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Review of the Mechanisms of Action of Antiepileptic Drugs

  • Pharmacology and Pathophysiology
  • Mechanisms of Action of Antiepileptic Drugs
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Abstract

Summary

Antiepileptic drugs (AEDs) have measurable effects on neuronal membrane and synaptic function. These mechanisms of action partially predict effectiveness in animal models of epilepsy and in human epilepsy. Carbamazepine, phenytoin, lamotrigine, oxcarbazepine and valproic acid (sodium valproate) block voltagedependent sodium channels. Ethosuximide reduces T-type calcium currents. Phenobarbital (phenobarbitone), benzodiazepines, gabapentin, vigabatrin, tiagabine, valproic acid and felbamate enhance the neuronal inhibition induced by y-aminobutyric acid (GABA). Felbamate also decreases the activity of excitatory neurotransmitters.

AEDs with known mechanisms of action will further increase the range of options for patients with epilepsy. A rational approach to poly therapy may emerge in the near future, in which medications with complementary, synergistic mechanisms of action are used. Until then, cautious use of medications alone and in combination, with consideration given to mechanisms of action, will enable the large majority of patients with epilepsy to achieve the best possible control of their seizures within the limits of current therapy.

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References

  1. Merritt HH, Putnam TJ. Sodium diphenyl hydantoinate in the treatment of convulsive disorders. JAMA 1938; 111: 1068–73

    Article  Google Scholar 

  2. Merritt HH, Putnam TJ. New series of anticonvulsant drugs tested by experiments on animals. Arch Neurol Psychiatry 1938; 39: 1003–15

    Article  CAS  Google Scholar 

  3. French JA, Dichter MA, Leppik IE, editors. New antiepileptic drug development: preclinical and clinical aspects. Amsterdam: Elsevier, 1993: 1–255

    Google Scholar 

  4. Ballenger Jc. The clinical use of carbamazepine in affective disorders. J Clin Psychiatry 1988; 49: 13–21

    PubMed  Google Scholar 

  5. Sidebottom A, Maxwell S. The medical and surgical management of trigeminal neuralgia. J Clin Ph arm Ther 1995; 20: 31–5

    Article  CAS  Google Scholar 

  6. Sweet WH. The treatment of trigeminal neuralgia (tic douloureux). N Engl J Med 1986; 315: 174–7

    Article  PubMed  CAS  Google Scholar 

  7. Post RM, Leverich GS, Rosoff AS, et al. Carbamazepine prophylaxis in refractory affective disorders: a focus on longterm follow-up. J Clin Psychopharmacol 1990; 10: 318–27

    Article  PubMed  CAS  Google Scholar 

  8. Kerr BM, Thummel KE, Wurden CJ, et al. Human liver carbamazepine metabolism. Role of CYP3A4 and CYP2C8 in 10.11-epoxide formation. Biochem Pharmacol 1994; 47: 1969–79

    CAS  Google Scholar 

  9. Rataud J, Debarnot F, Mary Y, et al. Comparative study of voltage-sensitive sodium channel blockers in focal ischaemia and electric convulsions in rodents. Neurosci Lett 1994; 172: 19–23

    Article  PubMed  CAS  Google Scholar 

  10. Willow M, Catterall WA. Inhibition of binding of[3H]Batrachotoxinin A 20-gamma-benzoate to sodium channels by the anticonvulsant drugs diphenylhydantoin and carbamazepine. Mol Pharmacol 1982; 22: 627–35

    PubMed  CAS  Google Scholar 

  11. Macdonald RL. Antiepileptic drug actions. Epilepsia 1989; 30: S19–28

    Article  PubMed  Google Scholar 

  12. McLean MJ, Macdonald RL. Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 1986; 237: 1001–11

    PubMed  CAS  Google Scholar 

  13. Kohlhardt M, Fichtner H, Frobe U, et al. On the mechanism of drug-induced blockade of Na+ currents: interaction of antiarrhythmic compounds with DPI-modified single cardiac Na+ channels. Circ Res 1989; 64: 867–81

    Article  PubMed  CAS  Google Scholar 

  14. Courtney KR, Etter EF. Modulated anticonvulsant block of sodium channels in nerve and muscle. Eur J Pharmacol 1983; 88: 1–9

    Article  PubMed  CAS  Google Scholar 

  15. Woodbury DM. Effect of diphenylhydantoin on electrolytes and on sodium turnover in brain and other tissues of normal, hypernatremic and postictal rats. J Pharmacol Exp Ther 1955; 115: 74–95

    PubMed  CAS  Google Scholar 

  16. Yaari Y, Selzer M, Pincus J. Phenytoin: mechanisms of its anticonvulsant action. Ann Neurol 1986; 20: 171–84

    Article  PubMed  CAS  Google Scholar 

  17. Macdonald RL, Kelly KM. Mechanisms of action of currently prescribed and newly developed antiepileptic drugs. Epilepsia 1994; 35: S41–50

    Article  PubMed  Google Scholar 

  18. Ferrendelli JA, Mathews GC. Neuropharmacology of antiepileptic medications: mechanisms of action. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. Philadelphia: Lea & Febiger, 1993: 735–41

    Google Scholar 

  19. Delgado-Escueta AV, Horan MP. Phenytoin: biochemical membrane studies. Adv Neurol 1980; 27: 377–98

    PubMed  CAS  Google Scholar 

  20. Hood TW, Siegfried J, Haas HL. Analysis of carbamazepine actions in hippocampal slices of the rat. Cell Mol Neurobiol 1983; 3: 213–22

    Article  PubMed  CAS  Google Scholar 

  21. Schachter Sc. Efficacy and safety of lamotrigine, a new anticonvulsant. Today Ther Trends 1995; 12: 135–43

    Google Scholar 

  22. Cohen AF, Land GS, Breimer DD, et al. Lamotrigine, a new anticonvulsant: pharmacokinetics in normal humans. Clin Pharmacol Ther 1987; 42: 535–41

    Article  PubMed  CAS  Google Scholar 

  23. Reynolds E, Milner G, Matthew D, et al. Anticonvulsant therapy, megaloblastic haemopoesis and folic acid metabolism. Q J Med 1966; 35: 521–37

    CAS  Google Scholar 

  24. Leach MJ, Marden CM, Miller AA. Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action. Epilepsia 1986; 27: 490–7

    Article  PubMed  CAS  Google Scholar 

  25. McGeer EG, Zhu SG. Lamotrigine protects against kainate but not ibotenate lesions in rat striatum. Neurosci Lett 1990; 112: 348–51

    Article  PubMed  CAS  Google Scholar 

  26. Schutz H, Feldmann KF, Faigel JW, et al. The metabolism of 14C-oxcarbazepine in man. Xenobiotica 1986; 16: 769–78

    Article  PubMed  CAS  Google Scholar 

  27. Schmutz M, Brugger F, Gentsch C, et al. Oxcarbazepine: preclinical anticonvulsant profile and putative mechanisms of action. Epilepsia 1994; 35: S47–50

    Article  PubMed  Google Scholar 

  28. McLean MJ, Schmutz M, Wamil AW, et al. Oxcarbazepine: mechanisms of action. Epilepsia 1994; 35: S5–9

    Article  PubMed  Google Scholar 

  29. Wamil AW, Portet CH, Jensen PK, et al. Oxcarbazepine and its monohydroxy metabolite limit action potential firing by mouse central neurons in cell culture. Epilepsia 1991; 32: 65–6

    Google Scholar 

  30. Pape HC, Budde T, Mager R, et al. Prevention of Ca(2+)mediated action potentials in GABAergic local circuit neurones of rat thalamus by a transient K+ current. J Physiol 1994; 3: 403–22

    Google Scholar 

  31. Coulter DA, Huguenard JR, Prince DA. Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons. Neurosci Lett 1989; 98: 74–8

    Article  PubMed  CAS  Google Scholar 

  32. Chen A, Weston JK, Bratton AC. Anticonvulsant activity and ethosuximide. Epilepsia 1963; 4: 66–76

    Article  PubMed  CAS  Google Scholar 

  33. Coulter DA, Huguenard JR, Prince DA. Characterization of ethosuximide reduction oflow-threshold calcium current in thalamic neurons. Ann Neurol 1989; 25: 582–93

    Article  PubMed  CAS  Google Scholar 

  34. Balding Jr F, Geller HM. Sodium valproate enhancement of gamma-aminobutyric acid (GAB A) inhibition: electrophysiological evidence for anticonvulsant activity. J Pharmacol Exp Ther 1981; 217: 445–50

    PubMed  Google Scholar 

  35. Bejsovec MR, Kulenda Z, Ponca F. Familial intrauterine convulsions in pyridoxine dependency. Arch Dis Child 1967; 42: 201–8

    Article  PubMed  CAS  Google Scholar 

  36. Meldrum BS. Epilepsy and gamma-aminobutyric acid-mediated inhibition. Int Rev Neurobiol 1975; 17: 1–36

    Article  PubMed  CAS  Google Scholar 

  37. Meldrum B. GABA-agonists as anti-epileptic agents. Adv Biochern Psychopharmacol 1981; 26: 207–17

    CAS  Google Scholar 

  38. Dichter MA, Ayala GF. Cellular mechanisms of epilepsy: a status report. Science 1987; 237: 157–64

    Article  PubMed  CAS  Google Scholar 

  39. Bourgeois BF, Dodson WE, Ferrendelli JA. Primidone, phenobarbital, and PEMA: II. Seizure protection, neurotoxicity, and therapeutic index of varying combinations in mice. Neurology 1983; 33: 291–5

    Article  PubMed  CAS  Google Scholar 

  40. Macdonald RL, McLean MJ, Skerritt JH. Anticonvulsant drug mechanisms of action. Fed Proc 1985; 44: 2634–9

    PubMed  CAS  Google Scholar 

  41. Twyman R, Rogers C, Macdonald R. Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital. Ann Neurol 1989; 25: 213–20

    Article  PubMed  CAS  Google Scholar 

  42. Heyer E, Macdonald R. Barbiturate reduction of calcium-dependent action potentials: correlation with anesthetic action. Brain Res 1982; 236: 157–71

    Article  PubMed  CAS  Google Scholar 

  43. Rogawski MA, Porter RJ. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 1990; 42: 223–86

    PubMed  CAS  Google Scholar 

  44. Fransen A, Quistroff B, Schousboe A. Phenobarbital protects cerebral cortex neurones against toxicity induced by kainate but not by other excitatory amino acids. Neurosci Lett 1990; 111: 233–8

    Article  Google Scholar 

  45. Mehta AK, Ticku MK. Benzodiazepine and beta-carboline interactions with GABAA receptor-gated chloride channels in mammalian cultured spinal cord neurons. J Pharmacol Exp Ther 1989; 249: 418–23

    PubMed  CAS  Google Scholar 

  46. Leiderman DB. Gabapentin as add-on therapy for refractory partial epilepsy: results of five placebo-controlled trials. Epilepsia 1994; 35: S74–6

    Article  PubMed  Google Scholar 

  47. Blum RA, Comstock TJ, Sica DA, et al. Pharmacokinetics of gabapentin in subjects with various degrees of renal function. Clin Pharmacol Ther 1994; 56: 154–9

    Article  PubMed  CAS  Google Scholar 

  48. Goa KL, Sorkin EM. Gabapentin: a review of its pharmacological properties and clinical potential in epilepsy. Drugs 1993; 46: 409–27

    Article  PubMed  CAS  Google Scholar 

  49. Ramsey RE, Slater JD. Antiepileptic drugs in clinical development. In: French JE, Dichter MA, Leppik IE, editors. New anti epileptic drug development: preclinical and clinical aspects. Amsterdam: Elsevier Science Publishers, 1993: 45–67

    Google Scholar 

  50. Rock DM, Kelly KM, Macdonald RL. Gabapentin actions on ligand- and voltage-gated responses in cultured rodent neurons. Epilepsy Res 1993; 16: 89–98

    Article  PubMed  CAS  Google Scholar 

  51. Macdonald RL, Kelly KM. Antiepileptic drug mechanisms of action. Epilepsia 1993; 34: S1–8

    Article  PubMed  CAS  Google Scholar 

  52. Taylor CP, Vartanian MG, Yuen PW, et al. Potent and stereospecific anticonvulsant activity of 3-isobutyl GABA relates to in vitro binding at a novel site labeled by tritiated gabapentin. Epilepsy Res 1993; 14: 11–5

    Article  PubMed  CAS  Google Scholar 

  53. Taylor CP. Emerging perspectives on the mechanism of action of gabapentin. Neurology 1994; 44: S10–6

    Article  PubMed  CAS  Google Scholar 

  54. Connelly JE. Vigabatrin. Ann Pharmacother 1993; 27: 197–204

    PubMed  CAS  Google Scholar 

  55. Hoke JF, Yuh L, Antony KK, et al. Pharmacokinetics of vigabatrin following single and multiple oral doses in normal volunteers. J Clin Pharmacol 1993; 33: 458–62

    PubMed  CAS  Google Scholar 

  56. Richens A. Potential antiepileptic drugs: vigabatrin. In: Levy R, Mattson R, Meldrum B, et al., editors. Antiepileptic drugs. New York: Raven Press, 1989: 937–46

    Google Scholar 

  57. Jung MJ, Lippert B, Betcalf BW, et al. Gamma-vinyl GAB A (4-amino-hex-5-enoic acid), a new selective irreversible inhibitor of GABA-T; effect on brain GABA metabolism in mice. J Neurochem 1977; 29: 797–802

    Article  PubMed  CAS  Google Scholar 

  58. Mengel H. Tiagabine. Epilepsia 1994; 35: S81–4

    Article  PubMed  Google Scholar 

  59. Braestrup C, Nielsen EB, Sonnewald U, et al. (R)-N-(4,4-bis(3-methyl-2-thienyl)but-3-en-l-yl)nipecotic acid (tiagabine) binds with high affinity to the brain GAB A uptake carrier. J Neurochem 1990; 54: 639–64

    Article  PubMed  CAS  Google Scholar 

  60. Zaccara G, Messori A, Moroni E. Clinical pharmacokinetics of valproic acid — 1988. Clin Pharmacokinet 1988; 15: 367–89

    Article  PubMed  CAS  Google Scholar 

  61. Piredda SG, Woodhead JH, Swinyard EA. Effect of stimulus intensity on the profile of anticonvulsant activity of phenytoin, ethosuximide and valproate. J Pharmacol Exp Ther 1985; 232: 741–5

    PubMed  CAS  Google Scholar 

  62. Ferrendelli JA, Holland KD, McKeon AC, et al. Comparison of the anticonvulsant activities of ethosuximide, valproate, and a new anticonvulsant, thiobutyrolactone. Epilepsia 1989; 30: 617–22

    Article  PubMed  CAS  Google Scholar 

  63. Griffith WH, Taylor L. Sodium valproate decreases synaptic potentiation and epileptiform activity in hippocampus. Brain Res 1988; 474: 155–64

    Article  PubMed  CAS  Google Scholar 

  64. Loscher W. Valproate-induced changes in GAB A metabolism at the subcellular level. Biochem Pharmacol 1981; 30: 1364–6

    Article  PubMed  CAS  Google Scholar 

  65. Gram L. Experimental studies and controlled clinical testing of valproate and vigabatrin. Acta Neurol Scand 1988; 78: 241–70

    Article  PubMed  CAS  Google Scholar 

  66. Kelly KM, Gross RA, Macdonald RL. Valproic acid selectivity reduces the low-threshold (T) calcium current in rat nodose neurons. Neurosci Lett 1990; 116: 233–8

    Article  PubMed  CAS  Google Scholar 

  67. Wagner ML. Felbamate: a new antiepileptic drug. Am J Hosp Pharm 1994; 51: 1657–66

    PubMed  CAS  Google Scholar 

  68. Swinyard EA, Sofia RD, Kupferberg HJ. Comparative anticonvulsant activity and neurotoxicity of fe1bamate and four prototype antiepileptic drugs in mice and rats. Epilepsia 1986; 27: 27–34

    Article  PubMed  CAS  Google Scholar 

  69. Rho JM, Donevan SD, Rogawski MA. Mechanism of action of the anticonvulsant felbamate: opposing effects on N-methylD-aspartate and gamma-aminobutyric acidA receptors. Ann Neurol 1994; 35: 229–34

    Article  PubMed  CAS  Google Scholar 

  70. Schachter Sc. Advances in the assessment of refractory epilepsy. Epilepsia 1993; 34: S24–30

    Article  PubMed  Google Scholar 

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Schachter, S.C. Review of the Mechanisms of Action of Antiepileptic Drugs. CNS Drugs 4, 469–477 (1995). https://doi.org/10.2165/00023210-199504060-00009

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