Skip to main content
Log in

Dose-Related Adverse Effects of Anticonvulsants

  • Review Article
  • Drug Experience
  • Published:
Drug Safety Aims and scope Submit manuscript

Summary

The serum concentration at which a given drug has full efficacy in delivering seizure control bears no predictable relationship to the concentration at which adverse effects will appear. In theory, the threshold for adverse effects should be considerably higher than that for efficacy. For each agent this obviously happens most of the time, or the anticonvulsant would not be on the market, but there are also patients in whom this relationship is reversed. The adverse effects of this class of drugs are discussed from three points of view: the adverse effect type, the kinetic factors that so frequently determine the presence of adverse effects, and the specific characteristics of each drug. Some less well recognised adverse effects syndromes that are not strictly dose related are considered. The importance of adverse effects in therapeutic monitoring is then addressed, and some strategies for maximising efficacy without the burden of long term functional impairment or distress are discussed. The usefulness of monotherapy is stressed with due attention to rational choice of second drugs, when necessary, based on mechanisms of antiepileptic action and adverse effects profiles. While most of these symptoms evolve gradually, there are times when acute, drastic, and even life threatening clinical overdose situations present themselves. Special attention is given to these scenarios, drawing on the drug profiles and clinical pharmacokinetics that define these events to propose methods of coping with the problems efficiently and effectively.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Riker WK, Downes H, Olsen GD, et al. Conjugate lateral gaze nystagmus and free phenytoin concentrations in plasma: lack of correlation. Epilepsia 1978; 19: 93–8

    Article  PubMed  CAS  Google Scholar 

  2. Troupin AS, Ojemann LM, Halpern LM, et al. Tegretol® (carbamazepine) — a double-blind comparison with Dilantin® (phenytoin). Neurology 1977; 27: 511–9

    Article  PubMed  CAS  Google Scholar 

  3. Devinsky O. Clinical uses of the quality-of-life in epilepsy inventory. Epilepsia 1993; 34Suppl. 4: s39–S44

    Article  PubMed  Google Scholar 

  4. Schain RJ, Ward JW, Guthrie D. Carbamazepine as an anticonvulsant in children. Neurology 1977; 27: 476–80

    Article  PubMed  CAS  Google Scholar 

  5. Rodin EA, Rim CS, Kitano H, et al. A comparison of the effectiveness of primidone versus carbamazepine in epileptic outpatients. J Nerv Ment Dis 1976; 163: 41–6

    Article  PubMed  CAS  Google Scholar 

  6. Dodrill CB. Diphenylhydantoin serum levels, toxicity, and neuropsychological performance in patients with epilepsy. Epilepsia 1975; 16: 593–600

    Article  PubMed  CAS  Google Scholar 

  7. Yanai J, Bergman I. Neuronal deficits after neonatal exposure to phenobarbital. Exp Neurol 1981; 73: 199–208

    Article  PubMed  CAS  Google Scholar 

  8. Meador KJ, Loring DW, Moore EE, et al. Comparative cognitive effects of phenobarbital, phenytoin, and valproate in healthy adults. Neurology 1995; 45: 1494–9

    Article  PubMed  CAS  Google Scholar 

  9. Troupin AS, Green JR, Levy RH. Carbamazepine as an anticonvulsant — a pilot study. Neurology 1974; 24: 863–9

    Article  PubMed  CAS  Google Scholar 

  10. Johannessen SI, Henriksen O. Comparison of the serum concentration profiles of tegretol and two new slow release preparations. In: Wolf P, Dam M, Janz D, et al., editors. Advances in epileptology. New York: Raven Press; 16: 421–4

  11. Klotz U. Bioavailability of a slow release preparation of valproic acid under steady-state conditions. Int J Clin Pharmacol Ther Toxicol 1982; 20(1): 24–6

    PubMed  CAS  Google Scholar 

  12. Rambeck B. Pharmacologic interactions of methsuximide with phenobarbital and phenytoin in hospitalized epileptic patients. Epilepsia 1979; 20: 147–56

    Article  PubMed  CAS  Google Scholar 

  13. Richens A, Ahmad S. Controlled trial of sodium valproate in severe epilepsy. BMJ 1975; 4: 255–6

    Article  PubMed  CAS  Google Scholar 

  14. Leppik IE. Felbamate. Epilepsia 1995; 36Suppl. 2: s66–S72

    Article  PubMed  CAS  Google Scholar 

  15. Troupin AS, Friel PN, Wilensky AJ, et al. Evaluation of clorazepate (Tranxene®) as an anticonvulsant — a pilot study Neurology 1979; 29: 458–66

    Article  PubMed  CAS  Google Scholar 

  16. Mattson RH, Cramer JA, Williamson PD, et al. Valproic acid in epilepsy: clinical and pharmacological effects. Ann Neurol 1978; 3: 20–5

    Article  PubMed  CAS  Google Scholar 

  17. Bowdle TA, Patel IH, Levy RH, et al. Valproic acid. Dosage and plasma protein binding and clearance. Clin Pharmacol Ther 1980; 28: 486–92

    Article  PubMed  CAS  Google Scholar 

  18. Fraser GD, Ludden TM, Evens RP, et al. Displacement of phenytoin from plasma binding sites by salicylate. Clin Pharmacol Ther 1980; 27: 165–9

    Article  PubMed  CAS  Google Scholar 

  19. Boggs J, Delorenzo RJ. The use of antiepileptic medications in renal and liver disease. In: Wyllie E. The treatment of epilepsy: principles and practices. Philadelphia: Lea & Febiger, 1993: 835–43

    Google Scholar 

  20. Troupin AS, Johannessen SI. Epilepsy in the elderly: a pharmacologic perspective. In: Smith DB, editor. Epilepsy: current approach to diagnosis and therapy. New York: Raven Press, 1990: 141–53

    Google Scholar 

  21. Whyte MP, Dekaban AS. Metabolic fate of phenobarbital. A quanitative study of p-hydroxyphenobarbital elimination in man. Drug Metab Disp 1977; 5: 63–70

    CAS  Google Scholar 

  22. Leppik IE. Antiepileptic drugs in development: prospects for the near future. Epilepsia 1994; 35 (suppl. 4): S29–S40

    Article  PubMed  Google Scholar 

  23. Hussein G, Troupin AS, Montouris GD. Gabapentin interaction with felbamate. Neurology. In press

  24. Glaser GH. Diphenlyhydantoin: toxicity. In: Woodbury DM, Penry JK, Schmidt RP, editors. Antiepileptic Drugs. New York: Raven Press, 1972: 219–26

    Google Scholar 

  25. Dodrill CB, Troupin AS. Neuropsychological effects of carbamazepine and phenytoin: a reanalysis. Neurology 1991; 41: 141–4

    Article  PubMed  CAS  Google Scholar 

  26. Troupin AS, Ojemann LM, Dodrill CB. Mephenytoin (Mesantoin®) — a reappraisal. Epilepsia 1976; 17: 403–14

    Article  PubMed  CAS  Google Scholar 

  27. Troupin AS, Ojemann LM. Paradoxical intoxication — a complication of anticonvulsant administration. Epilepsia 1975; 16: 753–8

    Article  PubMed  CAS  Google Scholar 

  28. Kalff R, Houtkooper MA, Meyer JW, et al. Carbamazepine and serum sodium levels. Epilepsia 1984; 25: 390–7

    Article  PubMed  CAS  Google Scholar 

  29. Kerr BM, Levy RH. Carbamazepine epoxide. In: Levy R, Mattson R, Penry JK, et al., editors. Antiepileptic drugs. New York: Raven Press, 1989: 505–20

    Google Scholar 

  30. Murphy JV, Marquard K. Asymptomatic hyperammonemia in patients receiving valproic acid. Arch Neurol 1982; 39: 591–2

    Article  PubMed  CAS  Google Scholar 

  31. Tartara A, Manni R. Sodium valproate ‘encephalopathy’: report of three cases with generalised epilepsy. Ital J Neurol Sci. 1985; 6: 93–5

    Article  PubMed  CAS  Google Scholar 

  32. Karas BJ, Wilder BJ, Hammond EJ, et al. Treatment of valproate tremors. Neurology 1983; 39: 1380–2

    Article  Google Scholar 

  33. Jeavons PM, Clark JE, Harding GFA. Valproate and curly hair [letter]. Lancet 1977; 1977; 359

    Google Scholar 

  34. Farwell JR, Lee YJ, Hirtz DG, et al. Phenobarbital for febrile seizures — effects on intelligence and on seizure recurrence. N Engl J Med 1990; 322: 364–9

    Article  PubMed  CAS  Google Scholar 

  35. Reynolds EH, Travers RD. Serum anticonvulsant concentrations in epileptic patients with mental symptoms. A preliminary report. Br J Psychiatry 1974; 124: 440–5

    Article  PubMed  CAS  Google Scholar 

  36. Rivinus TM. Psychiatric effects of the anticonvulsant regimens. J Clin Psychopharmacol 1982; 2: 165–92

    Article  PubMed  CAS  Google Scholar 

  37. Sher A, Andersen JM, Bhatia SC. Primidone-induced catatonic schizophrenia. Drug Intell Clin Pharm 1983; 17: 551–2

    PubMed  CAS  Google Scholar 

  38. Dreifuss FE. Ethosuximide toxicity. In: Levy RH, Mattson R, Meldrum BM, editors. Antiepileptic Drugs. 3rd ed. New York: Raven Press, 1989: 699–705

    Google Scholar 

  39. Brown TR. Methsuximide. In: Levy RH, Mattson R, Meldrum BM, editors. Antiepileptic Drugs. 3rd ed. New York: Raven Press, 1989: 707–14

    Google Scholar 

  40. Lander CM, Eadie MJ, Tyrer J. Interactions between anticonvulsants. Proc Aust Assoc Neuro 1975; 12: 111–16

    CAS  Google Scholar 

  41. Richens A. Clinical pharmacokinetics of Gabapentin. In: Chadwick D, editor. New trends in epilepsy management: the role of Gabapentin. London: Royal Society of Medicine Services 1993: 41–6

    Google Scholar 

  42. McLean MJ. Gabapentin. Epilepsia 1995; 36Suppl. 2: s73–S86

    Article  PubMed  CAS  Google Scholar 

  43. Messenheimer JM. Lamotrigine. Epilepsia 1995; 36Suppl. 2: s97–S94

    Google Scholar 

  44. Troupin AS, Maguire D, Haddad H, et al. Phenacemide: a new clinical pharmacologic perspective. J Epilepsy 1991; 4: 189–98

    Article  Google Scholar 

  45. Houghton GW, Richens A. The effect of benzodiazepines and pheneturide on phenytoin metabolism in man. Br J Clin Pharmacol 1974; 1: 344–5

    Google Scholar 

  46. Troupin AS. Antiepileptic drug therapy: a clinical overview. In: Wyllie E, editor. Treatment of epilepsy: principles and practice. Philadelphia: Lea & Febiger, 1993: 785–90

    Google Scholar 

  47. Kaneko S, Otani K, Fukushima Y, et al. Teratogenicity of antiepileptic drugs: analysis of possible risk factors. Epilepsia 1988; 29: 459–67

    Article  PubMed  CAS  Google Scholar 

  48. Dodrill CB. Effects of antiepileptic drugs on behaviour. In: Devinsky O, Theodore WH, editors. Epilepsy and behaviour. New York: Wiley-Liss, 1991: 37–46

    Google Scholar 

  49. Jeavons PM, Clark JE. Sodium valproate in treatment of epilepsy. BMJ 1974; 2: 584–6

    Article  PubMed  CAS  Google Scholar 

  50. Comstock EG, Falkner TP, Boisaubin EV. Studies on the efficacy of gastric lavage as practiced in the large metropolitan hospital. Clin Toxicol 1981; 18: 581–97

    Article  PubMed  CAS  Google Scholar 

  51. Cooney DO. Activated charcoal: antidotal and other medicinal uses. New York, Marcel Dekker, 1980

    Google Scholar 

  52. Rumack BH, Rosen P. Emesis: safe and effective? [editorial]. Ann Emerg Med 1981; 10: 551

    Article  PubMed  CAS  Google Scholar 

  53. Spivey WH. Flumenazil and seizures: analysis of 43 cases. Clin Ther 1992; 14(2): 292–305

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Troupin, A.S. Dose-Related Adverse Effects of Anticonvulsants. Drug-Safety 14, 299–328 (1996). https://doi.org/10.2165/00002018-199614050-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00002018-199614050-00004

Keywords

Navigation