Current Anaesthesia & Critical Care (2003) 14, 38 ^ 46 c 0953-71 12/03/$ - see front matter  2003 Elsevier Science

Ltd. All rights reserved. doi:10.1016/S0953-71 12(03)00056 -5

PHARMACOLOGY

Muscle relaxants: past, present and future

C. Prior
Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK

KEYWORDS Neuromuscular nondepolarizing agents, Neuromuscular junction, Acetylcholine, Nicotinic

Summary Muscle relaxants are an irreplaceable item within the modern surgical toolkit.Their almost universal use during surgical procedures of medium-to-long duration means that it is essential that all anaesthetists must have a comprehensive knowledge of their history and the future prospects for their continued evolution. In the context of identifying theideal muscle relaxant, this review focuses on those areas of muscle relaxant action that are either highly desirable or highly undesirableFand discusses the extent to which any identied problems have, or have not, been overcome with the existing range of clinically available muscle relaxant compounds. Pharmacodynamic topics covered include the actions of muscle relaxants on the range of dierent subtypes of nicotinic acetylcholine receptors, the actions of muscle relaxants on motor nerve terminals and the major non-neuromuscular actions of muscle relaxants. From a pharmacokinetic perspective, how the pharmacological and chemical properties of muscle relaxants inuence the clinical properties and uses of the compounds are discussed.
 2003 Elsevier Science Ltd All rights reserved. c

INTRODUCTION
Muscle relaxants selectively depress skeletal muscle function, producing a paralysis of normal motor activity. They are primarily used to prevent movement during surgical procedures, although they also have an important role in the intensive care unit (ICU) where they are used to paralyse patients requiring mechanical ventilation. Many agents produce skeletal muscle paralysis including high doses of general anaesthetics, centrally acting agents such as the benzodiazepines that depress motor cortex outow, local anaesthetics that inhibit action potential conduction in motor axons and compounds such as dantrolene sodium that inhibits Ca2+ mobilization within skeletal muscle bres. However, none of these produces the total and selective paralysis required for surgical procedures. From a practical perspective, clinical muscle relaxants block acetylcholine (ACh) mediated transmission at the neuromuscular junction. They do this by virtue of an action on the nicotinic acetylcholine receptors (nAChRs) located on the motor endplate. Depolarizing muscle relaxants such as suxaCorrespondence to: CP.Tel: +44(0)141548 2459; Fax: +44 (0) 141552 2562; E-mail: c.b.prior@strath.ac.uk

methonium are agonists at nAChRs. They produce neuromuscular block since over-stimulation of the nAChRs leads to the skeletal muscle membrane surrounding the motor endplate becoming inexcitable. Non-depolarizing muscle relaxants (Fig. 1) are antagonists of the action of ACh on motor endplate nAChRs and, as such, can prevent signal conduction and produce neuromuscular block. Along with the introduction of antimicrobial drugs and aseptic techniques, the development of safe and effective muscle relaxant drugs ranks as one of the most signicant advances in surgical procedures in the 20th century. Any anaesthetic agent, given in a suciently high dose, will produce skeletal muscle paralysis, but this carries with it the serious risk of adverse cardiovascular and respiratory depression. Being able to produce skeletal muscle paralysis independent of a depressant eect on CNS function means that lower, and safer, doses of the general anaesthetic can be employed.Thus, muscle relaxants will always remain a very important part of any surgical drug regime and an awareness of the current developments in the eld of muscle relaxants is important to surgeons and anaesthetists throughout the world. This review will present an overview of our current understanding of the pharmacodynamic and

MUSCLE RELAXANTS: PAST,PRESENTAND FUTURE

39

R4 N+ R1 N R2 O R3 N H3C

O C O N+ CH2 CH2

Pancuronium Vecuronium R1 R2 R3 R4 CH3 CH3 OC(O)CH3 OC(O)CH3

H3CO N+ H3CO CH2 CH3 O

Rapacuronium --CH2CHCH 2 OC(O)CH3 OC(O)CH2CH3

HO

CH2

--CH3 OC(O)CH3 OC(O)CH3

Rocuronium

OCH3 O O (CH2)5 O CH3 N+ OCH3 CH2 H3CO H3CO OCH3

CH2 CH2 C

C CH2 CH2

Tubocurarine

Atracurium
OCH3

OCH3

N+ HO O H

CH3 CH3

H3CO N+ H3CO CH2 CH3 (CH2)3 O O C (CH2)2 CH CH (CH2)2 O C O CH3 (CH2)3 CH2 N+

OCH3 H H3C H3C OCH3 H3CO OCH3 OCH3 N+ HO O

OCH3

Mivacurium
H3CO OCH3 OCH3

Figure 1 Chemical structures of the main non-depolarizing muscle relaxants that are, or have been, used in clinical practice. T main groupings of compounds exist.Those based on an aminosteroid nucleus (top panels) and those based on benzoisoquinoline wo moieties (lower panels).

pharmacokinetic actions of non-depolarizing muscle relaxants and how these relate to their clinical proles. Such a review will, inevitably, be fairly general, but it is hoped that sucient leads will be provided to allow the interested reader to explore further into what is still, even in the modern age of genomics and proteomics, a complex and sometimes poorly understood area of medicine.

PHARMACOLOGICAL ACTIONOF MUSCLE RELAXANTS

Actions of muscle relaxants on nAChRs
To appreciate the pharmacological actions of nondepolarizing muscle relaxants, it is necessary to be familiar with the structure and function of nAChRs. As long ago as 1950, it was recognized that nAChRs are heterogeneous, and that subtypes can be pharmacologically

identied.The earliest, and probably most important division of nAChRs into subtypes was the recognition of C6 and C10 receptors.1 C6 -receptors were characterized in the autonomic ganglia of the cat superior cervical ganglia, were blocked by hexamethonium (hence the name) and are often now referred to as the neuronaltype of nAChR. C10 -receptors were characterized as the postjunctional nicotinic ACh receptor at the neuromuscular junction, were blocked (depolarizing) preferentially by decamethonium (hence C10) and are often now referred to as the muscle-type of nAChR. Modern molecular genetics has taken our understanding of the subtypes of nAChRs considerably further.2 Gene products for at least 17 dierent peptide subunits of the nAChR have now been identied (10 dierent a-subunits, four dierent b-subunits, one g-subunit, one d-subunit and one e-subunit). All nAChR are ligand-gated nonselective transmembrane cation channels assembled from ve of these subunits (Fig. 2). Muscle-type nAChRs are composed of two x a1-subunits along with one each

40

CURRENT ANAESTHESIA & CRITICAL CARE

Figure 2 Molecular composition of nAChRs: (A) Cross-sectional view from the side showing the goblet-shaped structure of the transmembrane assembly (B) View from top showing the arrangement of the ve subunits around the central ion channel pore (top, . muscle-type nAChR; centre, heteromeric neuronal-type nAChR; bottom, homomeric neuronal-type nAChR).The two ACh binding sites are atthe interface of the a-subunits and their neighbouring subunit.The homomeric neuronal-type nAChR is proposed to have ve ACh binding sites. However, in common with all other subtypes of nAChRs, it is thought to open when ACh is bound to just two non-adjacent sites.

of the b1 and d-subunits and either an e-subunit (fetal receptors) or a g-subunit (adult receptors). Neuronaltype nAChRs are composed of either two a-subunits and three b-subunits (heteromeric neuronal-type receptors) or, in the case of the a7 a8, a9 and a10 subunits can , be composed of ve identical subunits (homomeric neuronal-type receptors). The exact combination of the different subunits in the heteromeric neuronal-type of nAChRs is unknown and probably variedFgiving rise to further multiple subtypes of neuronal-type nAChRs. In addition to the various subtypes of nAChRs diering with respect to their pharmacological specicity, they also show some functional variability. Although the subtypes of nAChRs are all referred to as non-selective cation channels in that they all show approximately equal permeabilities to sodium and potassium ions, there is a greater variability in the selectivity of the subtypes of the receptors for Ca2+ and this is believed to be of functional signicance in certain circumstances. The molecular biology revolution has provided new tools for the investigation of drug action. Perhaps the most widely used of these is the ability to express receptors in cultured cell lines to allow a detailed analysis of fundamental drug ^ receptor interactions. Several research groups have exploited gene expression techniques to investigate the interactions of muscle relaxants with subtypes of nAChRs.These studies have given much useful information on how muscle relaxants interact with nAChRs at the molecular level, including measures of absolute antagonistic potencies,3 identication of receptor binding determinants4 and how multiple drug combina-

tions aect drug ^ receptor interactions.5 In terms of the drug discovery process, an obvious advantage of expression systems is that one can rapidly (and cheaply) identify drug candidates that have both high potency and high receptor subtype specicity. However, a disadvantage is that even having identied a potential candidate, knowing how the compound does, or does not, interact with the various subtypes of nAChRs gives limited information about its clinical prole since much of this will be governed by unexplored pharmacokinetic factors. Nevertheless, expression systems may help to predict the occurrence of certain well-characterized adverse side-eects. Clinically, one would expect the cleanest prole for a muscle relaxant to be achieved by it having a very high selectivity for the muscle-type nAChR at the neuromuscular junction, without any inhibitory eect on any of the neuronal-type subtypes of nAChRs. Some agents, such as tubocurarine are poorly selective for the muscle type nAChR, also showing considerable potency at neuronaltype nAChRs. Others, such as vecuronium show a very marked selectivity for the muscle type of receptors. The actual clinical consequences of a lack of receptor subtype selectivity are, in reality, dicult to quantify. All nAChR antagonists are mono- or bisquaternary ammonium compounds and, as such, are highly charged molecules at physiological pH. This means that, under normal circumstances, they cannot cross the blood^ brain barrier and interact with nAChRs in the brain. Therefore, the incidence of side-eects due to an action in the brain is practically non-existent, even for

MUSCLE RELAXANTS: PAST,PRESENTAND FUTURE

41

compounds such as tubocurarine. The only area of susceptibility for the block of neuronal-type nAChRs is in autonomic gangliaFthat lie outside the blood^ brain barrier. Block of neuronal-type nAChRs in autonomic ganglia by compounds such as hexamethonium and trimetaphan does cause marked hypotension. However, the only muscle relaxant to produce hypotension as one of its more serious side-eects is tubocurarine and, despite its potency at neuronal-type nAChRs, this eect is more likely to be due to histamine release than ganglion block, since it is abolished by antihistamine agents.6

Actions of muscle relaxants on motor nerve terminals

Within a few years of the introduction of muscle relaxants into surgical practice it was already being suggested that they might have an eect on motor nerve terminals in addition to their postjunctional actions. At high frequencies of nerve stimulation, it was observed that antagonists of muscle-type nAChRs, even at low concentrations, could produce a waning of tetanic tension (Fig. 3). This tetanic fade was attributed to a combined eect of the compounds to both reduce postjunctional sensitivity to ACh and to modulate the release of ACh from the motor nerve terminals. Many studies have attempted to determine the nature of the prejunctional eects of muscle relaxants during tetanic stimulation and, although there is now widespread acceptance that muscle relaxants do modulate ACh release, the cellular mechanisms responsible are still, even today, the subjects of much controversy. An understanding of these processes is of particular importance in the eld of anaesthesia where the presence of either tetanic or train-of-four fade during postoperative recovery is routinely used as an indication of the level of residual neuromuscular block still present. Given that tetanic and train-of-four fade have been observed with all experimental and clinically evaluated muscle relaxants, the most obvious candidate for a preCONTROL

junctional site of action of muscle relaxants is a nicotinic ACh autoreceptor situated on the motor nerve terminal. It is true that certain muscle relaxants are known to have pharmacological actions aside from their eects on nAChRs that could manifest themselves as a prejunctional eect. Examples are the ability of tubocurarine to block potassium channels7 or the ability of pancuronium to block certain subtypes of muscarinic ACh receptors.8,9 However, such actions tend to be idiosyncratic and it is hard to imagine that all muscle relaxants would possess at least one action to aect nerve terminal function that was unrelated to their ability to inhibit the action of ACh on postjunctional nAChRs. Based on their location on axon terminals, and the ability of muscle relaxants such as tubocurarine to block ganglionic responses,10 most researchers have assumed that the prejunctional autoreceptors are neuronal-type nAChRs and that low specicity of muscle relaxants for the postjunctional muscle-type nAChRs accounts for their prejunctional eects.11,12 However, one aw with this assumption, not resolved in early studies, is that all muscle relaxants, including those such as vecuronium that possess negligible pharmacological activity ganglia13 and in the CNS,14 produce tetanic fade. Not only is there uncertainty surrounding the nature of the prejunctional nAChR, there is also a disagreement as to the eects mediated through the receptors.On one hand, it has been argued that the prejunctional nAChRs are autofacilitatory receptors that normally serve to enhance the mobilization of ACh for release during periods of sustained secretory activity.12 Blocking this autofacilitatory eect with a muscle relaxant depresses ACh release and hence enhances neuromuscular block during high-frequency nerve stimulation. Alternatively, it has been suggested that the prejunctional nAChRs are autoinhibitory and normally ACh acts at these receptors to depress its own release during periods of low secretory activity.11 Muscle relaxants, by blocking these receptors would enhance the release of ACh at low frequencies of stimulation, leading to an exaggerated frequencydependent depression in ACh release and this, coupled
2 M -CONOTOXIN GI

0.1 Hz

2 Hz

50 Hz

0.1 Hz

2 Hz

50 Hz

Figure 3 Representative examples of the train-of-four and tetanic fade produced by the naturally occurring antagonist of muscletype nAChRs, a-conotoxin GI. Tension traces in the absence (left) and presence (right) of 2 mMa-conotoxin were recorded from an isolated piece of rat hemi-diaphragm skeletal muscle stimulated indirectly (via its phrenic nerve) at 0.1, 2 Hz for 2 s and 50 Hz for 2 s. Calibrations bars: vertical, 2 g in all trace except the control 50 Hz tetanus where it is10 g; horizontal, 300 s for 0.1Hz traces, 5 s for 2 and 50 Hz traces.

42

CURRENT ANAESTHESIA & CRITICAL CARE

Muscle-type nAChR

Neuronal-type nAChR

Motor nerve terminal (+) ACh (-)

Motor endplate of skeletal muscle fibre

Figure 4 Model of putative nicotinic ACh autoreceptor regulation of ACh release from motor nerve terminals.

with the normal postjunctional blocking action of the compounds underlies their ability to produce tetanic and train-of-four fade. Within the last 5 years, extensive analysis of the prejunctional eects of a range of subtype selective nAChR agonists and antagonists has led to a model of autoreceptor regulation at the mammalian neuromuscular junction that reconciles many previous apparently conicting studies (Fig. 4). It has been proposed that there are both neuronal-type (inhibitory) and muscle-type (facilitatory) nicotinic ACh autoreceptors on motor nerve terminals that serve to regulate the supply of ACh for release at low and high frequencies of stimulation, respectively.15,16 How would ACh, acting through two dierent subtypes of prejunctional nAChRs, both presumably mediating an increase in cation permeability, produce both a facilitatory and an inhibitory eect on ACh release? The answer to this is largely unknown but it is likely that it might involve dierences in the distribution of the two classes of nAChR around the nerve terminal and also dierences in the functional ion selectivity of the two classes of nAChR, possibly with respect to their permeability to Ca2+.

GI tract or the CNS (the latter presumably due to a lack of access). However, the most important sites at which muscle relaxants can (and do) interact with mAChRs are the sino-atrial node of the heart and the lungs. An antagonistic action at pre- and postsynaptic M-2 receptors in the heart leads to vagal-block, which is characterized by tachycardia, some hypertension and/or a marked attenuation of the bradycardial response to vagal nerve stimulation. In agreement with their relative M-2 receptor potencies,8,9 vagal-block is most prominent with gallamine and the aminosteroid muscle relaxants such as pancuronium and rocuronium, being less marked with either the monoquaternary aminosteroids (e.g. vecuronium) or the benzoisoquinolines (e.g. atracurium, mivacurium).The relatively predictable vagolytic actions of compounds such as pancuronium and rocuronium are not usually seen as problematical and are even thought by some to be a good counter to the cardiodepressant eect of most general anaesthetics. In addition to an eect on M-2 receptors in the heart some muscle relaxants are thought, at clinical doses, to block postjunctional M-3 and prejunctional M-2 receptors at the parasympathetic (vagal) neuroeector junctions in the lungs. The former would inhibit ACh-induced bronchoconstriction whilst the latter, by blocking a negativefeedback eect of ACh on vagal nerve terminals, would increase bronchoconstriction. Thus, any clinical eect of muscle relaxants on airway calibre is dicult to predict, being critically dependent on the relative mix of pharmacological actions. However, the M-2 receptor blockingeect has been mooted as the mechanism for the severe bronchospasm that can be seen with rapacuronium under certain conditions.17

Non-cholinergic actions of muscle relaxants

Probably, the most serious side-eect of muscle relaxants not associated with cholinergic systems is the ability of the benzoisoquinolinium-based compounds (e.g. tubocurarine, atracurium and mivacurium) to trigger mast cell degranulation and hence histamine release.18 This can result in skin ushing, bronchospasm, tachycardia and a transient fall in blood pressure. The hypotension seen as a side-eect of tubocurarine is due to this eect and not due to ganglion block since it is attenuated by antihistamine drugs such as promethazine.6 The histamine-releasing problems associated with atracurium have been resolved through the development of cisatracurium. Atracurium has four chiral centres and the synthetic process by which the compound is produced results in a mixture of 10 dierent optical enantiomers. Each of these enantiomers has a dierent pharmacology. Cisatracurium (Nimbex, 51W89) is one of the active enantiomers comprising around 15% of the total. On its own, cisatracurium is a more potent muscle relaxant that atracurium (approximately four-fold) with a slightly longer duration

NON-NEUROMUSCULAR ACTIONS OF MUSCLE RELAXANTS

Anti-muscarinic actions of muscle relaxants
The ability of muscle relaxants to interact with nAChRs has been discussed in detail above. However, ACh also acts at muscarinic ACh receptors (mAChRs) and therefore it is not surprising that some muscle relaxants also have some antimuscarinic actions, particularly at the M2 and M-3 subtypes of mAChRs. Clinically, little action is seen that is attributable to inhibition of mAChRs in the

MUSCLE RELAXANTS: PAST,PRESENTAND FUTURE

43

of action. However, unlike the raw isomeric mix of atracurium, cisatracurium is devoid of histamine release properties19 and so does not produce any hypotension. When compared to atracurium, the only major problem associated with cisatracurium is pharmacoeconomic. Production of a single optical enantiomer requires either a complex stereospecic synthetic pathway or alternatively an eective enantiomer separation technique, both of which will potentially increase the production cost.

300 Vecuronium Onset time (s) Rocuronium 200 Rapacuronium (1.5) 100 Mivacurium 0 0.01 Rapacuronium (2.5)

0.10

1.00

10.00

Dose (mg/kg)

KINETICS OF MUSCLE RELAXANT ACTION

Onset of action
A clean, side-eect free, action is an important prerequisite for any muscle relaxant. However, it is not the only factor that inuences clinical success. Of equal importance is the time course of action of the agent. The nature of their use requires that muscle relaxants have a predictable time course of action and that, within the group of available compounds, the entire range of required clinical durations is covered. One particular area that has been the focus of much research over the last 20 years has been the development of muscle relaxants with a short onset and short duration of action that can be safely used for rapid-sequence intubation. Currently, the most widely used agent for this purpose is the depolarizing muscle relaxant suxamethonium, which produces a rapid onset (around 1min) and short-lived (2^ 6 min) neuromuscular block. However, the agonistbased mechanism of action of suxamethonium creates a number of potential problems including damaging muscle fasciculations, excessive stimulation of mAChRs and an inability to intentionally reverse the neuromuscular block should any problems arise. For this reason, for many individuals the development of a rapid onset nondepolarizing muscle relaxant that can successfully compete with, and even replace suxamethonium has long been the life-fullling goal of their endeavours. In order to develop a clinically acceptable nondepolarizing muscle relaxant with a rapid onset and short duration of action, it is necessary to have some idea as to what pharmacodynamic and pharmacokinetic factors can inuence the time course of action of a muscle relaxant. There is little doubt that one important pharmacodynamic factor that inuences the onset of action of muscle relaxants is the potency of the compound. It has been shown that molar potency is inversely related to speed of onset for a range of muscle relaxants of very dierent clinical durations20,21 (see also Fig. 5). The only exception to this general rule appears to be atracurium, possibly because it is an enantiomeric mixture of several active compounds of markedly diering neuromuscular

Figure 5 Graphical representation of the relationship between clinical potency and onset time for a group of four dierent muscle relaxants. Plotted points are mean and SD and data is fromTable1of ref. 36.Each relaxant has been used at an approximately equi-eective neuromuscular blocking dose. Despite this, note the nearly seven-fold range of onsettimes.

blocking potencies.22 There are two unfortunate consequence of any relationship between potency and onset. The rst is pharmacoeconomic in that any developmental strategy that deliberately focuses on the search for a low potency drug in the hope of nding something with a fast onset will inevitably result in a product with relatively higher manufacture (and therefore market) cost. The second issue is pharmacological. As the potency of the muscle relaxant at the neuromuscular junction goes down, the incidence of untoward side-eects at clinically eective doses will increase. Rapacuronium is an aminosteroid muscle relaxant that is 15^20 times less potent than vecuronium, requiring around 2 mg kg-1 for skeletal muscle paralysis in human. In terms of its onset, it can produce maximum neuromuscular block in around 60 s, comparable with suxamethonium and suggesting that the goal of a non-depolarizing alternative to suxamethonium might be achievable.23,24 However, a number of clinical studies have shown that rapacuronium can produce a dose-related increase in airway pressure25 and even, in children, severe bronchspasm,26 probably because of a block of M-2 mAChRs in the lungs17 (see above).This has led to serious concern as to its widespread introduction. If the goal of a fast onset neuromuscular block is not to be found in the development of new nAChR antagonists with optimized pharmacodynamic proles then what other pharmacokinetic strategies might exist to help achieve the desired end-point using existing medium-duration muscle relaxants. Firstly, using a supra-maximal dose of muscle relaxant is one means to accelerate its onset of action. Thus, a bolus injection of rocuronium at twice its ED95 for neuromuscular block will produce paralysis within 60 ^120 s and can be used for rapid-sequence intubation.27 An obvious drawback with this high-dose approach is an increased subsequent duration of action of the muscle relaxant and an increased risk of dose-related adverse side-eects. Two other possibilities include the use of cocktails and

44

CURRENT ANAESTHESIA & CRITICAL CARE particular age.32 Thus, it is very dicult to predict the exact outcome of any particular regime in a patient. These problems mean that it is unlikely that priming will ever become widely established as a means to facilitate rapid-sequence intubation with medium-duration muscle relaxants.

priming doses. Many clinicians have experimented with combinations of two or more muscle relaxants based on the notion of a supra-additive (e.g. synergistic) action of the mixture. Clinical evidence28 ^31 does support the existence of synergism with certain drug combinations particularly where an aminosteroid relaxant (e.g. vecuronium, rocuronium) is combined with a benzoisoquinolinium relaxant (e.g. cisatracurium, mivacurium). However, this is likely to be a result of pharmacokinetic interactions rather than pharmacodynamic interactions at the level of the postjunctional nAChRs since isolated receptor studies have mostly failed to demonstrate any eect other than a simple additive action.5 In priming, pretreatment of a patient with a small (typically 10% of ED95 dose) subparalytic dose of a muscle relaxant shortly before paralysis is required allows full muscle relaxation to be achieved rapidly with the remainder of the intubating dose. The priming principle has been widely attempted with many dierent muscle relaxants, with variable reported success. However, it is generally accepted that the benecial eects of the approach are small and the potential for untoward problems great. In particular, the large variability in patient response to the priming dose often means that even at 10% of the ED95, an unacceptable percentage of patients may develop clinical weakness from the priming dose alone.31 Also the eectiveness and safety of priming is critically dependent on the drug used, the exact regime used (i.e. percentage priming dose and time between priming dose and main dose) and the patient status; in

Reversal of action
Any prolonged period of postoperative muscle paralysis is associated with costly patient monitoring (because of the need for continued ventilatory support) and an increased risk of adverse complications such as hypostatic pneumonia. Therefore, considerable importance is placed on the ability to rapidly terminate the action of muscle relaxants at the conclusion of the surgical procedure. Several dierent approaches have been taken to developing muscle relaxant regimes that can be rapidly terminated (Fig. 6). One of these is the development of compounds with an inherent molecular instability that are rapidly degraded (either spontaneously or through enzymatic action) once injected into the body. Perhaps the best example of how degradation can inuence the time course of action of a muscle relaxant comes not from the competitive (non-depolarizing) class of agents but from the depolarizing (non-competitive) class. The elimination of suxamethonium is known to involve its metabolism by pseudocholinesterase in the plasma. This eect is very rapid, the drug having a typical duration of action of 2^ 6 min following intravenous administration.

(+)

(-) ACh nAChR

(+)

(+)

AntiAChE

AChE MR (+) (-)

CA (+)

Active receptor/agonist complex

Inactive receptor/antagonist complex

Figure 6 Schematic diagram of the four main mechanisms available for the rapid reversal of the neuromuscular blocking action of a non-depolarizing muscle relaxant; including inhibition of ACh metabolism (A), spontaneous (B) and AChE-facilitated (C) degradation ofthe muscle relaxant and chemical chelation ofthe muscle relaxant (D).MR, muscle relaxant; AChE, acetylcholinesterase; CA, chelating agent; (+), promotes neuromuscular transmission; (), reduces neuromuscular transmission.

MUSCLE RELAXANTS: PAST,PRESENTAND FUTURE

45

Figure 7 Chemical structure of Org 25969 .The molecule is a ring of eight 1^4 linked glucose molecules, each with a thiolated acid residue (positively charged) on carbon-6. The acid sidechains increase the attraction between the cyclodextrin molecule and the basic (negatively charged) rocuronium molecule.

the aminosteroidal neuromuscular blocking drugs, and in particular rocuronium. The muscle relaxant binds to the cyclodextrin in a one-to-one molecular complex rendering it pharmacologically inactive. Preclinical investigations have established that the chelating agent can produce reversal of neuromuscular block comparable to that seen with the anticholinesterase agent neostigmine. However, the cyclodextrin has no signicant cardiovascular eects of its own and as such represents a signicant improvement over neostigmine.33,34

WHAT DOES THE FUTUREHOLD FOR MUSCLE RELAXANTS?

Since their introduction nearly half a century ago, muscle relaxants have undergone an evolutionary process that started with dirty compounds such as tubocurarine, fazidinium and gallamine with their long time course of action and serious cholinergic and non-cholinergic side-eects and, most recently, has reached the stage where anaesthetists have access to compounds such as rocuronium and cisatracurium that have short-tointermediate duration of action and a relatively clean clinical prole. Will the evolution continue? What are the next targets to aim for? Many have now accepted that rapid onset comes at an appreciable cost (increased incidence of side-eects) and ultimately, whether any new muscle relaxant ever establishes itself within the anaesthetists armamentarium will depend on a patientby-patient analysis of the cost:benet ratio. Certainly,

CH2SCH2CH2CO2Na

OH

OH OH OH

O O O

O H

O O O H

C H

SC H O 2 CH 2C C C O O O

2 2 2N

Individuals with impaired pseudocholinesterase activity are known to suer prolonged neuromuscular block following administration of suxamethonium that, because of the depolarizing nature of the neuromuscular block, is unresponsive to any therapeutic intervention. Compounds whose action is inuenced by their chemical degradation usually have a short duration of action and require either repeated bolus administration or continuous infusion to maintain paralysis for a long period of time. When delivery of new drug is stopped, the rapid elimination of any compound remaining in the circulation leads to a rapid recovery from neuromuscular block. One clear advantage of this form of drug elimination is that it is independent of metabolism within either the liver or kidneys and therefore the kinetics of these compounds are not unduly altered in patients with impaired renal or hepatic function. Atracurium and cisatracurium undergo spontaneous degradation through a process known as Hofmann elimination while mivacurium is metabolized by plasma pseudocholinesterase. Mivacurium, like suxamethonium, produces an inappropriately long neuromuscular block in patients with low or atypical pseudocholinesterase activity but, unlike suxamethonium, this can be terminated by the action of an anticholinesterase drug (see below). Not all clinically eective competitive nAChR antagonists are fragile enough to rely on spontaneous (or enzymatic) degradation for the termination of their action. However, the established mechanism for the reversal of neuromuscular block is to inhibit the metabolism of ACh at the neuromuscular junction with a selective acetylcholinesterase agent such as neostigmine. It is precisely because competitive (non-depolarizing) but not noncompetitive (depolarizing) muscle relaxants can be reversed by an anticholinesterase that so much time and eort has been placed on looking for a fast-acting nondepolarizing replacement for suxamethonium over the last few decades. However, anticholinesterase agents themselves are not without their own set of problems. They facilitate the action of ACh at all cholinergic synapses.Therefore, in addition to their neuromuscular effect, they will lead to an over-stimulation of ganglionic nicotinic synapses (resulting in marked eects on the cardiovascular system such as bradycardia and hypotension) and an over-stimulation of muscarinic synapses in the parasympathetic nervous system (resulting in increased bronchial and salivary secretions, diarrhoea and abdominal cramps)Falthough these latter eects are moderated by the co-administration of the mAChR antagonist atropine. Therefore, one of the most exciting recent developments in the area of neuromuscular reversal is the emerging concept of using chelation as a means to remove a muscle relaxant from the system and hence accelerate recovery. The experimental compound Org25969 (Fig. 7) is a substituted cyclodextrin derivative that has extremely high binding anities for

CH2SCH2CH2CO2Na O OH OH O

2C

2N

C H

C H O H O H

2C

2S

2S

C H

O H

O H

C H

2C

CH2SCH2CH2CO2Na

2C

2N

OH

O
OH

CH SCH CH CO Na CH SCH CH CO Na CH2SCH2CH2CO2Na

Rocuronium Molecule

OH

O O O

OH O

O H C H

O O O H H H O a
2N

SC H C C O 2 CH 2C C C O O O

46

CURRENT ANAESTHESIA & CRITICAL CARE

there are still those who believe the goal of a short-acting non-depolarizing replacement for suxamethonium is still achievable, typied by the recent extensive study of the tropinyl diester derivative TAAC3, a non-depolarizing muscle relaxant with a rapid onset and ultra-short duration of action.35 Whether such new compounds fare better than rapacuronium, which showed considerable promise prior to its widespread introduction and the consequent identication of use-limiting adverse side-effects, is yet to be seen.

REFERENCES
1. Paton W D, Zaimis E J. The methonium compounds. Pharmacol Rev 1952; 4: 219253. 2. Deneris E S, Connolly J, Rogers S W, Duvoisin R. Pharmacological and functional diversity of neuronal nicotinic acetylcholine receptors. Trends Pharmacol Sci 1991; 12(1): 3440. 3. Paul M, Kindler C H, Fokt R M, Dresser M J, Dipp N C, Yost C S. The potency of new muscle relaxants on recombinant muscle-type acetylcholine receptors. Anesth Analg 2002; 94(3): 597603. 4. Garland C M, Foreman R C, Chad J E, Holden-Dye L, Walker R J. The actions of muscle relaxants at nicotinic acetylcholine receptor isoforms. Eur J Pharmacol 1998; 357(1): 8392. 5. Paul M, Kindler C H, Fokt R M, Dipp N C, Yost C S. Isobolographic analysis of non-depolarising muscle relaxant interactions at their receptor site. Eur J Pharmacol 2002; 438 (12): 35-43. 6. Hatano Y, Fukuda K, Arai T, Tamai S, Harioka T. Histamine H1 antagonist alone attenuates d-tubocurarine-induced hypotension. Anesthesiology 1985; 63(6): 730731. 7. Ishii T M, Maylie J, Adelman J P. Determinants of apamin and dtubocurarine block in SK potassium channels. J Biol Chem 1997; 272(37): 2319523200. 8. Vizi E S, Lendvai B. Side effects of nondepolarizing muscle relaxants: relationship to their antinicotinic and antimuscarinic actions. Pharmacol Ther 1997; 73(2): 7589. 9. Hou V Y, Hirshman C A, Emala C W. Neuromuscular relaxants as antagonists for M2 and M3 muscarinic receptors. Anesthesiology 1998; 88(3): 744750. 10. Birmingham A T, Hussain S Z. A comparison of the skeletal neuromuscular and autonomic ganglion-blocking potencies of five non-depolarizing relaxants. Br J Pharmacol 1980; 70(3): 501506. 11. Wilson D F, West A E, Lin Y. Inhibitory action of nicotinic antagonists on transmitter release at the neuromuscular junction of the rat. Neurosci Lett 1995; 186(1): 2932. 12. Bowman W C, Prior C, Marshall I G. Presynaptic receptors in the neuromuscular junction. Ann N Y Acad Sci 1990; 604: 6981. 13. Durant N N, Marshall I G, Savage D S, Nelson D J, Sleigh T, Carlyle I C. The neuromuscular and autonomic blocking activities of pancuronium, Org NC 45, and other pancuronium analogues, in the cat. J Pharm Pharmacol 1979; 31(12): 831836. 14. Chiodini F C, Tassonyi E, Fuchs-Buder T, Fathi M, Bertrand D, Muller D. Effects of neuromuscular blocking agents on excitatory transmission and gamma-aminobutyric acidA-mediated inhibition in the rat hippocampal slice. Anesthesiology 1998; 88(4): 10031013. 15. Tian L, Prior C, Dempster J, Marshall I G. Nicotinic antagonistproduced frequency-dependent changes in acetylcholine release from rat motor nerve terminals. J Physiol 1994; 476(3): 517529. 16. Prior C, Tian L, Dempster J, Marshall I G. Prejunctional actions of muscle relaxants: synaptic vesicles and transmitter mobilization as sites of action. Gen Pharmacol 1995; 26(4): 659-666.

17. Emala C W, Hirshman C A. A Mechanism for bronchospasm induced by rapacuronium: M-2 muscarinic receptor antagonism. Anesthesiology 2001; 95: A1360. 18. Naguib M, Samarkandi A H, Bakhamees H S, Magboul M A, elBakry A K. Histamine-release haemodynamic changes produced by rocuronium, vecuronium, mivacurium, atracurium and tubocurarine. Br J Anaesth 1995; 75(5): 588592. 19. Doenicke A, Soukup J, Hoernecke R, Moss J. The lack of histamine release with cisatracurium: a double-blind comparison with vecuronium. Anesth Analg 1997; 84(3): 623628. 20. Kopman A F. Pancuronium, gallamine, and d-tubocurarine compared: is speed of onset inversely related to drug potency? Anesthesiology 1989; 70(6): 915920. 21. Kopman A F, Klewicka M M, Kopman D J, Neuman G G. Molar potency is predictive of the speed of onset of neuromuscular block for agents of intermediate, short, and ultrashort duration. Anesthesiology 1999; 90(2): 425431. 22. Kopman A F, Klewicka M M, Neuman G G. Molar potency is not predictive of the speed of onset of atracurium. Anesth Analg 1999; 89(4): 10461049. 23. Wierda J M, van den Broek L, Proost J H, Verbaan B W, Hennis P J. Time course of action and endotracheal intubating conditions of Org 9487, a new short-acting steroidal muscle relaxant; a comparison with succinylcholine. Anesth Analg 1993; 77(3): 579584. 24. Miguel R, Witkowski T, Nagashima H et al. Evaluation of neuromuscular and cardiovascular effects of two doses of rapacuronium (ORG 9487) versus mivacurium and succinylcholine. Anesthesiology 1999 Dec; 91(6): 1648-1654. 25. Blobner M, Mirakhur R K, Wierda J M et al. Rapacuronium 2.0 or 2.5 mg kg1 for rapid-sequence induction: comparison with succinylcholine 1.0 mg kg1. Br J Anaesth 2000; 85(5): 724731. 26. Meakin G H, Pronske E H, Lerman J et al. Bronchospasm after rapacuronium in infants and children. Anesthesiology 2001; 94(5): 926927. 27. Cooper R, Mirakhur R K, Clarke R S, Boules Z. Comparison of intubating conditions after administration of Org 9246 (rocuronium) and suxamethonium. Br J Anaesth 1992; 69(3): 269273. 28. Meretoja O A, Brandom B W, Taivainen T, Jalkanen L. Synergism between atracurium and vecuronium in children. Br J Anaesth 1993 71(3): 440-442. 29. Motamed C, Donati F. Intubating conditions and blockade after mivacurium, rocuronium and their combination in young and elderly adults. Can J Anaesth 2000; 47(3): 225231. 30. Kim K S, Chun Y S, Chon S U, Suh J K. Neuromuscular interaction between cisatracurium and mivacurium, atracuvium, vecuronium or rocuronium administered in combination. Anesth 1998; 53: 872878. 31. Kopman A F, Khan N A, Neuman G G. Precurarization and priming: a theoretical analysis of safety and timing. Anaesth Analg 2002; 93 (5): 1253-1256. 32. Aziz L, Jahangir S M, Choudhury S N, Rahman K, Ohta Y, Hirakawa M. The effect of priming with vecuronium and rocuronium on young and elderly patients. Anesth Analg 1997; 85(3): 663666. 33. Bom A, Cameron K, Clark J K et al. Chemical chelation as a novel method of NMB reversalFdiscovery of Org 25969. Eur J Anaesthesiol 2001; 18 (Suppl 23): 99 (Abstract 16). 34. van Egmond J, van de Pol F, Booji L, Bom A. Neuromuscular blockade induced by steroidal NMBs can be rapidly reversed by Org 25969 in the anaesthetised monkey. Eur J Anaesthesiol 2001; 18 (Suppl 23): 100 (Abstract 19). 35. Gyermek L, Lee C, Cho Y M, Nguyen N, Tsai S K. Neuromuscular pharmacology of TAAC3, a new nondepolarizing muscle relaxant with rapid onset and ultrashort duration of action. Anesth Analg 2002; 94(4): 879885. 36. Mirakhur R K, McCourt K C. Rapacuronium: clinical pharmacology. Eur J Anaesthesiol 2001; 23 Suppl: 7782.