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Anesthesiology:
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The Continuing Search for a Succinylcholine Replacement

Caldwell, James E. M.B.Ch.B.

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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). 1 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. 2–4
Structurally, GW280430A is an asymmetric mixed-tetrahydroisoquinolinium chlorofumarate. 5 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. 6 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. 3,4 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). 2 This narrow range of onset times is remarkable for a nondepolarizing relaxant and resembles more the tight distribution of onset time seen with succinylcholine. 7 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. 8 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.
This 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.
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. 9,10 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. 7,11 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. 2 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. 2 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. 2 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. 2 The structural group to which GW280430A belongs has the propensity to release histamine, 12 and GW280430A appears to share this. In doses of 3xED95 and above, histamine release with consequent hypotension, tachycardia, and flushing were noted. What does this mean for the clinical potential of the drug? In all likelihood, clinicians would accept a low risk of histamine-related effects if the drug could truly replace succinylcholine. It appears however, that histamine release may be an actual clinical problem.
One of the principal uses for a drug such as GW280430A is to facilitate rapid tracheal intubation. The onset of GW280430A is slightly slower than that of succinylcholine, so clinicians will tend to increase doses to promote good conditions for tracheal intubation. This phenomenon has been documented with mivacurium, 13,14 rocuronium, 13 and cisatracurium, 15 in which doses in the range of 2.5–5.0xED95 are used to speed onset of paralysis prior to tracheal intubation. This experience suggests that clinicians push doses of muscle relaxants upward to improve conditions for tracheal intubation. It is likely that should GW280430A enter clinical use, doses of 3xED95 or greater would be administered. In this dose range, it seems that significant histamine release with consequent adverse effects would occur.
The recent experience with rapacuronium is relevant to consideration of GW280430A and its clinical potential. 16 To summarize, rapacuronium is a steroidal muscle relaxant with a rapid onset and short duration. 17 In clinical trials, there was an incidence of bronchospasm of approximately 9%. 18 This was not thought to be of sufficient clinical importance to prevent the general release of the drug. Under the realities of widespread clinical use, there occurred several cases of life-threatening bronchospasm with rapacuronium, particularly in children. 16 As a result, 19 months after its release rapacuronium was withdrawn by the manufacturer. Is there evidence of such a potential problem with GW280430A? The answer, unfortunately, is yes. GW280430A clearly can stimulate release of histamine. In the study of Belmont et al., clinically significant histamine release occurred in one of four subjects who received 0.54 mg/kg (3.0xED95) and in three of four volunteers receiving 0.72 mg/kg (4xED95). These doses might conceivably be used clinically. 2
What can we conclude from these articles? They demonstrate that developing a nondepolarizing replacement for succinylcholine is a realistic possibility. GW280430A has a time course of action very close to that of succinylcholine. There is, however, a large question mark over its histamine-releasing potential. GW280340A may never be released into clinical practice, but it is quite conceivable that a drug closely related to it will be.
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References

1. Savarese JJ, Caldwell JE, Lien CA, Miller RD: Pharmacology of muscle relaxants and their antagonists, Anesthesia, 5th edition. Edited by Miller RD. New York, Churchill Livingstone, 2000, pp 412–90

2. Belmont MR, Lien CA, Tjan J, Bradley E, Stein B, Patel SS, Savarese JJ: Clinical pharmacology of GW280430A in humans. A nesthesiology 2004; 100: 768–73

3. 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. A nesthesiology 2004; 100: 846–51

4. 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. A nesthesiology 2004; 100: 835–45

5. Boros EE, Samano V, Ray JA, Thompson JB, Jung DK, Kaldor I, Koble CS, Martin MT, Styles VL, Mook RA Jr, Feldman PL, Savarese JJ, Belmont MR, Bigham EC, Boswell GE, Hashim MA, Patel SS, Wisowaty JC, Bowers GD, Moseley CL, Walsh JS, Reese MJ, Rutkowske RD, Sefler AM, Spitzer TD: Neuromuscular blocking activity and therapeutic potential of mixed-tetrahydroisoquinolinium halofumarates and halosuccinates in rhesus monkeys. J Med Chem 2003; 46: 2502–15

6. McNulty M, Brown A, Johnson T, Spitzer TD, Savarese J: The ultra-short acting nondepolarizing relaxant GW280430A undergoes rapid degradation by chemical mechanisms. A nesthesiology 2000; 93: A-1037

7. Wright PM, Caldwell JE, Miller RD: Onset and duration of rocuronium and succinylcholine at the adductor pollicis and laryngeal adductor muscles in anesthetized humans. A nesthesiology 1994; 81: 1110–5

8. Kopman AF, Klewicka MM, Neuman GG: Reexamined: The recommended endotracheal intubating dose for nondepolarizing neuromuscular blockers of rapid onset. Anesth Analg 2001; 93: 954–9

9. Kopman AF, Yee PS, Neuman GG: Relationship of the train-of-four fade ratio to clinical signs and symptoms of residual paralysis in awake volunteers. A nesthesiology 1997; 86: 765–71

10. Eriksson LI, Sundman E, Olsson R, Nilsson L, Witt H, Ekberg O, Kuylenstierna R: Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: Simultaneous videomanometry and mechanomyography of awake human volunteers. A nesthesiology 1997; 87: 1035–43

11. Dhonneur G, Kirov K, Slavov V, Duvaldestin P: Effects of an intubating dose of succinylcholine and rocuronium on the larynx and diaphragm: An electromyographic study in humans. A nesthesiology 1999; 90: 951–5

12. Savarese JJ, Wastila WB: The future of the benzylisoquinolinium relaxants. Acta Anaesthesiol Scand Suppl 1995; 106: 91–3

13. Pino RM, Ali HH, Denman WT, Barrett PS, Schwartz A: A comparison of the intubation conditions between mivacurium and rocuronium during balanced anesthesia. A nesthesiology 1998; 88: 673–8

14. Motamed C, Donati F: Intubating conditions and blockade after mivacurium, rocuronium and their combination in young and elderly adults. Can J Anaesth 2000; 47: 225–31

15. Doenicke AW, Czeslick E, Moss J, Hoernecke R: Onset time, endotracheal intubating conditions, and plasma histamine after cisatracurium and vecuronium administration. Anesth Analg 1998; 87: 434–8

16. Rajchert DM, Pasquariello CA, Watcha MF, Schreiner MS: Rapacuronium and the risk of bronchospasm in pediatric patients. Anesth Analg 2002; 94: 488–93

17. Kahwaji R, Bevan DR, Bikhazi G, Shanks CA, Fragen RJ, Dyck JB, Angst MS, Matteo R: Dose-ranging study in younger adult and elderly patients of ORG 9487, a new, rapid-onset, short-duration muscle relaxant. Anesth Analg 1997; 84: 1011–8

18. Moore EW, Hunter JM: The new neuromuscular blocking agents: Do they offer any advantages? Br J Anaesth 2001; 87: 912–25

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