Glasgow Meeting - May 2003

Interactions With Neuromuscular Blocking Agents

Christoph H. Kindler, M.D. Department of Anaesthesia, University Clinics Basel, Kantonsspital, CH-4031 Basel, Switzerland

Tel: ++41 61 265 72 54; Fax: ++41 61 265 73 20; Email: ckindler@uhbs.ch

Neuromuscular blocking agents (NMBAs) interact with many different drugs including general anaesthetics and other NMBAs themselves (1, 2). Searching MEDLINE with the exact title of this abstract "Interactions with neuromuscular blocking agents" produces 1511 results (22 February 2003). Thus, it is not possible to give a comprehensive overview of all known interactions of NMBAs. In addition, many of these interactions, although scientifically interesting, are not clinically relevant. Besides pharmacological interactions, certain diseases and pathophysiological states such as myasthenia gravis, myotonia, muscular dystrophy, hypothyreosis, cancer, hypo- and hyperkalaemia, acidosis, hypothermia, and disturbed liver or kidney function also influence the effects of NMBAs. At a molecular level of the acetylcholine receptor, other drugs interact with NMBAs by direct competition at the binding sites for acetylcholine, allosteric modulation of the receptor, or direct interference with ion flux through the central ion channel of the receptor. In addition, some drugs interact with NMBAs on a pharmacokinetic level by interfering with their distribution and elimination. This lecture can therefore only focus on some selected interactions of NMBAs with other commonly used drugs, having potential clinical implication and of general interest to anaesthetists.

In the 1970s it was first reported that volatile anaesthetics themselves produce muscle relaxation in addition to enhancing the neuromuscular blockade of NMBAs (3,4). These observations stimulated many clinical studies examining different combinations of NMBAs and volatile anaesthetics: for example, isoflurane and enflurane potentiate a pancuronium-induced block more than halothane, and a vecuronium-induced block is most potently enhanced by enflurane (5). Interestingly, volatile anaesthetics have smaller effects on benzylisoquinoline (atracurium, cisatracurium, mivacurium)–induced blockade than on steroid (vecuronium, pancuronium, rocuronium)–induced blockade (6). In general, the conclusion is that all volatile anaesthetics, including sevoflurane and even xenon (7), potentiate all NMBAs, including the very fast acting and recently withdrawn rapacuronium (8) as well as the depolarising suxamethonium (9). Until recently, the interactions of NMBAs with volatile anaesthetics were mostly examined with acceleromyography and electromyography, but were not defined at the receptor level. Using a heterologous expression model, Paul and co-workers found that volatile anaesthetic-induced enhancement of neuromuscular blockade is the result of a combined drug effect on the pure muscle-type nicotinic acetylcholine receptor(10).

Intravenous anaesthetics

Intravenous anaesthetics have a lower muscle-relaxing effect than volatile anaesthetics (11, 12), although a recent report suggests significant enhancement of dtubocurarine-induced twitch depression by propofol in animals (13). This finding is consistent with an earlier clinical study showing that the increase of masseter muscle tone following administration of suxamethonium is lower following propofol induction compared with a thiopental induction (14).

Many investigators have studied interactions of NMBAs among themselves and a few anaesthetic careers were indeed built on the results of such studies. The most important interactions among NMBAs per se are summarized in the review article of Cammu (1). Many studies suggest that drug combinations with dissimilar molecular structures are more synergistic than combinations with similar molecular structures(15).

Local anaesthetics, antibiotics, anticonvulsants, magnesium, diuretics, corticosteroids, and other agents

Many other drugs that are regularly or occasionally used by anaesthetists interact with NMBAs; most of these drugs enhance an induced neuromuscular blockade and include: local anaesthetics, aminopenicillins, aminoglycosides, polymyxins, clindamycin, magnesium, calcium channel blockers, lithium, high-dose furosemide, cyclosporin, alpha2-agonists, and beta-agonists. Recently it has been shown that corticosteroids also inhibit the acetylcholine receptor at concentrations that are found in patients receiving steroids as part of their treatment regimen. The observed additive inhibition of the acetylcholine receptor by corticosteroids and NMBAs may contribute to the pathophysiology of prolonged weakness in some critically ill patients ("blocking agent–corticosteroid myopathy") (16). In contrast, a few drugs are also known to counteract an induced neuromuscular blockade. Phosphodiesterase inhibitors antagonize the neuromuscular blocking effect of d-tubocurarine in vitro (17). Hence, it is noteworthy that phosphodiesterase inhibitors and beta-adrenergic agonists affect non-depolarising muscle relaxation in opposite directions. Patients receiving chronic therapy with anticonvulsants also show resistance to NMBAs (18, 19). This antagonistic effect is much smaller with benzylisoquinoline NMBAs compared with steroidal NMBAs (20).

The reversal of neuromuscular blockade, as currently done with inhibition of the enzyme acetylcholine esterase (neostigmin, pyridostigmine, edrophonium) has important limitations: 1) the mechanism of reversal is indirect, i.e. after administration of the acetylcholine esterase inhibitor, enzymatic degradation of acetylcholine in the synaptic cleft is reduced thereby increasing the numbers of acetylcholine molecules competing for the binding sites with the NMBA; 2) the efficacy is limited and residual block occurs because reversal is dependent on the increase of actelylcholine concentration and the decrease of the concentration of the NMBA according to its inherent rate of elimination; 3) reversal is inadequate or impossible against profound block because of the competitive nature of the interaction between acetylcholine and the NMBA; 4) true rescue reversal in a "cannot ventilate – cannot intubate" situation does not exist; and 5) the effect of acetylcholine esterase inhibitors is not selective, but also potentiates neurotransmission at muscarinic acetylcholine receptors leading to bradycardia, hypotension, bronchoconstriction, nausea and diarrhoea. Therefore, in clinical practice, acetylcholine esterase inhibitors are combined with atropine or glycopyrrolate to antagonize the muscarinic effects of acetylcholine; however, these muscarinic antagonists themselves cause a number of side-effects such as tachycardia, dry mouth, gastrointestinal and urogenital dysfunction. For these reasons a novel and alternative mode of reversing neuromuscular blockade was developed by chemical encapsulation (chelation, complexation) of NMBAs by a host molecule ( γ-cyclodextrins).

The γ-cyclodextrins consist of a ring of eight linked sugar molecules with a very water soluble hydrophilic exterior and a hydrophobic interior, which binds the steroid nucleus of NMBAs with a 1:1 ratio (Figure 1) (21-23).

Fig 1. A γ-cyclodextrin molecule with water soluble, negatively charged carboxyl groups (black boxes) and the lipophilic cavity containing the steroidal rings of a neuromuscular blocking agent.

This complex (the γ-cyclodextrin molecule with the encapsulated NMBA) is then rapidly eliminated in the urine leading to a complete and almost immediate removal of NMBA from plasma and a rapid complete reversal (recovery to the TOF ratio >0.9 within a few minutes). The γ-cyclodextrins are much more effective against steroidal (especially rocuronium) than benzylisoquinoline NMBAs. The obvious advantages of this future mode of neuromuscular blockade reversal include: 1) no "recurarisation" or residual block occurs; 2) no cardiovascular or other cholinergic side-effects; and 3) the existence of a true rescue reversal. While γ-cyclodextrins have already been successfully tested in cats, guinea pigs, mice and monkeys, initial human studies are currently being planned with a pure per-6-deoxy-per-6-sulfanyl-γ-cyclodextrin derivative (ORG 25969). Before introduction into clinical practice, complex γ-cyclodextrin formation with endogenous hormones and with other exogenous drugs and metabolites must be ruled out and the efficacy during adverse conditions such as profound block, hypothermia, acidosis and kidney or hepatic failure must be tested. Once established in clinical practice, the γ-cyclodextrins may substantially change our anaesthetic techniques. Fewer NMBAs will be used and the need for suxamethonium may be completely eliminated, since even patients scheduled for very short procedures needing a rapid-sequence induction can be given large doses of rocuronium, which then can be rapidly encapsulated by administration of a γ-cyclodextrin.

I thank Dr. James Caldwell, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, for valuable discussion during the preparation of this abstract.

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