Advertisement

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

  • Vladimir NigrovicEmail author
  • Anton Amann
Article

Abstract

The goal of the study was to simulate twitch strength and neuromuscular block produced by nondepolarizing muscle relaxants. Methods: In the proposed model, affinities of the two binding sites at a single postsynaptic receptor for acetylcholine (A) and the muscle relaxant (D) define the formation of three complexes with A only, three complexes with D only, and two complexes with both A and D. Twitch strength was postulated to be a function of the receptors with both binding sites occupied by A, and two constants. Neuromuscular block (NMB) was calculated from NMB=1-twitch. Results: Stimulus-induced release of A results in rapid, but transient, changes in the concentrations of free A, the eight complexes, and the unoccupied receptors. Muscle relaxants that display either a congruous or an inverse pattern of affinities for the binding sites relative to those of A produce NMB vs. [D] curves with slightly different slopes but markedly different estimates for IC50. Depending on the number of activated receptors at the end plates of muscle fibers, the simulations represent the distributions of contracting fibers in a whole muscle. Conclusion: Simulations of competition between A and D for binding to two sites at a receptor reveal that the potencies of muscle relaxants, defined by IC50, and the slopes of the NMB vs. [D] curves depend on (1) the affinities of D for the two binding sites, (2) the orientation of the affinities relative to those of A, and (3) the affinities of A for the same two sites.

simulation neuromuscular transmission simulation, twitch simulation, neuromuscular block acetylcholine nondepolarizing muscle relaxants 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    C. Hull, B. H. Van, K. McLeod, A. Sibbald, and M. Watson. A pharmacodynamic model for pancuronium. Br. J. Anaesth. 50:1113-1123 (1978).Google Scholar
  2. 2.
    L. Sheiner, D. Stanski, S. Vozeh, R. Miller, and J. Ham. Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d-tubocurarine. Clin. Pharmacol. Ther. (St. Louis) 25:358-371 (1979).Google Scholar
  3. 3.
    F. Donati and C. Meistelman. A kinetic-dynamic model to explain the relationship between high potency and slow onset time for neuromuscular blocking drugs. J. Pharmacokinet. Biopharm. 19:537-552 (1991).Google Scholar
  4. 4.
    J. H. Proost, J. M. K. H. Wierda, and D. K. F. Meijer. 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. 24:45-77 (1996).Google Scholar
  5. 5.
    J. Laurin, F. Donati, F. Nekka, and F. Varin. Peripheral link model as an alternative for pharmacokinetic-pharmacodynamic modeling of drugs having a very short elimination half-life. J. Pharmacokinet. Pharmacodyn. 28:7-25 (2001).Google Scholar
  6. 6.
    W. C. Bowman. Pharmacology of neuromuscular function, 2nd edition. Wright, London, 1990.Google Scholar
  7. 7.
    S. Feldman. Neuromuscular Block. Butterworth-Heinemann, Oxford, 1996.Google Scholar
  8. 8.
    D. R. Bevan, J. C. Bevan, and F. Donati. Muscle Relaxants in Clinical Anesthesia. Year Book Medical Publishers, Inc., Chicago, 1988.Google Scholar
  9. 9.
    S. M. Sine and T. Claudio. Gamma-and delta-subunits regulate the affinity and the cooperativity of ligand binding to the acetylcholine receptor. J. Biol. Chem. 266:19369-19377 (1991).Google Scholar
  10. 10.
    S. E. Pedersen and J. B. Cohen. D-Tubocurarine binding sites are located at α-γ and α-δ subunit interfaces of the nicotinic acetylcholine receptor. Proc. Natl. Acad. Sci. USA. 87:2785-2789 (1990).Google Scholar
  11. 11.
    D. M. Fambrough, D. B. Drachman, and S. Satyamurti. Neuromuscular junction in myasthenia gravis: Decreased acetycholine receptors. Science 182:293-295 (1973).Google Scholar
  12. 12.
    A. Pestronk, S. Drachman, and G. Self. Measurement of junctional acetylcholine receptors in myasthenia gravis: Clinical correlates. Muscle and Nerve 8:245-251 (1985).Google Scholar
  13. 13.
    T. L. Rosenberry. Quantitative simulations of endplate currents at neuromuscular junctions based on the reaction of acetylcholine with acetylcholine receptors and acetylcholinesterase. Biophys. J. 26:263-290 (1979).Google Scholar
  14. 14.
    F. Hobbinger. Pharmacology of Anticholinesterase Drugs. In: E. Zaimis (ed): Neuromuscular junction. Springer-Verlag Berlin, 1976, 487-581.Google Scholar
  15. 15.
    T. L. Rosenberry. Acetylcholinesterase. Adv. Enzymol. 43:103-218 (1975).Google Scholar
  16. 16.
    A. Fersht. Enzyme Structure and Mechanism. 2nd ed, W. H. Freeman and Co., New York, 1985.Google Scholar
  17. 17.
    G. H. Fletcher and J. H. Steinbach. Ability of nondepolarizing neuromuscular blocking drugs to act as partial agonists at fetal and adult mouse nicotinic receptors. Mol. Pharmacol. 49:938-947 (1996).Google Scholar
  18. 18.
    B. E. Amaki, B. E. Waud, and D. R. Waud. Atracurium-receptor kinetics: Simple behavior from a mixture. Anesth. Analg. 64:777-780 (1985).Google Scholar
  19. 19.
    A. Kopman, M. Klewicka, and G. Neuman. An alternate method for estimating the dose-response relationships of neuromuscular blocking drugs. Anesth. Analg. 90:1191-1197 (2000).Google Scholar
  20. 20.
    E. S. Vizi and B. Lendvai. Side effects of nondepolarizing muscle relaxants: Relationship to their antinicotinic and antimuscarinic actions. Pharmacol. Ther. 73:75-89 (1997).Google Scholar
  21. 21.
    E. G. Bradshaw, N. J. N. Harper, B. J. Pleuvry, and C. Y. Modla. Differing potencies of muscle relaxants on rat and guinea-pig phrenic nerve preparations. J. Pharm. Pharmacol. 38:623-624 (1986).Google Scholar

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  1. 1.Departments of Anesthesiology and PharmacologyMedical College of OhioToledo
  2. 2.Department of Anesthesiology and Critical Care MedicineLeopold-Franzens UniversityInnsbruckAustria
  3. 3.The Swiss Federal Institute of TechnologyZurichSwitzerland

Personalised recommendations