title: Is time to peak effect of neuromuscular blocking agents dependent on dose? Testing the concept of buffered diffusion.
abstract: OBJECTIVE
  For neuromuscular blocking agents, an inverse relationship between potency and time to peak effect has been observed. To test the hypothesis that this relationship is due to buffered diffusion, we investigated the influence of dose on time to peak effect. Pharmacokinetic-pharmacodynamic simulations were performed to support the expected relationships between potency, dose, peak effect and time to peak effect.
  
  
  METHODS
  Pigs (20-28 kg body weight) were anaesthetized with ketamine and midazolam, followed by pentobarbital and fentanyl intravenously. Neuromuscular block was measured by stimulating the peroneal nerve supramaximally at 0.1 Hz and measuring the response of the tibialis anterior muscle mechanomyographically. After an initial dose to establish the individual ED90 of a neuromuscular blocking agent (rocuronium, vecuronium, pipecuronium or d-tubocurarine), five different doses of the same compound were administered to each animal, aiming at 20%, 40%, 60%, 75% or 90% block, in a random order. Doses were given 45 min after complete recovery of the twitch response.
  
  
  RESULTS
  For rocuronium and pipecuronium, time to peak effect increased with dose, whereas dose did not affect time to peak effect of vecuronium and d-tubocurarine. Simulations predict that time to peak effect decreases with dose if buffered diffusion is taken into account.
  
  
  CONCLUSIONS
  The results suggest that buffered diffusion does not play a dominant role in the time to peak effect of neuromuscular blocking agents. Therefore it is unlikely that the observed inverse relationship between potency and time to peak effect of neuromuscular blocking agents in the clinical range is due to buffered diffusion.
authors.affiliation: Department of Anaesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. j.h.proost@rug.nl
authors.forename: J H
authors.initials: JH
authors.lastname: Proost
authors.forename: M C
authors.initials: MC
authors.lastname: Houwertjes
authors.forename: J M K H
authors.initials: JM
authors.lastname: Wierda
mesh_terms: D000818:Animals; D002021:Buffers; D004058:Diffusion / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008297:Male; D009466:Neuromuscular Blocking Agents / Q000008:administration & dosage*; D013552:Swine; D013997:Time Factors
chemical_list: D002021:Buffers; D009466:Neuromuscular Blocking Agents