, Volume 13, Issue 4, pp 266–275 | Cite as

Interactions with Antiepileptic Drugs

  • Alan Richens
Review Article


Most of the currently available antiepileptic drugs have a low therapeutic ratio and therefore a drug interaction causing elevation of the serum level of one of these compounds can readily lead to drug intoxication. Phenytoin, in particular, is vulnerable because its metabolism is dose-related and at therapeutic serum levels the enzyme system involved in its degradation is easily inhibited by concurrent drug administration.

As multiple drug therapy has traditionally been practised in the management of epilepsy, clinically important interactions are common. Furthermore, most of the drugs used in the treatment of major epilepsies are potent inducers of hepatic microsomal enzymes and can therefore stimulate the metabolism of concurrently-administered drugs to such an extent that they may be rendered ineffective. The use of one drug alone is recommended, where possible, in the management of epilepsy.


Phenobarbitone Epileptic Patient Griseofulvin Sodium Valproate Primidone 
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  1. Ahmad, S.: Renal insensitivity to frusemide caused by chronic anticonvulsant therapy. British Medical Journal 3: 657–659 (1974).PubMedCrossRefGoogle Scholar
  2. Braithwaite, R.A.; Flanagan, R.A. and Richens, A.: Steady-state plasma nortriptyline concentrations in epileptic patients. British Journal of Clinical Pharmacology 2: 469–471 (1975).PubMedCrossRefGoogle Scholar
  3. Brooks, S.M.; Werk, E.E.; Ackerman, S.J.; Sullivan, I. and Thrasher, K.: Adverse effects of phenobarbital on corticosteroid metabolism in patients with bronchial asthma. New England Journal of Medicine 286: 1125–1128 (1972).PubMedCrossRefGoogle Scholar
  4. Busfield, D.; Child, K.J.; Atkinson, R.M. and Tomich, E.G.: An effect of phenobarbitone on blood levels of griseofulvin in man. Lancet 2: 1042 (1963).PubMedCrossRefGoogle Scholar
  5. Cereghino, J.J.; Van Meter, J.C.; Brock, J.T.; Penry, J.K.; Smith, L.D. and White, B.G.: Preliminary observations of serum carbamazepine concentration in epileptic patients. Neurology (Minneap.) 23: 357–366 (1973).CrossRefGoogle Scholar
  6. Christensen, L.K. and Skovsted, L.: Inhibition of drug metabolism by chloramphenicol. Lancet 2: 1397–1399 (1969).PubMedCrossRefGoogle Scholar
  7. Conney, A.H.: Pharmacological implications of microsomal enzyme induction. Pharmacol. Rev. 19: 317–366 (1967).PubMedGoogle Scholar
  8. Data, J.L.; Wilkinson, G.R. and Nies, A.S.: Interaction of quinidine with anticonvulsant drugs. New England Journal of Medicine 294: 699–702 (1976).PubMedCrossRefGoogle Scholar
  9. Eadie, M.J. and Tyrer, J.H.: Anticonvulsant Therapy. Pharmacological Basis and Practice, p.64 (Churchill Livingstone, Edinburgh 1974).Google Scholar
  10. Edwards, V.E. and Eadie, M.J.: Clonazepam —clinical study of its effectiveness as an anticonvulsant. Proceedings of the Australian Association of Neurology 10: 61–66 (1973).Google Scholar
  11. Fincham, R.W.; Schottelius, D.D. Sahs, A.L.: The influence of diphenylhydantoin on primidone metabolism. Archives of Neurology (Chicago) 30: 259–262 (1974).CrossRefGoogle Scholar
  12. Hansen, J.M.; Kristensen, M.; Skovsted, L. and Christensen, L.K.: Dicoumarol-induced diphenylhydantoin intoxication. Lancet 2: 265–266 (1966).PubMedCrossRefGoogle Scholar
  13. Hansen, J.M.; Kristensen, M. and Skovsted, L.: Sulthiame (Ospolot) as inhibitor of diphenylhydantoin metabolism. Epilepsia (Amsterdam) 9: 17–22 (1968).CrossRefGoogle Scholar
  14. Hansen, J.M.; Siersbaek-Nielsen, K.; Kristensen, M.; Skovsted, L. and Christensen, L.K.: Effect of diphenylhydantoin on the metabolism of dicoumarol in man. Acta Neurologica Scan-dinavica 189: 15–19 (1971).Google Scholar
  15. Hempel, E. and Klinger, W.: Drug stimulated biotransformation of hormonal steroid contraceptives: clinical implications. Drugs 12: 442–448 (1976).PubMedCrossRefGoogle Scholar
  16. Houghton, G.W. and Richens, A.: Inhibition of phenytoin metabolism by sulthiame in epileptic patients. British Journal of Clinical Pharmacology 1: 59–66 (1974a).PubMedCrossRefGoogle Scholar
  17. Houghton, G.W. and Richens, A.: Phenytoin intoxication induced by sulthiame in epileptic patients. Journal of Neurology, Neurosurgery and Psychiatry 37: 275–281 (1974b).CrossRefGoogle Scholar
  18. Houghton, G.W. and Richens, A.: The effect of benzodiazepines and pheneturide on phenytoin metabolism in man. British Journal of Clinical Pharmacology 1: 344–345 (1974c).Google Scholar
  19. Huisman, J.W.; van Heycop Ten Ham, M.W. and van Zijl, C.H.W.: Influence of ethylphenacemide on serum levels of other antiepileptic drugs. Epilepsia (Amsterdam) 11: 207–215 (1970).CrossRefGoogle Scholar
  20. Johannessen, S.I. and Strandjord, R.E.: The influence of phenobarbitone and phenytoin on carbamazepine serum levels; in Schneider et al. (Eds) Clinical Pharmacology of Antiepileptic Drugs (Springer-Verlag, Heidelberg 1976).Google Scholar
  21. Karlin, J.M. and Kutt, H.: Acute diphenylhydantoin intoxication following halothane anaesthesia. Journal of Paediatrics 76: 941 (1970).CrossRefGoogle Scholar
  22. Karlsson, E.; Collste, P. and Rawlins, M.D.: Plasma levels of lignocaine during combined treatment with phenytoin and procainamide. European Journal of Clinical Pharmacology 7: 455–459 (1974).PubMedCrossRefGoogle Scholar
  23. Kater, R.M.H.; Roggin, G.; Tobon, F.; Zieve, P. and Iber, F.L.: Increased rate of clearance of drugs from the circulation of alcoholics. American Journal of the Medical Sciences 258: 35–39 (1969).PubMedCrossRefGoogle Scholar
  24. Kutt, H.; Winters, W. and McDowell, F.: Depression of parahydroxylation of diphenylhydantoin by antituberculous chemotherapy. Neurology (Minneapolis) 16: 594–602 (1966).CrossRefGoogle Scholar
  25. Kutt, H.: Diphenylhydantoin. Interactions with other drugs in man; in Woodbury, Penry and Schmidt (Eds) Antiepileptic Drugs, p. 168 (Raven Press, New York 1972).Google Scholar
  26. Kutt, H.: Biochemical and genetic factors regulating Dilantin metabolism in man. Annals of the New York Academy of Science 179: 704–722 (1971).CrossRefGoogle Scholar
  27. Kutt, H.: Interactions of antiepileptic drugs. Epilepsia (New York) 16: 393–402 (1975).Google Scholar
  28. Kutt, H. and McDowell, F.: Management of epilepsy with diphenylhydantoin. Journal of the American Medical Association 203: 969–972 (1968).PubMedCrossRefGoogle Scholar
  29. Laenger, H. and Detering, K.: Antiepileptic drugs and failure of oral contraceptives. Lancet 2: 600 (1974).CrossRefGoogle Scholar
  30. Lancet Annotation: Paracetamol hepatotoxicity. Lancet 2: 1189 (1975).Google Scholar
  31. Latham, A.N.: Some observations on the value of serum drug concentrations and urinary D-glucaric acid determinations in assessing the effects of some anticonvulsant drugs on hepatic enzyme activity. Ph.D. Thesis, University of London (1974).Google Scholar
  32. Latham, A.N. and Richens, A.: Pheneturide, a more potent liver enzyme inducer in man than phenobarbitone? British Journal of Clinical Pharmacology 47: 615P (1973).Google Scholar
  33. Levi, A.J.; Sherlock, S. and Walker, D.: Phenylbutazone and isoniazid metabolism in patients with liver disease in relation to previous drug therapy. Lancet 2: 1275–1279 (1968).CrossRefGoogle Scholar
  34. Loga, S.; Curry, S. and Lader, M.: Interactions of orphenadrine and phenobarbitone with chlorpromazine; plasma concentrations and effects in man. British Journal of Clinical Pharmacology 2: 197–208 (1975).PubMedCrossRefGoogle Scholar
  35. Lunde, P.K.M.; Rane, A.; Yaffe, S.J.; Lund, L. and Sjöqvist, F.: Plasma protein binding of diphenylhydantoin in man. Clinical Pharmacology and Therapeutics 11: 846–855 (1970).PubMedGoogle Scholar
  36. Lusins, J.D. and Jutkowitz, R.: Residual cerebellar systems dysfunction and peripheral neuropathy after diphenylhydantoin therapy. Mount Sinai Journal of Medicine 39: 617–621 (1972).PubMedGoogle Scholar
  37. MacDonald, M.G. and Robinson, D.S.: Clinical observations of possible barbiturate interference with anticoagulation. Journal of the American Medical Association 204: 97–100 (1968).PubMedCrossRefGoogle Scholar
  38. Meikle, A.W.; Jubiz, W.; Matsukura, S.; West, C.D. and Tyler, F.H.: Effects of diphenylhydantoin on the metabolism of metyrapone and release of ACTH in man. Journal of Clinical Endocrinology and Metabolism 29: 1553–1558 (1969).PubMedCrossRefGoogle Scholar
  39. Mezey, E.: Ethanol metabolism and ethanol-drug interactions. Biochemical Pharmacology 25: 869–975 (1976).PubMedCrossRefGoogle Scholar
  40. Olesen, O.V.: The influence of disulfiram and calcium carbide on the serum diphenylhydantoin. Excretion of HPPH in the urine. Archives of Neurology (Chicago) 16: 642–644 (1967).CrossRefGoogle Scholar
  41. Padgham, C. and Richens, A.: Quinine metabolism: a useful index of hepatic drug metabolising capacity in man? British Journal of Clinical Pharmacology 1: 352–353 (1974).Google Scholar
  42. Penttilä, O.; Neuvonen, P.J.; Aho, K. and Lehtovaara, R.: Interaction between doxycycline and some antiepileptic drugs. British Medical Journal 2: 470–472 (1974).PubMedCrossRefGoogle Scholar
  43. Petruch, F.; Schüppel, R.V.A. and Steinhilber, G.: Effect of diphenylhydantoin on hepatic drug hydroxylation. European Journal of Clinical Pharmacology 7: 281–285 (1974).PubMedCrossRefGoogle Scholar
  44. Pugh, R.N.H.; Geddes, A.M. and Yeoman, W.B.: Interaction of phenytoin and chlorpheniramine. British Journal of Clinical Pharmacology 2: 173–174 (1975).PubMedCrossRefGoogle Scholar
  45. Rawlins, M.D.; Collste, P.; Bertilsson, L. and Palmer, L.: Distribution and elimination kinetics of carbamazepine in man. European Journal of Clinical Pharmacology 8: 91–96 (1975).PubMedCrossRefGoogle Scholar
  46. Reynolds, E.H.; Fenton, G.; Fenwick, P.; Johnson, A. and Laundy, M.: Interaction of phenytoin and primidone. British Medical Journal 2: 594–595 (1975).PubMedCrossRefGoogle Scholar
  47. Richens, A.: A study of the pharmacokinetics of phenytoin (diphenylhydantoin) in epileptic patients and the development of a nomogram for making dose increments. Epilepsia 16: 627–646 (1975).PubMedCrossRefGoogle Scholar
  48. Richens, A.: Drug Treatment of Epilepsy (Henry Kimpton, London 1976).Google Scholar
  49. Richens, A. and Ahmad, S.: Controlled trial of sodium valproate in severe epilepsy. British Medical Journal 4: 255–256 (1975).PubMedCrossRefGoogle Scholar
  50. Richens, A. and Houghton, G.W.: Effect of drug therapy on the metabolism of phenytoin; in Schneider et al. (Eds) Clinical Pharmacology of Anti-Epileptic Drugs (Springer-Verlag, Heidelberg 1975).Google Scholar
  51. Richens, A. and Houghton, G.W.: Drug combinations and interactions in severe epilepsy. Proceedings of 6th International Symposium on Epilepsy. Brussels, September 15–18 (1976).Google Scholar
  52. Richens, A.; Scoular, I.T.; Ahmad, S. and Jordan, B.J.: Pharmacokinetics and efficacy of Epilim in patients receiving long-term therapy with other antiepileptic drugs; in Legg (Ed) Clinical and Pharmacological Aspects of Sodium Valproate (Epilim) in the Treatment of Epilepsy (MCS Consultants, England 1976).Google Scholar
  53. Richens, A. and Woodford, F.P.: Anticonvulsant Drugs and Enzyme Induction (Associated Scientific Publishers, Amsterdam 1976).Google Scholar
  54. Rigelman, S.; Rowland, M. and Epstein, W.L.: Griseofulvin-phenobarbital interaction in man. Journal of the American Medical Association 213: 426–431 (1970).CrossRefGoogle Scholar
  55. Roe, T.F.; Podosin, R.L. and Blaskovics, M.E.: Drug interaction: diazoxide and diphenylhydantoin. Journal of Pediatrics 87: 480–484 (1975).PubMedCrossRefGoogle Scholar
  56. Silver, J.: Vitamin D therapy for children on anticonvulsants. New England Journal of Medicine 293: 1106 (1975).PubMedGoogle Scholar
  57. Sjö, O.; Hvidberg, E.F.; Naestoft, J. and Lund, M.: Pharmacokinetics and side effects of clonazepam and its 7-amino-metabolite in man. European Journal of Clinical Pharmacology 8: 249–254 (1975).PubMedCrossRefGoogle Scholar
  58. Solomon, H.M. and Schrogie, J.J.: The effect of phenyramidol on the metabolism of diphenylhydantoin. Clinical Pharmacology and Therapeutics 8: 554–556 (1967).PubMedGoogle Scholar
  59. Sutton, G. and Kupferberb, H.J.: Isoniazid as an inhibitor of primidone metabolism. Neurology (Minn.) 25: 1179–1181 (1975).CrossRefGoogle Scholar
  60. Vajda, F.J.E.; Prineas, R.J. and Lovell, R.R.H.: Interaction between phenytoin and the benzodiazepines. British Medical Journal 1: 346 (1971).PubMedCrossRefGoogle Scholar
  61. Vakil, S.D.; Critchley, E.M.R.; Philips, J.C.; Fahim, Y.; Haydock, C.; Cocks, A. and Dyer, T.: The effect of sodium valproate (Epilim) on phenytoin and phenobarbitone blood levels; Legg (Ed) Clinical and Pharmacological Aspects of Sodium Valproate (Epilim) in the treatment of Epilepsy (MCS Consultants, England 1976).Google Scholar
  62. Viala, A.; Cano, J.P.; Dravet, L.; Tassinari, C.A.; Roger, J. and Angeletti-Philippe, A.: Blood levels of diazepam (Valium) and N-desmethyl diazepam in the epileptic child. Psychiatry, Neurology and Neurosurgery 74: 153–158 (1971).Google Scholar

Copyright information

© ADIS Press 1977

Authors and Affiliations

  • Alan Richens
    • 1
    • 2
  1. 1.Department of Clinical PharmacologySt. Bartholomew’s HospitalLondonEngland
  2. 2.Centre for EpilepsyChalfont St. PeterBuckinghamshireEngland

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