Modeling of Twitch Fade Based on Slow Interaction of Nondepolarizing Muscle Relaxants with the Presynaptic Receptors

  • Shashi B. Bhatt
  • Anton Amann
  • Vladimir NigrovicEmail author

Nondepolarizing muscle relaxants (MRs) diminish the indirectly evoked single twitch due to their binding to the postsynaptic receptors. Additionally, the MRs produce progressive diminution of successive twitches upon repetitive stimulation (fade). Our study addresses the generation of fade as observed under clinical situation. The study was conducted in two phases. In the clinical part, we have evaluated the time course of twitch depression and fade following the administration of several doses of three MRs (rocuronium, pancuronium, and cisatracurium). In the second part, we have modified our model of neuromuscular transmission to simulate the time course of twitch depression and fade. The MR was assumed to bind to a single site on the presynaptic receptor to produce fade. The rates of interaction with the presynaptic receptors were characterized in terms of the arbitrarily assigned equilibrium dissociation constant and the half-life for dissociation of the presynaptic complex. A method was developed to relate the release of acetylcholine to the occupancy of the presynaptic receptors. The strength of the first and the fourth twitch was calculated from the peak concentration of the activated postsynaptic receptors, i.e., of those receptors with both sites occupied by acetylcholine. Our results indicate that, while the affinity of the MR for the presynaptic receptor plays little role in the time course of fade, the rate of dissociation of the complex between the presynaptic receptors and the muscle relaxant may be critical in determining the time course of fade. Tentative estimates of this parameter are offered.


twitch fade nondepolarizing muscle relaxants modeling simulation methods 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bowman W.C. (1980). Prejunctional and postjunctional cholinoceptors at the neuromuscular junction. Anesth. Analg. 59:935–943PubMedCrossRefGoogle Scholar
  2. 2.
    Suzuki T., Munakate K., Watanabe N., Fukano N., Saeki S. (2003). Comparative fading responses induced by mivacurium, cisatracurium, and d-tubocurarine in the evoked muscular compound action potentials of the cat. J. Anaesth. 17:98–103Google Scholar
  3. 3.
    Hong S.J. and Chang C.C. (1991). Run-down of neuromuscular transmission during repetitive nerve activity by nicotinic antagonists is not due to desensitization of the postsynaptic receptors. Br. J. Pharmacol. 102:817–822PubMedGoogle Scholar
  4. 4.
    Nigrovic V. and Amann A. (2003). Competition between acetylcholine and a nondepolarizing muscle relaxant for binding to the postsynaptic receptors at the motor end plate: Simulation of twitch strength and neuromuscular block. J.Pharmcokinet. Pharmacodyn. 30:23–51CrossRefGoogle Scholar
  5. 5.
    Gibaldi M. and Perrier D. (1982). Pharmacokinetics, 2nd edn. Marcel Dekker Inc., New YorkGoogle Scholar
  6. 6.
    Nigrovic V., Proost J.H., Amann A., and Bhatt S. (2005). Volume of the effect compartment in simulations of neuromuscular block. Theoret. Bio. Med. Model. 2:41 ( Scholar
  7. 7.
    Fambrough D.M., Drachman D.B., Satyamurti S. (1973). Neuromuscular junction in myasthenia gravis: decreased acetylcholine receptors. Science 182:293–295PubMedCrossRefGoogle Scholar
  8. 8.
    Rosenberry T.L. (1979). Quantitative simulations of endplate currents at neuromuscular junctions based on the reaction of acetylcholine with acetylcholine receptors and acetylcholinesterase. Biophys. J. 26:263–290PubMedGoogle Scholar
  9. 9.
    Pearce A.C., Casson W.R., Jones R.M. (1985). Factors affecting train-of-four fade. Br. J. Anaesth. 57:602–606PubMedCrossRefGoogle Scholar
  10. 10.
    Power S.J., Pearce A.C., Jones R.M. (1988). Fade profiles during spontaneous offset of neuromuscular blockade: vecuronium and gallamine compared. Br. J. Anaesth. 60:486–490PubMedCrossRefGoogle Scholar
  11. 11.
    Power S.J. and Jones R.M. (1987). Relationship between single twitch depression and train-of-four fade: Influence of relaxant dose during onset and spontaneous offset of neuromuscular blockade. Anesth. Analg. 66:633–636PubMedCrossRefGoogle Scholar
  12. 12.
    Caroll M.T., Mirakhur R.K., Lowry D.W., McCourt K.C., Kerr C. (1998). Neuromuscular blocking effects and train-of-four fade with cisatracurium: comparison with other nondepolarizing relaxants. Anaesthesia 53:1169–1173CrossRefGoogle Scholar
  13. 13.
    Weiss M and Kang W. (2004). Inotropic effect of digoxin in humans: pharmacokinetic/pharmacodynamic model based on slow receptor binding. Pharm. Res. 21:231–236PubMedCrossRefGoogle Scholar
  14. 14.
    Shimada S., Nakajima Y., Yamamoto K., Sawada Y., Iga T. (1996). Comparative pharmacodynamics of eight calcium channel blocking agents in Japanese essential hypertensive patients. Biol. Pharm. Bull. 19:430–437PubMedGoogle Scholar
  15. 15.
    Brockes J.P. and Hall Z.W. (1975). Acetylcholine receptors in normal and denervated rat diaphragm muscle. I. Purification and interaction with [125I]-α-bungarotoxin. Biochemistry 14:2092–2099PubMedCrossRefGoogle Scholar
  16. 16.
    Paton W.D. and Waud D.R. (1967). The margin of safety of neuromuscular transmission. J. Physiol 191:59–90PubMedGoogle Scholar
  17. 17.
    Graham G.G., Morris R., Pybus D.A., Torda T.A., Woodey R. (1986). Relationship of train-of-four ratio to twitch depression during pancuronium-induced neuromuscular blockade. Anesthesiology 65:579–5832PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Shashi B. Bhatt
    • 1
  • Anton Amann
    • 2
    • 3
  • Vladimir Nigrovic
    • 1
    Email author
  1. 1.Department of AnesthesiologyMedical University of OhioToledoUSA
  2. 2.Department of Anesthesiology and Critical Care MedicineLeoplod-Franzens UniversityInnsbruckAustria
  3. 3.Department of Environmental SciencesFederal Institute of TechnologyZürichSwitzerland

Personalised recommendations