Antiseizure drugs protect against seizures by interacting with one or more molecular targets in the brain. The ultimate effect of these interactions is to inhibit the local generation of seizure discharges, both by reducing the ability of neurons to fire action potentials at high rate as well as reducing neuronal synchronization. In addition, antiseizure drugs inhibit the spread of epileptic activity to nearby and distant sites, either by strengthening the inhibitory surround mediated by GABAergic interneurons or by reducing glutamate-mediated excitatory neurotransmission (the means through which a presynaptic neuron depolarizes and excites a postsynaptic follower neuron). The specific actions of antiseizure drugs on their targets are broadly described as: (1) modulation of voltage-gated sodium, calcium, or potassium channels; enhancement of fast GABA-mediated synaptic inhibition; modification of synaptic release processes; and (4) diminution of fast glutamate-mediated excitation. These actions can be viewed in the context of the balance between excitation mediated by glutamatergic neurons and inhibition mediated by GABAergic neurons. A propensity for seizure generation occurs when there is an imbalance favoring excitation over inhibition, which can result from either excessive excitation or diminished inhibition or both. Treatments, therefore, that either inhibit excitation or enhance inhibition have antiseizure actions to reduce seizure generation. Inhibition of excitation can be produced by effects on intrinsic excitability mechanisms in excitatory neurons (eg, sodium channel blockers) or on excitatory synaptic transmission (eg, modification of release of the excitatory neurotransmitter glutamate; AMPA receptor antagonists). Enhancement of inhibition is produced by increased activation of GABAA receptors, the mediators of inhibition in cortical areas relevant to seizures. Some drug treatments (eg, benzodiazepines, phenobarbital) act as positive allosteric modulators of GABAA receptors, whereas others (eg, tiagabine, vigabatrin) lead to increased availability of neurotransmitter GABA. Voltage-gated potassium channels of the Kv7 type also serve as an inhibitory influence on epileptiform activity. Retigabine (ezogabine), a positive allosteric modulator of Kv7 channels, exerts a unique antiseizure action by virtue of its ability to enhance the natural inhibitory influence of these channels. The specific sites at excitatory and inhibitory neurons and synapses where currently available antiseizure drugs act to exert these diverse actions are illustrated in Figure 24–1. Table 24–2 lists the various targets at which currently available antiseizure drugs are thought to act and the drugs that act on those targets. For some drugs, there is no consensus as to the specific molecular target (eg, valproate, zonisamide, rufinamide) or there may be multiple targets (eg, topiramate, felbamate).