The Phamtacokinetics and Pharmacodynamics of the Stereoisomers of Mivacurium in Patients Receiving Nitrous Oxide/Opioid/Barbiturate Anesthesia
Cynthia A. LienVirginia D. SchmithPatricia B. EmbreeMatthew R. BelmontWilliam A. WarginJohn J. Savarese
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Abstract:
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.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 micrograms.kg-1.min-1. Sixty minutes later, the infusion rate was doubled to 10 micrograms.kg-1.min-1, 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.During the 5-micrograms.kg-1.min-1 infusion, patients developed 83.2 +/- 13.6% neuromuscular block. Increasing the infusion to 10 micrograms.kg-1.min-1 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 5-micrograms.kg-1.min-1 infusion, the steady-state clearances of the potent cis-trans and trans-trans isomers were 106 +/- 67 and 63 +/- 34 ml.min-1.kg-1, respectively; the clearance 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 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.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.Keywords:
Pharmacodynamics
Nitrous oxide
Cis–trans isomerism
Barbiturate
Though a change from oral morphine dosage forms to transdermal fentanyl patches achieved good pain relief in 70% of cancer patients, the remaining 30 % still showed poor pain control or fentanyl vitiation. In some cases when pain control was poor, effective pain-relief was only sustained for 3 days. This suggests that the absorption of fentanyl was being hampered in such cases.In view of these findings, we investigated the relationship between the amount of fentanyl released and plasma fentanyl concentrations. To estimate amounts of fentanyl delivered into the skin, we measured the amount of fentanyl remaining in fentanyl patches after 3 days of continuous use. Amounts of fentanyl remaining in the patches ranged from 41-58%, which was close to the design residual amount of 40%. However, the amount of fentanyl release varied between patches applied to patients at home and those applied to hospitalized patients, and the fentanyl was more steadily released from patches applied to the sides of the body or back than those applied to the chest. The fentanyl release also varied with the caregivers who were applying them.Thus, it is essential to apply patches according to the instructions to ensure steady release. In this study, we observed that plasma fentanyl concentrations rapidly decreased for some patients 3 days after patch application so in such cases, patches should be changed every 2 days.
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Summary Although often felt to be relatively innocuous, nitrous oxide can have significant metabolic effects in settings of abnormal vitamin B 12 and B 12 ‐related metabolism in children. These conditions can be genetic or environmental. Symptoms may not appear until days to weeks after exposure to nitrous oxide. Although overt genetic diseases are relatively uncommon, the implications of nitrous oxide interactions with much more frequent but less symptomatically obvious single nucleotide polymorphisms are potentially more concerning. In addition, nitrous oxide can have direct and differing neurotoxic effects on both immature and aged brain, the clinical impact of which remains undetermined.
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As one of the important of greenhouse gases,the source of nitrous oxide is described,as well as the producing mechanism,the nitrous oxide flux at water-air interface in Taihu Lake is inspected and the daily change characteristics of nitrous oxide flux in the four seasons are analyzed.The results show that the Taihu Lake is the resource of nitrous oxide at most time and the collection at short time.Nitrous oxide fluxes in spring,summer,autumn and winter are 0.018 mg/(m2·h),0.065 mg/(m2·h),0.003 mg/(m2·h) and-0.002 mg/(m2·h) respectively.Nitrous oxide flux in summer is high,but low in other seasons.
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Objective To compare the effects of Rui Fentanyl and Fentanyl on cognitive functionsfor elderly patients after surgery. Methods 84 cases undergoing non-cardiac selective operation between January,2013 and October,2014 in our hospital were selected as the research object.The patients received surgery under general anesthesia and were randomly divided into Rui Fentanyl group and Fentanyl group. The Rui Fentanyl group adopted the target controlled injection with Rui Fentanyl with propofol and the Fentanyl group was for Fentanyl with propofol. The postoperative eye-open time,extubation time and language awakening and response time were compared in the two groups. The simple mental state survey scale( MMSE) was used to evaluate cognitive situation of the two groups at 6 h before operation and 2 h,4 h and 6 h after operation.Results The eye-open time,extubation time and language awakening and response time in the Rui Fentanyl group were much shorter than those in the Fentanyl group( P 0. 05) and had statistical difference.The MMSE scores of the two groups on 2 h after operation significantly reduced than before,but the MMSE scores of the Rui Fentanyl group at 2 h,4 h and 6 h after operation were higher than those of the Fentanyl group( P0.05) and had great statistical significance.Conclusions The Rui Fentanyl and Fentanyl can cause postoperative cognitive dysfunction for elderly patients,but the Rui Fentanyl has weaker effects than the Fentanyl group. The postoperative open-eye time and revival time were shorter.
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