Clinical Pharmacokinetics

, Volume 43, Issue 2, pp 71–81 | Cite as

Antiepileptic-Induced Resistance to Neuromuscular Blockers

Mechanisms and Clinical Significance
  • Sulpicio G. Soriano
  • J. A. Jeevendra Martyn
Leading Article


Abstract Prolonged administration of antiepileptic drugs is associated with several drug interactions. In the field of anaesthesia and critical care, patients exhibit both sensitivity and resistance to non-depolarising neuromuscular blockers (NDNMBs) after acute and long-term administration of antiepileptic drugs, respectively. Although antiepileptic therapy alone has only mild neuromuscular effects, acutely administered antiepileptic drugs can potentiate the neuromuscular effects of NDNMBs as a result of direct pre- and post-junctional effects. Resistance to NDNMBs during long-term antiepileptic therapy is due to multiple factors operating alone or in combination, including induction of hepatic drug metabolism, increased protein binding of the NDNMBs and/or upregulation of acetylcholine receptors.


Carbamazepine Antiepileptic Drug Acetylcholine Receptor Vecuronium Atracurium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported in part by grants from NIH GM 31569-20, GM 61411-4, and GM55082-6 and Shriners Hospital for Children (to J.A.J.M.). The authors declare no competing financial interest.


  1. 1.
    Roth S, Ebrahim ZY. Resistance to pancuronium in patients receiving carbamazepine. Anesthesiology 1987; 66: 691–3PubMedCrossRefGoogle Scholar
  2. 2.
    Ornstein E, Matteo RS, Young WL, et al. Resistance to metocurine-induced neuromuscular blockade in patients receiving phenytoin. Anesthesiology 1985; 63: 294–8PubMedCrossRefGoogle Scholar
  3. 3.
    Hickey DR, Sangwan S, Bevan JC. Phenytoin-induced resistance to pancuronium: use of atracurium infusion in management of a neurosurgical patient. Anaesthesia 1988; 43(9): 757–9PubMedCrossRefGoogle Scholar
  4. 4.
    Alloul K, Whalley DG, Shutway F, et al. Pharmacokinetic origin of carbamazepine-induced resistance to vecuronium neuromuscular blockade in anesthetized patients. Anesthesiology 1996; 84: 330–9PubMedCrossRefGoogle Scholar
  5. 5.
    Soriano SG, Sullivan LJ, Venkatakrishnan K, et al. Pharmacokinetics and pharmacodynamics of vecuronium in children receiving phenytoin or carbamazepine for chronic anticonvulsant therapy. Br J Anaesth 2001; 86(2): 223–9PubMedCrossRefGoogle Scholar
  6. 6.
    Spacek A, Neiger FX, Krenn CG, et al. Rocuronium-induced neuromuscular block is affected by chronic carbamazepine therapy. Anesthesiology 1999; 90: 109–12PubMedCrossRefGoogle Scholar
  7. 7.
    Soriano SG, Kaus SJ, Sullivan LJ, et al. Onset and duration of action of rocuronium in children receiving chronic anticonvulsant therapy. Paediatr Anaesth 2000; 10: 133–6PubMedCrossRefGoogle Scholar
  8. 8.
    Jellish WS, Modica PA, Tempelhoff R. Accelerated recovery from pipecuronium in patients treatment with chronic anticonvulsant therapy. J Clin Anesth 1993; 5: 105–8PubMedCrossRefGoogle Scholar
  9. 9.
    Hans P, Ledoux D, Bonhomme V, et al. Effect of plasma anticonvulsant level on pipecuronium-induced neuromuscular blockade. J Neurosurg Anesthesiol 1995; 4: 254–8CrossRefGoogle Scholar
  10. 10.
    Tempelhoff R, Modica PA, Jellish WS. Resistance to atracurium-induced neuromuscular blockade in patients with intractable seizure disorders treated with anticonvulsants. Anesth Analg 1990; 71: 665–9PubMedCrossRefGoogle Scholar
  11. 11.
    Ornstein E, Matteo RS, Schwartz AE, et al. The effect of phenytoin on the magnitude and duration of neuromuscular block following atracurium or vecuronium. Anesthesiology 1987; 67: 191–6PubMedCrossRefGoogle Scholar
  12. 12.
    Spacek A, Neiger FX, Spiss CK, et al. Atracurium-induced neuromuscular block is not affected by chronic anticonvulsant therapy with carbamazepine. Acta Anaesthesiol Scand 1997; 41: 1308–11PubMedCrossRefGoogle Scholar
  13. 13.
    Ornstein E, Matteo RS, Weinstein JA, et al. Accelerated recovery from doxacurium-induced neuromuscular blockade in patients receiving chronic anticonvulsant therapy. J Clin Anesth 1991; 3(2): 108–11PubMedCrossRefGoogle Scholar
  14. 14.
    Spacek A, Neiger FX, Spiss CK, et al. Chronic carbamazepine therapy does not influence mivacurium-induced neuromuscular blockade. Br J Anaesth 1996; 77: 500–2PubMedCrossRefGoogle Scholar
  15. 15.
    Jellish WS, Thalji Z, Brundidge PK, et al. Recovery from mivacurium-induced neuromuscular blockade is not affected by anticonvulsant therapy. J Neurosurg Anesthesiol 1996; 8: 4–8PubMedCrossRefGoogle Scholar
  16. 16.
    Naguib M, Flood P, McArdle JJ, et al. Advances in neurobiology of the neuromuscular junction: implications for the anesthesiologist. Anesthesiology 2002; 96(1): 202–31PubMedCrossRefGoogle Scholar
  17. 17.
    Martyn JAJ. Basic and clinical pharmacology of the acetylcholine receptor: implication for the use of neuromuscular relaxants. Keio J Med 1995; 44: 1–8PubMedCrossRefGoogle Scholar
  18. 18.
    Moorthy SS, Krishna G, Dierdorf SF. Resistance to vecuronium in patients with cerebral palsy. Anesth Analg 1991; 73(3): 275–7PubMedCrossRefGoogle Scholar
  19. 19.
    Theroux MC, Akins RE, Barone C, et al. Neuromuscular junctions in cerebral palsy: presence of extrajunctional acetylcholine receptors. Anesthesiology 2002; 96(2): 330–5PubMedCrossRefGoogle Scholar
  20. 20.
    Shayevitz JR, Matteo RS. Decreased sensitivity to metocurine in patients with upper motoneuron disease. Anesth Analg 1985; 64(8): 767–72PubMedCrossRefGoogle Scholar
  21. 21.
    Ibebunjo C, Martyn JA. Fiber atrophy, but not changes in acetylcholine receptor expression, contributes to the muscle dysfunction after immobilization. Crit Care Med 1999; 27(2): 275–85PubMedCrossRefGoogle Scholar
  22. 22.
    Ibebunjo C, Nosek MT, Itani MS, et al. Mechanisms for the paradoxical resistance to d-tubocurarine during immobilization-induced muscle atrophy. J Pharmacol Exp Ther 1997; 283: 443–51PubMedGoogle Scholar
  23. 23.
    Waud BE, Waud DR. The relation between tetanic fade and receptor occlusion in the presence of competitive neuromuscular block. Anesthesiology 1971; 35(5): 456–64PubMedCrossRefGoogle Scholar
  24. 24.
    Anderson GD. A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother 1998; 32(5): 554–63PubMedCrossRefGoogle Scholar
  25. 25.
    Hachad H, Ragueneau-Majlessi I, Levy RH. New antiepileptic drugs: review on drug interactions. Ther Drug Monit 2002; 24(1): 91–103PubMedCrossRefGoogle Scholar
  26. 26.
    Devlin JC, Head-Rapson AG, Parker CJ, et al. Pharmacodynamics of mivacurium chloride in patients with hepatic cirrhosis. Br J Anaesth 1993; 71(2): 227–31PubMedCrossRefGoogle Scholar
  27. 27.
    Fisher DM, Canfell PC, Fahey MR, et al. Elimination of atracurium in humans: contribution of Hofmann elimination and ester hydrolysis versus organ-based elimination. Anesthesiology 1986; 65(1): 6–12PubMedCrossRefGoogle Scholar
  28. 28.
    Kisor DF, Schmith VD, Wargin WA, et al. Importance of the organ-independent elimination of cisatracurium. Anesth Analg 1996; 83(5): 1065–71PubMedGoogle Scholar
  29. 29.
    Martyn JA, Goudsouzian NG, Chang Y, et al. Neuromuscular effects of mivacurium. Anesthesiology 2000; 92(1): 31–7PubMedCrossRefGoogle Scholar
  30. 30.
    Atherton DP, Hunter JM. Clinical pharmacokinetics of the newer neuromuscular blocking drugs. Clin Pharmacokinet 1999; 36(3): 169–89PubMedCrossRefGoogle Scholar
  31. 31.
    Patsalos PN, Duncan JS. Antiepileptic drugs: a review of clinically significant drug interactions. Drug Saf 1993; 9(3): 156–84PubMedCrossRefGoogle Scholar
  32. 32.
    Honkakoski P, Auriola S, Lang MA. Distinct induction profiles of three phenobarbital-responsive mouse liver cytochrome P450 isozymes. Biochem Pharmacol 1992; 43(10): 2121–8PubMedCrossRefGoogle Scholar
  33. 33.
    Honkakoski P, Negishi M. Regulation of cytochrome P450 (CYP) genes by nuclear receptors. Biochem J 2000; 347(Pt 2): 321–37PubMedCrossRefGoogle Scholar
  34. 34.
    Pirttiaho HI, Sotaniemi EA, Pelkonen RO, et al. Hepatic blood flow and drug metabolism in patients on enzyme-inducting anticonvulsants. Eur J Clin Pharmacol 1982; 22: 441–5PubMedCrossRefGoogle Scholar
  35. 35.
    Perucca E, Hedges A, Makki KA, et al. A comparative study of the relative enzyme inducing properties of anticonvulsant drugs in epileptic patients. Br J Clin Pharmacol 1984; 18(3): 401–10PubMedCrossRefGoogle Scholar
  36. 36.
    Perucca E. Clinical implications of hepatic microsomal enzyme induction by antiepileptic drugs. Pharmacol Ther 1987; 33(1): 139–44PubMedCrossRefGoogle Scholar
  37. 37.
    Patsalos PN, Duncan JS, Shorvon SD. Effect of the removal of individual antiepileptic drugs on antipyrine kinetics, in patients taking polytherapy. Br J Clin Pharmacol 1988; 26(3): 253–9PubMedCrossRefGoogle Scholar
  38. 38.
    Duncan JS, Patsalos PN, Shorvon SD. Effects of discontinuation of phenytoin, carbamazepine, and valproate on concomitant antiepileptic medication. Epilepsia 1991; 32(1): 101–15PubMedCrossRefGoogle Scholar
  39. 39.
    Wen X, Wang JS, Kivisto KT, et al. In vitro evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9). Br J Clin Pharmacol 2001; 52(5): 547–53PubMedCrossRefGoogle Scholar
  40. 40.
    Levy RH. Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia 1995; 36 Suppl. 5: S8–13PubMedCrossRefGoogle Scholar
  41. 41.
    Wood M. Plasma binding and limitation of drug access to site of action. Anesthesiology 1991; 75: 721–3PubMedCrossRefGoogle Scholar
  42. 42.
    Abramson FP. Parallel induction of plasma alpha 1-acid glycoprotein concentration and antipyrine clearance by drugs. Prog Clin Biol Res 1989; 300: 427–35PubMedGoogle Scholar
  43. 43.
    Contin M, Riva R, Albani F, et al. Alpha 1-acid glycoprotein concentration and serum protein binding of carbamazepine and carbamazepine-10,11 epoxide in children with epilepsy. Eur J Clin Pharmacol 1985; 29(2): 211–4PubMedCrossRefGoogle Scholar
  44. 44.
    Kremer JM, Wilting J, Janssen LH. Drug binding to human alpha-1-acid glycoprotein in health and disease. Pharmacol Rev 1988; 40: 1–47PubMedGoogle Scholar
  45. 45.
    Fink H, Blobner M, Martyn JAJ. Systemic inflammation leads to resistance to atracurium without increasing membrane expression of acetylcholine receptors. Anesthesiology 2003; 98: 82–8PubMedCrossRefGoogle Scholar
  46. 46.
    Martyn JAJ, Wang C, Itani MS. α1-acid glycoprotein but not albumin can reverse the neuromuscular effects of d-tubocurarine in mice [abstract]. Anesth Analg 1993; 76: S245Google Scholar
  47. 47.
    Gray HS, Slater RM, Pollard BJ. The effect of acutely administered phenytoin on vecuronium-induced neuromuscular blockade. Anaesthesia 1989; 44: 379–81PubMedCrossRefGoogle Scholar
  48. 48.
    Norris FH, Colella J, McFarlin D. Effect of diphenylhydantoin on neuromuscular synapse. Neurology 1968; 14: 869–76CrossRefGoogle Scholar
  49. 49.
    Pincus JH, Yaari Y, Argov Z. Phenytoin: electrophysiological effects at the neuromuscular junction. Adv Neurol 1980; 27: 363–76PubMedGoogle Scholar
  50. 50.
    Nguyen A, Ramzan I. Acute in vitro neuromuscular effects of carbamazepine and carbamazepine-10-11-epoxide. Anesth Analg 1997; 84: 886–90PubMedGoogle Scholar
  51. 51.
    Nguyen A, Ramzan I. In vitro neuromuscular effects of valproic acid. Br J Anaesth 1997; 78(2): 197–200PubMedCrossRefGoogle Scholar
  52. 52.
    Hogue Jr CW, Ward JM, Itani MS, et al. Tolerance and upregulation of acetylcholine receptors follow chronic infusion of d-tubocurarine. J Appl Physiol 1992; 72(4): 1326–31PubMedGoogle Scholar
  53. 53.
    Kim CS, Arnold FJ, Itani MS, et al. Decreased sensitivity to metocurine during long term phenytoin therapy may be attributable to protein binding and acetylcholine receptor changes. Anesthesiology 1992; 77: 500–6PubMedCrossRefGoogle Scholar
  54. 54.
    Brotherton WP, Matteo RS. Pharmacokinetics and pharmacodynamics of metocurine in humans with and without renal failure. Anesthesiology 1981; 55(3): 273–6PubMedCrossRefGoogle Scholar
  55. 55.
    Platt PR, Thackray NM. Phenytoin-induced resistance to vecuronium. Anaesth Intensive Care 1993; 21: 185–91PubMedGoogle Scholar
  56. 56.
    Whalley DG, Ebrahim ZY. Influence of carbamazepine on the dose-response relationship of vecuronium. Br J Anaesth 1994; 72: 125–6PubMedCrossRefGoogle Scholar
  57. 57.
    Tempelhoff R, Modica PA, Spitznagel EL. Anticonvulsants therapy increases fentanyl requirements during anaesthesia for craniotomy. Can J Anaesth 1990; 37: 327–32PubMedCrossRefGoogle Scholar
  58. 58.
    Martyn JA, Greenblatt DJ. Plasma protein binding of drugs after severe burn injury. Clin Pharmacol Ther 1984; 35: 535–9PubMedCrossRefGoogle Scholar
  59. 59.
    Hans P, Brichant JF, Pieron F, et al. Elevated plasma alpha1-acid glycoprotein levels: lack of connection to resistance to vecuronium blockade induced by anticonvulsant therapy. J Neurosurg Anesthesiol 1997; 9: 3–7PubMedCrossRefGoogle Scholar
  60. 60.
    Spacek A, Nickl S, Neiger FX, et al. Augmentation of the rocuronium-induced neuromuscular block by the acutely administered phenytoin. Anesthesiology 1999; 90(6): 1551–5PubMedCrossRefGoogle Scholar
  61. 61.
    Martyn JA, White DA, Gronert GA, et al. Up-and-down regulation of skeletal muscle acetylcholine receptors: effects on neuromuscular blockers. Anesthesiology 1992; 76(5): 822–43PubMedCrossRefGoogle Scholar
  62. 62.
    Melton AT, Antognini JF, Gronert GA. Prolonged duration of succinylcholine in patients receiving anticonvulsants: evidence for mild upregulation of acetylcholine receptors?. Can J Anaesth 1993; 40: 939–42PubMedCrossRefGoogle Scholar
  63. 63.
    Theroux MC, Brandom BW, Zagnoev M, et al. Dose response of succinylcholine at the adductor pollicis of children with cerebral palsy during propofol and nitrous oxide anesthesia. Anesth Analg 1994; 79(4): 761–5PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Sulpicio G. Soriano
    • 1
  • J. A. Jeevendra Martyn
    • 2
  1. 1.Harvard Medical SchoolChildren’s HospitalBostonUSA
  2. 2.Harvard Medical SchoolMassachusetts General Hospital and Shriners Hospital for ChildrenBostonUSA

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