State of the art in neuromuscular blockade

Claude Meistelman, Department of Anaesthesiology

School of Medicine of Nancy, France, e-mail: c.meistelman@chu-nancy.fr

For many years the development of new muscle relaxants or reversal agents has been empirical. The past few years have been dominated by the idea of finding an “ideal muscle relaxant”.

There is ample evidence that potent non depolarising muscle relaxants have slower onset times than less potent drugs with similar physicochemical properties. These facts can be explained by the concept of the margin of safety. A critical number of receptors at the neuromuscular junction must be occupied before appearance of neuromuscular block, and at least 90% of the receptors must be occupied before block is complete at the adductor pollicis. When the drug reaches the synaptic cleft, most molecules will bind to receptors which are present with a high density. As the concentration of free drug decreases, more molecules are driven in and the process will continue until the concentrations of free drug within and outside the synaptic cleft are equal. This process is known as buffered diffusion. When a potent drug is administered, less molecules are given than in a case of a less potent drug and the onset will be slower compared to onset of weak potency NDMR. This phenomenon is probably what contributes to the slower onset time for cisatracurium than atracurium. Based on theoretical calculations and experimental data, the ED95 might be greater at least  0.3-0.5 mg/kg to produce a short onset of action. However, for very short acting drugs, the ideal ED95 might be greater (0-5-1.0 mg/kg) because rapid metabolism destroys some of the muscle relaxant given before it reaches the neuromuscular junction. A new group of muscle relaxants (bisquaternary tropinyl diester compounds) is currently under testing in animals. It exhibits, in different animal species, rapid onset and an ultra short duration of action, even shorter than those of succinylcholine, in the cat. The short duration of action can be explained by the presence of its rapidly hydrolysable acetoxy radicals. In the cat, the cardiac vagal blocking effect in equipotent doses is larger than those of atracurium, mivacurium and vecuronium, is similar to that of rocuronium, and is of lesser degree than that of pancuronium. An other muscle relaxant, GW280430A, is an asymmetrical chlorofumarate compound which is degradated by chemical mechanisms in vitro. In human volunteers, the onset and duration of action are similar to what is observed in patients following succinylcholine and there is a lack of cumulation. Further studies are needed to determine the potential side effects. Whatever muscle relaxant, the limiting factor appears to be the time required for the drug to reach the neuromuscular junction which in turn depends on cardiac output, the distance of the muscle from the central circulation, and muscle blood flow.

            Up to know it has been almost impossible to fulfil the criteria of the ideal muscle relaxant. It has been recently suggested that an alternative may be to facilitate early recovery of neuromuscular block. All clinically used reversal agents temporarily inactive acetylcholinesterase and increase the amount of acetylcholine at the postsynaptic membrane. However, they are not true antagonists because their action is mainly by increasing the amount of acetylcholine at the endplate. The mechanism of action of anticholinesterase drugs has another consequence: a ceiling effect. Thus, increasing the dose beyond a certain point does not increase their ability to reverse the blocking effects of non depolarising muscle relaxants. The increase in acetylcholine induced by reversal agents does not remain limited to the neuromuscular junction but also leads to non selective activation of muscarinic receptors thus causing bradycardia, hypotension or increased salivation. It has been recently hypothesized that chelation or chemical encapsulation of non depolarising muscle relaxants by an exogenous host molecule might promote dissociation from their site of action and result in the reversal of neuromuscular block. Cyclodextrins, a group of cyclic oligosaccharides known for their ability to encapsulate lipophilic guest molecules such as steroids have been investigated. Initial studies have confirmed that among many compounds, Org 25969 has the ability to form complexes with steroidal neuromuscular relaxants. In monkeys, 1 mg/kg Org 25969 reversed the rocuronium-induced block in a rapid and efficacious fashion to produce 90% recovery from neuromuscular block within 3 minutes, whereas 40 µg/kg neostigmine produced the same level of recovery in more than 6 minutes. Several studies have confirmed that Org 25969 induces selective reversal of neuromuscular block induced by steroidal muscle relaxants, particularly rocuronium, but  it is less active against neuromuscular block induced by other muscle relaxants such as d-tubocurarine, atracurium or mivacurium. Because this supramolecular mechanism of action does not involve direct interaction with the cholinergic system, the reversal by these compounds, is not accompanied by cardiovascular side effects usually attendant with acetylcholinesterase inhibitors such as neostigmine.

            In conclusion the lower is the potency; the faster is the onset of action. However up to now it has been difficult to find the optimal compromise between the wanted neuromuscular effects (rapid onset, short duration of action) and the potential side effects. The development of new reversal agents could be an alternative by facilitating very early and safe reversal of neuromuscular block. Further developments in this direction are awaited.