Pharmacokinetics of Atracurium and Laudanosine in the Elderly

Abstract

The pharmacokinetics of a bolus dose of atracurium 0.6 mg kg-1 and its metabolite laudanosine were studied in 11 elderly (mean age 80.9 yr) and 10 young patients (mean age 23.8 yr) undergoing elective surgery. The elimination half-life (T1/2 beta) of atracurium was significantly longer in the elderly group (23.1 v. 20.1 min), but there was no significant difference between the two groups in clearance (Cl), the volume of distribution (V beta) or the mean residence time (MRT) of atracurium. Laudanosine T1/2 beta was also significantly longer (229.1 v. 173.1 min) and the clearance significantly slower (4.85 v. 7.29 ml min-1 kg-1) in the elderly. There was, however, no significant difference in V beta for laudanosine between the two groups. These data suggest that atracurium depends to a small extent on the liver or the kidney for its metabolism and excretion, and that, as these routes of excretion are less efficient in the elderly, T1/2 beta is prolonged in this age group. The deteriorating function of these organs with increasing age may also explain the altered pharmacokinetics of laudanosine.

Clinical Pharmacokinetics of Neuromuscular Blocking Drugs

“…Elimination of atracurium occurs in both tissue and plasma, making traditional I-compartment pharmacokinetic models inaccurate. Therefore, the area under the plasma concentration-time curve (AUC) was used to calculate pharmacokinetic variables (Fahey et al 1984;Kent et al 1989;Ward et al 1983) or 2-compartment models were modified to account for different elimination rate constants from the central and peripheral compartments (Fisher et al 1986Kitts et al 1990).…”

“…Since these age-related changes occur simultaneously, neither the t' l2/3 nor the recovery from the neuromuscular blockade alters with age ). In the elderly, however, the t' l2/3 may be longer and the V d larger (Kent et al 1989;Kitts et al 1990) than in young adults, which could prolong recovery from neuromuscular blockade in the elderly, particularly after multiple or large doses. Thermal injury (Maratke et al 1989) did not alter atracurium pharmacokinetics but caused significant resistance to the neuromuscular effects of this compound, reflected by a 3-to 4-fold increase in the concentration of the drug required to produce a given degree of twitch depression.…”

“…Furthermore, the concentrations used by Nigrovic et al (1989) were many times greater than those occurring under clinical conditions. (1989) 4.8 Kent et al (1989) Abbreviations: Cmax = peak plasma concentration; t'l2~ = elimination half-life; CL/F = apparent clearance.…”

Evaluating the 10X Uncertainty Factor for Children and Elderly with Data-Derived Values for Neuromuscular Blocking Agents

“…The highest kinetic (1.9) and dynamic (1.4) ratios among infants and children were used to calculate the composite factor. Kent et al (1989) studied the pharmacokinetics of a bolus dose of atracurium 0.6 mg/kg in 11 elderly patients (80.9 + 8.2 years) and compared the results to those in 10 young adults (23.8 + 4.3 years) ( Table 3). The ratios of kinetic parameters between the two groups were 1.3 to 1.6.…”

Pharmacokinetic Modelling of a Parent Drug and its Metabolite

“…To help resolve this question, several groups of investigators have reported on the time course of the plasma concentrations oflaudanosine after the administration of a single intravenous bolus injection of atracurium (Fahey et al 1985;Kent et al 1989;Vandenbrom et al 1990;Ward et al 1987). Immediately after administration of atracurium (2 min), the concentrations oflaudanosine were highest and decreased during the next 8 to 10 min.…”