Pharmacokinetics and Neuromuscular Blocking Effects of Atracurium Besylate and Two of Its Metabolites in Patients with Normal and Impaired Renal Function

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Abstract
The pharmacokinetics of atracurium, laudanosine and the quaternary alcohol were studied in patients with normal and impaired renal function following intravenous administration of atracurium. Anaesthesia consisted of thiopental, fentanyl, halothane and nitrous oxide in oxygen. Plasma and urine concentrations of the parent compound and its degradation products were measured by high performance liquid chromatography. Renal failure was defined as a creatinine clearance of less than 5 ml/min; it caused no significant differences in the pharmacokinetics of atracurium but did result in a different pharmacokinetic profile of laudanosine, with a 3-fold increase in the mean (± SD) terminal half-life (176 ± 84 and 516 ± 262 minutes for patients with normal and impaired renal function, respectively). Moreover, the half-life of the quaternary alcohol increased from 27.1 ± 8.3 minutes in patients with normal renal function to 42.5 ± 8.3 minutes in those with impaired renal function (mean ± SD). Renal elimination of unchanged atracurium accounted for 11% of the administered dose and at least 27% of the total degradation of atracurium occurred via ester hydrolysis. The neuromuscular function was monitored by measuring the twitch tension of the adductor pollicis muscle elicited by stimulation of the ulnar nerve at 0.1Hz. The total duration of neuromuscular blockade (51.8 ± 11.5 minutes) and the recovery index (9.6 ± 2.0 minutes) are shortened in patients with impaired renal function, compared with those with normal renal function (64.1 ± 7.2 and 16.7 ± 4.1 minutes, respectively), indicating that sensitivity to the neuromuscular blocking action of atracurium may be altered by renal failure.