Aeds Have Many Distinct Cellular Mechanisms Of Action

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Clinicians have a wide range of AEDs to choose from. There are 23 distinct chemical entities marketed worldwide for epilepsy therapy. Some of these agents are known to be useful for a limited range of seizure types. For example, ethosuximide is largely exclusively used in childhood absence. Tiagabine, vigabatrin, phenytoin, carbamaze-pine, and oxcarbazepine are mainly useful for partial and primarily generalized seizures.

The other agents, including valproate, topiramate and levetiracetam, have broader utility. With very few exceptions, each AED acts in a mechanistically distinct way. This is not the situation in other therapeutic areas. For example, the triptans used to abort migraine attacks all act in a similar fashion as agonists of serotonin 5-HTj B and 5-HTjd receptors; the selective serotonin reuptake inhibitors used to treat depression all block the serotonin transporter; the many statins are all HMG-CoA reductase inhibitors; and the proton pump inhibitors all have the same molecular target. In contrast, each AED generally acts on a unique set of molecular targets. Even when they share the same molecular target, as is the case for AEDs that act on voltage-activated sodium channels, the biophysical details for each drug are sufficiently different that the mechanisms must be considered distinct.1 For example, there may be important differences in binding rate, binding affinity,2 the ability to block open channels3 or effects on persistent sodium current4, or effects on other ion channels, as is the case for lamotrigine, where modulation of voltage-activated calcium channels may be relevant to its therapeutic activity. Another major class of AED actions relates to interactions with GABA-mediated inhibition. Some drugs, most notably benzodiazepines and phenobarbital, but also felbamate and topiramate, positively modulate GABAA receptors. The specific actions of these agents are distinct. For example, benzodiazepines and phenobarbital modulate GABAa receptors at distinct sites and in different ways. Unlike benzodiaz-epines, phenobarbital, felbamate and topiramate act on targets other than GABAA receptors that likely contribute to therapeutic activity. Vigabatrin inhibits GABA transaminase, whereas tiagabine blocks the GAT-1 GABA transporter; each of these agents affects the dynamics of inhibitory function in dramatically different ways. Other AEDs exert their anticonvulsant action through novel targets. For example, LEV acts through SV2A, a ubiquitous synaptic vesicle protein, whereas gabapentin and pregabalin act through a2ยง , a novel presynaptic protein associated with voltage-activated calcium channels.5'6

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Getting to Know Anxiety

Getting to Know Anxiety

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