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

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 0.1 Hz. 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.

Clinical Pharmacokinetics of Neuromuscular Blocking Drugs

“…The t' 12!3 of the monoquaternary alcohol is similar to that of the parent compound (27 min), but, unlike atracurium, it is significantly longer in patients with renal failure (Vandenbrom et al 1990). The accumulated pharmacokinetic knowledge of atracurium biotransformation fully justifies using rapidly metabolised drugs for short procedures.…”

“…Doxacurium ) and pipecuronium (Agoston & Richardson 1985) have a long duration of action comparable with that of pancuronium; however, both appear to be free of cardiovascular side effects. The pharmacokinetics of atracurium (Vandenbrom et al 1990;Ward & Weatherley 1986), vecuronium (Bencini et al 1986a), pipecuronium (Caldwell et al 1989), doxacurium (Dresner et al 1990) and rocuronium (Wierda et al 1991 a) have been reported. There is limited information on the pharmacokinetics of mivacurium (De Bros et al 1987).…”

The distribution of laudanosine in tissues after death from atracurium injection

“…Atracurium undergoes spontaneous degradation via Hofman elimination, a non-enzymatic breakdown process occurring at physiological pH and temperature, to produce laudanosine ( Fig. 1) and pentamethylene-1,5 diacrylate [3]. There is also some ester hydrolysis by non-specific plasma esterases.…”

Postoperative Resistenzentwicklung gegenüber Atracurium

“…Das Computertomogramm des Thorax zeigte Infiltrationen im Bereich des rechten Unterlappens sowie eine abszeßverdächtige Verdichtung im Bereich des Mittellappens. Entsprechende Veränderungen fanden sich bei Urämikern [8,19]. Zur antibiotischen Abdeckung erhielt der Patient Cefotiam, Gentamycin und Metronidazol.…”