Page 263 - ILAE_Lectures_2015

their traditional counterparts. One exception is sodium valproate, which is assumed to have
multiple mechanisms of action on the basis that extensive laboratory investigations have
failed to find a single mechanism that would explain its broad spectrum of clinical activity.
In the case of modern drugs, such as topiramate, levetiracetam and zonisamide, the evidence
for multifactorial pharmacology is compelling. The use of AEDs with multiple mechanisms
of action may confer certain advantages when treating patients with multiple seizure types or
in whom the diagnosis is initially unclear. Such drugs cover all the pharmacological bases,
with limited potential for overload on any given system. This may reduce the likelihood of
tolerance and increase the possibility of synergism between mechanisms but has also been
suggested to elevate the propensity for adverse effects.

Conclusions

The explosion in licensing of new drugs for epilepsy throughout the 1990s and the early part
of this century has been paralleled by remarkable advances in our understanding of how
antiepileptic agents exert their effects at the cellular level. Among currently available
compounds the predominant mechanisms of action include blockade of voltage-gated sodium
and calcium channels, activation of voltage-gated potassium channels, allosteric activation
of GABAA receptors, augmentation of GABA turnover, blockade of glutamate receptors,
inhibition of carbonic anhydrase, and modulation of synaptic vesicles. This new-found
pharmacological knowledge is tempered to some extent by the apparent absence of an
association between mode of action and clinical activity, either in terms of efficacy or
tolerability. It is possible to make some general observations, not least of which is the fact
that drugs with a single selective mechanism tend to have a narrow spectrum of efficacy,
although even here there are exceptions (c.f. benzodiazepines). Knowing how AEDs work
has important implications for clinical practice, particularly when selecting an alternative
drug to replace for a previously ineffective agent or when adding a new drug to an existing
regimen. Why pharmacology fails to predict clinical activity per se is unclear but probably
reflects an as yet incomplete understanding of both drug and disease mechanisms.

Further reading

BENARROCH EE. GABAA receptor heterogeneity, function, and implications for epilepsy. Neurology 2007; 68: 612-
4.
BENARROCH EE. Potassium channels: brief overview and implications in epilepsy. Neurology 2009; 72: 664-9.
BIALER M, WHITE HS. Key factors in the discovery and development of new antiepileptic drugs. Nat Rev Drug Discov
2010; 9: 68-82.
BRODIE MJ, COVANIS A, GIL-NAGEL A et al. Antiepileptic drug therapy: does mechanism of action matter?
Epilepsy Behav 2011; 21: 331-41.
KÖHLING R. Voltage-gated sodium channels in epilepsy. Epilepsia 2002; 43: 127895.
KWAN P, SILLS GJ, BRODIE MJ. The mechanisms of action of commonly used antiepileptic drugs. Pharmacol Ther
2001; 90: 2134.
MELDRUM BS, ROGAWSKI MA. Molecular targets for antiepileptic drug development. Neurotherapeutics 2007: 4:
1861.
ROGAWSKI MA. AMPA receptors as a molecular target in epilepsy therapy. Acta Neurol Scand 2013; 197 (suppl): 9-
18.
ROGAWSKI MA, LÖSCHER W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci 2004; 5: 55364.