A Pharmacodynamic Explanation for the Rapid Onset/Offset of Rapacuronium Bromide 

After obtaining approval from our local institutional review board and informed consent from each participant, we studied 10 healthy paid volunteers who were classified as American Society of Anesthesiologists physical status 1, 20-42 yr old, and underwent anesthesia but no surgery. These volunteers were the control group for another study to determine the influence of renal failure on the pharmacokinetics of rapacuronium (the findings of that study are reported separately [7]). Volunteers were not receiving any drugs that might influence their neuromuscular response to rapacuronium. Demographic data for these persons are reported elsewhere. [7] 

After an overnight fast, the volunteers had an intravenous catheter placed in an upper extremity. After administration of 5 [micro sign]g/kg fentanyl, anesthesia was induced with 2-3 mg/kg propofol and their tracheas were intubated without the aid of a muscle relaxant. A left-sided 35 or 37 French gauge double-lumen tracheal tube (Broncho-Cath; Mallinckrodt Medical, St. Louis, MO) was inserted with the distal cuff positioned above the carina and the proximal cuff at the vocal cords. [6]The tube was secured at the lip and by inflating the distal cuff. The lungs were ventilated mechanically through the distal lumen, thereby isolating the proximal cuff from airway pressure changes. Anesthesia was then maintained with propofol infused at approximately 150 [micro sign]g [middle dot] kg^-1[middle dot] min^-1. An intravenous catheter was placed in the contralateral arm to sample blood and a catheter was placed in a radial artery. Core temperature [8]and end-tidal carbon dioxide tension were maintained at normal levels.

After the volunteers lost consciousness, a single 5-s, 50-Hz supramaximal tetanic stimulus [9]was applied to the ulnar nerve via subcutaneous 27-gauge needles at the wrist followed by supramaximal train-of-four stimuli every 12 s. Mechanical twitch response of the adductor pollicis was measured with a calibrated force displacement transducer; preload was maintained at 250 g. Supramaximal train-of-four stimuli were applied to the larynx via surface electrodes applied over the cricoid notch and the forehead. [10]The pilot tube of the proximal cuff of the tracheal tube was inflated to 30 mmHg⁶and connected to a pressure transducer.

The twitch tension of the adductor pollicis and the laryngeal muscles was amplified, digitized, displayed, and recorded on-line and on a strip chart. The first twitch response of each train-of-four (T1) was stable for more than 15 min before rapacuronium administration. The ratio of the fourth component to the first component of each train-of-four stimuli was determined. Values for twitch tension during recovery were normalized to the plateau value at recovery.

Rapacuronium (1.5 mg/kg) was administered over 5 s into a rapidly flowing intravenous line. Twitch tension was recorded until T1 recovered completely and the train-of-four ratio was more than 0.9. Arterial blood (5 ml) was sampled 0.5, 1, 2, 4, 6, 8, 10, and 20 min after rapacuronium administration. Venous blood (5 ml) was sampled before and 3, 7, 10, 20, 30, 45, 60, 75, 90, and 120 min after rapacuronium administration. Arterial blood samples were obtained in less than 5 s, venous samples were collected in less than 10 s, and the midpoint of the sampling interval was recorded. Sodium dihydrogen phosphate buffer (0.8 M) was added immediately to samples to prevent degradation of rapacuronium. Blood was centrifuged within 30 min of sampling, and plasma was stored at -20 [degree sign]C. Concentrations of rapacuronium and its primary 3-OH metabolite, ORG9488, were determined by Corning Hazelton Labs (Hazelton, WI) using a high-pressure liquid chromatography-mass spectrometry technique. The assay is linear for concentrations greater than 2 ng/ml for rapacuronium and ORG9488, and it has a coefficient of variation less than 11% for rapacuronium and less than 32% for ORG9488.

For each volunteer, (log) arterial and venous concentrations of rapacuronium during the 20 min after its administration were plotted against time. Arterial concentrations were connected and assessed visually for deviations from venous values. Because these analyses suggested minimal differences between arterial and venous concentrations (see Results), venous concentrations after 20 min and all arterial concentrations were used in the pharmacodynamic analysis.

The pharmacodynamic characteristics of rapacuronium were determined using a semiparametric approach [11]in which the time course of the plasma concentrations of rapacuronium and ORG9488 are described by linear interpolation of the preceding and subsequent measured values. For example, a measured rapacuronium concentration of 1,500 ng/ml at 10 min and 1,000 ng/ml at 15 min would yield an interpolated concentration of 1,300 ng/ml at 12 min. During the 0.5 min after administration of rapacuronium, rapacuronium and ORG9488 concentrations are assumed to increase linearly from a concentration of 0 ng/ml at 0 min to the concentration observed at 0.5 min. This approach is based on the observation of Ducharme et al. [12]that arterial concentrations of vecuronium increase, rather than decrease, in the period immediately after administration and then peak approximately 0.5 min after bolus administration; it presumably describes the early time course better than would a compartmental model that assumes a monotonic decrease in the plasma concentration. Arterial concentrations were used to describe the plasma concentration profile for the 20 min after rapacuronium administration; thereafter, venous concentrations were used in the analysis.

Concentrations of rapacuronium and ORG9488 at the effect site were permitted to equilibrate with their plasma concentrations with the rate constant [small kappa, Greek]^oe; this rate constant was permitted to differ between the two muscle groups. Equilibration of ORG9488 between plasma and the effect compartment was assumed to have the same rate constant as for rapacuronium. The effective concentration of muscle relaxant at the effect site (C^effective) was assumed to be the sum of the effect site concentrations of rapacuronium and that of ORG9488, with the latter adjusted for its potency (potency ratio [middle dot] effect site concentration of ORG9488). We tested four relative potencies [C⁵⁰(rapacuronium)/C⁵⁰(ORG9488)]-0, 1, 1.5, and 2-for ORG9488. Twitch depression for each muscle group was assumed to relate to the effective concentration of muscle relaxant at the effect site according to the Hill equation:Equation 1where [small gamma, Greek] is the Hill factor governing sigmoidicity of the concentration-effect relation and C⁵⁰is the effect site concentration of the muscle relaxant depressing twitch tension by 50%.

These analyses were performed using a population approach (values for all volunteers were analyzed simultaneously to determine typical values for the population) using NONMEM's first-order conditional estimate method. We permitted [small kappa, Greek]^eo, C⁵⁰, and [small gamma, Greek] and interindividual variability for each of these parameters to differ between the muscle groups; that is, a volunteer whose value for [small gamma, Greek](adductor pollicis) was greater than the typical value need not have a value for [small gamma, Greek](laryngeal adductor) that was larger than the typical value for that parameter. This analysis was performed for each of the four ORG9488:rapacuronium potency ratios. The potency ratio that resulted in the best objective function was selected for further analysis. NONMEM's post hoc step was applied to that model to determine values of the pharmacodynamic parameters for each volunteer. For each of C⁵⁰, [small kappa, Greek]^eo, and [small gamma, Greek], the ratio for these values for the two muscle groups was determined. Mean values of these ratios were compared to 1.0 using the Student's t test. In addition, the influence of demographic characteristics and preoperative laboratory values was assessed visually and using the Student's t test.

The magnitude of maximal twitch depression (expressed as the percentage depression from the predrug control value) and the time from administration of rapacuronium to 10%, 50%, and maximum twitch depression were determined. The time from administration of rapacuronium to 10%, 25%, 50%, and 90% recovery of T1 (based on the T1 value obtained after complete recovery of neuromuscular function), and the time from 25% to 75% recovery of T1 were determined. Values are presented as the mean +/− SD; mean values for muscle groups were compared using the Student's t test for paired data (two-tailed). P < 0.05 was considered significant.

Two volunteers experienced 92% and 94% depression, respectively, at the laryngeal muscles. The remaining volunteers had more than 95% depression at the laryngeal muscles, and all participants had complete twitch depression at the adductor pollicis. The times to maximum depression and 10% recovery of T1 were faster at the laryngeal muscles than at the adductor pollicis (Table 1, Figure 1). The times to 10% and 50% depression and 25%, 50%, and 90% recovery were similar for the two muscle groups.

For nine participants, arterial and venous concentrations of rapacuronium were nearly identical (Figure 2). For the remaining participant, venous concentrations were slightly less than or similar to corresponding arterial concentrations. Rapacuronium and ORG9488 were detected in all postdose samples.

Analyses in which potency ratios of ORG9488 to rapacuronium ranged from 0 to 2 all yielded an excellent fit of the pharmacodynamic model to the effect data for both muscle groups; the objective function was least with a potency ratio of 2 (Table 2, Figure 3and Figure 4).

With the optimal model, [small kappa, Greek]^eo(laryngeal adductors) was greater than [small kappa, Greek]^eo(adductor pollicis)(Table 3and Table 4); that is, equilibration was faster at the laryngeal adductors than at the adductor pollicis muscle. There was no difference between the two muscle groups in C⁵⁰or in the Hill factor. Although values for [small kappa, Greek]^eo, C⁵⁰, and [small gamma, Greek] for each muscle depended on the value of the potency ratio used in the analysis (Table 2), differences between muscle groups did not vary with the potency ratio. Values for [small kappa, Greek]^eo(laryngeal muscles) were larger for women than for men (1.35 +/− 0.50 min^-1vs. 0.51 +/− 0.41 min^-1, respectively; P < 0.02 by the Student's t test for unpaired data); for [small kappa, Greek]^eo(adductor pollicis), the differences approached statistical significance (0.92 +/− 0.65 vs. 0.35 +/− 0.33 min^-1, P = 0.0505). Values for C⁵⁰and [small gamma, Greek] did not vary with gender, and there was no apparent relation among [small kappa, Greek]^eo, C⁵⁰, or [small gamma, Greek] for either muscle group and height, weight, or preoperative values for hematocrit, albumin, bilirubin, creatinine, or serum glutamate oxaloacetate transaminase.

The time to complete depression of the adductor pollicis and the time to maximal depression of the laryngeal muscles after administration of 1.5 mg/kg rapacuronium were comparable to those observed for 1 mg/kg succinylcholine in a recent study [13]from our institution in which anesthetic and monitoring conditions were similar to those in the current study. In addition, the time to 25% recovery of adductor pollicis twitch tension after rapacuronium administration was only slightly longer than after succinylcholine (8 +/− 2 min). [13]Therefore, rapacuronium's time course at the adductor pollicis and the laryngeal muscles in this study is similar to that of succinylcholine. [13]In addition, the time to maximum depression of the adductor pollicis and the laryngeal muscles is faster than that for 0.8 mg/kg rocuronium, [13]which is the nondepolarizing muscle relaxant with the fastest onset.

To explain the rapid onset of rapacuronium, we determined its pharmacodynamic characteristics. Although we did not determine the pharmacodynamics of other muscle relaxants, values for rapacuronium can be compared with historical data for other nondepolarizing muscle relaxants from our laboratory and others obtained under similar study and anesthetic conditions and using similar modeling approaches. The primary difference between rapacuronium and other nondepolarizing muscle relaxants is the rate at which concentrations in plasma and effect site equilibrate ([small kappa, Greek]^eo) for the adductor pollicis and the laryngeal muscles. Values for [small kappa, Greek]^eo(adductor pollicis) are approximately 2.4 times that for rocuronium [5](0.168 +/− 0.063 per min) and 3.4 times that for vecuronium [14](0.12 +/− 0.05 per min); values for [small kappa, Greek]^eo-(laryngeal adductors) are approximately 2.4 times that for rocuronium [5](0.26 +/− 0.06 per min) and 3.5 times that for vecuronium [14](0.18 +/− 0.07 per min). These large [small kappa, Greek]^eovalues presumably explain the rapid onset of rapacuronium.

Kopman [15]reported an inverse correlation between the potency of nondepolarizing muscle relaxants (as defined by the dose producing 95% twitch depression and, by extension, by plasma concentration) and their speed of onset. This is our explanation of Kopman's observations: Injection of a bolus dose produces a gradient of muscle relaxant from plasma to neuromuscular junction. The neuromuscular junction drains relaxant from the plasma in two ways, by binding of relaxant to the receptor and by equilibration with extracellular fluid adjacent to the receptor (this is the biophase). Assuming that a given degree of paralysis results from binding of a fixed number of receptors, the higher plasma concentration produced by a less potent relaxant increases the magnitude of this gradient (more molecules of a less potent relaxant are available in plasma to fill the biophase and receptors in a given period). This is analogous to the effect of a high versus a low tissue-blood partition coefficient: A depot with a high partition coefficient takes longer to fill than one with a low partition coefficient. However, we do not use the term partition coefficient because partitioning between plasma and the biophase may differ as a function of saturable binding at the neuromuscular junction. Our explanation for the effect of potency on onset time (i.e., differences in partitioning for drugs of different potency) is consistent with Hull's receptor buffering theory [16](that nearly all relaxant molecules at the neuromuscular junction are bound) but does not require the assumption that the quantity of drug bound to the receptor is large compared with that in the adjacent extracellular fluid.

The other factor that influences the time course of concentrations of the muscle relaxant at the effect site is its time course in plasma. A more rapid decrease in the plasma concentration of a muscle relaxant (i.e., a shorter distribution half-life), as might result from either a larger clearance or a larger distributional clearance, would hasten the time at which the concentration peaked at the effect site (and would also decrease the magnitude of the peak concentration at the effect site, possibly necessitating a larger dose). In turn, the peak effect of equipotent doses would occur earlier with a larger clearance. For example, succinylcholine's onset was markedly delayed in a volunteer with atypical plasma cholinesterase activity (the time to peak effect of a subparalyzing dose was 6 min)[17]; presumably this resulted because that volunteer had a markedly decreased plasma clearance of succinylcholine. Thus the finding that rapacuronium's clearance in the volunteers in the current study [7](8.55 to 10.25 ml [middle dot] kg^-1[middle dot] min^-1) is larger than that of vecuronium [14](5.1 ml [middle dot] kg^-1[middle dot] min^-1) and rocuronium [18](2.89 ml [middle dot] kg^-1[middle dot] min^-1) may also contribute to the rapid onset of rapacuronium's effect. However, rapacuronium's clearance is markedly less than that of the potent isomers of mivacurium [19](56-63 ml [middle dot] kg^-1[middle dot] min^-1for the trans-trans isomer and 105-106 ml [middle dot] kg^-1[middle dot] min^-1for the cis-trans isomer), suggesting that differences in clearance are not sufficient to explain the speed of onset. In turn, the rapid onset of rapacuronium is determined in large part by the rapid equilibration between plasma concentrations and effect.

As with other muscle relaxants, the laryngeal muscles equilibrate more rapidly than do the adductor pollicis muscles. Using the approach described earlier, this indicates either that, compared with the adductor pollicis, the laryngeal muscles have a greater blood flow volume per gram of tissue or their partition coefficient is smaller. The results of the current study (and those of previous similar studies) do not offer insight into the relative contribution of each of these factors. Of note, the ratio for [small kappa, Greek]^eovalues for the laryngeal adductors and the adductor pollicis ([tilde operator] 1.6) is similar to that reported previously for vecuronium [6]and rocuronium. [5] 

We found no difference in steady state sensitivity between the adductor pollicis and the laryngeal muscles. This is in contrast to the relative resistance of the laryngeal muscles (i.e., requiring a 20% larger steady state plasma concentration compared with the adductor pollicis) observed in other studies for both vecuronium [6]and rocuronium. [5]We cannot explain this difference between rapacuronium and other nondepolarizing muscle relaxants.

Values for [small kappa, Greek]^eo(laryngeal adductors) were greater for women than for men; a similar comparison for [small kappa, Greek]^eo(adductor pollicis) found nearly significant differences. This suggests that the onset of rapacuronium may be faster in women than in men. However, intraindividual variability may be sufficient to mask a gender-related difference in onset.

The results for neuromuscular effects of rapacuronium in the current study differ minimally from those from a similar study by Debaene et al. [20]They administered rapacuronium in doses of 0.75, 1.5, and 2 mg/kg and measured laryngeal muscle function using a similar technique; however, plasma was not sampled to determine concentrations of rapacuronium. With their 1.5 mg/kg dose, the time to peak effect was 96 +/− 20 s at the adductor pollicis and 62 +/− 13 s at the laryngeal muscles, findings that are similar to values we achieved in the current study. However, they reported that the time to 25% recovery was faster at the laryngeal adductors than at the adductor pollicis muscles, but we observed no difference between muscle groups in the time to 25% recovery. We cannot explain this discrepancy between the two studies.

One limitation of our study is the lack of information regarding the potency of ORG9488. Schiere et al. [21]administered ORG9488 to patients anesthetized with nitrous oxide and isoflurane (end-tidal concentrations not specified) and reported that the C⁵⁰of ORG9488 was 2,060 ng/ml. However, these investigators did not administer rapacuronium to these same patients on a separate occasion (as has been done for vecuronium and its metabolite [22]) so as to determine the relative potency of rapacuronium and ORG9488 or their relative equilibration rates. Despite the lack of comparative data, Schiere et al. concluded that “Org 9488 is more potent … than Org 9487 [rapacuronium].” In the absence of definitive information regarding the relative potency of rapacuronium and ORG9488, we evaluated four different potency ratios (ranging from ORG9488 being inactive to it being twice as potent as rapacuronium). Although each of these analyses yielded slightly different results for [small kappa, Greek]^eo, C (⁵⁰), and [small gamma, Greek], the ratio of values for the two muscle groups varied minimally with different potency ratios (Table 2). Thus the possible misspecification of the potency and equilibration rate of the metabolite appears to have only a minimal effect on our results. As expected, values for C⁵⁰varied most with different potency ratios.

Another limitation is that we used arterial (early) and venous (late) concentrations of rapacuronium in the pharmacodynamic analysis. This decision was based on our lack of arterial values after 20 min and the similarity of arterial and venous concentrations throughout the 20-min period when both were measured. The similarity of arterial and venous plasma concentrations of rapacuronium suggests that venous values can probably be used in both pharmacokinetic and pharmacodynamic analyses of rapacuronium. However, we did not compare arterial and venous concentrations of rapacuronium in the 2-min period immediately after drug administration, the time at which the difference is expected to be largest.

Finally, instead of fitting a compartmental model to our data for rapacuronium plasma concentrations, we used a semiparametric modeling approach that assumes that the plasma concentration versus time course can be described by linear interpolation of the measured values. In addition, we assumed that the rapacuronium plasma concentration during the first 0.5 min increased in a linear manner from a value of 0 at time 0 to the value measured at 0.5 min. If these assumptions are flawed, the reliability of our estimates would be affected. An alternate study design in which rapacuronium was administered as a 5- to 10-min infusion might have permitted us to use a compartmental model to describe the plasma concentration values and to avoid the assumptions used in our model.

In conclusion, the onset of rapacuronium is rapid at the adductor pollicis and the laryngeal adductor muscles. The more rapid onset of rapacuronium compared with other nondepolarizing muscle relaxants results from more rapid equilibration between its plasma concentrations and the effect site. This more rapid equilibration correlates with the low potency of rapacuronium and suggests that limited partitioning between plasma and the effect site facilitates onset. The rapid time course of rapacuronium suggests that it rivals succinylcholine in facilitating tracheal intubation.

The authors thank Greg Barnes of Mallinckrodt Medical, Irvine, California, for providing the tracheal tubes.