The continuing search for a succinylcholine replacement.

THE introduction of succinylcholine into clinical practice in 1951 was a seminal development in the history of anesthesia. Since that time, anesthesiologists have had access to a neuromuscular blocking drug (muscle relaxant) with a very rapid onset and a duration of action of approximately 10 min. The clinical utility of succinylcholine has been counterbalanced by its many undesirable effects, ranging from the relatively benign (fasciculations) to life-threatening events (hyperkalemia or malignant hyperthermia). The adverse effects of succinylcholine are almost all related to its depolarizing mechanism of action. Consequently, there has been a continual search for a nondepolarizing muscle relaxant that can replicate both the rapid onset and short duration of succinylcholine. In this issue of the Journal, three articles report on preclinical and preliminary clinical investigations of such a drug, GW280430A. Structurally, GW280430A is an asymmetric mixed-tetrahydroisoquinolinium chlorofumarate. Of the drugs in clinical practice, the one to which it bears the closest structural resemblance is mivacurium. The exact mechanism underlying its short duration is not fully elucidated; it appears to undergo rapid degradation in the plasma by chemical (nonenzymatic) mechanisms. GW280430A has been studied in a variety of animal species—cat, dog, and rhesus monkey—with promising results for onset and duration and a good safety profile with regard to histamine-releasing potential. In assessing the possible clinical utility of this drug, its apparent strengths must be weighed against its potential for adverse effects. In humans, the onset of GW280430A over the range of 1.8–4.0xED95 doses is 1.5–1.7 min and it has a very narrow range (1.1–2.0 min). This narrow range of onset times is remarkable for a nondepolarizing relaxant and resembles more the tight distribution of onset time seen with succinylcholine. However, this result may be an artifact due to the small number and physiologic homogeneity of the volunteer subjects studied; it is unlikely to represent the true distribution in patients. Regardless, the onset, although perhaps not as rapid as that of succinylcholine, may be sufficient to facilitate rapid-sequence intubation in most clinical situations. Of some interest is that onset time did not diminish with doses greater than 1.9xED95. This may again be due to the small number of subjects, or it might be an example of the diminishing return observed as onset times approach the limit determined by circulation time and diffusion of drug into the neuromuscular junction. In addition to its rapid onset, GW280430A has a very short duration of action. In a dose of 0.4 mg/kg (2.2xED95), recovery to a train-of-four ratio of 0.9 took only 14 min. This may be regarded as essentially complete recovery for a nondepolarizing muscle relaxant. An equivalent degree of recovery for succinylcholine would be represented by the single twitch recovering to between 90% and 100% of predrug level. For a standard intubating dose of 1.0 mg/kg, this time interval is between 8 and 12 min. It appears that in respect to its duration of action, GW280430A resembles succinylcholine more closely than does any previous nondepolarizing muscle relaxant. Of particular interest, pharmacologic antagonism with edrophonium 0.5 mg/kg can decrease significantly the already short recovery time of GW280430A. The possibility exists, therefore, that edrophonium-accelerated recovery from GW280430A might have a time course that replicates that of succinylcholine. Increasing the dose of GW280430A does not seem to carry a great penalty in respect to the increase in duration of action. The numbers in each dose group are too small to make definitive conclusions, but, for example, increasing the dose from 0.36 to 0.72 mg/kg increases recovery time to a train-of-four ratio of 0.9, from 11.9 to only 15.1 min. The other notable aspect of the drug is a lack of cumulative effect. The recovery slopes, as represented by the 5–95% or 25–75% intervals, are unaffected by the dose or duration of administration. In summary, the time course of action of GW280430A more closely resembles succinylcholine than does any other nondepolarizing muscle relaxant to date. In addition to its positive characteristics, there are some potential problems with GW280430A. The structural group to which GW280430A belongs has the proThis Editorial View accompanies the following articles: Belmont MR, Lien CA, Tjan J, Bradley E, Stein B, Patel SS, Savarese JJ: Clinical pharmacology of GW280430A in humans. ANESTHESIOLOGY 2004; 100:768–73; Savarese JJ, Belmont MR, Hashim MA, Mook RA Jr, Boros EE, Samano V, Patel SS, Feldman PL, Schultz J-AI, McNulty M, Spitzer T, Cohn DL, Morgan P, Wastila WB: Preclinical pharmacology of GW280430A (AV430A) in the rhesus monkey and in the cat: A comparison with mivacurium. ANESTHESIOLOGY 2004; 100:835–45; Heerdt PM, Kang R, The’ A, Hashim M, Mook RJ Jr, Savarese JJ: Cardiopulmonary effects of the novel neuromuscular blocking drug GW280430A (AV430A) in dogs. ANESTHESIOLOGY 2004; 100:846–51.