Pharmacokinetics and Pharmacodynamics of a Second Dose of Atracurium in Anaesthetised Patients

To determine whether the rapid onset of a second dose of a muscle relaxant was explained by pharmacokinetic (PK) or pharmacodynamic (PD) factors, atracurium PK-PD modelling was performed after 2 bolus doses of 0.5 mg/kg given approximately 1 hour apart to 6 anaesthetised patients. Neuromuscular function was monitored using single twitch stimulation during onset and train-of-four during recovery. Arterial concentrations were measured every 10 seconds for the first 2 minutes following each atracurium injection, then at frequent intervals thereafter. After the second dose, in spite of mean residual atracurium plasma concentrations of 227 µg/L, kinetics were unchanged. In contrast, onset times were markedly more rapid after the second dose (1.6 ± 0.1 vs 9.0 ± 1.8 minutes after the first dose) and clinical recovery prolonged (55.8 ± 2.2 vs 42.5 ± 2.0 minutes after the first dose). Taking into account residual plasma concentrations and neuromuscular block, the equilibration rate constant between plasma and effect site concentrations, Keo, was not significantly altered (0.035 ± 0.001 vs 0.043 ± 0.004 min−1). Therefore, the Keo seems to represent the rate of transfer to the neuromuscular junction without the confounding effect of receptor occupancy. Conversely, onset times would be extremely dependent on receptor events. Hence, the more rapid onset time following the second atracurium dose is most likely caused by residual concentrations at the effect site.