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The pharmacokinetics and pharmacodynamics of the stereoisomers of mivacurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia.

TitleThe pharmacokinetics and pharmacodynamics of the stereoisomers of mivacurium in patients receiving nitrous oxide/opioid/barbiturate anesthesia.
Publication TypeJournal Article
Year of Publication1994
AuthorsLien CA, Schmith VD, Embree PB, Belmont MR, Wargin WA, Savarese JJ
Date Published1994 Jun
KeywordsAdult, Fentanyl, Humans, Isoquinolines, Male, Middle Aged, Nerve Block, Neuromuscular Junction, Neuromuscular Nondepolarizing Agents, Nitrous Oxide, Oxygen, Stereoisomerism

BACKGROUND: Mivacurium consists of a mixture of three stereoisomers: cis-trans (34-40%), trans-trans (52-60%), and cis-cis (4-8%). These isomers differ in potency (the trans-trans and the cis-trans isomers are equipotent and the cis-cis isomer is 1/13th as potent a neuromuscular blocking agent) and in rates of in vitro hydrolysis (in vitro half-lives are less than 2 min for the cis-trans and trans-trans isomers and 276 min for the cis-cis isomer). The current study was undertaken to determine the pharmacokinetic profile of the individual stereoisomers of mivacurium, to evaluate the dose-proportionality of the more potent trans-trans and cis-trans isomers, and to evaluate the pharmacodynamics of mivacurium in healthy adult patients receiving a consecutive two-step infusion of mivacurium.

METHODS: Eighteen ASA physical status 1 or 2 adult male patients undergoing elective surgery under nitrous oxide/oxygen/fentanyl anesthesia were studied. Neuromuscular function was monitored using a mechanomyograph at a frequency of 0.15 Hz. An infusion of mivacurium was begun at 5 Sixty minutes later, the infusion rate was doubled to 10, and, 60 min after that, the infusion was discontinued. All patients were allowed to recover spontaneously from mivacurium-induced neuromuscular block. Venous blood samples were drawn for the determination of the plasma concentrations of each isomer of mivacurium by a stereospecific high performance liquid chromatographic method. Pharmacokinetic parameters were determined using noncompartmental analysis.

RESULTS: During the infusion, patients developed 83.2 +/- 13.6% neuromuscular block. Increasing the infusion to 10 increased the depth of block to 99.0 +/- 2.0%. After discontinuation of the infusion, patients returned to 25% of their baseline muscle strength in 9.3 +/- 3.7 min and had 25-75% and 5-95% recovery indexes of 7.2 +/- 1.8 and 16.8 +/- 3.7 min, respectively. The volumes of distribution (V beta) of the cis-trans, trans-trans, and cis-cis isomers were 0.29 +/- 0.24, 0.15 +/- 0.05, and 0.34 +/- 0.08 l/kg, respectively. During the infusion, the steady-state clearances of the potent cis-trans and trans-trans isomers were 106 +/- 67 and 63 +/- 34, respectively; the clearance of the less potent cis-cis isomer was 4.6 +/- 1.1 The elimination half-lives of the cis-trans and trans-trans isomers were 1.8 +/- 1.1 and 1.9 +/- 0.7 min, respectively, and that of the cis-cis isomer was 52.9 +/- 19.8 min. Clearance of the cis-trans and trans-trans isomers did not vary with infusion rate.

CONCLUSIONS: The short elimination half-lives and high metabolic clearances of the potent cis-trans and trans-trans isomers are consistent with the short duration of action of mivacurium. The cis-cis isomer does not appear to produce significant neuromuscular block as evident by the return of twitch height to baseline despite persistent cis-cis isomer concentrations.

Alternate JournalAnesthesiology
PubMed ID8010476