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CHAPTER 24 Antiseizure Drugs 411

epilepsy. The vagus nerve stimulator (VNS) is an implanted exerts a unique antiseizure action by virtue of its ability to enhance
programmable pulse generator with a helical electrode that is the natural inhibitory influence of these channels. The specific
wrapped around the left vagus nerve in the neck. The device, sites at excitatory and inhibitory neurons and synapses where cur-
which continuously delivers open-loop stimulation according rently available antiseizure drugs act to exert these diverse actions
to a duty cycle, is approved for the treatment of drug-refractory are illustrated in Figure 24–1. Table 24–2 lists the various targets
focal seizures but may also be a good option for symptomatic at which currently available antiseizure drugs are thought to act
(or cryptogenic) generalized epilepsies of the Lennox-Gastaut and the drugs that act on those targets. For some drugs, there is
type, including those with intractable atonic seizures. Another no consensus as to the specific molecular target (eg, valproate,
device for the treatment of medically refractory focal epilepsy is zonisamide, rufinamide) or there may be multiple targets (eg,
the responsive neurostimulator (RNS). The RNS is a closed-loop topiramate, felbamate).
system that detects a pattern of abnormal electrical activity in the
seizure focus and then delivers electrical stimulation to prevent
seizure occurrence. Other devices, using various paradigms of PHARMACOKINETICS
electrical stimulation, are in clinical development. One of these,
a deep brain stimulation device, has been approved in Canada Chronic antiseizure drug administration prevents the occurrence
and Europe but not in the USA. of seizures, which can, on occasion, be life threatening. There-
fore, adequate drug exposure must be continuously maintained.
However, many antiseizure drugs also have a narrow therapeutic
MECHANISMS OF ACTION window; dosing must therefore avoid excessive, toxic exposure.
An understanding of the pharmacokinetic properties of the drugs
Antiseizure drugs protect against seizures by interacting with is essential. It is also necessary for the clinician to be cognizant of
one or more molecular targets in the brain. The ultimate effect special factors that affect dosing; these factors include nonlinear
of these interactions is to inhibit the local generation of seizure relationships between dose and drug exposure and the influence
discharges, both by reducing the ability of neurons to fire action of hepatic or renal impairment on clearance (see Chapters 3
potentials at high rate as well as reducing neuronal synchroniza- and 4). Further, drug-drug interactions occur with many of the
tion. In addition, antiseizure drugs inhibit the spread of epileptic agents—a special issue since the drugs are often used in combi-
activity to nearby and distant sites, either by strengthening the nation. For some antiseizure drugs, drug-drug interactions are
inhibitory surround mediated by GABAergic interneurons or by complex (see Chapter 66). For example, addition of a new drug
reducing glutamate-mediated excitatory neurotransmission (the may affect the clearance of the current medication such that
means through which a presynaptic neuron depolarizes and excites the dose of the current medication must be modified. Further,
a postsynaptic follower neuron). The specific actions of antiseizure the current medication may necessitate a different dosing of the
drugs on their targets are broadly described as: (1) modulation new drug—different from dosing in a drug-naïve subject. Many
of voltage-gated sodium, calcium, or potassium channels; antiseizure drugs are metabolized by hepatic enzymes, and some,
(2) enhancement of fast GABA-mediated synaptic inhibition; such as carbamazepine, oxcarbazepine, eslicarbazepine acetate,
(3) modification of synaptic release processes; and (4) diminution phenobarbital, phenytoin, and primidone, are strong inducers
of fast glutamate-mediated excitation. These actions can be viewed of hepatic cytochrome P450 and glucuronyl transferase enzymes.
in the context of the balance between excitation mediated by A new antiseizure drug may increase the concentration of an
glutamatergic neurons and inhibition mediated by GABAergic existing drug by inhibiting its metabolism; alternatively, the new
neurons. A propensity for seizure generation occurs when there is drug may reduce the concentration by inducing the metabolism
an imbalance favoring excitation over inhibition, which can result of the existing drug. Other antiseizure drugs are excreted in the
from either excessive excitation or diminished inhibition or both. kidney and are less susceptible to drug-drug interactions. Some
Treatments, therefore, that either inhibit excitation or enhance antiseizure drugs have active metabolites. The extent of conver-
inhibition have antiseizure actions to reduce seizure generation. sion to the active forms can be affected by the presence of other
Inhibition of excitation can be produced by effects on intrinsic drugs. Some antiseizure drugs, such as phenytoin, tiagabine,
excitability mechanisms in excitatory neurons (eg, sodium channel valproate, diazepam, and perampanel, are highly (>90%) bound
blockers) or on excitatory synaptic transmission (eg, modification to plasma proteins. These drugs can be displaced from plasma
of release of the excitatory neurotransmitter glutamate; AMPA proteins by other protein-bound drugs, resulting in a temporary
receptor antagonists). Enhancement of inhibition is produced by rise in the free fraction. Since the free (unbound) drug is active,
increased activation of GABA receptors, the mediators of inhibi- there can be transient toxicity. However, systemic clearance
A
tion in cortical areas relevant to seizures. Some drug treatments increases along with the increased free fraction, so the elevation
(eg, benzodiazepines, phenobarbital) act as positive allosteric in free concentration is eventually corrected. Some antiseizure
modulators of GABA receptors, whereas others (eg, tiagabine, drugs, notably levetiracetam, gabapentin, and pregabalin, are
A
vigabatrin) lead to increased availability of neurotransmitter not known to have drug interactions. Antiseizure drugs can also
7 type also interact with other medications. Importantly, oral contraceptive
GABA. Voltage-gated potassium channels of the K v
serve as an inhibitory influence on epileptiform activity. Retiga- levels may be reduced by strong inducers, resulting in failure of
bine (ezogabine), a positive allosteric modulator of K 7 channels, birth control.
v