, De Pandey KM. Effect of diazepam on neuromuscular transmission and its interaction with non-depolarising muscle relaxants. Anaesth Intensive Care 1976; 4: 122-125.
125 Martins HF. The influence of diazepam on the dosage of muscle-relaxants during anaesthesia. Anaesthetist 1975; 24: 1-5.
126 Wali FA. Myorelaxant effect of diazepam. Interactions with neuromuscular blocking agents and cholinergic drugs. Acta Anaesthesiol Scand 1985; 29: 785-789.
127 Driessen JJ, Vree TB, van Egmond J et al. In vitro interaction of diazepam and oxazepam with pancuronium and suxamethonium. Br J Anaesth 1984; 56: 1131-1138.
128 Fiekers JF, Hendersen F, Marshall IG, Parsons RL. Comparative effects of clindamycin and lincomycin on end-plate currents and quantal content at neuromuscular junction. J Pharmacol Exp Ther 1983; 227: 308-315.
129 Fiekers JF, Marshall IG, Parsons RL. Clindamycin and lincomycin alter miniature endplate current decay. Nature 1979; 281: 680-682.
130 Wright JM, Collier B. Characterisation of the neuromuscular block produced by clindamycin and lincomycin. Can J Physiol Pharmacol 1976; 54: 937-944.
131 Rubbo JT, Gergis SD, Sokoll MD. Comparative neuromuscular effects of lincomycin and clindamycin. Anesth Analg 1977; 56: 329-332.
132 Becker LD, Miller RD. Clindamycin enhances a non-depolarising neuromuscular blockade. Anesthesiology 1976; 45: 84-87.
133 de Gouw NE, Crul JF, Vandermeersch E et al. Interaction of antibiotics on pipercuronium induced neuromuscular blockade. J Clin Anesth 1993; 5: 212-215.
134 Raines A, Dretchen KL. Neuroexcitatory and depressant effects at the cat soleus neuromuscular junction. Epilepsia 1975; 16: 469-476.
135 Jadhav JH, Balsara JJ, Joshi VV, Salunkhe DS. The effect of metronidazole on striated muscle. Eur J Pharmacol 1974; 25: 263.
136 Mclndewar IC, Marshall RJ. Interactions between neuromuscular blocking drug Org NC 45 and some anaesthetic analgesic and antimicrobial agents. Br J Anaesth 1981; 53: 785-792.
137 Shima H. The effect of corticosteroids on the recovery from vecuronium-induced block. Jpn J Anesthesiol 1990; 39: 619-625.
138 Durant NN, Briscoe JR, Katz RL. The effects of acute and chronic hydrocortisone treatment on neuromuscular blockade in the anesthetized cat. Anesthesiology 1984; 61: 144-150.
139 Naguib M, Gyasi HK. Antioestrogenic drugs and atracurium - a possible interaction? Can Anaesth Soc J 1986; 33: 682-683.
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