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Correspondence  |   November 1999
Rapid Onset/Offset of Rapacuronium Bromide Explained? 
Author Notes
  • Associate Professor
  • Professor
  • Research Group for Experimental Anesthesiology and Clinical Pharmacology
  • Department of Anesthesiology
  • University of Groningen
  • Groningen, The Netherlands
Article Information
Correspondence
Correspondence   |   November 1999
Rapid Onset/Offset of Rapacuronium Bromide Explained? 
Anesthesiology 11 1999, Vol.91, 1554. doi:
Anesthesiology 11 1999, Vol.91, 1554. doi:
To the Editor:—
The recent article by Wright et al.  1 provided interesting and important information on the pharmacokinetic/pharmacodynamics of rapacuronium at the laryngeal adductors and the adductor pollicis. However, we have a number of comments and concerns.
In the Discussion section, the authors mention the observed inverse correlation between the potency (ED95) of nondepolarizing muscle relaxants and their speed of onset, and present their explanation, referencing Hull. 2 We would like to call the readers’ attention to other work in the field, in particular that of Donati and Meistelman, 3 who explained these observations on the basis of “buffering” and presented a plausible pharmacokinetic/pharmacodynamic model quantifying the influence of the acetylcholine receptor concentration and affinity on the time course of action.
The aforementioned explanation is based on the buffering phenomenon by the acetylcholine receptors in the neuromuscular junction (page 20 of Wright et al.’s article). Although there is evidence for the buffering effect in iontophoretic studies in vitro  , there is no convincing evidence that buffering plays a role under clinically relevant conditions; therefore, the explanation is still a hypothesis. In addition, the authors do not give an explanation for the rapid offset of rapacuronium.
In the Discussion section, the authors state, “Despite the lack of comparative data, Schiere et al.  concluded that Org 9488 is more potent than Org 9487 (rapacuronium),” suggesting that there was no solid base for this statement. At that time, however, Schiere et al.  already had the data from a similar study on rapacuronium 4 and therefore could make this statement on a sound scientific base. In addition, Wright et al.  disputed the study design used by Schiere et al.  , in which the same patients did not receive both rapacuronium and Org 9488 on separate occasions. It should be clear that such a crossover design cannot be performed in a study in surgical patients. The cited study of Caldwell et al.  5 was conducted in volunteers. Of course, if the main goal of a study is the assessment of the relative potency of two compounds, a crossover design is preferable. However, if the primary aim of the study is to delineate the pharmacokinetics and clarify the pharmacokinetic/pharmacodynamic relationships in surgical patients, the study design of Schiere et al.  might be preferable.
References 
References 
Wright PMC, Brown R, Lau M, Fisher DM: A pharmacodynamic explanation for the rapid onset/offset of rapacuronium bromide. ANESTHESIOLOGY 1990; 90:16–23
Hull CJ: Pharmacokinetics for Anaesthesia. Oxford, Butterworth-Heinemann, 1991, pp 333–6
Donati F, Meistelman C: A kinetic-dynamic model to explain the relationship between high potency and slow onset time for neuromuscular blocking drugs. J Pharmacokinet Biopharm 1991; 19:537–52
Schiere S, Proost JH, Schuringa M, Wierda JMKH: Pharmacokinetics and pharmacokinetic-dynamic relationship between rapacuronium (Org 9487) and its 3-desacetyl metabolite (Org 9488). Anesth Analg 1999; 88:640–7
Caldwell JE, Szenohradszky J, Segredo V, Wright PM, McLoughlin C, Sharma ML, Gruenke LD, Fisher DM, Miller RD: The pharmacodynamics and pharmacokinetics of the metabolite 3-desacetylvecuronium (ORG 7268) and its parent compound, vecuronium, in human volunteers. J Pharmacol Exp Ther 1994; 270:1216–22