A comparison of the infusion pharmacokinetics and pharmacodynamics of cisatracurium, the 1R‐cis 1′R‐cis isomer of atracurium, with atracurium besylate in healthy patients

Abstract

SummaryWe 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 ¹1 and 10 patients (Group A) were given atracurium 0.5 mg.kg ¹1. 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 mg.kg ¹1 .min ¹1 was started in Group C and an infusion of atracurium 10 mg.kg ¹1.min ¹1 was started in Group A. The infusion rates were adjusted to maintain the first twitch of the train-offour at 5% of control. The times to 90% and maximum depression of the first twitch of the trainof-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 ¹1 ) and the cis-cis group the lowest (499 ml.min ¹1). The clearance of cisatracurium (425 ml.min ¹1 ) 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 onefifth of that after atracurium. The neuromuscular blocking agent atracurium besylate consists of three groups of geometric isomers: three cis-cis, four cis-trans and three trans-trans [1]. The properties of each of the isomers have been studied to determine whether any possess fewer side-effects than the parent drug. One of the cis-cis isomers, cisatracurium (51W89: 1R-cis 1 0 R-cis atracurium) makes up 15% of atracurium

Dose-response relationships for edrophonium and neostigmine antagonism of atracurium and cisatracurium- induced neuromuscular block

“…For instance, when the reversal was attempted at 10% T1 recovery from cisatracurium block, 4.2 times as much edrophonium as neostigmine was required to achieve 50% T1, but 6.6 times as much is needed to reach a TOF ratio of 0.5 (Tables II, III). In this respect, our results are consistent with our previously published results and those of other investigators [17][18][19][20][21][22][23] who reported similar observations with other non-depolarizing neuromuscular blockers. The reported neostigmine:edrophonium potency ratio for train-of-four, 10 min after injection of the antagonist (following return to 10% first twitch height) was 10.4 for mivacurium, 20 13.5 for atracurium, 22 26 for vecuronium, 18 27.5 for rocuronium, 19 24 for pancuronium and 29 for tubocurarine.…”

“…In this study, spontaneous recovery for the first 10 min following return to 10% first twitch height, T1 and TOF proceeded at similar rates with atracurium and cisatracurium ( Figures 1-4 and Table I). Similarly, Smith and colleagues 17 reported that recovery times after a bolus dose of atracurium 0.5 mg·kg -1 or cisatracurium 0.1 mg·kg -1 were similar. We also noted that at five minutes edrophonium was more effective in reversing twitch depression induced by cisatracurium than atracurium (Table II).…”

Clinical pharmacology of cisatracurium during nitrous oxide-propofol anesthesia in children

“…The intravenous dosage of cisatracurium in infants and children is no more than 0.2 mg/kg (4 × ED 95 ) [4][5][6][7]. On the basis of previous findings, we determined the maximal dosage of cisatracurium to be 4 times ED 95 .…”

Chirality and anaesthetic drugs: A review and an update

“…Since the mid-1990s, a number of preclinical and human studies established the efficacy and safety of cisatracurium. [43–46] The example of cisatracurium demonstrates that isolation of one of the stereoisomer may result in improvement over a parent racemic compound, which can translate into clinical practice.…”