8 Interactions involving relaxants

8 Interactions involving relaxants B R I A N J. P O L L A R D S.Pharm, MD, FRCA Professor of Anaesthesia University Department of Anaesthesia, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK

When more than one drug is used at the same time, there is the potential for an interaction. If a muscle relaxant is being used, there must already be at least one other drug in use, the anaesthetic agent. It is common to use several drugs simultaneously during an anaesthetic, for example, systemic analgesics or antibiotics. In addition, the patient may be receiving therapy for a pre-existing medical disorder. As the number of drugs in use at a time increases, so does the potential for interactions and with the large and increasing number of drugs available on the market it is certain that this problem is set to rise rather than fall. This article examines many of the common interactions involving muscle relaxants which may be encountered during anaesthesia. Key words: neuromuscular blocking agents; drug interactions; general anaesthesia, Most drug interactions can be anticipated. It should therefore be possible to avoid them, to adapt a technique to allow for them, or to use them to advantage. Interactions which are expected are not usually a problem unless the interaction does not occur, or is different to that which was expected due to other mechanisms (or indeed other drug interactions which have modified the interaction). Far more worrying are unpredictable interactions because the potential exists for serious consequences. This chapter will not consider drug effects which are caused by allergic or anaphylactic mechanisms. In most cases it may be difficult or even impossible to determine the underlying mechanism although it will be outlined if known.

SITE OF MUSCLE RELAXANT INTERACTIONS The neuromuscular junction is the primary location for interactions concerning muscle relaxants. A n y increase or decrease in release, mobilization, storage, or synthesis of acetylcholine will alter neuromuscular block as will inhibition or potentiation of the action of cholinesterase. The two alphasubunits on the post-junctional membrane are surrounded by different BailliOre's Clinical Anaesthesiology-Vol. 12, No. 2, June 1998 ISBN 0-7020-2403-1 0950-3501/98/020283 + 18 $12.00/00

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protein molecules, and drug binding may be different on the two alphasubunits. Binding to other parts of the receptor/ion channel complex may also occur, resulting in closed channel block, open channel block, or distortion of the receptor's milieu. Receptors are constantly being synthesized and replaced, and it is conceivable that a drug could affect this process, although the onset of action would be slow (several days). Because the release of acetylcholine is triggered by an impulse arriving down the nerve, any agent which retards impulse generation or propagation may affect a neuromuscular block. An effect on the excitation contraction coupling process may also modify the action of a muscle relaxant. Extrajunctional binding sites exist for many drugs, and interactions on these sites are mainly pharmacokinetic in nature. Binding to non-specific acceptor sites (e.g. plasma proteins) will introduce alterations in the volume of distribution, rate of metabolism and/or elimination. V O L A T I L E AGENTS The interaction between the volatile anaesthetic agents and the muscle relaxants is useful clinically. At high concentrations volatile agents alone will depress neuromuscular transmission and so potentiation of the muscle relaxants by the volatile agents is hardly surprising. This effect is shared by all volatile agents in current clinical use. The extent of the potentiation depends upon the volatile agent:muscle relaxant combination. Isoflurane and enflurane potentiate tubocurarine and pancuronium more than does halothane (Fogdall and Miller, 1975). Enflurane is, however, more potent than either halothane or isoflurane on a vecuronium neuromuscular block (Swen et al, 1985). Enfiurane, isoflurane and halothane all potentiate an atracurium block to a similar degree (Rupp et al, 1985). Isoflurane and desflurane both equally potentiate mivacurium and rocuronium blocks (Kumar et al, 1996a,b) although desflurane was 20% more effective than isoflurane at potentiating a vecuronium block (Wright et al, 1995). The potentiating effect of sevoflurane is similar to that of isoflurane. A suxamethonium neuromuscular block is also potentiated by volatile agents (Donati and Bevan, 1982), and it has been suggested that a depolarizing block may change more rapidly from a phase I to a phase II type in the presence of a volatile agent (Hilgenberg and Stoelting, 1981). It is interesting to note that there may be changes in the extent of potentiation with time. Enflurane has been reported to retard the reversal of a pancuronium neuromuscular block (Delisle and Bevan, 1982) although the reversibility of atracurium or vecuronium are less affected by volatile agents than are the longer acting relaxants (Engbaek et al, 1983). The mechanism by which the volatile agents potentiate muscle relaxants is unknown. An increase in muscle blood flow, and hence delivery of relaxant to the neuromuscular junction, a decrease in the release of acetylcholine from the nerve endings and an action on the post-junctional membrane have all been proposed. The muscle blood flow hypothesis

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seems unlikely because the volatile agents still show potentiation in vitro. Waud and Waud (1979) demonstrated a greater effect on tetanic stimuli than on single twitches, thus suggesting that the interaction was prejunctional in origin. Depression of carbachol induced depolarization of the endplate (Waud and Waud, 1975), interference with the acetylcholine receptor protein (Young et al, 1981) and reduction in ion channel conductance at the endplate (Gage and Hamill, 1976; Bean et al, 1981) have also been demonstrated. In view of the high lipid solubility of the volatile agents, it is also tempting to speculate that interactions could be due to nonspecific effects upon the cell membrane. Other factors, including a direct action on muscle contraction or calcium flux (Diamond and Berman, 1980), are also possible. It is very likely that more than one mechanism is involved simultaneously, and different volatile agents may not all be acting in exactly the same manner. BENZODIAZEPINES

Reports concerning the effects of the benzodiazepines on neuromuscular transmission are conflicting. Studies in laboratory animals have demonstrated potentiation of muscle relaxants by benzodiazepines (Driessen et al, 1983), an action which is not mediated through benzodiazepine receptors. No similar effects have been demonstrated clinically and the benzodiazepines are usually regarded as having no effect on neuromuscular block (Bradshaw and Maddison, 1979; Cronnelly et al, 1983). INTRAVENOUS AGENTS Thiopentone has been reported to potentiate the effects of muscle relaxants (Cronnelly et al, 1983). However, no effect was reported for methohexitone on a pipecuronium neuromuscular block (Dutre et al, 1992). Etomidate may potentiate vecuronium and pancuronium (Booij and Crul, 1979) but not suxamethonium or pipecuronium (Dutre et al, 1992). Ketamine has been shown to potentiate tubocurarine, pancuronium, suxamethonium, vecuronium and atracurium (Amaki et al, 1978). Propofol has been shown to potentiate vecuronium, pancuronium, and suxamethonium in vitro (Fragan et al, 1983), but there is no evidence for any interaction clinically. In general, there appears to be a reduction in sensitivity of the postjunctional membrane to acetylcholine with most, if not all, intravenous agents. Torda and Gage (1977) performed micro-electrode studies, and demonstrated a reduction in the amplitude of endplate potentials, and it is possible that channel block might be involved (Bowman, 1985) even though channel block is usually seen only at higher drug concentrations. An increased release of acetylcholine has been described, although ketamine may conversely decrease acetylcholine release (Amaki et al, 1978). Finally, it must be remembered that a direct effect on skeletal muscle is possible.

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L O C A L ANALGESICS All of these agents are capable of producing neuromuscular block alone and also of potentiating muscle relaxants (Matsuo et al, 1978). The mechanism appears to involve both a decrease in responsiveness of the post-junctional membrane and a decrease in acetylcholine release (Matsuo et al, 1978). The local analgesics might also act through calcium inhibition or directly on the muscle contractile mechanism (Huan, 1981). Procaine inhibits plasma cholinesterase and so the action of any other drug which is broken down by plasma cholinesterase (suxamethonium and mivacurium) will therefore be prolonged, particularly in the presence of an atypical cholinesterase.

OPIOID ANALGESICS Opioid analgesics are commonly used during anaesthesia and often administered concurrently with muscle relaxants. Soteropoulos and Standaert (1973) demonstrated that morphine depressed both twitch tension and posttetanic facilitation. This was antagonized partly by naloxone, although naloxone alone had a similar qualitative effect to morphine. The likely mechanism is a reduction in acetylcholine release (Frederickson and Pinsky, 1971). However, McIndewar and Marshall (1981) were unable to demonstrate any interaction. In the rat diaphragm in vitro, pethidine augumented twitch height, but there was a slowly developing block at higher concentrations (Boros et al, 1984). These concentrations are considerably greater than are likely to be reached in general clinical use. Bell and Rees (1974) examined a series of opioid agonists and antagonists and showed that the order of potency among the series for neuromuscular effects did not correlate with the known order of potency for the opioid receptors, making it likely that the action at the neuromuscular junction is not mediated through opioid receptors.

DIURETICS This broad family of drugs includes osmotic diuretics (mannitol), carbonic anhydrase inhibitors (acetazolamide) and loop diuretics (frusemide). Frusemide potentiates a tubocurarine block (Miller et al, 1976), and will also accelerate recovery from a pancuronium block (Azar et al, 1980). In vitro studies with frusemide have shown a biphasic response with potentiation of both tubocurarine and suxamethonium at low concentrations and antagonism at higher concentrations (Sappaticci et al, 1982). Chlorthalidone, chlorothiazide and acetazolamide potentiate a neuromuscular block in animals, although there have been no reports of an effect in man with these agents or with mannitol (Miller et al, 1976). The mechanism of all of these actions is unknown.

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ANTIBIOTICS

Aminoglycosides Most interest has centred around the aminoglycoside antibiotics. Neomycin, streptomycin, dihydro-streptomycin, tobramycin, gentamicin, vancomycin and kanamycin can all produce neuromuscular block alone. They also potentiate tubocurarine, pancuronium, gallamine, suxamethonium and vecuronium (Burkett et al, 1979; Bmckner et al, 1980; Torda, 1980). The rapidity of onset and intensity of effect vary according to the dose absorbed and the route of administration, but enough can be absorbed from irrigation of the intrapleural space, peritoneal cavity or even a wound. Sufficient neomycin has also been absorbed by mouth to result in a measurable effect. It is interesting to note that netilmicin has been reported to be devoid of any neuromuscular action (Bendtsen et al, 1983.) The mechanism of action of the aminoglycoside antibiotics on a neuromuscular block is unclear. Similarities exist between the effect of the aminoglycosides and that of magnesium (L'Hommedieu et al, 1983). Neomycin, streptomycin and gentamicin reduce acetylcholine output (Torda, 1980; Singh et al, 1982; Fiekers, 1983a) and also reduce postjunctional endplate sensitivity (Singh et al, 1982; Fiekers, 1983b). Streptomycin has also been reported to possess a local analgesic-like effect on nerves and also possibly to affect muscle contraction. It is likely that there is both a pre-junctional and a post-junctional mechanism, the proportion differing depending upon the muscle and the drug. The block produced by the aminoglycoside antibiotics is not antagonized by anticholinesterases although it is partly antagonized by calcium and 4-aminopyridine (Sobek, 1982).

Polymyxins and colistin These antibiotics potentiate muscle relaxants (Singh et al, 1982). The combination of polymyxin with neomycin has been shown to be especially potent (Lee and de Silva, 1979). The mechanism of action is not understood. A decrease in acetylcholine output and a decrease in receptor sensitivity have been proposed (Singh et al, 1982). This block may be difficult to antagonize. An anticholinesterase may make it worse, although limited antagonism may be produced by 4-aminopyridine (Lee et al, 1978).

Lincosamines Lincomycin and clindamycin will both potentiate a neuromuscular block (Singh et al, 1982; A1 Ahdal and Bevan, 1995), probably through a combination of pre-junctional and post-junctional actions (Tang and Schroeder, 1968). This block is also difficult to antagonize. Anticholinesterases either have a little effect or accentuate the block (Tang and Schroeder, 1968; Singh et al, 1982) whereas the administration of 4-aminopyridine will produce limited antagonism (Booij et al, 1978).

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Penicillins, cephalosporins, metronidazole and erythromycin One report has suggested that metronidazole may weakly potentiate a vecuronium block (McIndewar and Marshall, 1981). It is likely that these drugs have no measurable effects on a neuromuscular block.

Tetracyelines Weak potentiation has been reported (Singh et al, 1982) which is of no clinical significance.

Chloramphenicol Chloramphenicol may have an effect on acetylcholine-operated ion channels (Henderson et al, 1986) although any clinical significance is unlikely.

ANTICONVULSANTS Resistance is seen in many patients receiving long-term treatment with phenytoin (Ornstein et al, 1987; Hickey et al, 1988). There is an increase in relaxant requirements to achieve a given degree of block, an increase in the infusion rate required to maintain a steady-state block and reduction in the duration of action of a bolus dose. This interaction has also been observed with carbamazepine (Alloul et al, 1996) and sodium valproate (Blanc-Bimar et al, 1979). When phenytoin was administered acutely to a patient with a steady-state neuromuscular block, however, potentiation of the block occurred (Gray et al, 1989), an effect unlikely to be of clinical significance. The mechanism underlying these interactions is not known. An increased binding of metocurine to plasma proteins has been demonstrated in the presence of phenytoin, and phenytoin therapy has been reported to exacerbate pre-existing myasthenia gravis (Kornfeld, 1976). Phenytoin and carbamazepine have both been shown to decrease acetylcholine release (Alderdice and Trommer, 1980). Carbamezepine, phenobarbitone and ethosuximide all decrease the sensitivity of the post-junctional membrane to acetylcholine (Alderdice and Trommer, 1980).

ADRENERGIC AGONISTS AND ANTAGONISTS The centrally acting o~-agonists clonidine and dexmedetomidine have no effect on a vecuronium block (Takahashi and Nishikawa, 1995; Weinger et al, 1995). The c~l-agonists and antagonists have been studied very little but appear also to be devoid of effect. However, salbutamol has been shown to potentiate both pancuronium and vecuronium (Salib and Donati, 1993).

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Beta-blocking agents potentiate neuromuscular block both clinically (Rozen and Whan, 1972) and in vitro (Bowman and Nott, 1969) and also exacerbate the symptoms of myasthenia gravis (Hughes and Zacharias, 1976). It nevertheless seems unlikely that beta-blockers have any significant effects in normal clinical practice, although the duration of action of suxamethonium may be prolonged by an inhibition of plasma cholinesterase.

CALCIUM ANTAGONISTS Verapamil and nifedipine potentiate a non-depolarizing neuromuscular block in vitro and in vivo (Anderson and Marshall, 1985). Verapamil has been reported to increase weakness in a patient with Duchenne's muscular dystrophy (Zalman et al, 1983). Nicardipine decreases the requirements of vecuronium in the anaesthetized patient (Kawabata et al, 1994). The mechanism of action of the calcium antagonists on a neuromuscular block remains to be elucidated. Verapamil possesses a local analgesic-like effect and blocks ion channels at the neuromuscular junction. There is also a direct effect on skeletal muscle (Anderson and Marshall, 1985).

GANGLIONIC BLOCKERS The ganglionic blocking agents hexamethonium, pentolinium and trimetaphan have a neuromuscular blocking action alone in vitro (Pollard, 1991). They also prolong the action of the non-depolarizing neuromuscular blocking agents (Deacock and Hargrove, 1962; Pollard, 1991). A suxamethonium block is extended by trimetaphan in vivo due to the reduction in the rate of breakdown of suxamethonium (Poulton et al, 1979). The mechanism underlying the interaction between the neuromuscular blocking agents and the ganglion blocking agents is not clear. The prejunctional cholinergic receptors on the neuromuscular junction may resemble those nicotinic cholinergic receptors on autonomic ganglia more than they do the post-junctional cholinergic receptors (Bowman, 1980). Perhaps, therefore, ganglionic blocking agents reinforce the action of a muscle relaxant by additionally blocking pre-junctional receptors--in which case the addition of a pre-junctional action from a ganglionic blocking agent should potentiate a pancuronium block (principally postjunctional) more than a tubocurarine block (both pre-junctional and postjunctional). This has not been borne out experimentally (Pollard, 1991). In addition, antagonism of the neuromuscular blocking agent is seen with lower concentrations of ganglionic blocker (Pollard, 1991) followed by potentiation at higher concentrations. It is likely that this observation is due to a dynamic interaction between two antagonists with different affinities (Ginsborg and Stephenson, 1974).

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ANTI-ARRHYTHMIC AGENTS The anti-arrhythmic agents include beta-blockers, calcium channel blockers, phenytoin, lignocaine, disopyramide, bretylium, quinidine and proeainamide. Quinidine and procainamide potentiate both a depolarizing and nondepolarizing neuromuscular block (Harrah et al, 1970). The mechanism is not known, but it seems likely that both a pre-junctional and a postjunctional action are involved. Both quinidine and procainamide have also been reported to precipitate a myasthenic episode in susceptible patients (Kornfeld et al, 1976). Disopyramide potentiates a non-depolarizing neuromuscular block in vitro (Healy et al, 1981), although no clinical effect has been reported. The same is true for bretylium (Welch and Waud, 1982). STEROIDS The steroids comprise a large family with a common central structure and a wide variety of pharmacological actions. A tubocurarine neuromuscular block was antagonized by low concentrations of dexamethasone, but potentiated at higher concentrations (Leeuwin et al, 1981). Antagonism has been shown between corticosteroids and muscle relaxants (van Wilgenberg, 1979), and resistance to vecuronium reported in a patient receiving longterm testosterone therapy (Reddy et al, 1989). The mechanism is not known. An increase in acetylcholine release (Leeuwin et al, 1981), depression of excitability of the post-junctional membrane (van Wilgenberg, 1979), inhibition of phosphodiesterase (Liu, 1984), increase in prejunctional choline uptake (Leeuwin and Valdsema-Currie, 1980) and inhibition of cholinesterase are all possible. The interaction is unlikely to be of clinical importance. IMMUNOSUPPRESSANTS Cyclosporin potentiates atracurium and vecuronium. Azathioprine was shown to antagonize both a tubocurarine and a pancuronium neuromuscular block by Dretchen et al (1976), although Glidden et al (1988) failed to confirm this interaction. These drugs may also prolong the action of suxamethonium, probably through inhibition of plasma cholinesterase. PHOSPHODIESTERASE INHIBITORS Aminophylline antagonizes a pancuronium block. Theophylline, caffeine and certain other xanthines facilitate neuromuscular transmission in vitro, an action which might result in a reduction of the expected effect of a neuromuscular blocking agent. The mechanism may be related to changes in cyclic AMP levels, although Kramer and Wells (1980) were unable to demonstrate a relationship between inhibition of phosphodiesterase and the

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increase in muscular contraction in vitro. Adenosine depresses neuromuscular transmission, an effect which is counteracted by aminophylline. Theophylline is a potent antagonist at adenosine receptors in concentrations lower than those at which it inhibits phosphodiesterase. It is possible therefore that the effects of phosphodiesterase inhibitors on neuromuscular transmission are mediated through adenosine receptors. MISCELLANEOUS DRUGS

Penicillamine No reports exist of any interaction between penicillamine and muscle relaxants although it has been reported to precipitate a myasthenic episode (Russell and Lindstrom, 1978).

Phenothiazines An increase in weakness in a myasthenic patient has been reported with chlorpromazine therapy although no direct effect on neuromuscular block has been described.

Ecothiopate Ecothiopate eye drops are used in the management of glaucoma. Sufficient may be absorbed for a parenteral effect to be seen, due to inhibition of plasma cholinesterase. The duration of action of suxamethonium is prolonged (Donati and Bevan, 1981) and it is possible that mivacurium may be similarly affected.

Hypotensive agents Neither glyceryl trinitrate nor sodium nitroprusside have an effect on a neuromuscular block. A C I D - B A S E BALANCE Changes in acid-base balance are common during anaesthesia or intensive care management. It is common practice deliberately to induce an acute respiratory alkalosis during anaesthesia. At the termination of surgery, residual narcosis may result in hypoventilation with a sudden change to an acute respiratory acidosis. An acid-base disturbance may already exist due to a pre-existing medical condition upon which these acute changes will be superimposed. It is clearly important therefore to consider whether or not the action of a neuromuscular blocking agent is affected by changes in acid-base balance although the pH in the arterial blood may not exactly reflect that in the muscle or at the neuromuscular junction.

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A tubocurarine block has been demonstrated to be potentiated-by acidosis. The implication is that hypoventilation and hence acute respiratory acidosis in the early post-operative period may give rise to difficulties in reversal, or even to re-appearance of a block (Miller et al, 1975). Not all of the neuromuscular blocking agents are similarly affected, however, Pancuronium or vecuronium appear to be affected little by changes in acid-base status, although neostigmine induced antagonism of a pancuronium block was impaired by a co-existent acidosis (Miller and Roderick, 1978). The effect of CO2-induced acid-base changes has been reexamined more recently (Aziz et al, 1994). Acidosis was shown to increase the potency of rocuronium, vecuronium and tubocurarine (monoquaternary drugs) but to have no effect on pancuronium, pipecuronium or metocurine (bisquaternary drugs). The situation is therefore still unclear. POTASSIUM Changes in the extracellular potassium concentration affect the excitability of cells. An increase in extracellular potassium concentration leads to an increase in acetylcholine release and a decrease in the sensitivity to tubocurarine or pancuronium (Waud and Waud, 1980) within the range encountered clinically (an increase in potassium from 3.5 to 5.0 mMol/1 increased the requirement by approximately one-third). Conversely, a decrease in plasma potassium concentration leads to a reduced requirement for non-depolarizing relaxants. The amount of neostigmine required for reversal is higher (Miller and Roderick, 1978; Waud et al, 1982) and the risk of recurarization increased in hypokalaemia. LITHIUM Lithium potentiates tubocurarine, pancuronium and suxamethonium (Hill et al, 1977) and may produce muscular weakness when given alone in the absence of a neuromuscular blocking agent. The mechanism probably involves a decrease in acetylcholine release. CALCIUM The release and mobilization of chemical transmitters and messengers and also excitation contraction coupling are all dependent upon calcium ions. Some of the actions of calcium oppose one another and it may be difficult to predict the exact result. There is potentiation of pancuronium or tubocurarine by an increase in calcium concentration in vitro (Waud and Waud, 1980). However, a clinical report which described anaesthesia in a patient with a raised serum calcium secondary to hyperpathyroidism showed the duration of action of suxamethonium to be prolonged but that of atracurium to be decreased.

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The mechanisms are unclear. An increase in calcium concentration will produce an increase in acetylcholine release. Calcium has also been reported to decrease the sensitivity of the post-junctional membrane (Waud and Waud, 1980) and also to enhance excitation contraction coupling. An increase in calcium concentration may be expected partly to antagonize a non-depolarizing neuromuscular block; it may also help to antagonize a block which is due partly to antibiotics.

MAGNESIUM Magnesium opposes calcium at the neuromuscular junction and it potentiates neuromuscular blocking agents (Ghoneim and Long, 1970; Skaredoff et al, 1982; Fuchs-Buder et al, 1995). The interaction is of clinical importance because magnesium is routinely used in pre-eclampsia for the management of arrythmias, and also during open heart surgery. Hypomagnesaemia may be seen in patients with malnutrition and also in patients on the critical care unit. The mechanism by which magnesium affects neuromuscular transmission is in many respects related to an opposing effect on calcium (Ghoneim and Long, 1970). There is a reduction in acetylcholine release and it is likely that the main effect is pre-junctional. A number of other divalent cations exist which behave in a manner very similar to that of magnesium. These cations include manganese, beryllium, lead and cadmium (Forshaw, 1977; Schopp, 1978).

COMBINATIONS OF N O N - D E P O L A R I Z I N G AGENTS If two drugs act in exactly the same way on the same receptor system then, when they are given simultaneously, their effects would be additive. This belief was supported by Riker and Wescoe who, in 1951, examined combinations of two neuromuscular blocking agents in cats. They showed that the effect of consecutive doses of either gallamine or tubocurarine had the same effect whether the second dose followed the same agent, or the other agent. The implication was that their effects were additive. Wong and Jones (1971) studied the same two agents, tubocurarine and gallamine. They reasoned that because they had significant and different cardiovascular side-effects, mixing the two would allow the use of less of each, thereby reducing dose-dependent side-effects. They were surprised that less was needed for relaxation than predicted and proceeded to examine the combination in the rabbit. They concluded that there existed 'a synergistic effect of tubocurarine and gallamine' (Wong and Jones, 1971). They also suggested that the reason for this observation might be that the two drugs acted in different ways at the neuromuscular junction. More extensive clinical studies confirmed the synergistic interaction between tubocurarine and gallamine and also reported a similar interaction between other relaxants.

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In the 1980s studies began to show that synergism existed with some combinations, but not with others. Interest was immediately revived and the number of studies examining combinations multiplied. Table 1 contains an overall summary and it is now clear that certain combinations are additive and others supra-additive. For a more detailed discussion the reader is referred to other texts (Pollard, 1991, 1994). There are many variables to be considered in the clinical situation; these include uptake, binding, metabolism, redistribution and regional blood flow patterns. The majority of those do not apply when using an in vitro preparation yet synergism is still seen, implying an action at the neuromuscular junction. The reasons for the interaction between the nondepolarizing neuromuscular blocking agents are, as yet, not clear. Possible mechanisms include differential actions upon the pre-junctional and post-junctional acetylcholine receptors; differential sensitivity of the two alpha subunit acetylcholine recognition sites; effects on cholinesterase. Pharmacokinetic effects outside the neuromuscular junction appear to be unlikely. What is interesting, however, is that drugs from the same family series (e.g. two steroids or two benzyliosquinoliniums) tend to be either additive or only very weakly supra-additive, whereas drugs from two different families tend to interact supra-additively (Table 1). SUXAMETHONIUM AND O T H E R RELAXANTS The depolarizing agent suxamethonium has the fastest onset of any of the muscle relaxants in present use. It is the drug of choice when the airway has to be secured without delay. It is not common practice to continue with the use of suxamethonium for longer procedures, but to administer subsequently a non-depolarizing relaxant to maintain paralysis. Suxamethonium before a non-depolarizing agent Although there is conflicting evidence, it is generally believed by most clinicians that a prior dose of suxamethonium allows the use of a smaller dose of non-depolarizing relaxant for continuation of the block. It is likely that this simply reflects the fact that a more dense block is required for intubation than for surgical relaxation. Precurarization before suxamethonium Suxamethonium has a number of unwanted and potentially hazardous sideeffects many of which seem to be related to the muscular fasciculations. If a small dose of a non-depolarizing relaxant is administered before suxamethonium, the fasciculations and also the adverse effects are lessened. This subparalysing dose of non-depolarizing agent (e.g. tubocuraine 3-5 mg, atracurium 3 rag) delays the onset of suxamethonium and shortens its duration of action. It is therefore common practice to increase the dose of suxamethonium slightly when following a small dose of

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non-depolarizing agent. It is likely that the mechanism behind the benefit of precurarization is a decrease in the side-effects of suxamethonium and the subsequent requirement for an increased dose of suxamethonium lies simply in the partial sub-clinical non-depolarizing block.

Suxamethonium after a non-depolarizing agent Towards the end of a surgical procedure the surgeon may notice the waning effect of a neuromuscular block. The block was adequate for surgery but a slightly deeper block is needed to facilitate closure of the surgical incision. Some anaesthetists advocate the administration of a small dose of suxamethonium at this time. The effect of this small dose of suxamethonium may, however, be quite unpredictable, depending upon the non-depolarizing agent in use, the exact degree of block present, the total dose administered and the dose of suxamethonium. No written guidelines are available, probably because they are impossible to construct. This technique is best avoided. The use of an additional dose of non-depolarizing agent, or even a different non-depolarizing agent, is more logical.

CONCLUSION There are an enormous number of references on the subject of drug interactions which involve muscle relaxants. As more drugs are released onto the market the number of potential and actual interactions is likely to increase still further. Interactions may be difficult to predict; some may be advantageous and some disadvantageous. If neuromuscular function is monitored every time a neuromuscular blocking agent is used, then much of the unpredictability is removed from the equation.

Acknowledgements Parts of this chapter have already been published in two other sources and are reproduced by kind permission of their respective publishers. The material is reproduced from Pollard (1994, Interactions involving muscle-relaxants, In Pollard BJ (ed.) Applied Neuromuscular Pharmacology, pp 202-248. Oxford: Oxford University Press) and Pollard (1995, Drug interactions, In Harper NJN and Pollard BJ (eds) Muscle Relaxants in Anaesthesia, pp 177-197. London: Edward Arnold).

REFERENCES AI Ahdal O & Bevan DR (1995) Clindamycin-induced neuromuscular blockade. Canadian Journal of Anaesthesia 42: 614-617. Alderdice MT & Trommer BA (1980) Differential effects of the anticonvulsants phenobarbital ethosuximide and carbamazepine on neuromuscular transmission. Journal of Pharmacology and Experimental Therapeutics 215: 92-96. Alloul K, Whalley DG, Shutway F et al (1996) Pharmacokinetic origin of carbamazepine-induced resistance to vecuronium neuromuscular blockade in anaesthetized patients. Anesthesiology 84: 330-339.

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