THE PHARMACOKINETICS AND PHARMACODYNAMICS OF THE STEREOISOMERS OF MIVACURIUM IN PATIENTS RECEIVING NITROUS OXIDE OPIOID/BARBITURATE ANESTHESIA/

Background: Mivacurium consists of a mixture of three stereoisomers: c is-trans (34-40%), trans-trans (52-60%), and cis-cis (4-8%). These iso mers differ in potency (the trans-traits and the cis-transisomers 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-liv es are less than 2 min for the cis-trans and trans-trans isomers and 2 76 min for the cis-cis isomer). The current study was undertaken to de termine the pharmacokinetic profile of the individual stereoisomers of mivacurium, to evaluate the dose-proportionality of the more potent t rails-trans and cis-trans isomers, and to evaluate the pharmacodynamic s of mivacurium in healthy adult patients receiving a consecutive two- step infusion of mivacurium. Methods: Eighteen ASA physical status 1 o r 2 adult male patients undergoing elective surgery under nitrous oxid e/oxygen/fentanyl anesthesia were studied. Neuromuscular function was monitored using a mechanomyograph at a frequency of 0.15 Hz. An infusi on of mivacurium was begun at 5 mu g . kg(-1) . min(-1). Sixty minutes later, the infusion rate was doubled to 10 mu g . kg(-1) . min(-1), a nd, 60 min after that, the infusion was discontinued. All patients wer e allowed to recover spontaneously from mivacurium-induced neuromuscul ar block. Venous blood samples were drawn for the determination of the plasma concentrations of each isomer of mivacurium by a stereospecifi c high performance liquid chromatographic method. Pharmacokinetic para meters were determined using noncompartmental analysis. Results: Durin g the 5-mu g . kg(-1) . min(-1) Infusion, patients developed 83.2 +/- 13.6% neuromuscular block. Increasing the infusion to 10 mu g . kg(-1) . min(-1) increased the depth of block to 99.0 +/- 2.0% After discont inuation of the infusion, patients returned to 25% of their baseline m uscle strength in 9.3 +/- 3.7 min and had 25-75% and 5-95% recovery in dexes of 7.2 +/- 1.8 and 16.8 +/- 3.7 min, respectively. The volumes o f distribution (V-beta) of the cis-trans, trails-trans, and cis-cis is omers were 0.29 +/- 0.24, 0.15 +/- 0.05, and 0.34 +/- 0.08 l/kg, respe ctively. During the 5-mu g . kg(-1) . min(-1) infusion, the steady-sta te clearances of the potent cis-trans and trans-trans isomers were 106 +/- 67 and 63 +/- 34 ml . min(-1) . kg(-1), respectively; the clearan ce of the less potent cis-cis isomer was 4.6 +/- 1.1 ml . min(-1) . kg (-1). The elimination half-lives of the cis-trans and trans-trans isom ers were 1.8 +/- 1.1 and 1.9 +/- 0.7 min, respectively, and that of th e 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 pot ent cis-trans and trans-trans isomers are consistent with the short du ration of action of mivacurium. The cis-cis isomer does not appear to produce significant neuromuscular block as evident by the return of tw itch height to baseline despite persistent cis-cis isomer concentratio ns.