Effects of Phenytoin on Rocuronium-induced Neuromuscular Blockade Using a Rat Phrenic Nerve-diaphragm Preparation

Lee, Yoon Kyung; Park, Soo Kyoung; Kim, Jong Wook; Yang, Hong Seok; Han, Sung Min

Abstract

BACKGROUND: Chronic anticonvulsant therapy with phenytoin antagonizes the action of nondepolarizing muscle relaxants. Rocuronium is a new non depolarizing muscle relaxant of rapid onset and intermediate duration. This study was designed to investigate the effects of phenytoin on rocuronium-induced neuromuscular blockade using a rat phrenic nerve-diaphragm preparation.
METHODS
Male Sprague-Dawley rats (200 g, n = 70) were randomly allocated into a control group (C, n = 10), three phenytoin-pretreated groups (PP, n = 30) and three phenytoin-non-pretreated groups (PNP, n = 30). In phenytoin-pretreated groups, phenytoin 50 mg/kg/day was administered intraperitoneally once a day for one day (PP1D), seven days (PP7D) or twenty eight days (PP28D). Animals were anesthetized with 40 mg/kg of thiopental sodium intraperitoneally and the diaphragm with the phrenic nerve were dissected, and the phrenic nerve-diaphragm preparation was suspended in 100 ml of Krebs solution in an organ bath. The bath was aerated with 95% O2-5% CO2 at 32oC, and the phrenic nerve was stimulated with supramaximal intensity using a stimulator. Twitch responses were measured using a precalibrated force displacement transducer and recorded. The cumulative dose-response relationships of rocuronium and phenytoin were determined. After one hour's stabilization, rocuronium 100 microgram was added to the bath, and when a stable 3-5 twitch was obtained, incremental 50 microgram doses of rocuronium were added to obtain more than 95% neuromuscular twitch inhibition at 0.1 Hz. In the phenytoin-non-pretreated group, phenytoin was administered simultaneously with the initial dose of rocuronium to a phenytoin concentration of 1 microgram/ml (PNP1), 10 microgram/ml (PNP10), or 100 microgram/ml (PNP100) in Krebs solution. Data were analyzed by probit and logistic models. In the PP group, the plasma concentration of phenytoin was analyzed by high performance liquid chromatography.
RESULTS
The dose-response curve of rocuronium was significantly shifted to the left in the PNP100 group (P < 0.05), and significantly shifted to the right in the PP28D group (P < 0.05). The plasma phenytoin concentration was found to be directly proportional to the duration of the phenytoin pretreatment.
CONCLUSIONS
The potency of rocuronium is reduced in chronic phenytoin therapy and increased after an acute high dose of phenytoin.