A Pharmacokinetic Explanation for Increasing Recovery Time Following Larger or Repeated Doses of Nondepolarizing Muscle Relaxants

&NA; The authors used pharmacokinetic and pharmacodynamic modeling to explain the time course of neuromuscular blockade following single or multiple doses of three nondepolarizing muscle relaxants. Published and unpublished pharmacokinetic and pharmacodynamic data for 13 normal subjects were used to simulate the duration of neuromuscular blockade (time from administration of the muscle relaxant to 25% recovery of control twitch tension) following six successive doses of atracurium (150–400 &mgr;g/kg initially, followed by 100 &mgr;g/kg), vecuronium, or pancuronium (30–80 &mgr;g/kg initially, followed by 20 &mgr;g/kg). With atracurium, duration of action was similar for the second and sixth doses, regardless of the initial dose. With vecuronium (initial doses of 30–80 &mgr;g/kg) and pancuronium (initial doses of 30–60 &mgr;g/kg), duration of action was longer after the sixth dose than after the second; with larger initial doses of pancuronium (70 and 80 &mgr;g/kg), duration of action was similar following the second and sixth doses. The authors also determined two recovery times (time for twitch tension to recover from 5–25% and from 25–75% of control value) for varying single doses of atracurium, vecuronium, or pancuronium. When the dose of atracurium was increased from 200 to 400 &mgr;g/kg, neither recovery time increased. When the dose of vecuronium was increased from 40 to 80 &mgr;g/kg, 5–25% recovery time increased from 6.0 ± 2.5 min to 8.8 ± 4.0 min (mean ± SD) and 25–75% recovery time increased from 8.7 ± 4.3 min to 12.6 ± 4.4 min. When the dose of pancuronium was increased from 40 to 80 &mgr;g/kg, 5–25% recovery time increased from 20.2 ± 5.5 min to 36.5 ± 14.1 min and 25–75% recovery time increased from 35.9 ± 13.0 min to 78.8 ± 23.7 min. These results are consistent with data obtained in clinical studies of single and multiple doses of these muscle relaxants and demonstrate that the duration of neuromuscular action of pancuronium is most affected, and atracurium less affected, by increased and repeated doses.