Hostname: page-component-cd9895bd7-p9bg8 Total loading time: 0 Render date: 2024-12-27T12:35:05.441Z Has data issue: false hasContentIssue false
  • English
  • Français

Is time to peak effect of neuromuscular blocking agents dependent on dose? Testing the concept of buffered diffusion

Published online by Cambridge University Press:  01 July 2008

J. H. Proost ,
M. C. Houwertjes  and
J. M. K. H. Wierda
J. H. Proost*
Affiliation:
University of Groningen, University Medical Center Groningen, Department of Anaesthesiology, Research Group for Experimental Anesthesiology and Clinical Pharmacology, Groningen, The Netherlands
M. C. Houwertjes
Affiliation:
University of Groningen, University Medical Center Groningen, Department of Anaesthesiology, Research Group for Experimental Anesthesiology and Clinical Pharmacology, Groningen, The Netherlands
J. M. K. H. Wierda
Affiliation:
University of Groningen, University Medical Center Groningen, Department of Anaesthesiology, Research Group for Experimental Anesthesiology and Clinical Pharmacology, Groningen, The Netherlands
*
Correspondence to: Johannes H. Proost, Department of Anaesthesiology, University Medical Center Groningen, University of Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands. E-mail: j.h.proost@rug.nl; Tel: +31 50 3613633; Fax: +31 50 3613763
Get access

Summary

Background and objectives

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.

Keywords

NEUROMUSCULAR BLOCKING AGENTSPHARMACOKINETICSPHARMACODYNAMICSSWINE
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 25 , Issue 7 , July 2008 , pp. 572 - 580
Copyright
Copyright © European Society of Anaesthesiology 2008

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1.Donati, F. Effect of dose and potency on onset. Anaesth Pharmacol Rev 1993; 1: 34–43.Google Scholar
2.Wierda, JMKH, Proost, JH, Muir, AW, Marshall, RJ. Design of drugs for rapid onset. Anaesth Pharmacol Rev 1993; 1: 57–68.Google Scholar
3.Wierda, JMKH, Proost, JH. Structure-pharmacodynamic-pharmacokinetic relationships of steroidal neuromuscular blocking agents. Eur J Anaesthesiol 1995; 12 (Suppl 11): 45–54.Google Scholar
4.Proost, JH, Wierda, JMKH. Pharmacokinetic aspects of the onset of action of neuromuscular blocking agents. Anaesthesiol Intensivmed Notfallmed Schmerzther 2000; 35: 98–100.Google ScholarPubMed
5.Beaufort, TM, Nigrovic, V, Proost, JH, Houwertjes, MC, Wierda, JMKH. Inhibition of the enzymic degradation of suxamethonium and mivacurium increases the onset time of submaximal neuromuscular block. Anesthesiology 1998; 89: 707–714.CrossRefGoogle ScholarPubMed
6.Sheiner, LB, Stanski, DR, Vozeh, S, Miller, RD, Ham, J. Simultaneous modeling of pharmacokinetics and pharmacodynamics: application to d-tubocurarine. Clin Pharmacol Ther 1979; 25: 358–371.CrossRefGoogle ScholarPubMed
7.Donati, F, Meistelman, C. A kinetic-dynamic model to explain the relationship between high potency and slow onset time for neuromuscular blocking drugs. J Pharmacokinet Biopharm 1991; 19: 537–552.CrossRefGoogle ScholarPubMed
8.Proost, JH, Wierda, JMKH, Meijer, DKF. An extended pharmacokinetic/pharmacodynamic model describing quantitatively the influence of plasma protein binding, tissue binding, and receptor binding on the potency and time course of action of drugs. J Pharmacokinet Biopharm 1996; 24: 45–77.CrossRefGoogle ScholarPubMed
9.Proost, JH, Wright, PMC. A pharmacokinetic-dynamic explanation of the rapid onset/offset of rapacuronium. Eur J Anaesthesiol 2001; 18 (Suppl. 23): 83–89.Google Scholar
10.Armstrong, DL, Lester, HA. The kinetics of tubocurarine action and restricted diffusion within the synaptic cleft. J Physiol (Lond) 1979; 294: 365–386.CrossRefGoogle ScholarPubMed
11.Hull, CJ. Pharmacodynamics of non-depolarizing neuromuscular blocking agents. Br J Anaesth 1982; 54: 169–182.CrossRefGoogle ScholarPubMed
12.Hull, CJ. Pharmacokinetics for Anaesthesia. Oxford: Butterworth-Heinemann, 1991: 332–336.Google Scholar
13.Law Min, JC, Bekavac, I, Glavinovic, MI, Donati, F, Bevan, DR. Iontophoretic study of speed of action of various muscle relaxants. Anesthesiology 1992; 77: 351–356.CrossRefGoogle Scholar
14.Glavinovic, MI, Law Min, JC, Kapural, L, Donati, F, Bevan, DR. Speed of action of various muscle relaxants at the neuromuscular junction binding vs buffering hypothesis. J Pharmacol Exp Ther 1993; 265: 1181–1186.Google ScholarPubMed
15.Proost, JH, Eleveld, DJ. Performance of an iterative two-stage Bayesian technique for population pharmacokinetic analysis of rich data sets. Pharm Res 2006; 23: 2748–2759.CrossRefGoogle ScholarPubMed
16.Proost, JH, Schiere, S, Eleveld, DJ, Wierda, JMKH. Simultaneous versus sequential pharmacokinetic-pharmacodynamic population analysis using an iterative two-stage Bayesian technique. Biopharm Drug Dispos 2007; 28: 455–473.CrossRefGoogle ScholarPubMed
17.De Haes, A, Proost, JH, Kuks, JBM, van den Tol, DC, Wierda, JMKH. Pharmacokinetic-pharmacodynamic modeling of rocuronium in myasthenic patients is improved by taking into account the number of unbound acetylcholine receptors. Anesth Analg 2002; 95: 588–596.CrossRefGoogle ScholarPubMed
18.De Haes, A, Proost, JH, De Baets, MH, Stassen, MHW, Houwertjes, MC, Wierda, JMKH. Pharmacokinetic-pharmacodynamic modeling of rocuronium in case of a decreased number of acetylcholine receptors: a study in myasthenic pigs. Anesthesiology 2003; 98: 133–142.CrossRefGoogle ScholarPubMed
19.Ducharme, J, Varin, F, Bevan, DR, Donati, F. Importance of early blood sampling on vecuronium pharmacokinetic and pharmacodynamic parameters. Clin Pharmacokinet 1993; 24: 507–518.CrossRefGoogle ScholarPubMed
20.Beaufort, TM, Proost, JH, Kuizenga, K, Houwertjes, MC, Kleef, UW, Wierda, JMKH. Do plasma concentrations obtained from early arterial blood sampling improve pharmacokinetic/pharmacodynamic modeling? J Pharmacokinet Biopharm 1999; 27: 173–190.CrossRefGoogle ScholarPubMed
21.Viby-Mogensen, J, Østergaard, D, Donati, F et al. Pharmacokinetic studies of neuromuscular blocking agents: Good Clinical Research Practice. Acta Anaesthesiol Scand 2000; 44: 1169–1190.CrossRefGoogle ScholarPubMed
22.Healy, TEJ, Pugh, ND, Kay, B, Sivalingam, T, Petts, HV. Atracurium and vecuronium: effect of dose on the time of onset. Br J Anaesth 1986; 58: 620–624.CrossRefGoogle ScholarPubMed
23.Murray, DJ, Mehta, MP, Choi, WW et al. The neuromuscular blocking and cardiovascular effects of doxacurium chloride in patients receiving nitrous oxide narcotic anesthesia. Anesthesiology 1988; 69: 472–477.CrossRefGoogle ScholarPubMed
24.Bowman, WC, Rodger, IW, Houston, J, Marshall, RJ, McIndewar, I. Structure : action relationships among some desacetoxy analogues of pancuronium and vecuronium in the anesthetized cat. Anesthesiology 1988; 69: 57–62.CrossRefGoogle ScholarPubMed
25.Kopman, AF. Pancuronium, gallamine, and d-tubocurarine compared – is speed of onset inversely related to drug potency. Anesthesiology 1989; 70: 915–920.CrossRefGoogle ScholarPubMed
26.Kopman, AF, Klewicka, MM, Kopman, DJ, Neuman, GG. Molar potency is predictive of the speed of onset of neuromuscular block for agents of intermediate, short, and ultrashort duration. Anesthesiology 1999; 90: 425–431.CrossRefGoogle Scholar
27.De Haes, A, Houwertjes, MC, Proost, JH, Wierda, JMKH. An isolated, antegrade, perfused, peroneal nerve anterior tibialis muscle model in the rat: a novel model developed to study the factors governing the time course of action of neuromuscular blocking agents. Anesthesiology 2002; 96: 963–970.CrossRefGoogle Scholar
28.Marshall, RJ. Cardiovascular effects of neuromuscular blocking drugs. Curr Opinion Anesthesiol 1991; 4: 599–602.CrossRefGoogle Scholar
29.Szmuk, P, Ezri, T, Chelly, JE, Katz, J. The onset time of rocuronium is slowed by esmolol and accelerated by ephedrine. Anest Analg 2000; 90: 1217–1219.CrossRefGoogle ScholarPubMed
30.Bergeron, L, Bevan, DR, Berrill, A, Kahwaji, R, Varin, F. Concentration–effect relationship of cisatracurium at three different dose levels in the anesthetized patient. Anesthesiology 2001; 95: 314–323.CrossRefGoogle ScholarPubMed
31.Nigrovic, V. Multiple estimates of EC50. Anesthesiology 2002; 97: 284.CrossRefGoogle ScholarPubMed
32.Van der Graaf, PH, Danhof, M. Analysis of drug-receptor interactions in vivo: a new approach in pharmacokinetic-pharmacodynamic modelling. Int J Clin Pharmacol Ther 1997; 25: 442–446.Google Scholar