Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 34 Treatment of Seizure Disorders

MAJOR DRUG CLASSES

Ion channel modulators

GABA/glutamate modulators

Therapeutic Overview

Epilepsy is a chronic disorder characterized by recurrent, self-limited seizures. Seizures occur when there is abnormal, excessive firing of neurons synchronized throughout a localized or generalized population of neurons. Approximately 0.8% of the population suffers from epilepsy, with most patients having their first seizure before 18 years of age. Recurrent seizures, if frequent, interfere with a patient’s ability to carry out day-to-day activities. However, judicious use of antiepileptic medications allows approximately 75% of patients to remain seizure-free.

Seizures are classified into two major types, partial or focal seizures and generalized seizures. Partial seizures arise in a localized region in one cerebral hemisphere and are accompanied by focal electroencephalographic (EEG) abnormalities. In contrast, generalized seizures involve all, or large parts, of both cerebral hemispheres, with EEG features indicating simultaneous hemispheric involvement.

Partial seizures are further classified as simple, complex, or secondarily generalized tonic-clonic. The seizures are termed simple if consciousness is preserved and complex if consciousness is impaired or lost. In partial complex seizures, motor activity often appears as a complicated and seemingly purposeful movement. If the seizure focus synchronizes and activates neurons in surrounding areas, the partial seizure can secondarily generalize to involve the entire brain and result in tonic-clonic manifestations, which involve rigid extension of the trunk and limbs (tonic phase) and rhythmic contractions of the arms and legs (clonic phase).

In generalized seizures, large areas of the brain are involved at the onset. Generalized seizures are classified by the presence or absence of specific patterns of motor convulsions and include generalized tonic-clonic seizures, in which widespread convulsions occur, absence seizures, characterized by impaired consciousness only, and other types of seizures including myoclonic, clonic, tonic, or atonic, depending on the specific clinical manifestations. The classification of seizures and their characteristics are presented in the Therapeutic Overview Box.

Status epilepticus is a life-threatening neurological disorder characterized by continuous seizures within a

Abbreviations

EEG

Electroencephalogram

GABA

γ-Aminobutyric acid

NMDA

N-methyl-D-aspartate

short time period. A patient is considered to be in status epilepticus if seizures last at least 30 minutes without recovery of consciousness between seizures. Status epilepticus can lead to systemic hypoxia, acidemia, hyperpyrexia, cardiovascular collapse, and renal shutdown and is a medical emergency.

All people are capable of experiencing seizures. Brain insults such as fever, hypoglycemia, hyponatremia, and extreme acidosis or alkalosis can trigger a seizure, but if the condition is corrected, seizures do not recur. In addition, recent studies have provided evidence for several polymorphisms in genes coding for both ligand-gated and voltage-gated ion channels that are linked to various types

Therapeutic Overview

Partial (Focal) Seizures

Simple seizures

No loss of consciousness, may or may nor be preceded by an aura, includes sensory, motor, autonomic, or psychic features

Complex seizures

Impaired consciousness, dreamy dysaffective state with or without automatisms

Secondarily generalized tonic-clonic seizures

Evolves from simple or complex partial seizure, impaired consciousness with rigid extension of trunk and limbs (tonic phase) and rhythmic contractions of arms and legs (clonic phase)

Generalized Seizures

Tonic-clonic (grand mal) seizures

As above for partial with secondarily generalized tonic-clonic seizures

Absence seizures

Abrupt loss of consciousness with staring and cessation of ongoing activity with or without eye blinks

Other types of seizures

Myoclonic—sporadic, isolated jerking movements

Clonic—repetitive jerking movements

Tonic—muscle stiffness and rigidity

Atonic (atypical)—loss of muscle tone

of familial epilepsy. The causes of isolated seizures and epilepsy (recurrent seizures) are summarized in Box 34-1.

BOX 34–1 Causes of Seizures

Birth and perinatal injuries

Vascular insults

Head trauma

Congenital malformations

Metabolic disturbances (e.g., serum Na+, glucose, Ca++, urea)

Drugs or alcohol, including withdrawal from barbiturates and other central nervous system depressants

Neoplasia

Infection

Hyperthermia in children

Genetic

Idiopathic

The goal of antiepileptic drug therapy is to prevent seizures while minimizing side effects, by using the simplest drug regimen. If seizures continue after drug therapy begins and dose increases are inadvisable because of side effects, at least one and sometimes another drug should be tried as monotherapy before the use of two drugs simultaneously is considered. Discontinuation of antiepileptic medication after several seizure-free years depends on the diagnosis (type of seizure and epileptic syndrome), cause, and response to therapy. Antiepileptic drugs may be discontinued in patients with certain epileptic syndromes but should be continued for life in patients with others such as recurrent seizures caused by a structural lesion.

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.

BOX 34–2 Drugs Recommended for Specific Seizure Types

Partial (focal) Seizures

Carbamazepine*

Gabapentin

Lamotrigine

Leviracetam

Oxcarbazepine

Phenytoin

Pregabalin

Tiagabine

Topiramate

Valproic acid

Zonisamide

Tonic/Atonic or Myoclonic

Lamotrigine

Topiramate

Valproic acid*

Generalized Tonic-clonic (grand mal) Seizures

Carbamazepine

Lamotrigine

Leviracetam

Phenobarbital

Phenytoin

Primidone

Topiramate

Valproic acid*

Absence (petit mal) Seizures

Ethosuximide*

Lamotrigine

Topiramate

Valproic acid

Status Epilepticus

Diazepam or lorazepam*

Phenytoin

* Represents primary therapeutic agent.

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.

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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.

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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.

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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.

BOX 34–3 Mechanisms of Action of Antiseizure Drugs

Voltage-gated Na+ Channel Blockers

Phenytoin

Carbamazepine

Oxcarbazepine

Lamotrigine

Topiramate

Valproic acid

Zonisamide

T-type Ca++ Channel Blockers

Ethosuximide

Valproic acid

Zonisamide

GABA Enhancers

Barbiturates

Benzodiazepines

Clonazepam

Tiagabine

Topiramate

Glutamate Modulators

Felbamate

Topiramate

Carbonic Anhydrase Inhibitors

Topiramate

Zonisamide (weak)

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.

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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 provide for slow rhythmic firing of thalamic neurons and are thought to be involved in generating cortical discharge characteristic of absence seizures. Ethosuximide, valproic acid, and zonisamide have all been shown to inhibit these low threshold currents, the former two at clinically relevant concentrations. It is likely that the effectiveness of ethosuximide and valproic acid for absence seizures reflects their action on these Ca++ currents, whereas the efficacy of valproic acid for partial and tonic-clonic seizures may reflect its inhibitory effects at both Na+ and Ca++channels.

Pregabalin and gabapentin, which are used for adjunctive treatment of partial seizures, bind with high affinity to an auxillary subunit of voltage-gated Ca++ channels at nerve terminals (N and P/Q types), thereby decreasing Ca++-mediated neurotransmitter release.

GABA/Glutamate Modulators

As mentioned, excessive neuronal firing may occur as a consequence of either decreased inhibition or increased excitation of neurons. GABA, the major inhibitory neurotransmitter in the brain, activates ligand-gated Cl channels (see Chapter 31), thereby hyperpolarizing neurons and rendering them less likely to activate. GABAA receptors contain separate and distinct binding sites for both the benzodiazepines and barbiturates (see Chapter 31). Benzodiazepines enhance the actions of GABA by increasing the frequency of Cl channel openings, whereas barbiturates prolong the duration of Clchannel openings upon activation of the receptor by GABA. The benzodiazepine clonazepam is used both as monotherapy and as adjunctive therapy for akinetic and myoclonic seizures and in absence seizures in patients who fail to respond to ethosuximide. Clorazepate is used only as adjunctive therapy, and diazepam and lorazepam are used for the treatment of status epilepticus. Among the barbiturates, phenobarbital and mephobarbital are used for generalized tonic-clonic and partial seizures. Although all barbiturates suppress seizures, they are not useful clinically because they have strong sedative effects.

Topiramate, which is used as adjunctive therapy for partial and generalized tonic-clonic seizures, increases GABAA-mediated Cl currents. This action does not appear to be mediated by either a benzodiazepine-like or barbiturate-like mechanism. Rather, studies suggest that topiramate binds to membrane channels at phosphorylation sites within the channel to elicit an allosteric effect. This mechanism has been postulated to mediate the ability of topiramate to both enhance GABAA receptor activity and inhibit activation of glutamate AMPA/kainate ionotropic receptors, both of which inhibit neuronal firing.

In addition to potentiating GABA inhibition by actions at the GABAA receptor, several drugs increase GABA activity by either decreasing its reuptake or inhibiting its catabolism. Tiagabine blocks the reuptake of GABA into presynaptic neurons and glia after its release, thus increasing the synaptic concentration of GABA and prolonging its action. Similarly, vigabatrin, which is not yet marketed in the United States, is an irreversible inhibitor of GABA transaminase, the enzyme mediating the catabolism of GABA.

In addition to enhancing inhibitory GABAergic transmission, several drugs effective for the treatment of seizures inhibit excitatory glutamate transmission. As mentioned, topiramate inhibits activation of glutamate AMPA/kainate receptors, while the anticonvulsant felbamate appears to block a recognition site within the ion channel of glutamate N-methyl-D-aspartate (NMDA) receptors. In addition, studies have suggested that part of the mechanism of action of both lamotrigine and topiramate, and perhaps phenobarbital, may involve inhibition of glutamate receptors.

Pharmacokinetics

Many antiepileptic drugs are available as brand name and generic products, and differences in formulation result in a wide range in bioavailability among different preparations of a given drug. This can lead to problems in seizure control when formulations are changed and should be considered when prescribing antiepileptic drugs.

Because antiepileptic drugs are used to treat a chronic medical condition, they must be absorbed orally and cross the blood-brain barrier. Most antiepileptic drugs are metabolized by the hepatic cytochrome P450 system with the metabolites excreted by the kidney; several antiepileptic drugs have active metabolites.

Many antiepileptic drugs are highly bound to plasma proteins, which is clinically important because the usual determinations of blood concentrations indicate total drug (bound plus free) in serum, even though it is only free drug that is active. The half-life of antiepileptic agents varies with the age of the patient and exposure to other drugs. The pharmacokinetic parameters of antiepileptic agents are summarized in Table 34-1. The pharmacokinetics of the benzodiazepines are presented in Chapter 31.

TABLE 34–1 Pharmacokinetic Parameters

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Primary Agents

Carbamazepine is metabolized in the liver to produce an epoxide, which is relatively stable and accumulates in the blood. This metabolite has antiepileptic properties and may contribute to the neurotoxicity that can develop in patients taking carbamazepine. Carbamazepine also induces its own metabolism, with the rate of metabolism increasing during the first 4 to 6 weeks. After this time, larger doses become necessary to maintain constant serum concentrations.

Ethosuximide has a long half-life, which allows for once-a-day dosing. However, it has significant gastrointestinal side effects that are frequently intolerable with once-a-day dosing and may be reduced with divided dosing, which reduces the peak plasma concentration and thereby reduces the incidence of side effects.

Lamotrigine exhibits negligible first-pass metabolism, has a variable half-life, and is inactivated and excreted as a glucuronic acid.

Phenytoin metabolism is characterized by saturation, or zero-order kinetics (see Chapter 2). At low doses there is a linear relationship between the dose and the serum concentration of the drug. At higher doses, however, there is a much greater rise in serum concentration for a given increase in dose (nonlinear), because when serum concentrations rise above a certain value, the liver enzymes that catalyze phenytoin metabolism become saturated. The dose at which this transition occurs varies from patient to patient but is usually between 400 and 600 mg/day (Fig. 34-5). Because of this kinetic pattern, doses of phenytoin must be individualized.

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FIGURE 34–5 Relationship between the dose and steady-state plasma concentration of phenytoin is illustrated for two patients. In both patients there is a linear relationship between the dose and plasma concentration at low doses. As the dose increases, there is a transition to a nonlinear relationship. This transition occurs at different doses in each patient.

Valproic acid has a relatively short half-life and is metabolized by both the hepatic microsomal cytochrome P450 system and mitochondria to approximately the same extent.

Secondary Agents

Gabapentin is absorbed in a nonlinear fashion, with higher doses leading to decreased bioavailability. Gabapentin has a relatively short half-life, is not bound to plasma proteins or metabolized, and is excreted unchanged by the kidneys.

Leviracetam is nearly completely absorbed with low plasma protein binding. It is not metabolized by the liver cytochrome P450 system, and approximately two thirds of an administered dose is excreted unchanged by the kidneys.

Oxcarbazepine is completely absorbed and extensively metabolized by hepatic cytosolic enzymes to its active hydroxy metabolite, which is responsible for its clinical effects. The metabolite has a half-life of 8 to 10 hours and is excreted in the urine.

Pregabalin is well absorbed, but absorption decreases in the presence of food. Pregabalin does not bind to plasma proteins, is not appreciably metabolized, and is excreted unchanged in the urine.

Phenobarbital is a weak acid that is absorbed and rapidly distributed to all tissues with a half-life of approximately 100 hours. Phenobarbital is metabolized by and induces the hepatic microsomal cytochrome P450 system to accelerate its own metabolism and that of other drugs taken concurrently. Approximately 25% to 50% of an administered dose is excreted unchanged in the urine, while the metabolites are excreted in the urine as glucuronide conjugates.

Primidone is completely absorbed and metabolized in the liver to both phenobarbital and phenylethylmalonamide, both of which have antiepileptic action.

Tiagabine is well absorbed, but its rate of absorption is decreased by the presence of food. Tiagabine is oxidized to an inactive metabolite excreted in both the urine and feces. Hepatic enzyme induction by the concurrent administration of drugs such as phenobarbital or carbamazepine increases the clearance of tiagabine by approximately 60%, resulting in approximately a 50% decreased half-life.

Topiramate absorption and bioavailability are unaffected by food. Plasma protein binding depends on dose, and increased concentrations in the blood decrease the percent bound to proteins. Nearly 75% of an administered dose is excreted unchanged in the urine.

Zonisamide is well absorbed, and food does not affect its bioavailability. Zonisamide binds extensively to erythrocytes, resulting in an approximate eightfold higher concentration in erythrocytes than the plasma. Zonisamide is metabolized by CYP3A4, and the metabolite is excreted in the urine as a glucuronide conjugate.

Relationship of Mechanisms of Action to Clinical Response

As mentioned, antiepileptic medication is selected typically according to seizure type, and the goal of therapy is to prevent seizures and minimize side effects. To this end, relative serum concentration ranges for producing therapeutic responses with minimal side effects have been established for partial and generalized seizures. These “therapeutic” serum concentration ranges for the primary antiepileptic drugs are listed in Table 34-2 and have been determined empirically from general clinical experience in diverse and heterogeneous populations of patients. Thus these values should not be taken as absolute recommendations for individual patients, but they may be used as a guide.

TABLE 34–2 Effective Serum Concentrations of Antiepileptic Drugs Required for Specific Seizure Types

Drug

Therapeutic Serum Concentration (μg/mL)

Indication

Carbamazepine

4-12

Partial, including secondarily generalized

Generalized tonic-clonic (grand mal)

Ethosuximide

40-100

Absence (petit mal)

Lamotrigine

2-20

Partial, including secondarily generalized

Atypical absence, myoclonic, atonic

Phenytoin

5-25

Generalized tonic-clonic (grand mal)

10-20

Partial, including secondarily generalized

Valproic acid*

50-150

Generalized tonic-clonic (grand mal) with absence seizure

Absence (petit mal)

 

50-100

Atypical absence, myoclonic, atonic

* First choice for absence if primary generalized tonic-clonic seizure is also present.

Primary Agents

Carbamazepine is widely used and is highly efficacious for the treatment of partial and secondarily generalized tonic-clonic seizures. It has been reported to exacerbate absence and myoclonic seizures and should not be used for these disorders.

Ethosuximide is typically used for uncomplicated absence seizures, which respond well to this agent.

Lamotrigine has a broad anticonvulsant profile and is effective as both monotherapy and adjunctive therapy for partial and generalized seizures. It is as effective as carbamazepine and phenytoin for newly diagnosed partial or generalized seizures and is better tolerated than these agents. Lamotrigine has also been shown to be efficacious for Lennox-Gastaut syndrome (see following text).

Phenytoin is as effective as carbamazepine for partial and secondarily generalized tonic-clonic seizures. It can be administered as the parent drug or as the water-soluble prodrug fosphenytoin.

Valproic acid has the broadest spectrum of activity of all the antiepileptic agents. It is a primary agent for the treatment of partial complex, absence, primary generalized tonic-clonic, myoclonic, and atonic seizures. It is also effective for juvenile myoclonus, photosensitivity seizures, and Lennox-Gastaut syndrome (see following text).

Secondary Agents

Clonazepam is useful for absence seizures but is less effective than ethosuximide or valproic acid and should be used only if patients are resistant to these primary drugs. It is also used to treat myoclonic and atonic seizures that are resistant to other agents.

Felbamate is used either as monotherapy or in combination, and gabapentin is used as adjunctive therapy for partial and secondarily generalized seizures. Felbamate is also used for the treatment of Lennox-Gastaut syndrome (see following text).

Leviracetam is used as adjunctive therapy for partial, generalized, and myoclonic seizures.

Oxcarbazepine is used both as monotherapy and adjunctive for partial and secondarily generalized seizures. Like carbamazepine, oxcarbazepine can exacerbate myoclonic and absence seizures and should not be used for these indications. Oxcarbazepine may be better tolerated than carbamazepine and valproic acid for partial seizures.

Phenobarbital, which has been used as an antiepileptic for nearly 100 years, is effective for many different seizures types with the exception of absence seizures. It is not used much anymore, because it has been replaced with more efficacious drugs with fewer side effects. Phenobarbital and its congener primidone are used for partial and generalized tonic-clonic seizures.

Pregabalin and tiagabine are relatively newly developed agents currently used as adjunctive treatment for partial seizures.

Topiramate has a broad therapeutic profile with demonstrated efficacy as both monotherapy and adjunctive therapy for partial and primarily generalized tonic-clonic seizures. Topiramate is also efficacious for pediatric patients with refractory partial seizures and for Lennox-Gastaut syndrome (see following text).

Zonisamide is used as adjunctive therapy for partial seizures and is especially useful as monotherapy in children for multiple seizure types.

Lennox-Gastaut Syndrome

Lennox-Gastaut syndrome, also known as myoclonic-astatic epilepsy, accounts for 1% to 4% of patients with childhood epilepsy and 10% of patients with an epileptic onset of younger than 5 years of age. These children exhibit more than one type of seizure including atypical absence, tonic, and atonic-astatic (drop attack) seizures, which often lead to injury as a consequence of repeated falls. These children are also prone to develop status epilepticus. The syndrome is difficult to treat, and typically no single drug controls the seizures. Agents used for treatment include felbamate, lamotrigine, topiramate, and valproic acid.

Status Epilepticus

The general strategy for treating status epilepticus involves support of cardiovascular and respiratory systems and treatment of seizure activity. Initially, a rapid-acting antiepileptic such as diazepam (10 mg at a rate of 1 to 2 mg/min) or lorazepam (4 mg at a rate of 1 mg/min) should be administered intravenously to stop the seizures; the doses should be repeated after 5 minutes if a response is not obtained. Because the effects of these compounds wear off rapidly, therapy with phenytoin or fosphenytoin (20 mg/kg administered intravenously at a rate of 30 to 50 mg/min) should also be instituted. Because phenytoin can produce hypotension or cardiac dysrhythmias if administered too rapidly, the patient must be monitored closely.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Antiepileptic drugs cross the blood-brain barrier and have potential to cause systemic and neurological toxicity. The problems encountered for the primary drugs are listed in the Clinical Problems Box. Side effects of antiepileptic drugs occur in 30% to 50% of patients. However, these are frequently tolerable and require monitoring only. In other cases side effects can be reduced or eliminated by changing the dose or administration schedule. In 5% to 15% of patients, another antiepileptic drug must be prescribed because of toxicity. Serious idiosyncratic effects, such as allergic reactions, are rare but can be life-threatening. They usually occur within several weeks or months of starting a new drug and tend to be dose-independent. Most antiepileptic drugs should be introduced slowly to minimize side effects.

The side effects associated with the use of the benzodiazepines are presented in Chapter 31.

Primary Agents

Carbamazepine often leads to nausea and visual disturbances during initiation of therapy, but these adverse effects can be minimized by slow introduction of the drug. With high initial doses or rapid dose escalation, carbamazepine has been associated with rash. Carbamazepine may have hematological effects, particularly leukopenia or sometimes thrombocytopenia, which may disappear with continued use. The most problematic hematological effect is depression of granulocytes. If good seizure control is achieved and other serious side effects are absent, an absolute granulocyte count of 1000/mm3 or more is acceptable. An aplastic anemia syndrome is associated with carbamazepine but is very infrequent (less than 1 in 50,000).

Ethosuximide leads to dose-related side effects including nausea, vomiting, lethargy, hiccups, and headaches. Psychotic behaviors can be precipitated, and blood dyscrasias and bone marrow suppression have been reported, but rarely.

Lamotrigine produces dose-related side effects that include dizziness, headache, diplopia, nausea, and sleepiness. A rash can occur as either a dose-related or idiosyncratic reaction but seems to be most closely related to the rate of increase in the dose. Ataxia can sometimes occur.

Phenytoin is generally considered to be a safe drug. Dose-related side effects include ataxia and nystagmus, commonly detected when total serum concentrations exceed 20 µg/mL. Other side effects of long-term phenytoin therapy are hirsutism, coarsening of facial features, gingival hyperplasia, and osteomalacia. These should be considered when prescribing phenytoin for children. Less common reactions are hepatitis, a lupus-like connective tissue disease, lymphadenopathy, and pseudolymphoma.

Valproic acid may produce nausea, vomiting, and lethargy, particularly early in therapy. The availability of enteric-coated tablets of valproic acid has led to a significant decrease in the gastrointestinal side effects. Elevation of liver enzymes and blood ammonia levels in patients receiving valproic acid is common. Fatal hepatitis may occur, but overall the risk is small (approximately 1 in 40,000). However, this risk is increased considerably in patients younger than 2 years of age treated with multiple antiepileptic drugs. Two uncommon dose-related side effects of valproic acid are thrombocytopenia and changes in coagulation parameters, resulting from depletion of fibrinogen. However, these changes usually are not serious. Other side effects of valproic acid are weight gain, alopecia, and tremor.

Secondary/Adjunctive Agents

Felbamate is generally used for epilepsy refractory to other medications because it can lead to aplastic anemia, which occurs in approximately 1 in 5000 patients and is more common in individuals with blood dyscrasias and autoimmune disease. It has also been shown to lead to hepatic failure.

Gabapentin is a relatively safe drug that is well tolerated and devoid of pharmacokinetic interactions with other agents. It can produce transient fatigue, dizziness, edema, and weight gain and can lead to motor disorders. Gabapentin can exacerbate myoclonic seizures.

Leviracetam causes dizziness and irritability and can induce psychotic-like reactions, especially in individuals with a previous psychiatric illness.

Oxcarbazepine produces nausea, vomiting, diplopia, and ataxia. Multiorgan hypersensitivity reactions have been reported, and cross-reactivity with carbamazepine is not uncommon.

Phenobarbital frequently produces depression of central nervous system function, resulting in sedation. Cognitive disturbances are not uncommon, particularly in children. Additional adverse effects in children include motor hyperactivity, irritability, decreased attention, and mental slowing.

Pregabalin produces dizziness, ataxia, blurred vision, dry mouth, and peripheral edema, leading to weight gain.

Tiagabine produces abdominal pain and nausea and should be taken with food to minimize these actions. It also has been reported to impair cognition and produce confusion.

Topiramate often leads to cognitive disturbances characterized by impaired memory and decreased concentration. It also produces nervousness, weight loss, and diplopia. Renal stones have been reported, likely as a consequence of the ability of topiramate to cause a metabolic acidosis resulting from carbonic anhydrase inhibition.

Zonisamide side effects include lethargy, dizziness, anorexia, ataxia, and weight loss. It may also induce psychotic-like reactions, dizziness, and confusion. In children, hyperthermia and heat stroke have been reported.

Antiepileptic Drugs during Pregnancy

Because antiepileptic agents are taken for many years or a lifetime, the issue of taking these drugs during pregnancy is important. During pregnancy, 25% of epileptic women experience an increase in seizure frequency, 25% experience a decrease in seizure frequency, and 50% do not experience any change. The possibility of seizures puts both the mother and child at risk. The teratogenic properties of antiepileptic drugs are also a concern. Although fetal exposure to phenytoin, carbamazepine, valproic acid, and phenobarbital has been associated with congenital anomalies, including cardiac, urinary tract, and neural tube defects and cleft palate, most pregnant patients exposed to antiepileptic drugs deliver normal infants. Children of mothers who have epilepsy are at increased risk for malformations even if antiepileptic drugs are not used during pregnancy. Whenever possible, women with epilepsy should be counseled before they become pregnant. If discontinuation of

CLINICAL PROBLEMS

Carbamazepine

Induction of its own metabolism

Nausea and visual disturbances (dose-related)

Granulocyte suppression

Aplastic anemia (idiosyncratic)

Ethosuximide

Stomach aches and vomiting

Hiccups

Lamotrigine

Rash

Phenytoin

Ataxia and nystagmus (dose-related)

Cognitive impairment

Hirsutism, coarsening of facial features, gingival hyperplasia

Saturation metabolism kinetics

Valproic Acid

Tremor

Nausea and vomiting

Elevated liver enzymes

Weight gain

antiepileptic medication is not an option, monotherapy with the lowest possible dose of the antiepileptic agent should be used.

Newborn infants of mothers who have received phenobarbital, primidone, or phenytoin during pregnancy may develop a deficiency of vitamin K-dependent clotting factors, which can result in serious hemorrhage during the first 24 hours of life. This situation can be prevented by administering vitamin K to the newborn shortly after birth.

Drug Interactions

Antiepileptic drugs can induce or inhibit certain isozymes of cytochrome P450, resulting in drug interactions, not only with other antiepileptic drugs but also with a wide range of therapeutic agents. In general, enzyme inducers decrease serum concentrations of other drugs, whereas enzyme inhibitors increase concentrations. In addition, many antiepileptic drugs are highly bound to plasma proteins, which can also lead to significant drug interactions. For example, valproic acid may increase the toxicity of phenytoin by displacing phenytoin from plasma binding sites. It is critical to be aware of the possibility of drug interactions as a consequence of the pharmacokinetic characteristics of the antiepileptic drugs.

New Horizons

The genetics of epilepsy is being studied intensely to identify mutations leading to aberrant neuronal firing and to develop therapies directed at these newly identified targets. Genes identified to date associated with epilepsy include likely candidates such as voltage-gated (Na+, Ca++, K+, Cl) and ligand-gated (nicotinic acetylcholine and GABAA receptor) ion channels, as well as several novel genes. Although these mutations are easily investigated, their role in the pathogenesis of epilepsy remains to be determined.

Another area of considerable interest is the role of cortical malformations in the development of epilepsy, many of which are associated with seizures that cannot be controlled with currently available drugs. High-resolution magnetic resonance imaging scanning has detected very small malformations in patients who were previously classified as having cryptogenic epilepsy. Understanding how these malformations lead to seizures could provide the basis for developing appropriate therapy for these patients.

In addition to pharmacological therapy, some patients with seizures benefit from surgery. One goal of surgical therapy is to remove identifiable lesions such as arteriovenous malformations, brain tumors, abscesses, and hematomas. The overall results have been gratifying. Another goal of surgery has been to treat patients who are refractory to drug therapy. Seizures in such patients must originate in a well-circumscribed region of the brain that can be removed without risk of producing a major neurological handicap. Epilepsy surgery is usually undertaken at a specialized comprehensive epilepsy center.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Primary Antiepileptic Drugs

Carbamazepine (Carbatrol, Tegretol)

Diazepam (Valium)

Ethosuximide (Zarontin)

Lamotrigine (Lamictal)

Lorazepam (Ativan)

Phenytoin (Dilantin)

Valproic acid (Depakene, Depakote, Divalproex)

Secondary Antiepileptic Drugs, Including Adjuncts

Acetazolamide (Diamox)

Clonazepam (Klonopin)

Felbamate (Felbatol)

Gabapentin (Neurontin)

Levetiracetam (Keppra)

Methsuximide (Celontin)

Oxcarbazepine (Trileptal)

Phenobarbital (Luminal)

Pregabalin (Lyrica)

Primidone (Mysoline)

Tiagabine (Gabitril)

Topiramate (Topamax, Topamax Sprinkle)

Zonisamide (Zonegran)

FURTHER READING

Drugs for epilepsy. Treat Guidel Med Lett. 2005;3:75-82.

García-Morales et al. 2007 García-Morales I, Rieger JS, Gil-Nagel A, Fernández JL. Antiepileptic drugs: From scientific evidence to clinical practice. Neurologist. 2007;13:S20-S28.

Karceski SC. Seizure medications and their side effects. Neurology. 2007;69:E27-E29.

Loring et al. 2007 Loring DW, Marino S, Meador KJ. Neuropsychological and behavioral effects of antiepilepsy drugs. Neuropsychol Rev. 2007;17:413-425.

Stafstrom CE. Epilepsy: A review of selected clinical syndromes and advances in basic science. J Cereb Blood Flow Metab. 2006;26:983-1004.

Wiebe et al. 2008 Wiebe S, Téllez-Zenteno JF, Shapiro M. An evidence-based approach to the first seizure. Epilepsia. 2008;49(Suppl 1):50-57.

SELF-ASSESSMENT QUESTIONS

1. A 6-year-old girl and her mother come to see you because the girl’s teacher has observed episodes of staring and inability to communicate. These episodes last 3 to 5 seconds and occur 10 to 20 times during the school day. An EEG shows synchronized three-per-second spike-wave discharges generalized over the entire cortex. Which antiepileptic medication would you try first in this young girl?

A. Phenytoin

B. Clonazepam

C. Primidone

D. Carbamazepine

E. Ethosuximide

2. A young patient’s seizures have been well controlled with phenytoin for many years. He recently has had two seizures, and you determine that the phenytoin concentration in his blood is low because of his recent growth. You increase the phenytoin dose, calculating the increased dose based on his weight gain (same mg/kg as before). Several weeks later the patient calls up and tells you that he has not had any seizures but he is having trouble walking and is dizzy. Which of the following statements best describes what has happened?

A. The patient did not follow your instructions and has been taking too many pills.

B. After the dose increase, phenytoin was eliminated by zero-order kinetics, and serum concentrations were in the toxic range.

C. His metabolism of phenytoin has increased as a result of induction of liver microsomal enzymes.

D. His phenytoin concentrations are too low.

E. An inner ear infection has developed.

3. What is the best initial treatment for a 3-year-old girl experiencing generalized tonic-clonic seizures daily?

A. Brain surgery to remove the focus of her seizures

B. Monotherapy with primidone

C. Treatment with carbamazepine

D. Treatment with phenytoin

E. No drug therapy at this time

4. Generalized tonic-clonic seizures are characterized by a sustained depolarization of cortical neurons with action potentials. Which of the following characteristics of a new drug for the treatment of generalized tonic-clonic seizures would you like to see?

A. Adenosine agonist

B. Block GABA receptors

C. Block of repetitive neuronal firing

D. Block synchronization of inhibitory neurons

E. NMDA antagonist

5. A 45-year-old woman with new-onset seizures is started on an antiepileptic drug. She initially does well, but she has two seizures approximately 4 weeks after the start of treatment. She has taken the same number of pills each day, but her plasma concentration of the drug has decreased. Which antiepileptic drug is she taking?

A. Ethosuximide

B. Primidone

C. Phenytoin

D. Carbamazepine

E. Valproic acid