Pharmacokinetics and pharmacodynamics of atracurium in infants and children.

To determine whether maturational changes in body composition and organ function affect distribution and elimination of and sensitivity to atracurium, the authors determined the pharmacokinetics and pharmacodynamics of atracurium in six infants and five children and compared these results with those obtained in five adults. Atracurium, 15.8 +/- 1.7 micrograms.kg-1.min-1, was infused iv for 6-11 min to subjects anesthetized with nitrous oxide (60%) and halothane (0.9 MAC, age-adjusted) and twitch tension of the adductor pollicis muscle was measured. Plasma samples were obtained for 120 min; concentrations of atracurium were determined using a liquid chromatographic assay. A two-compartment pharmacokinetic model, adapted to account for elimination of atracurium from both central and peripheral compartments, was fit to the plasma concentration data; an effect-compartment model was fit to the twitch tension data. Volume of distribution at steady state (210 +/- 118, 129 +/- 44, and 100 +/- 22 ml/kg for infants, children, and adults, respectively) and total clearance (7.9 +/- 2.0, 6.8 +/- 1.6, and 5.3 +/- 0.9 ml.kg-1.min-1 for the three groups) decreased with increasing age. Neither elimination half-life (20.0 +/- 5.1, 17.2 +/- 5.1, and 15.7 +/- 2.5 min for the three groups) nor the steady state plasma concentration that resulted in 50% neuromuscular blockade (363 +/- 118, 444 +/- 121, and 436 +/- 122 ng/ml for the three groups) varied with age. The authors conclude that these results are consistent with and explain the previously reported findings that recovery from the neuromuscular effects of atracurium is minimally affected by age.(ABSTRACT TRUNCATED AT 250 WORDS)

The neuromuscular blocking effects and pharmacokinetics of ORG 9426 and ORG 9616 in the cat.

The neuromuscular blocking effects and pharmacokinetics of ORG 9426, 1.5 mg/kg and ORG 9616, 1.2 mg/kg iv, two new nondepolarizing neuromuscular blocking drugs, were studied in 28 cats (i.e., 14 cats with each drug) with and without renal pedicle ligation. A gas chromatographic assay was used to determine the concentrations of ORG 9426 and ORG 9616 and its desacetyl metabolites in plasma, urine, bile, and liver. The duration of neuromuscular blockade of both drugs was not altered by ligation of renal pedicles. Plasma clearance of ORG 9426 was slower in cats with ligated renal pedicles (P less than 0.01). With ORG 9616, mean elimination half-life was slower and mean residence time longer in cats with renal pedicle ligation. Otherwise, there was no significant differences with any pharmacokinetic variables in cats with and without renal pedicle ligation. Only 8.7 +/- 5.7% (SD) and 6.0 +/- 2.8% of an injected dose of ORG 9426 and ORG 9616 was excreted into the urine, respectively. Conversely, 54.4 +/- 9.2% and 52.4 +/- 9.2% of an injected dose of ORG 9426 and 35.7 +/- 12.2% and 46.8 +/- 9.7% of ORG 9616 were excreted into the bile in cats without and with renal pedicle ligation, respectively. Finally, 21.3 +/- 6.5% and 33.5 +/- 15.6% of ORG 9426 and 14.0 +/- 3.2% and 18.1 +/- 5.6% of ORG 9616 were in the liver 6 h after injection in cats without and with renal pedicle ligation respectively. The authors were able to account for the biodisposition of 84.4% and 85.9% of an injected dose of ORG 9426 in cats without and with renal pedicle ligation respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and pharmacodynamics of atracurium in the elderly.

To evaluate the effect of aging on the distribution, clearance, and neuromuscular junction sensitivity to atracurium, the authors determined the pharmacokinetics and pharmacodynamics of atracurium in five healthy elderly subjects (74-76 yr) during halothane-nitrous oxide anesthesia and compared these values to those obtained previously in five healthy young adults (22-44 yr). A brief (6.0-13.0 min) infusion of atracurium was administered until twitch tension was suppressed by approximately 70%, and atracurium plasma concentration and twitch tension data were used to determine pharmacokinetic and pharmacodynamic parameters for each patient. Total clearance (Cltotal) was similar in elderly and young adults. However, clearance via the liver and/or kidney (Clorgan) was lower in elderly patients, whereas clearance due to Hofmann elimination and ester hydrolysis (Clnonorgan) was higher. Volume of distribution at steady state (Vss) was larger in elderly patients. The increase in Vss without an age-related increase in Cltotal resulted in a longer elimination half-life [21.8 (+)/- 3.3 vs. 15.7 (+)/- 2.5 min (mean (+)/- SD)] in elderly patients. The steady state plasma concentration of atracurium required to suppress twitch tension by 50% was similar in elderly and young adults. The authors conclude that the pharmacokinetics, but not the pharmacodynamics, of atracurium differ significantly between elderly and young adults. As a result, repeated doses will be required with similar frequency in young and elderly adults, but recovery from comparable levels of neuromuscular blockade may be slightly prolonged in elderly patients.

Cerebrospinal fluid concentrations of laudanosine after administration of atracurium.

The concentration of laudanosine in cerebrospinal fluid (CSF) was measured in four patients undergoing brain electrode placement after the administration of atracurium. CSF: plasma laudanosine concentration ratios ranged from less than 1 to 14%, with a range of CSF laudanosine concentrations of less than 2-14 ng ml-1. One patient had no detectable laudanosine in CSF, but sampling in this patient was possible for only 30 min. There was no atracurium detectable in the CSF of any patient. We conclude that laudanosine crosses the blood-brain barrier and further study of its central nervous system effects in man is warranted.

Electroencephalographic effects of laudanosine in an animal model of epilepsy.

We examined the effects of laudanosine, one of the principal metabolites of atracurium, on the electroencephalogram (EEG) in an animal model of induced epilepsy. Fourteen rabbits were anaesthetized with 4% halothane in oxygen, the trachea intubated and the lungs ventilated mechanically with 30% oxygen and 1% halothane in nitrogen. Animals were assigned randomly to receive either an infusion of laudanosine (laudanosine group, n = 7) at a rate calculated to produce plasma concentrations similar to those found following the clinical use of atracurium, or an equal volume of normal saline (control group, n = 7). To induce an epileptogenic focus, gelfoam sponges soaked in a pH-adjusted 4% cefazolin solution were applied bilaterally to the parietal cortical surface. This resulted in the production of spike and burst EEG activity in all animals. However, scoring the frequency of the spikes and bursts revealed no significant differences between the laudanosine and control groups. We conclude that, in this animal model of epilepsy, no increased incidence of seizure activity was produced by mean plasma laudanosine concentrations as great as 0.8 micrograms ml-1. These results suggest that the routine use of atracurium is unlikely to provoke seizures, even in the presence of an epileptogenic focus.

The influence of renal failure on the pharmacokinetics and duration of action of pipecuronium bromide in patients anesthetized with halothane and nitrous oxide.

The authors determined the pharmacokinetics and duration of action of a bolus dose of pipecuronium bromide (0.07 mg.kg-1) in 40 patients anesthetized with halothane and nitrous oxide. Twenty were patients with normal renal function, undergoing a variety of surgical procedures, and 20 were undergoing cadaver renal transplantation because of end-stage renal disease. Plasma concentrations of pipecuronium were measured for 6 h after administration using a sensitive and specific capillary gas chromatographic assay. Plasma concentration versus time data were analyzed by nonlinear regression and fit to a two-compartment or three-compartment model; in addition, the data were analyzed by a non-compartmental method based on statistical moments. Neuromuscular blockade was assessed by measuring the mechanical evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. The pharmacokinetic parameters derived by compartmental modelling were (normal vs. renal failure, respectively): volume of distribution at steady state (309 +/- 103 vs. 442 +/- 158 ml.kg-1, mean +/- SD), plasma clearance, (2.4 +/- 0.6 vs. 1.6 +/- 0.6 ml.kg-1.min-1), mean residence time (140 +/- 63 vs. 329 +/- 198 min), and elimination half-life (137 +/- 68 vs. 263 +/- 168 min). The same parameters as derived by the non-compartmental method were (normal vs. renal failure, respectively): volume of distribution at steady state (307 +/- 80 vs. 426 +/- 119 ml.kg-1, mean +/- SD), plasma clearance (2.4 +/- 0.6 vs. 1.6 +/- 0.6 ml.kg-1.min-1), mean residence time (134 +/- 41 vs. 323 +/- 228 min), and elimination half-life (118 +/- 35 vs. 247 +/- 168 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Pipecuronium and pancuronium: comparison of pharmacokinetics and duration of action.

The pharmacokinetics of pipecuronium 0.07 mg kg-1 and pancuronium 0.1 mg kg-1 were compared in 39 ASA class I or II patients. Plasma concentrations of these agents were measured for 6 h following administration, using a sensitive and specific capillary gas chromatographic assay. Concentration v. time data were analysed by non-linear regression and fitted to a two- or three-compartment model as appropriate. Neuromuscular blockade was assessed by measuring the mechanical evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. Pipecuronium had a larger steady-state volume of distribution (Vss) (309 (SD 103) ml kg-1) and greater plasma clearance (Cl) (2.4 (0.6) ml kg-1 min-1) than pancuronium (199 (54) ml kg-1 and 1.5 (0.4) ml kg-1 min-1, respectively). The volumes of the central compartment, distribution and elimination half-lives and mean residence times were similar for both agents and within the range expected for drugs of this type. The durations of action (injection to 25% recovery of twitch tension) of pipecuronium and pancuronium were similar: 98.0 (36.1) min and 117.2 (35.8) min, respectively. We conclude that the time courses of neuromuscular blockade following pipecuronium and pancuronium are similar, despite the differences in Vss and Cl.

The pharmacodynamics and pharmacokinetics of vecuronium in patients anesthetized with isoflurane with normal renal function or with renal failure.

The duration of action and the pharmacokinetics of vecuronium were compared in patients with and without renal function. Twenty patients were studied: 12 with renal failure who were to receive kidney transplants from cadaveric donors, and eight with normal renal function. After oral premedication with diazepam, 10 mg, anesthesia was induced with thiopental, 4 mg/kg iv, and maintained with the inhalation of 60% nitrous oxide and 0.9-1.1% isoflurane, end-tidal concentration, in 40% oxygen. The force of thumb adduction in response to supramaximal ulnar nerve stimulation was monitored and recorded. An intravenous bolus of vecuronium, 0.1 mg/kg, was administered after 15 min of a stable end-tidal isoflurane concentration, as measured by mass spectrometry. Venous blood was then sampled at frequent intervals for 4 h following the bolus. Vecuronium concentrations in plasma were quantified by a sensitive and specific gas chromatographic assay. Data were analyzed by nonlinear least squares regression and described by a two-compartment model. The duration of neuromuscular blockade was longer in patients with renal failure than in those with normal renal function. This increased duration may be related to both a decreased plasma clearance and a prolonged elimination half-life of vecuronium in the renal failure group.

Quantitation of pancuronium, 3-desacetylpancuronium, vecuronium, 3-desacetylvecuronium, pipecuronium and 3-desacetylpipecuronium in biological fluids by capillary gas chromatography using nitrogen-sensitive detection.

A sensitive and specific capillary gas chromatographic (GC) assay was developed for the quantitation of the quaternary ammonium steroidal neuromuscular blocking drugs pancuronium (PANC), vecuronium (VEC) and pipecuronium (PIP), as well as the metabolites 3-desacetylpancuronium (3-desPANC) and 3-desacetylvecuronium (3-des VEC) in plasma, bile and urine; the putative metabolite 3-desacetylpipecuronium (3-des PIP) was extracted and quantitated only in urine. The procedure employed a single dichloromethane extraction of the iodide ion-pairs of the monoquaternary or bisquaternary ammonium compounds (including internal and external standards) from acidified, ether-washed biological fluid followed by the formation of stable O-tert.-butyldimethylsilyl derivatives at the 3-hydroxy steroidal position of the metabolites. An automated capillary GC system fitted with a nitrogen-sensitive detector and an integrator was then used to analyze and quantitate both parent compounds and their derivatized metabolites. Optimal extraction, derivatization and GC conditions, as well as short-term stability and recoveries of these drugs and metabolites in plasma, are reported. Electron ionization mass spectrometry combined with GC was used to confirm the identities of compounds eluted from the column. The assay demonstrated a 10(3)-fold linear range up to 5000 ng/ml for PANC, VEC, 3-des VEC and PIP, and lower limits of detection with adequate precision of 2 ng/ml for PANC, VEC and PIP, and 4 ng/ml for 3-des VEC; 3-des PANC was linear from 8 to 500 ng/ml while 3-des PIP was linear from 25 to 1000 ng/ml. The precision (coefficient of variation) of the calibration curves for underivatized drugs and their derivatized metabolites over the linear ranges was 2-20% and the reproducibility of the assay over a range of clinical concentrations of these drugs found in human plasma was 5-16% for PANC, 2-4% for VEC and 6-11% for PIP. No interferences were detected in the assay of plasma samples from 106 surgical patients.

Vecuronium in alcoholic liver disease: a pharmacokinetic and pharmacodynamic analysis.

To determine the effect of alcoholic liver disease on the pharmacokinetics and pharmacodynamics of vecuronium, the authors administered vecuronium 0.1 mg.kg-1 iv to ten surgical patients with alcoholic liver disease and ten healthy surgical patients. All patients were anesthetized with nitrous oxide and isoflurane. We recorded and quantitated the force of thumb adduction in response to supramaximal ulnar nerve stimulation. Plasma concentrations of vecuronium and its 3-desacetyl metabolite were determined by a capillary gas chromatography assay. Only the time to attain 100% twitch depression (onset time) was prolonged in liver disease patients (2.8 +/- 0.7 min; mean +/- SD) as compared to control patients (1.9 +/- 0.4 min). The time from vecuronium administration to recovery of twitch tension was unaffected by alcoholic liver disease. The time to the reappearance of twitch response was 32.7 +/- 9.7 min in patients with liver disease and 36.8 +/- 15.5 min in controls. Plasma concentration-time data were fit to a two-compartment model. Vecuronium clearance, steady-state volume of distribution, and elimination half-time were unchanged by alcoholic liver disease. The authors conclude that alcoholic liver disease does not affect the pharmacokinetics or duration of action of vecuronium when an intravenous bolus dose of 0.1 mg.kg-1 is administered.

Continuous infusion of vecuronium: the effect of anesthetic agents.

The authors studied the effects of enflurane, isoflurane, and fentanyl, each in combination with 60% nitrous oxide, on the vecuronium infusion rate necessary to maintain constant 90% depression of control muscle twitch tension. Thirty healthy surgical patients were given an initial 0.1 mg/kg bolus of vecuronium, followed by an infusion of vecuronium at an initial rate of 1.0 microgram . kg-1 . min-1. After 1 h of steady-state 90% twitch depression, plasma vecuronium concentrations (Css90) were measured by capillary column gas chromatography. Total plasma clearance of vecuronium was estimated using Css90 values. Vecuronium infusion rates (mean +/- SD) were similar for patients given enflurane (0.28 +/- 0.13 microgram . kg-1 . min-1) and isoflurane (0.30 +/- 0.13 microgram . kg-1 . min-1), but significantly higher in patients given fentanyl (0.92 +/- 0.37 microgram . kg-1 . min-1). Values for Css90 in the patients receiving enflurane and isoflurane were similar (71 +/- 34 and 72 +/- 44 ng/ml, respectively), but significantly higher in those receiving fentanyl (165 +/- 48 ng/ml). Total plasma clearance was similar during enflurane, isoflurane, and fentanyl anesthesia (4.4 +/- 2.6, 4.6 +/- 1.2, and 5.6 +/- 1.9 ml X kg-1 min-1, respectively). The authors conclude that patients receiving isoflurane and enflurane require markedly lower vecuronium infusion rates to achieve 90% neuromuscular blockade than those receiving fentanyl. The enhancement of neuromuscular blockade by isoflurane and enflurane represents a change in the pharmacodynamics of vecuronium-induced neuromuscular blockade, rather than a change in pharmacokinetics.

The metabolic disposition of laudanosine in dog, rabbit, and man.

This paper summarizes the results of studies of the metabolic fate of laudanosine, a major degradation product of atracurium. Intravenous bolus doses of laudanosine (1-3 mg/kg) were administered to eight dogs and two rabbits anesthetized with halothane, and urine and bile samples were collected for up to 6 hr. Urine samples also were collected from two surgical patients given repetitive doses of atracurium. Metabolites were isolated from all samples using C18-Sep Paks. Treatment of the isolates with beta-glucuronidase followed by purification of the hydrolysate by preparative liquid chromatography provided metabolite fractions which were characterized by analytical liquid chromatography and capillary gas chromatography combined with nitrogen-phosphorus and/or electron ionization-mass spectrometric detection. Reference compounds were employed as chromatographic retention time markers. O-Trimethylsilyl, O-tert-butyldimethylsilyl, and N-trifluoroacetyl derivatives of the metabolites and reference compounds were used for gas chromatographic and mass spectrometric analysis. In all three species, the following metabolites of laudanosine were identified: pseudocodamine (4'-desmethyllaudanosine), pseudolaudanine (6-desmethyllaudanosine), laudanine (3'-desmethyllaudanosine), codamine (7-desmethyllaudanosine), N-norlaudanosine, N-norpseudocodamine, and N-norpseudolaudanine.

Pharmacology of laudanosine in dogs.

The authors determined the pharmacokinetics (including transfer into cerebrospinal fluid [CSF]) and the cardiovascular and central nervous system (CNS) effects of laudanosine, a metabolite of atracurium. Eight dogs were anesthetized with halothane; blood pressure and a fronto-occipital electroencephalographic lead were monitored. Laudanosine (1 mg . kg-1 iv) was administered as a bolus, and its concentrations in plasma, CSF, urine, and bile were determined by liquid chromatography. Three-compartment modeling of plasma laudanosine concentrations yielded an elimination half-life for laudanosine of 113 +/- 24 min (mean +/- SD) and a clearance of 25 +/- 8 ml . kg-1 . min-1. CSF concentrations of laudanosine were highest 5-10 min after iv injection of laudanosine and ranged in concentration from 208 to 572 ng . ml-1 (i.e., 36-87% of the corresponding plasma concentrations). Unchanged laudanosine was found in urine (0.5-12% of injected dose) and bile (less than 0.1%); metabolites of laudanosine were found in both fluids. After a 6-h sampling period, dogs were hyperventilated with halothane (FIO2 = 0.2) to a PaCO2 of 26-28 mmHg. Laudanosine was then administered 2 mg . kg-1 iv every 5 min. With cumulative doses of 2-8 mg . kg-1, all dogs showed signs of "awakening" from anesthesia. Cumulative doses of 14-22 mg . kg-1 produced seizure activity in all animals. Mean arterial blood pressure decreased significantly to 86% of control levels at 1 min following administration of laudanosine (1 mg . kg-1 iv) and returned to control levels 4 min later.(ABSTRACT TRUNCATED AT 250 WORDS)

Elimination of atracurium in humans: contribution of Hofmann elimination and ester hydrolysis versus organ-based elimination.

Atracurium, a nondepolarizing muscle relaxant, is eliminated through several pathways, including Hofmann elimination (spontaneous degradation in plasma and tissue at normal body pH and temperature) and ester hydrolysis (catalysis by nonspecific esterases). Because elimination of atracurium occurs in both tissue and plasma, traditional pharmacokinetic models assuming elimination from a single central compartment are inaccurate for atracurium. The authors developed a two-compartment pharmacokinetic model in which hepatic and/or renal elimination occurs from the central compartment (Cl organ), and Hofmann elimination and ester hydrolysis occur from both central and peripheral compartments (Cl nonorgan). To determine the in vitro rate constant for Hofmann elimination and ester hydrolysis, atracurium was added to whole blood kept at each patient's pH and temperature. The values for this rate constant ranged from 0.0193 to 0.0238 per min. When these values were applied to the pharmacokinetic model, Cl total, Cl organ, and Cl nonorgan were 4.8 +/- 1.1, 3.0 +/- 0.9, and 1.9 +/- 0.6 ml . kg-1 . min-1, respectively. The authors conclude that more than one-half of the clearance of atracurium occurs via pathways other than Hofmann elimination and ester hydrolysis.