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We have compared the pharmacokinetics of cisatracurium with atracurium when given by bolus dose followed by continuous infusion. Twenty healthy patients were anaesthetised with thiopentone, midazolam, fentanyl and 70% nitrous oxide in oxygen. Ten patients (Group C) were randomly allocated to receive cisatracurium 0.1 mg.kg-1 and 10 patients (Group A) were given atracurium 0.5 mg.kg-1. Neuromuscular block was monitored using a mechanomyograph. When the first twitch of the train-of-four had recovered to 5% of control, an infusion of cisatracurium 3 micrograms.kg-1.min-1 was started in Group C and an infusion of atracurium 10 micrograms.kg-1.min-1 was started in Group A. The infusion rates were adjusted to maintain the first twitch of the train-of-four at 5% of control. The times to 90% and maximum depression of the first twitch of the train-of-four were significantly longer after cisatracurium than atracurium (2.2 and 3.4 min compared with 1.3 and 1.8 min, respectively; p < 0.01 in each instance). No significant differences were found in recovery parameters between the two groups. Blood samples were taken at regular intervals following the bolus, during the infusion and for 8 h thereafter. The plasma samples were analysed using high-performance liquid chromatography for cisatracurium and atracurium (using a method which distinguishes between the three geometric isomer groups), laudanosine and monoquaternary alcohol. The results were analysed using the Non-linear Mixed Effects Model program. A two-compartment model was fitted to the data. The different isomer groups of atracurium have different pharmacokinetics, the trans-trans group having the highest clearance (1440 ml.min-1) and the cis-cis group the lowest (499 ml.min-1). The clearance of cisatracurium (425 ml.min-1) is less than that of cis-cis atracurium and its elimination half-life is longer (34.9 min and 21.9 min, respectively). The plasma concentration of laudanosine after cisatracurium was one-fifth of that after atracurium.

We have studied 12 critically ill, sedated patients who required a neuromuscular blocking drug to assist mechanical ventilation in an intensive care unit. Patients were randomized to receive an infusion of cis-atracurium 0.18 mg kg-1 h-1 (group 1, n = 6) or atracurium 0.6 mg kg-1 h-1 (group 2, n = 6) preceded, if necessary, by a bolus dose of 2 x ED95 of the same drug (cis-atracurium 0.1 mg kg-1 or atracurium 0.5 mg kg-1). Neuromuscular block was monitored using an accelerograph and the infusion rate adjusted regularly so that it was possible to detect the first response to train-of-four (TOF) stimulation of the ulnar nerve at the wrist. Blood samples were obtained for estimation of plasma cis-atracurium and laudanosine concentrations (group 1) or the three groups of atracurium isomers and laudanosine (group 2). There was no apparent haemodynamic or allergic response to either drug. The mean infusion time in group 1 was 37.6 h and in group 2, 27.5 h. On termination of the infusion, the time for the TOF ratio to reach 0.7 was similar in the two groups (group 1 = 60 min; group 2 = 62 min). The mean infusion rate of cis-atracurium was 0.19 mg kg-1 h-1 and of atracurium 0.47 mg kg-1 h-1 (expressed as mg of bis-cation): cis-atracurium was 2.5 times more potent than atracurium. Using the NONMEM program, a single compartment pharmacokinetic model was fitted to the plasma concentrations of cis-atracurium and the cis-cis, cis-trans and trans-trans isomers of atracurium. The mean population pharmacokinetic values for cis-atracurium were: volume of distribution (V) = 21,900 (SEM 416) ml; clearance (Cl) = 549 (79) ml min-1; half-life (T1/2) = 27.6 (3.6) min; and for the three groups of atracurium isomers were: cis-cis, V = 15,100 (720) ml, Cl = 449 (42) ml min-1, T1/2 = 23.4 (1.2) min; cis-trans, V = 18,000 (667) ml, Cl = 1070 (43) ml min-1, T1/2 = 11.7 (0.1); trans-trans, V = 13,100 (1280) ml, Cl = 1560 (55) ml min-1, T1/2 = 5.8 (0.4) min. Plasma laudanosine concentrations were lower in the cis-atracurium (peak value 1.3 micrograms ml-1) than in the atracurium (maximum 4.4 micrograms ml-1) group.

To ascertain the effects of chronic renal failure on the pharmacokinetics of 1R-cis 1'R-cis atracurium besylate (a stereoisomer, designated 51W89), we gave a bolus dose of 0.1 mg kg-1 (2 x ED95) to 17 patients with end-stage renal failure and to 15 patients with normal renal function undergoing elective surgery. All patients received thiopentone, fentanyl and midazolam i.v. and 70% nitrous oxide in oxygen. Blood samples were obtained over 8 h and plasma analysed for 51W89 and laudanosine concentration, using high pressure liquid chromatography. A two-compartment model was fitted to the 51W89 plasma concentration data using the NONMEM program, to estimate pharmacokinetic variables and to determine the influence of renal failure, age, weight and sex. Clearance of 51W89 was found to be reduced by 13% in renal failure. The typical value of T1/2 beta was 4.2 min longer in renal failure than in the healthy patients (34.2 vs 30.0 min, P < 0.005). In the healthy patients, clearance of 51W89 was greater in males, but it decreased with increasing age by approximately 1.5 ml min-1 yr-1. Mean plasma laudanosine concentrations were significantly higher in the renal failure group; nevertheless, they were approximately one-tenth of those reported after atracurium.

We have studied the pharmacodynamics of the 1R cis-1'R cis isomer of atracurium (51W89) in 15 healthy subjects and in 17 patients with chronic renal failure using a bolus dose of 51W89 0.1 mg kg-1 (2 x ED95). Fifteen patients with normal renal function were investigated also using an approximately equipotent dose of atracurium (0.4 mg kg-1). The compound surface action potential of the adductor pollicis muscle, in response to train-of-four stimulation of the ulnar nerve at the wrist, was recorded until recovery of the height of the first response of the train-of-four compared with baseline (T1:T0) had reached at least 85% and the train-of-four ratio (T4:T1) at least 80%. In the healthy and renal failure patients who received 51W89, there were no significant differences in any of the onset or recovery variables except for the time to 90% depression of T1:T0, which was longer in patients with renal failure (mean 3.7 min vs 2.4 min; P < 0.05). Of the healthy patients who were given either 51W89 or atracurium, there were no significant differences in the onset data, except for time to maximum block, which was longer in the 51W89 group (mean 7.7 min vs 6.2 min; P < 0.01). The mean times to 10%, 25%, 50% and 75% recovery of T1:T0 and the time for T4:T1 > 70% were significantly longer in patients receiving 51W89.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of the 1R cis-1'R cis-isomer of atracurium (51W89) and its metabolite, laudanosine, were studied in 11 healthy patients with normal renal function and in 12 patients with chronic renal failure undergoing regular dialysis. A bolus dose of 51W89 (0.1 mg/kg) was given, and the plasma concentration was measured at regular intervals for 480 min. The elimination half-life of 51W89 was significantly longer in renal failure patients than in healthy controls (38.9 min vs 30.6 min; P < 0.05). The plasma laudanosine levels were lower than those reported after an equipotent dose of atracurium besylate. 51W89 may have a prolonged effect in renal failure patients.

We have determined the central and steady state volumes of distribution of atracurium 0.25 mg kg-1 in 41 healthy adult patients. Volume of distribution, corrected for body weight (ml kg-1); correlated negatively with body weight (r = -0.612 for central volume of distribution; r = -0.737 for the steady state volume of distribution). When expressed as an absolute volume, neither central nor steady state volume of distribution correlated significantly with body weight (r = 0.120 and r = 0.131, respectively). These data cast doubt upon the necessity for the dose of atracurium to be related to body weight in the healthy adult population.

We have measured in 38 patients the plasma concentration profile of atracurium and its effect on the electromyographic first response of the train-of-four. One of three techniques was used to supplement anaesthesia with 66% nitrous oxide in oxygen, 0.9% isoflurane (end-tidal), 0.5% halothane (end-tidal) or midazolam 3-10 mg. A four-parameter threshold pharmacodynamic model was fitted to the data in each patient. Compared with a group of patients anaesthetized with an i.v. technique, the steady-state plasma concentration producing 50% block (Cpss50) was reduced by halothane, and to a greater extent by isoflurane. The rate constant for exit from the effect compartment (k(eo)) correlated negatively with age and was greater in female patients, but unaffected by anaesthetic technique. The values of gamma, the slope of the concentration-response curve, and of the threshold (Cpss theta) were not affected significantly by age, sex or anaesthetic technique.

We have defined the pharmacokinetics of atracurium besylate 0.25 mg kg-1 in 41 patients anaesthetized with 0.9% isoflurane end-tidal, 0.5% halothane end-tidal or midazolam 3-10 mg as a supplement to 66% nitrous oxide in oxygen. The pharmacokinetic profile was affected by age, sex and anaesthetic technique. Advancing age was associated with a reduced clearance and a longer elimination half-time; clearance was greater and elimination half-time was shorter in males than in females. Clearance was also greater in patients anaesthetized with isoflurane than with the two other techniques. Age, sex and anaesthetic technique did not significantly affect the volume of distribution.

The electromyographic response to a short infusion of atracurium 0.25 mg kg-1 was recorded using the train-of-four (TOF) technique, and the plasma atracurium concentration profile measured, in 10 healthy patients. The TOF ratio (T4:T1) was depressed over a time course which did not conform to the predictions of an effect compartment model; the fit of such a model, when possible, was associated with large residual errors. In contrast, the absolute height of the fourth response of the TOF (T4:T0) may be fitted by a standard effect compartment model with smaller errors. This residual error was reduced further on fitting a threshold effect compartment model to the data set T4:T0. The parameter values of such a model were related closely to those for the first response (T1:T0). The kinetics of the effect compartments for the first and fourth response of the TOF were similar, whilst the CPss50 for the fourth response was approximately 67% that for the first response.

We have assessed the profiles of plasma concentration of atracurium and its neuromuscular blocking effect on the first response of the train-of-four measured by electromyography after a short infusion of atracurium 0.25 mg kg-1, in 38 patients anaesthetized by one of three techniques. Measures of the temporal profile of neuromuscular block were found to correlate with pharmacokinetic variables. When anaesthetic technique was taken into account in a multivariate model, the time to onset of 10% deprssion of T1:T0 correlated positively with the central volume of distribution (P less than 0.05). The change in T1:T0 during the 1 min after 10% depression, and the logit of maximum depression were both correlated negatively with the central volume of distribution (P less than 0.05 and P less than 0.01, respectively). Both the times to 20% and 50% recovery of T1:T0 correlated strongly negatively with clearance (P less than 0.0001 for both measures). The findings support the conclusion that the effect of atracurium is dependent upon its disposition.

The plasma concentration of atracurium and the electromyographic depression of the first response of the train-of-four (T1:T0) were measured during and after recovery from a 10-min infusion of atracurium 0.25 mg kg-1 in 14 patients anaesthetized with 66% nitrous oxide and 0.9% isoflurane (end-tidal) in oxygen. A standard pharmaco-dynamic model was fitted to the data; a small but consistent discrepancy was found between the time and rate of onset of depression of the ratio T1:T0 and the predictions of the standard biophase model of best fit to the data. This discrepancy is reduced by the inclusion of a threshold term (CPss theta) in the model to represent the greatest steady state plasma concentration which would just fail to evoke an effect. The values of CPss theta correlated significantly with the values of CPss50 (r = +0.627; P less than 0.02). The estimates of CPss50 and keo from the two models are very similar; the estimate of gamma, the slope of the concentration-response curve, was less in the threshold model. The relationship of the present threshold model to existing knowledge of neuromuscular physiology is discussed.

Neostigmine 1.25 mg or 0.625 mg was used to antagonize neuromuscular blockade produced by either atracurium 0.5 mg kg-1 or vecuronium 0.1 mg kg-1 in four groups of patients (n = 45) when the first EMG response of the train-of-four (A') had recovered to 10% of control (A). The time for A'/A and the train-of-four ratio (D'/A') to reach 70% was recorded. It was found that, after both atracurium and vecuronium, neostigmine 1.25 mg considerably accelerated recovery and, when compared with previous results, differed little from neostigmine 5.0 mg or 2.5 mg. Neostigmine 0.625 mg also significantly accelerated recovery after atracurium and was comparable to neostigmine 1.25 mg. However, with neostigmine 0.625 mg after vecuronium, recovery of D'/A' (but not A'/A) was little faster than spontaneous. Neostigmine 1.25 mg appears to be almost as effective as neostigmine 5.0 mg or 2.5 mg in antagonizing considerable block (90% depression of twitch height) produced by either atracurium or vecuronium, but neostigmine 0.625 mg is not sufficient, especially after vecuronium.

The pharmacokinetic profiles of atracurium and one of its derivatives, laudanosine were studied following an i.v. bolus of atracurium 0.6 mg kg-1 administered to eight patients with hepatic cirrhosis and to seven healthy controls. The central volume of distribution of atracurium was greater in the patients with cirrhosis (104.6 ml kg-1) compared with the controls (69.6 ml kg-1) (P less than 0.05), as was the total volume of distribution (281.8 ml kg-1 and 202.1 ml kg-1, respectively) (P less than 0.05). There was no significant difference in the elimination half-life of atracurium between the two groups. The total volume of distribution of laudanosine was increased in cirrhotic patients (2.68 litre kg-1) (P less than 0.05), as was its elimination half-life (277 min in cirrhotic individuals; 168 min in controls) (P less than 0.05). There was no significant difference in the clearance of laudanosine between the two groups.

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.

A study of plasma atracurium and laudanosine concentrations was undertaken in 14 critically ill patients who received a bolus dose of atracurium 0.6 mg kg-1 followed by an infusion of 0.6 mg kg-1 h-1 for a period of 11-47 h. Seven of the patients had normal renal function and seven were in acute renal failure. In both groups plasma concentrations of atracurium reached a plateau of approximately 1300 ng ml-1 within 30 min of the bolus dose. The drug disappeared from the plasma within 120 min after discontinuation of the infusion. There was no difference between the two groups with respect to the pharmacokinetic parameters derived for atracurium. In the patients with normal renal function, plasma laudanosine concentration reached a plateau of approximately 1200 ng ml-1 within 10 h. In patients with renal failure there was a greater variation in the plasma laudanosine concentration: the highest value recorded was 4300 ng ml-1. Patients with renal failure had a significantly longer mean elimination half-life for laudanosine (1418 min v. 375 min; P less than 0.05) and Vd (4.52 litre kg-1 v. 2.40 litre kg-1; P less than 0.01) than the patients with normal renal function.