Anticonvulsants: aspects of their mechanisms of action

An ideal anticonvulsant drug would prevent or inhibit excessive pathological neuronal discharge without interfering with physiological neuronal activity and without producing untoward effects. Such an ideal compound is not yet available. However, during the last few years several new anticonvulsants have appeared (e.g. vigabatrine, gabapentin, topiramate, lamotrigine, tiagabine, felbamate and oxcarbazepine) which may challenge the older, more established substances (i.e. phenytoin, benzodiazepines, phenobarbital, valproate, carbamazepine and ethosuximide). Interestingly, several of the old and new anticonvulsants are beneficial in the treatment of various psychiatric conditions (most notably mood disorders) as well as neuropathic pain. The reason these various drugs are effective in the treatment of such disparate clinical conditions is unknown. The answer may be that the neuronal dysfunctions underlying these conditions are similar in a mechanistic sense, but are manifested in different neurons/locations of the nervous system, or that the drugs possess several mechanisms of action that contribute in different ways to the favourable effect depending on the condition studied. Even though all these drugs inhibit excessive neuronal activity, this acute effect appears to be produced by several mechanisms, which fall into three major categories: (1) blockade of voltage-gated sodium channels; (2) indirect or direct enhancement of inhibitory gamma-aminobutyric acid [GABAergic] neurotransmission; or (3) inhibition of excitatory glutamatergic neurotransmission. Moreover, several of these drugs fall into more than one category, and it is often unclear which category is responsible for a given effect of a drug. It is plausible that some of the beneficial effects observed in the clinic can be explained by the secondary neural depressant mechanisms of action of these substances, whereas other benefits may be due to long-term neuroplastic effects, which may either be common or different across the various conditions treated.