Cumulative characteristics of atracurium and vecuronium. A simultaneous clinical and pharmacokinetic study

BACKGROUND: Cumulative effects (increased 25-75% recovery time with increasing dose) are evident with vecuronium but not with atracurium. Pharmacokinetic simulations suggest that vecuronium's cumulation occurs as recovery shifts from distribution to elimination whereas atracurium's recovery always occurs during elimination. The purpose of this study was to examine this pharmacokinetic explanation. METHODS: We assigned 12 volunteers to receive atracurium of vecuronium on three occasions during nitrous oxide-isoflurane anesthesia. Evoked adductor pollicis twitch tension was monitored. On occasion 1, the dose expected to produce 95% block (ED95) was estimated for each subject. On occasions 2 and 3, 1.2 or 3.0 multiples of ED95 were given as a bolus. Plasma was sampled for 128 min to determine muscle relaxant concentrations; pharmacodynamic modeling was used to determine effect-compartment drug concentrations (Ce). For each drug, recovery time, recovery phase half-life (rate of decrease in Ce during recovery), and Ce at 25% and 75% recovery were compared between doses. RESULTS: Atracurium's recovery time increased 2.4 +/- 2.2 min (mean +/- SD) with the larger dose, less than the increase with vecuronium (8.2 +/- 3.8 min). Atracurium's recovery phase half-life was 14.6 +/- 1.7 and 20.1 +/- 2.3 min with the small and large doses (P < 0.05); vecuronium's recovery phase half-life increased similarly from 13.5 +/- 2.3 to 18.5 +/- 5.0 min (P < 0.05). At 75% recovery, vecuronium's Ce decreased from 65 +/- 18 ng/ml with the small dose to 55 +/- 15 ng/ml with the large dose (P < 0.05). Assuming that neuromuscular junction sensitivity was constant, this difference could be explained by considering neuromuscular effects of vecuronium's metabolite, 3-desacetylvecuronium. CONCLUSIONS: Although vecuronium was cumulative (as predicted), atracurium was also slightly cumulative. Inconsistent with our hypothesis, recovery phase half-lives for both drugs increased similarly between doses; therefore, differences in cumulation were not solely explained by pharmacokinetics of the muscle relaxant. It appears that 3-desacetylvecuronium contributes to vecuronium's cumulative effect, even after usual clinical doses.