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excitatory neurotransmission by reducing NMDA receptor activity and enhances inhibitory
neurotransmission by facilitating the responsiveness of GABAA receptors. Acetazolamide is
a classical carbonic anhydrase inhibitor which has been employed as an antiepileptic agent
with some success. Topiramate and zonisamide are known to share this mechanism but are
significantly less potent and have greater selectivity for individual isoenzymes (topiramate
inhibits CA-II and CA-IV). Recent evidence suggests that lacosamide may also inhibit
carbonic anhydrase, but this finding requires independent verification. Thus, carbonic
anhydrase inhibition can be considered as an AED mechanism of action but the extent to
which it contributes to the clinical activity of individual compounds remains to be
determined.

Implications of mechanisms of action

Efficacy
One of the more surprising aspects of AED pharmacology is the apparent lack of a direct
relationship between mode of action and efficacy. It is, however, possible to make the
following broad generalisations regarding spectrum of activity. Selective sodium channel
blockers (i.e. carbamazepine, phenytoin, oxcarbazepine, eslicarbazepine acetate) and
selective HVA calcium channel blockers (i.e. gabapentin, pregabalin) tend to have efficacy
against partial and primary generalised tonic-clonic seizures alone and are generally inactive
against or can exacerbate most other generalised epilepsies. This characteristic is shared with
selective GABA turnover drugs (i.e. vigabatrin, tiagabine) but interestingly not with selective
GABAA receptor drugs (i.e. phenobarbital, benzodiazepines) which are active in several
generalised epilepsy syndromes. Any compound that exerts its effects by blockade of T-type
LVA calcium channels, either wholly (i.e. ethosuximide) or in part (i.e. zonisamide), is likely
to be effective against absence seizures and drugs with multiple mechanisms of action (i.e.
sodium valproate, topiramate, levetiracetam, zonisamide) tend to be broad spectrum with
efficacy against a wide range of seizure types and in multiple syndromes. The spectrum of
efficacy associated with newer AED mechanisms, such as potassium channel activation and
AMPA receptor blockade, remains to be fully explored but is likely to similar to that observed
with sodium channel blockers.

Tolerability
All AEDs elicit dose-related adverse effects, the majority of which are CNS in origin (i.e.
somnolence, dizziness, ataxia, headache). For the most part, these side effects reflect a
general dampening of neuronal activity and are unconnected to specific mechanisms of
action, although paraesthesia with topiramate and zonisamide is likely to correspond to their
inhibition of carbonic anhydrase in the peripheral nervous system, as is their modest
propensity to cause renal calculi following prolonged exposure. Many antiepileptic agents
are also associated with one or more specific, dose-independent adverse reaction of variable
incidence. This category includes skin rash with phenytoin, carbamazepine, lamotrigine and
oxcarbazepine, which is unrelated to their common blockade of sodium channels and instead
reflects similarities in their chemical structures and the consequent propensity to elicit allergic
reactions. At present there is no obvious pharmacological explanation for weight gain with
sodium valproate and pregabalin, weight loss with topiramate, or gingival hyperplasia with
phenytoin. Other than renal calculi with carbonic anhydrase inhibitors, the only adverse
reaction with a convincing link to mechanism is visual field constriction with vigabatrin,
believed to be a function of its irreversible inhibition of GABA-transaminase.

Polypharmacology
While many AEDs can be categorised according to a single, principal mechanism of action,
it is increasingly recognised that several agents have multiple primary effects at therapeutic
concentrations (Table 1). Polypharmacology, or the possession of multiple mechanisms of
action within a single molecule, is more common among modern antiepileptic agents than