Abstract
The pharmacodynamics and pharmacokinetics of a new non-depolarizing neuromuscular blocking agent, Org 9426, were investigated. Ten patients undergoing elective head and neck surgery and anaesthetized with nitrous oxide, halothane and fentanyl, received a bolus dose of Org 9426 (I mg · kg−1, 3 × ED90). The isometric contractions of the adductor pollids muscle following ulnar nerve stimulation (0.1 Hz and intermittent TOF) were measured. Blood and urine were sampled over 8 and 24 hr, respectively. Concentrations of Org 9426 and its possible metabolites in plasma and urine were determined using HPLC. Pharmacokinelic variables were calculated by iterative linear least square regression analysis. Intubation conditions were excellent one minute after administration at a neuro-muscular block of 88 (13)% (Mean (CV)). Onset time until maximum block, duration until 25% recovery of twitch height, and recovery from 25 until 75% of twitch height were 1.7 (32), 53 (19) and 20 (37) min, respectively. The TOF reached a ratio of 0.7 after 87 (19) min. Half lives were 1.8(33), 19(34), 131 (62) min, respectively, in a three exponential decay; distribution volume at steady-state and plasma clearance were 0.264 (56) L · kg− 1 and 4.0 (21) ml · kg− 1 · min− 1, respectively. Plasma concentration at 25% recover)1 of the twitch height was 1.0 mg · L− 1. Within 24 h, 33 (37)% of Org 9426 was excreted unchanged in the urine. Metabolites were absent both in plasma and urine. We conclude that the difference in potency between Org 9426 and vecuronium is similar to the difference between their effective concentrations. Org 9426 mimics vecuronium in its time-course of action and pharmacokinetic behaviour and produces excellent intubaling conditions one minute following the administration of I mg · kg− 1.
Résumé
Nous avons évalué les profits pharmacocinétique et pharmaco-dynamique d’un nouveau myorelaxanl non-dépolarisant, le Org 9426. Lors d’interventions chirurgicales électives sur le cou on la tele, nous avons injecte 1 mg · kg− 1 (3 × DE90) d’Org 9426 à dix patients anesthésiés avec du protoxyde d’azote, de l’halothane et du fentanyl. Nous mesurions la réponse isométrique de l’adducteur du pouce à la stimulation du nerf cubital (0,1 Hz et train-de-quatre). Nous mesurions aussi les concentrations d’Org 9426 et de ses métabolites par chromatographie en phase liquide dans des échantillons de sang et durine prélevés pendant 8 et 24 h respectivement. Par analyse de regression, nous avons pu tracer le profil pharmacocinétique de l’Org 9426. Une minute après l’injection, les conditions d’intubations étaient excellentes alors que le bloc neuromusculaire était en moyenne de 88%. En moyenne, le temps de latence jusqu’au bloc maximal était de 1,7 min; sa durée jusqu ’ à recupération de 25% de la contraction était de 53 min et l’intervalle de recuperation 25– 75% était de 20 min. Le ratio T4/T1 du train-de-quatre atteint 0,7 après 87 min en moyenne. Les demivies d’élimination d’une courbe tri-e.xponentielle étaient de 1,8, 19 et 131 min alors que le volume de distribution à l’équilibre é’tait de 0,264 L · kg− 1 et la clairance plasmatique itait de 4,0 ml · kg− 1 min− 1. An moment oú la contraction était revenue à 25% du contrôle, la concentration plasmatique de l’Org 9426 était de 1,0 mg · L−1. En 24 heures, on retrouvait inchangé dans l’urine, 33% de la dose d’Org 9426 mats il n’y avail aucun metabolite dans le sang et dans l’urine. La difference de puissance entre l’Org 9426 et le vécuronium s’explique par le rapport de leurs concentrations ejficaces. L’Org 9426 offre un profit pharmacocinetique et d’action temporellement semblable à celui du vécuronium. A raison de 1 mg · kg− 1, il offre d’excellentes conditions pour l’intubation de la trochée une minute après al’injection iv.
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Wierda, J.M.K.H., Kleef, U.W., Lambalk, L.M. et al. The pharmacodynamics and pharmacokinetics of Org 9426, a new non-depolarizing neuromuscular blocking agent, in patients anaesthetized with nitrous oxide, halothane and fentanyl. Can J Anaesth 38, 430–435 (1991). https://doi.org/10.1007/BF03007578
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DOI: https://doi.org/10.1007/BF03007578