Mechanisms of Action

Antiepileptic drugs have been classified and selected for many years based on seizure type (Box 34-2). Although the intricate cellular alterations in the neuronal events mediating the generation of seizures is not totally understood, studies have provided evidence of likely alterations involved in both partial seizures and absence seizures to enable a mechanistic-based approach for treatment.

Partial seizures are thought to develop as a consequence of the loss of surround inhibition, a process that normally prevents the activation of neurons adjacent to a focus (Fig. 34-1). This loss of surround inhibition may result from impaired γ-aminobutyric acid (GABA) transmission, alterations in dendritic structure, changes in voltage-gated ion channel activity or density, or alterations in intracellular ion concentrations. If the seizure generalizes secondarily to involve both hemispheres, tonic-clonic effects are manifest. The tonic phase of muscle contraction is thought to reflect prolonged neuronal depolarization as a consequence of the loss of GABA-mediated inhibition and dominance of excitatory glutamate transmission. As the seizure evolves, neurons repolarize and afterhyperpolarizations are apparent, which reflect the reappearance of GABA-mediated inhibition and diminished glutamate excitation, producing the clonic phase. Thus drugs that increase surround inhibition and prevent the spread of synchronous activity are used for the treatment of partial seizures.

FIGURE 34–1 Seizure spread. In the partial (focal) seizure, activity begins in a localized area and spreads to adjacent and contralateral cortical regions. In the partial seizure, secondarily generalized, the locally generated seizure activates subcortical regions (A), which leads to activation of additional neurons (B), resulting in seizure spread throughout the entire cortex. The loss of surround inhibition is believed to underlie the spread of activity and may involve dampening of normal GABA-mediated inhibition.

Our understanding of the onset of generalized tonic-clonic seizures is limited. However, there are some clues concerning the cellular mechanisms underlying absence seizures, which are characterized by the sudden appearance of spike-wave discharges synchronized throughout the brain. The EEGs recorded during an absence seizure compared with a generalized tonic-clonic seizure are shown in Figure 34-2. Studies support a major role of thalamocortical circuits in the pathogenesis of absence seizures with abnormal oscillations between cortical and thalamic neurons. The circuit involves excitatory glutamatergic cortical pyramidal and thalamic relay neurons and inhibitory GABAergic thalamic reticular neurons (Fig. 34-3). Thalamic relay neurons exhibit spike-wave discharges that generate normal cortical rhythms and participate in the generation of sleep spindles. The normal bursting pattern of these neurons results from the activation (depolarization) of low voltage-gated T-type (transient inward current) Ca⁺⁺ channels, followed by hyperpolarization mediated by GABA released from thalamic reticular neurons. Thus drugs that block these T-type Ca⁺⁺ currents are effective for the treatment of absence seizures.

FIGURE 34–2 Comparison of electrical changes during a tonic-clonic and an absence seizure. A generalized tonic-clonic seizure begins with a tonic phase of rhythmic high-frequency discharges (recorded by surface EEG) with cortical neurons undergoing sustained depolarization, and the generation of protracted trains of action potentials (recorded intracellularly). Subsequently, the seizure converts to a clonic phase, characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials. During absence seizures a spike-and-wave discharge is recorded on the surface EEG; during the spike phase, neurons generate short-duration depolarizations and a burst of action potentials but neither exhibit sustained depolarization or produce sustained repetitive firing of action potentials, unlike during tonic-clonic seizures. This difference may explain why drugs that are effective against sustained firing in vitro are effective against tonic-clonic seizures, but not absence seizures, in humans.

FIGURE 34–3 Thalamocortical circuitry involved in the pathogenesis of absence seizures. Thalamic relay (TR) neurons exhibit spike-wave discharges that result from activation of T-type Ca⁺⁺ channels, followed by hyperpolarization mediated by GABA released from thalamic reticular (NRT) neurons.

Agents used for the treatment of epilepsy depress aberrant neuronal firing by primarily altering ion channel activity, enhancing GABA-mediated inhibitory neurotransmission, or dampening glutamate-mediated excitatory neurotransmission. It is important to note that although some drugs have a single mechanism of action, several of these agents have more than one mechanism. Anticonvulsant drugs classified according to mechanisms of action are listed in Box 34-3.

Ion Channel Modulators

The voltage-gated Na⁺ channel blockers are widely used antiseizure drugs with demonstrated effectiveness for partial and secondarily generalized seizures. These drugs include phenytoin, carbamazepine, oxcarbazepine, lamotrigine, topiramate, valproic acid, and zonisamide. These agents reduce the repetitive firing of neurons by producing a use-dependent blockade of Na⁺ channels (Fig. 34-4). By prolonging the inactivated state of the Na⁺ channel and thus the relative refractory period, these drugs do not alter the first action potential but rather reduce the likelihood of repetitive action potentials. Neurons retain their ability to generate action potentials at the lower frequencies common during normal brain function. Because these drugs block repetitive firing, they are better at controlling partial and tonic-clonic seizures than absence seizures.

FIGURE 34–4 Action of phenytoin on Na⁺ channel. A, Resting state in which Na⁺ channel activation gate (A) is closed. B, Arrival of an action potential causes depolarization and opening of activation gate (A), and Na⁺ flows into the cell. C, When depolarization continues, an inactivation gate (B) moves into the channel. Phenytoin prolongs the inactivated state of the Na⁺ channel, presumably by preventing reopening of the inactivation gate (B).

As indicated, T-type Ca⁺⁺ currents

Buy Membership for Basic Science Category to continue reading. Learn more here