Free
Correspondence  |   November 1999
Rapid Onset/Offset of Rapacuronium Bromide Explained? 
Author Notes
  • Professor of Anesthesia and Pediatrics
  • University of California–San Francisco
  • San Francisco, California 94143–0648
  • Senior Lecturer
  • Department of Anesthesia
  • University of Newcastle-upon-Tyne
  • Newcastle-upon-Tyne, United Kingdom
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:
In Reply:—
Proost et al.  have several concerns regarding our study. 1 First, they mention other work in the field. We might add the work of Stanski et al.  , 2 who proposed that “k  eo[the rate constant for equilibration between plasma and the effect site] will be directly proportional to perfusion of the neuromuscular junction and inversely proportional to the blood–muscle drug partition coefficient.” Proost et al.  ’s notion of buffering equates to that for partitioning, i.e.  , a larger tissue/plasma partition coefficient equates to a larger buffering. We assume that within a given series of muscle relaxants, the same magnitude of relaxation results from the action of a specific number of relaxant molecules at the effect site. A drug that has a small muscle/plasma partition coefficient (i.e.  , is poorly “buffered”) requires a large plasma concentration (necessitating a large dose) to yield a sufficient number of (unbuffered) molecules at the neuromuscular junction. Such a drug would have a fast onset, equivalent to the rapid equilibration observed with a poorly soluble inhaled drug such as nitrous oxide. Studies by Bowman et al.  , 3 Donati and Meistelman, 4 Kopman, 5 and from our group 6 support this relationship between k  eo, onset, and potency.
Second, Proost et al.  question whether a large k  eoalso explains rapacuronium's rapid offset of neuromuscular effect. A large k  eopermits a rapid plasma-effect site equilibration during both onset and offset. Thus, as soon as effect-site concentration peaks, the large k  eopermits effect-site concentration to track the rapidly decreasing plasma concentration. As previously explained, k  eoalso affects potency, i.e.  , the smaller the value for k  eo, the larger the dose required to achieve the same peak effect-site concentration. Thus, a smaller k  eorequires administration of a larger dose to achieve the same peak effect. In turn, the larger dose produces a slower recovery. These phenomenon are illustrated in figure 1
Fig. 1. Time course of effect at the adductor pollicis is shown for the same individual displayed in figure 3 in the study by Wright  et al.  1 The solid line displays the time course after a bolus rapacuronium dose of 1.5 mg/kg. The dotted line displays the time course predicted for the same bolus dose, assuming that  k  eois 2.4 times smaller,  i.e.  , a value similar to that for rocuronium  1 ; note that peak effect is less and recovery longer than with the larger  k  eo. The dashed line displays the predicted time course for a bolus dose (2.3 mg/kg) that yields that same peak effect-site concentration as the solid line, assuming the smaller  k  eo; note that recovery is yet longer. Therefore, a larger  k  eo(more rapid equilibration between plasma and effect site) speeds both onset and recovery. 
Fig. 1. Time course of effect at the adductor pollicis is shown for the same individual displayed in figure 3 in the study by Wright  et al.  1The solid line displays the time course after a bolus rapacuronium dose of 1.5 mg/kg. The dotted line displays the time course predicted for the same bolus dose, assuming that  k  eois 2.4 times smaller,  i.e.  , a value similar to that for rocuronium  1; note that peak effect is less and recovery longer than with the larger  k  eo. The dashed line displays the predicted time course for a bolus dose (2.3 mg/kg) that yields that same peak effect-site concentration as the solid line, assuming the smaller  k  eo; note that recovery is yet longer. Therefore, a larger  k  eo(more rapid equilibration between plasma and effect site) speeds both onset and recovery. 
Fig. 1. Time course of effect at the adductor pollicis is shown for the same individual displayed in figure 3 in the study by Wright  et al.  1 The solid line displays the time course after a bolus rapacuronium dose of 1.5 mg/kg. The dotted line displays the time course predicted for the same bolus dose, assuming that  k  eois 2.4 times smaller,  i.e.  , a value similar to that for rocuronium  1 ; note that peak effect is less and recovery longer than with the larger  k  eo. The dashed line displays the predicted time course for a bolus dose (2.3 mg/kg) that yields that same peak effect-site concentration as the solid line, assuming the smaller  k  eo; note that recovery is yet longer. Therefore, a larger  k  eo(more rapid equilibration between plasma and effect site) speeds both onset and recovery. 
×
. An additional factor contributing to rapacuronium's rapid recovery profile is its large plasma clearance. However, differences between drugs in their plasma clearances is not sufficient to explain differences in recovery profile: mivacurium's clearance far exceeds that of rapacuronium. In addition, rocuronium's recovery profile is similar to that of vecuronium despite its smaller clearance.
Proost et al.  note our statement that “despite [their] lack of comparative data, Schiere et al.  concluded…” When our manuscript was published in January 1999, the only public information regarding the study by Schiere et al.  was an abstract 7 that included no data regarding the potency of rapacuronium. Although we were aware of Schiere et al.  ’s results from unpublished sources, it would have been inappropriate for us to “scoop” them regarding their study that was published 2 months later!8 
Finally, Proost et al.  challenge our recommendations to study volunteers using a crossover design to determine the relative potency of rapacuronium and its metabolite. One assumption in analyzing data from an unpaired study is that groups differ only in a single factor, in this case, the drug under investigation. Unless subjects are carefully matched, this assumption may be flawed. One means to assure that subjects in different groups are comparable is to study each individual on more than one occasion, i.e.  , a crossover design. Proost et al.  are concerned that studies in volunteers undergoing anesthesia might not apply to patients undergoing anesthesia and surgery. We contend that anesthetized volunteers differ minimally from healthy patients undergoing minimally invasive surgery. If different surgical procedures affect the pharmacokinetics/pharmacodynamics of a compound, then studies need to be performed in patients undergoing those specific procedures; in turn, Schiere et al.  should report what types of procedures their patients underwent.
Kopman disputes our claim that time to 25% twitch recovery after rapacuronium is “only slightly longer than after succinylcholine.” As Kopman notes, data supporting our statement are provided in the same sentence. Rather than debate nuances of language, we note that the onset of rapacuronium is faster than that of presently available nondepolarizing muscle relaxants, and its recovery profile is matched only by mivacurium.
References 
References 
Wright PMC, Brown R, Lau M, Fisher DM: A pharmacodynamic explanation for the rapid onset/offset of rapacuronium bromide. ANESTHESIOLOGY 1999; 90:16–23
Stanski DR, Ham J, Miller RD, Sheiner LB: Pharmacokinetics and pharmacodynamics of d-tubocurarine during nitrous oxide-narcotic and halothane anesthesia in man. ANESTHESIOLOGY 1979; 51:235–41
Bowman W, Rodger I, Houston J, Marshall R, McIndewar I: Structure: action relationships among some desacetoxy analogues of pancuronium and vecuronium in the anesthetized cat. ANESTHESIOLOGY 1988; 69:57–62
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
Kopman AF: Pancuronium, gallamine, and d-tubocurarine compared: Is speed of onset inversely related to drug potency? ANESTHESIOLOGY 1989; 70:915–20
Fisher DM, Szenohradszky J, Wright PMC, Lau M, Brown R, Sharma M: Pharmacodynamic modeling of vecuronium-induced twitch depression: Rapid plasma-effect site equilibration explains faster onset at resistant laryngeal muscles than at the adductor pollicis. ANESTHESIOLOGY 1997; 86:558–66
Schiere S, Proost JH, Wierda JMKH: Pharmacokinetics and pharmacokinetic/pharmacodynamic (PK/PD) relationship of ORG 9488, the 3-desacetyl metabolite of ORG 9487 (abstract). ANESTHESIOLOGY 1997; 87:A377
Schiere S, Proost JH, Schuringa M, Wierda JM: Pharmacokinetics and pharmacokinetic-dynamic relationship between rapacuronium (Org 9487) and its 3-desacetyl metabolite (Org 9488). Anesth Analg 1999; 88:640–7
Fig. 1. Time course of effect at the adductor pollicis is shown for the same individual displayed in figure 3 in the study by Wright  et al.  1 The solid line displays the time course after a bolus rapacuronium dose of 1.5 mg/kg. The dotted line displays the time course predicted for the same bolus dose, assuming that  k  eois 2.4 times smaller,  i.e.  , a value similar to that for rocuronium  1 ; note that peak effect is less and recovery longer than with the larger  k  eo. The dashed line displays the predicted time course for a bolus dose (2.3 mg/kg) that yields that same peak effect-site concentration as the solid line, assuming the smaller  k  eo; note that recovery is yet longer. Therefore, a larger  k  eo(more rapid equilibration between plasma and effect site) speeds both onset and recovery. 
Fig. 1. Time course of effect at the adductor pollicis is shown for the same individual displayed in figure 3 in the study by Wright  et al.  1The solid line displays the time course after a bolus rapacuronium dose of 1.5 mg/kg. The dotted line displays the time course predicted for the same bolus dose, assuming that  k  eois 2.4 times smaller,  i.e.  , a value similar to that for rocuronium  1; note that peak effect is less and recovery longer than with the larger  k  eo. The dashed line displays the predicted time course for a bolus dose (2.3 mg/kg) that yields that same peak effect-site concentration as the solid line, assuming the smaller  k  eo; note that recovery is yet longer. Therefore, a larger  k  eo(more rapid equilibration between plasma and effect site) speeds both onset and recovery. 
Fig. 1. Time course of effect at the adductor pollicis is shown for the same individual displayed in figure 3 in the study by Wright  et al.  1 The solid line displays the time course after a bolus rapacuronium dose of 1.5 mg/kg. The dotted line displays the time course predicted for the same bolus dose, assuming that  k  eois 2.4 times smaller,  i.e.  , a value similar to that for rocuronium  1 ; note that peak effect is less and recovery longer than with the larger  k  eo. The dashed line displays the predicted time course for a bolus dose (2.3 mg/kg) that yields that same peak effect-site concentration as the solid line, assuming the smaller  k  eo; note that recovery is yet longer. Therefore, a larger  k  eo(more rapid equilibration between plasma and effect site) speeds both onset and recovery. 
×