Goodman and Gilman Manual of Pharmacology and Therapeutics

Section II
Neuropharmacology

chapter 21
Pharmacotherapy of the Epilepsies

Epileptic seizures often cause transient impairment of consciousness, leaving the individual at risk of bodily harm and often interfering with education and employment. Therapy is symptomatic: Available drugs inhibit seizures, but neither effective prophylaxis nor cure is available. The mechanisms of action of antiseizure drugs fall into 3 major categories:

1. Limiting the sustained, repetitive firing of neurons, an effect mediated by promoting the inactivated state of voltage-activated Na+ channels

2. Enhancing synaptic inhibition mediated γ-aminobutyric acid (GABA), a drug effect that may occur via presynaptic or postsynaptic action

3. Inhibition of voltage-activated Ca2+ channels responsible for T-type Ca2+ currents

Drugs effective against the most common forms of epileptic seizures, partial and secondarily generalized tonic-clonic seizures, appear to work by one of the first two mechanisms. Drugs effective against the less common absence seizure work by the third mechanism.

TERMINOLOGY AND EPILEPTIC SEIZURE CLASSIFICATION

The term seizure refers to a transient alteration of behavior due to the disordered, synchronous, and rhythmic firing of populations of brain neurons. The term epilepsy refers to a disorder of brain function characterized by the periodic and unpredictable occurrence of seizures. Seizures are thought to arise from the cerebral cortex, not from other CNS structures. Epileptic seizures are classified as partial seizures, those beginning focally in a cortical site, and generalized seizures, those that involve both hemispheres widely from the outset. The behavioral manifestations of a seizure are determined by the functions normally served by the cortical site at which the seizure arises. For example, a seizure involving motor cortex is associated with clonic jerking of the body part controlled by this region of cortex. A simple partial seizure is associated with preservation of consciousness. A complex partial seizure is associated with impairment of consciousness. The majority of complex partial seizures originate from the temporal lobe. Examples of generalized seizures include absence, myoclonic, and tonic-clonic. The type of epileptic seizure is one determinant of the drug selected for therapy. Table 21–1 presents more detailed information on the classification of seizures and available medications.

Table 21–1

Classification of Epileptic Seizures

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More than 50 distinct epileptic syndromes have been identified and categorized into partial versus generalized epilepsies. The partial epilepsies account for roughly 60% of all epilepsies. The etiology commonly consists of a lesion in some part of the cortex, such as a tumor, developmental malformation, or damage due to trauma or stroke. The generalized epilepsies account for ~40% of all epilepsies and the etiology is usually genetic. The most common generalized epilepsy, referred to as juvenile myoclonic epilepsy, accounts for ~10% of all epileptic syndromes. Like most of the generalized-onset epilepsies, juvenile myoclonic epilepsy is a complex genetic disorder that is probably due to inheritance of multiple susceptibility genes.

NATURE AND MECHANISMS OF SEIZURES AND ANTISEIZURE DRUGS

PARTIAL EPILEPSIES

Either reduction of inhibitory synaptic activity or enhancement of excitatory synaptic activity might be expected to trigger a seizure; pharmacological studies of seizures support this notion. The neurotransmitters mediating the bulk of synaptic transmission in the mammalian brain are amino acids, with GABA and glutamate being the principal inhibitory and excitatory neurotransmitters, respectively (see Chapter 14). Antagonists of the GABAA receptor or agonists of different glutamate-receptor subtypes (NMDA, AMPA, or kainic acid) trigger seizures in experimental animals in vivo. Conversely, drugs that enhance GABA-mediated synaptic inhibition or glutamate-receptor antagonists inhibit seizures in diverse models.

Electrophysiological analyses of individual neurons during a partial seizure demonstrate that the neurons undergo depolarization and fire action potentials at high frequencies (Figure 21–1). This pattern of neuronal firing is characteristic of a seizure and is uncommon during physiological neuronal activity. Thus, selective inhibition of this pattern of firing would be expected to reduce seizures with minimal unwanted effects. Inhibition of the high-frequency firing may be mediated by reducing the ability of Na+ channels to recover from inactivation (Figure 21–2). Depolarization-triggered opening of the Na+channels in the axonal membrane of a neuron is required for an action potential; after opening, the channels spontaneously close, a process termed inactivation. This inactivation is thought to cause the refractory period during which it is not possible to evoke another action potential. Because firing at a slow rate permits sufficient time for Na+ channels to recover from inactivation, inactivation has little or no effect on low-frequency firing. However, reducing the rate of recovery of Na+ channels from inactivation would limit the ability of a neuron to fire at high frequencies, an effect that likely underlies the effects of carbamazepine, lamotrigine, phenytoin, topiramate, valproic acid, and zonisamide against partial seizures.

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Figure 21–1 Cortical EEG, extracellular, and intracellular recordings in a seizure focus induced by local application of a convulsant agent to mammalian cortex. The extracellular recording was made through a high-pass filter. Note the high-frequency firing of the neuron evident in both extracellular and intracellular recording during the paroxysmal depolarization shift (PDS). (Modified with permission from Ayala GF, Dichter M, Gumnit RJ, et al. Genesis of epileptic interictal spikes. New knowledge of cortical feedback systems suggests a neurophysiological explanation of brief paroxysms. Brain Res, 1973;52:1–17. Copyright © Elsevier.)

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Figure 21–2 Antiseizure drug-enhanced Na+ channel inactivation. Some antiseizure drugs (shown in blue text) prolong the inactivation of the Na+ channels, thereby reducing the ability of neurons to fire at high frequencies. Note that the inactivated channel itself appears to remain open, but is blocked by the inactivation gate I. A, activation gate.

Enhancing GABA-mediated synaptic inhibition would reduce neuronal excitability and raise the seizure threshold. Several drugs are thought to inhibit seizures by regulating GABA-mediated synaptic inhibition through an action at distinct sites of the synapse. The principal postsynaptic receptor of synaptically released GABA is termed the GABAA receptor (see Chapters 14 and 17). Activation of the GABAA receptor inhibits the postsynaptic cell by increasing the inflow of Cl ions into the cell, which tends to hyperpolarize the neuron. Clinically relevant concentrations of both benzodiazepines and barbiturates enhance GABAA receptor–mediated inhibition through distinct actions on the GABAA receptor (Figure 21–3), and this enhanced inhibition probably underlies the effectiveness of these compounds against partial and tonic-clonic seizures in humans. At higher concentrations, such as might be used for status epilepticus, these drugs also can inhibit high-frequency firing of action potentials. A second mechanism of enhancing GABA-mediated synaptic inhibition is thought to underlie the antiseizure mechanism of tiagabine; tiagabine inhibits the GABA transporter, GAT-1, and reduces neuronal and glial uptake of GABA.

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Figure 21–3 Enhanced GABA synaptic transmission. In the presence of GABA, the GABAA receptor (structure on left) is opened, allowing an influx of Cl, which in turn increases membrane polarization. Some antiseizure drugs (show in larger blue text) act by reducing the metabolism of GABA. Others act at the GABAA receptor, enhancing Cl influx in response to GABA. As outlined in the text, gabapentin acts presynaptically to promote GABA release; its molecular target is currently under investigation. GABA molecules; GABA-T, GABA transaminase; GAT-1, GABA transporter.

GENERALIZED-ONSET EPILEPSIES: ABSENCE SEIZURES

In contrast to partial seizures, which arise from localized regions of the cerebral cortex, generalized-onset seizures arise from the reciprocal firing of the thalamus and cerebral cortex. Among the diverse forms of generalized seizures, absence seizures have been studied most intensively. The EEG hallmark of an absence seizure is generalized spike-and-wave discharges at a frequency of 3 per second (3 Hz). EEG spikes are associated with the firing of action potentials and the following slow wave with prolonged inhibition. These reverberatory, low-frequency rhythms are made possible by a combination of factors, including reciprocal excitatory synaptic connections between the neocortex and thalamus. One intrinsic property of thalamic neurons that is pivotally involved in the generation of the 3-Hz spike-and-wave discharges is the low threshold (“T-type”) Ca2+ current. T-type currents amplify thalamic membrane potential oscillations, with one oscillation being the 3-Hz spike-and-wave discharge of the absence seizure. Importantly, the principal mechanism by which anti–absence-seizure drugs (ethosuximide, valproic acid) are thought to act is by inhibition of the T-type Ca2+ channels (Figure 21–4). Thus, inhibiting voltage-gated ion channels is a common mechanism of action among antiseizure drugs, with anti–partial-seizure drugs inhibiting voltage-activated Na+ channels and anti–absence-seizure drugs inhibiting voltage-activated Ca2+ channels.

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Figure 21–4 Antiseizure drug-induced reduction of current through T-type Ca2+ channels. Some antiseizure drugs (shown in blue text) reduce the flow of Ca2+ through T-type Ca2+ channels, thereby reducing the pacemaker current that underlies the thalamic rhythm in spikes and waves seen in generalized absence seizures.

GENETIC APPROACHES TO THE EPILEPSIES. Genetic causes are solely responsible for rare epileptic forms inherited in an autosomal dominant or autosomal recessive manner. Genetic causes also are mainly responsible for more common forms such as juvenile myoclonic epilepsy (JME) or childhood absence epilepsy (CAE), the majority of which are likely due to inheritance of 2 or more susceptibility genes. Genetic determinants also may contribute some degree of risk to epilepsies caused by injury of the cerebral cortex. Because most patients with epilepsy are neurologically normal, elucidating the mutant genes underlying familial epilepsy in otherwise normal individuals is of particular interest. This has led to the identification of 25 distinct genes implicated in distinct idiopathic epilepsy syndromes that account for <1% of all of the human epilepsies. Almost all of the mutant genes encode voltage- or ligand-gated ion channels. Mutations have been identified in Na+, K+, Ca2+, and Cl channels, in channels gated by GABA and acetylcholine, and most recently, in intracellular Ca2+ release channels (RyR2) activated by Ca2+. The genotype-phenotype correlations of these genetic syndromes are complex. The cellular electrophysiological consequences of these mutations help describe the mechanisms of seizures and antiseizure drugs. For example, generalized epilepsy with febrile seizures (GEFS+) is caused by a point mutation in the β subunit of a voltage-gated Na+ channel (SCN1B). The phenotype of the mutated Na+ channel appears to involve defective inactivation.

ANTISEIZURE DRUGS: GENERAL CONSIDERATIONS

Table 21–2 presents proposed mechanisms of action of antiseizure drugs, classified according to likely molecular target and activity. It is important to select the appropriate drug or combination of drugs that best controls seizures in an individual patient at an acceptable level of untoward effects. As a general rule, complete control of seizures can be achieved in up to 50% of patients, while another 25% can be improved significantly. The degree of success varies as a function of seizure type, cause, and other factors. Drugs used currently frequently cause unwanted effects that range in severity from minimal impairment of the CNS to ideation and attempt of suicide to death from aplastic anemia or hepatic failure. To minimize toxicity, treatment with a single drug is preferred. If seizures are not controlled with the initial agent at adequate plasma concentrations, substitution of a second drug is preferred to the concurrent administration of another agent. However, multiple-drug therapy may be required, especially when 2 or more types of seizure occur in the same patient. Measurement of drug concentrations in plasma facilitates optimizing antiseizure medication. However, clinical effects of some drugs do not correlate well with their concentrations in plasma. The ultimate therapeutic regimen must be determined by clinical assessment of effect and toxicity. Many of these agents interact noticeably with other medications via induction or inhibition of hepatic CYPs and UGTs that are responsible for drug metabolism (Table 21–3).

Table 21–2

Proposed Mechanisms of Action of Antiseizure Drugs

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Table 21–3

Interactions of Antiseizure Drugs with Hepatic Microsomal Enzymes

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HYDANTOINS

PHENYTOIN

Phenytoin (DILANTIN) is effective against all types of partial and tonic-clonic seizures but not absence seizures.

PHARMACOLOGICAL EFFECTS. Phenytoin exerts antiseizure activity without causing general depression of the CNS. In toxic doses, it may produce excitatory signs and at lethal levels a type of decerebrate rigidity. Phenytoin limits the repetitive firing of action potentials evoked by a sustained depolarization. This effect is mediated by a slowing of the rate of recovery of voltage-activated Na+channels from inactivation, an action that is both voltage- (greater effect if membrane is depolarized) and use-dependent. At therapeutic concentrations, the effects on Na+ channels are selective, and no changes of spontaneous activity or responses to iontophoretically applied GABA or glutamate are detected. At concentrations 5- to 10-fold higher, multiple effects of phenytoin are evident, including reduction of spontaneous activity and enhancement of responses to GABA; these effects may underlie some of the unwanted toxicity associated with high levels of phenytoin.

PHARMACOKINETIC PROPERTIES. Phenytoin is available in 2 types of oral formulations that differ in their pharmacokinetics: rapid-release and extended-release forms. Once-daily dosing is possible only with the extended-release formulations, and due to differences in dissolution and other formulation-dependent factors, the plasma phenytoin level may change when converting from 1 formulation to another. Comparable doses can be approximated by considering “phenytoin equivalents,” but serum-level monitoring is necessary to assure therapeutic safety. Phenytoin is extensively bound (~90%) to serum proteins, mainly albumin. Increased proportions of free drug are evident in the neonate, in patients with hypoalbuminemia, and in uremic patients. Some agents can compete with phenytoin for binding sites on plasma proteins and increase free phenytoin. Valproate competes for protein binding sites and inhibits phenytoin metabolism, resulting in marked and sustained increases in free phenytoin. Measurement of free rather than total phenytoin permits direct assessment of this potential problem in patient management.

The plasma t1/2 of phenytoin (6 to 24 h at plasma concentrations < 10 μg/mL) increases with higher concentrations; as a result, plasma drug concentration increases disproportionately as dosage is increased, even with small adjustments for levels near the therapeutic range. The majority (95%) of phenytoin is metabolized by hepatic CYP2C9/10 and to a lesser extent CYP2C19 (see Table 21–3). Other drugs that are metabolized by these enzymes can inhibit the metabolism of phenytoin and increase its plasma concentration. Conversely, the degradation rate of other drugs that are substrates for these enzymes can be inhibited by phenytoin; one such drug is warfarin, and addition of phenytoin to a patient receiving warfarin can lead to bleeding disorders (see Chapter 30). Phenytoin has the capacity to induce CYPs (seeChapter 6); coadministration of phenytoin and medications metabolized by CYPs can lead to an increased degradation of such medications. For example, treatment with phenytoin can enhance the metabolism of oral contraceptives and lead to unplanned pregnancy. Phenytoin also has potential teratogenic effects. Carbamazepine, oxcarbazepine, phenobarbital, and primidone also can induce CYP3A4 and likewise might increase degradation of oral contraceptives.

The low water solubility of phenytoin hindered its intravenous use and led to production of fosphenytoin, a water-soluble prodrug. Fosphenytoin (CEREBYX, others) is converted into phenytoin by phosphatases in liver and red blood cells with a t1/2 of 8-15 min. Fosphenytoin is extensively bound (95-99%) to human plasma proteins, primarily albumin. Fosphenytoin is useful for adults with partial or generalized seizures when IV or intramuscular administration is indicated.

TOXICITY. The toxic effects of phenytoin depend on the route of administration, the duration of exposure, and the dosage. When fosphenytoin, the water-soluble prodrug, is administered intravenously at an excessive rate in the emergency treatment of status epilepticus, the most notable toxic signs are cardiac arrhythmias with or without hypotension, and/or CNS depression. Cardiac toxicity occurs more frequently in older patients and in those with known cardiac disease than young, healthy patients. These complications can be minimized by administering fosphenytoin at a rate of <150 mg of phenytoin sodium equivalents per minute. Acute oral overdosage results primarily in signs referable to the cerebellum and vestibular system; high doses have been associated with marked cerebellar atrophy. Toxic effects associated with chronic treatment also are primarily dose-related cerebellar-vestibular effects but also include other CNS effects, behavioral changes, increased frequency of seizures, GI symptoms, gingival hyperplasia, osteomalacia, and megaloblastic anemia. Hirsutism is an annoying untoward effect in young females. Usually, these phenomena can be diminished by adjustment of dosage. Serious adverse effects, including those on the skin, bone marrow, and liver, probably are manifestations of rare drug allergy and necessitate withdrawal of the drug. Moderate elevation of the plasma concentrations of hepatic transaminases sometimes are observed.

Gingival hyperplasia occurs in ~20% of all patients during chronic therapy. The condition can be minimized by good oral hygiene. Inhibition of release of antidiuretic hormone (ADH) has been observed. Hyperglycemia and glycosuria appear to be due to inhibition of insulin secretion. Osteomalacia, with hypocalcemia and elevated alkaline phosphatase activity, has been attributed to both altered metabolism of vitamin D and the attendant inhibition of intestinal absorption of Ca2+. Phenytoin also increases the metabolism of vitamin K and reduces the concentration of vitamin K–dependent proteins that are important for normal Ca2+ metabolism in bone. Hypersensitivity reactions include morbilliform rash in 2-5% of patients and occasionally more serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Hematological reactions include neutropenia and leukopenia. A few cases of red-cell aplasia, agranulocytosis, and mild thrombocytopenia also have been reported. Lymphadenopathy, resembling Hodgkin disease and malignant lymphoma, is associated with reduced immunoglobulin A (IgA) production. Hypoprothrombinemia and hemorrhage have occurred in the newborns of mothers who received phenytoin during pregnancy; vitamin K is effective treatment or prophylaxis.

PLASMA DRUG CONCENTRATIONS. A good correlation usually is observed between the total concentration of phenytoin in plasma and its clinical effect. Control of seizures generally is obtained with total concentrations > 10 μg/mL: toxic effects such as nystagmus develop at total concentrations ~20 μg/mL. Control of seizures generally is obtained with free phenytoin concentrations of 0.75-1.25 μg/mL.

DRUG INTERACTIONS. Drugs metabolized by CYP2C9 or CYP2C10 can increase the plasma concentration of phenytoin by decreasing its rate of metabolism. Carbamazepine, which may enhance the metabolism of phenytoin, causes a decrease in phenytoin concentration. Conversely, phenytoin reduces the concentration of carbamazepine.

THERAPEUTIC USES

Epilepsy. Phenytoin is one of the more widely used antiseizure agents, and it is effective against partial and tonic-clonic but not absence seizures. Phenytoin preparations differ significantly in bioavailability and rate of absorption. In general, patients should consistently be treated with the same drug from a single manufacturer. However, if it becomes necessary to switch between products, care should be taken to select a therapeutically equivalent product and patients should be monitored for loss of seizure control or onset of new toxicities.

Other Uses. Trigeminal and related neuralgias occasionally respond to phenytoin, but carbamazepine may be preferable.

ANTISEIZURE BARBITURATES

The pharmacology of the barbiturates as a class is described in Chapter 17; discussion in this chapter is limited to phenobarbital.

PHENOBARBITAL

Phenobarbital (LUMINAL, others) was of the more effective organic antiseizure agent. It has relatively low toxicity, and is inexpensive.

MECHANISM OF ACTION. Phenobarbital likely inhibits seizures by potentiation of synaptic inhibition through an action on the GABAA receptor. At therapeutic concentrations, phenobarbital increases the GABAA receptor–mediated current by increasing the duration of bursts of GABAA receptor–mediated currents without changing the frequency of bursts. At levels exceeding therapeutic concentrations, phenobarbital also limits sustained repetitive firing; this may underlie some of the antiseizure effects of higher concentrations of phenobarbital achieved during therapy of status epilepticus.

PHARMACOKINETIC PROPERTIES. Oral absorption of phenobarbital is complete but somewhat slow; peak concentrations in plasma occur several hours after a single dose. Phenobarbital is 40-60% bound to plasma and tissue proteins. Up to 25% of a dose is eliminated by pH-dependent renal excretion of the unchanged drug; the remainder is inactivated by hepatic CYPs. Phenobarbital induces UGTs as well as the CYP2C and CYP3A subfamilies, thereby stimulating degradation of drugs cleared by these mechanisms (oral contraceptives are metabolized by CYP3A4).

TOXICITY. Sedation, the most frequent undesired effect of phenobarbital, is apparent upon initiation of therapy, but tolerance develops during chronic medication. Nystagmus and ataxia occur at excessive dosage. Phenobarbital can produce irritability and hyperactivity in children, and agitation and confusion in the elderly. Scarlatiniform or morbilliform rash, possibly with other manifestations of drug allergy, occurs in 1-2% of patients. Exfoliative dermatitis is rare. Hypoprothrombinemia with hemorrhage has been observed in the newborns of mothers who have received phenobarbital during pregnancy; vitamin K is effective for treatment or prophylaxis. As with phenytoin, megaloblastic anemia that responds to folate and osteomalacia that responds to high doses of vitamin D occur during chronic phenobarbital therapy. Other adverse effects of phenobarbital are discussed in Chapter 17.

PLASMA DRUG CONCENTRATIONS. During long-term therapy, the plasma concentration of phenobarbital averages 10 μg/mL per daily dose of 1 mg/kg in adults and 5-7 μg/mL per 1 mg/kg in children. Plasma concentrations of 10-35 μg/mL are usually recommended for control of seizures. Sedation, nystagmus, and ataxia usually are absent at concentrations < 30 μg/mL during long-term therapy, but adverse effects may be apparent for several days at lower concentrations when therapy is initiated or whenever the dosage is increased. Concentrations > 60 μg/mL may be associated with marked intoxication in the nontolerant individual. The plasma phenobarbital concentration should be increased above 30-40 μg/mL only if the increment is adequately tolerated and only if it contributes significantly to control of seizures.

DRUG INTERACTIONS. Interactions between phenobarbital and other drugs usually involve induction of the hepatic CYPs by phenobarbital (see Table 21–3). The interaction between phenytoin and phenobarbital is variable. Concentrations of phenobarbital in plasma may be elevated by as much as 40% during concurrent administration of valproic acid.

THERAPEUTIC USES. Phenobarbital is an effective agent for generalized tonic-clonic and partial seizures. Its efficacy, low toxicity, and low cost make it an important agent for these types of epilepsy. However, its sedative effects and its tendency to disturb behavior in children have reduced its use as a primary agent.

IMINOSTILBENES

CARBAMAZEPINE

Carbamazepine (TEGRETOL, CARBATROL, others) is considered to be a primary drug for the treatment of partial and tonic-clonic seizures.

MECHANISM OF ACTION. Like phenytoin, carbamazepine limits the repetitive firing of action potentials evoked by a sustained depolarization by slowing the rate of recovery of voltage-activated Na+channels from inactivation. At therapeutic drug levels, the effects of carbamazepine are selective in that there are no effects on spontaneous activity or on responses to iontophoretically applied GABA or glutamate. The carbamazepine metabolite, 10,11-epoxycarbamazepine, also limits sustained repetitive firing at therapeutically relevant concentrations, suggesting that this metabolite may contribute to the antiseizure efficacy of carbamazepine.

PHARMACOKINETIC PROPERTIES. The pharmacokinetics of carbamazepine are complex. They are influenced by its limited aqueous solubility and by the capacity of carbamazepine to increase its conversion to active metabolites by hepatic CYPs (see Table 21–3). Carbamazepine is absorbed slowly and erratically after oral administration. Peak concentrations in plasma usually are observed 4-8 h after oral ingestion, but may be delayed by as much as 24 h, especially following the administration of a large dose. The drug distributes rapidly into all tissues. Approximately 75% of carbamazepine binds to plasma proteins and concentrations in the CSF appear to correspond to the concentration of free drug in plasma. Hepatic CYP3A4 is primarily responsible for biotransformation of carbamazepine to the 10, 11-epoxide. This metabolite is as active as the parent compound; its concentrations in plasma and brain may reach 50% of those of carbamazepine, especially during the concurrent administration of phenytoin or phenobarbital. The 10, 11-epoxide is metabolized further to inactive compounds that are excreted in the urine. Carbamazepine induces CYPs, and UGTs.

TOXICITY. Acute intoxication with carbamazepine can result in stupor or coma, hyperirritability, convulsions, and respiratory depression. During long-term therapy, the more frequent untoward effects of the drug include drowsiness, vertigo, ataxia, diplopia, and blurred vision. The frequency of seizures may increase, especially with overdosage. Other adverse effects include nausea, vomiting, serious hematological toxicity (aplastic anemia, agranulocytosis), and hypersensitivity reactions (dangerous skin reactions, eosinophilia, lymphadenopathy, splenomegaly). A late complication of therapy with carbamazepine is retention of water, with decreased osmolality and concentration of Na+ in plasma, especially in elderly patients with cardiac disease. Some tolerance develops to the neurotoxic effects of carbamazepine, and they can be minimized by gradual increase in dosage or adjustment of maintenance dosage. Various hepatic or pancreatic abnormalities have been reported during therapy with carbamazepine, most commonly a transient elevation of hepatic transaminases in plasma in 5-10% of patients. A transient, mild leukopenia occurs in ~10% of patients during initiation of therapy and usually resolves within the first 4 months of continued treatment; transient thrombocytopenia also has been noted. A persistent leukopenia may develop that requires withdrawal of the drug. Aplastic anemia occurs in ~1 in 200,000 patients. Possible teratogenic effects are discussed later in the chapter.

PLASMA DRUG CONCENTRATIONS. There is no simple relationship between the dose of carbamazepine and concentrations of the drug in plasma. Therapeutic concentrations are reported to be 6-12 μg/mL, although considerable variation occurs. Side effects referable to the CNS are frequent at concentrations > 9 μg/mL.

DRUG INTERACTIONS. Phenobarbital, phenytoin, and valproate may increase the metabolism of carbamazepine by inducing CYP3A4; carbamazepine may enhance the biotransformation of phenytoin. Concurrent administration of carbamazepine may lower concentrations of valproate, lamotrigine, tiagabine, and topiramate. Carbamazepine reduces both the plasma concentration and therapeutic effect of haloperidol. The metabolism of carbamazepine may be inhibited by propoxyphene, erythromycin, cimetidine, fluoxetine, and isoniazid.

THERAPEUTIC USES. Carbamazepine is useful in patients with generalized tonic-clonic and both simple and complex partial seizures (see Table 21–1). When it is used, renal and hepatic function and hematological parameters should be monitored. Carbamazepine is the primary agent for treatment of trigeminal and glossopharyngeal neuralgias. It is also effective for lightning-type (“tabetic”) pain associated with bodily wasting. About 70% of patients with neuralgia obtain continuing relief. Adverse effects require discontinuation of medication in 5-20% of patients. Carbamazepine is also used in the treatment of bipolar affective disorders (see Chapter 16).

OXCARBAZEPINE

Oxcarbazepine (TRILEPTAL, others) is a keto analog of carbamazepine. Oxcarbazepine is a prodrug that is almost immediately converted to its main active metabolite, a 10-monohydroxy derivative, which is inactivated by glucuronide conjugation and eliminated by renal excretion. Its mechanism of action is similar to that of carbamazepine. Oxcarbazepine is a less potent enzyme inducer than carbamazepine. Substitution of oxcarbazepine for carbamazepine is associated with increased levels of phenytoin and valproic acid, presumably because of reduced induction of hepatic enzymes. Oxcarbazepine does not induce the hepatic enzymes involved in its own degradation. Although oxcarbazepine does not appear to reduce the anticoagulant effect of warfarin, it does induce CYP3A and thus reduces plasma levels of steroid oral contraceptives. It is approved for monotherapy or adjunct therapy for partial seizures in adults, as monotherapy for partial seizures in children ages 4-16, and as adjunctive therapy in children 2 years of age and older with epilepsy.

SUCCINIMIDES

ETHOSUXIMIDE

Ethosuximide (ZARONTIN, others) is a primary agent for the treatment of absence seizures. Ethosuximide reduces low threshold Ca2+ currents (T-type currents) in thalamic neurons. At therapeutic concentrations, ethosuximide inhibits the T-type current without modifying the voltage dependence of steady-state inactivation or the time course of recovery from inactivation. Ethosuximide does not inhibit sustained repetitive firing or enhance GABA responses at clinically relevant concentrations.

PHARMACOKINETIC PROPERTIES. Absorption of ethosuximide is complete, with peak plasma concentrations occurring ~3 h after a single oral dose. Ethosuximide is not significantly bound to plasma proteins; during long-term therapy, its concentration in the CSF is similar to that in plasma. About 25% of the drug is excreted unchanged in the urine; the remainder is metabolized by hepatic enzymes. The plasma t1/2 is 40-50 h in adults and ~30 h in children.

TOXICITY. The most common dose-related side effects are GI complaints (nausea, vomiting, and anorexia) and CNS effects (drowsiness, lethargy, euphoria, dizziness, headache, and hiccough) to which some tolerance develops. Parkinson-like symptoms and photophobia also have been reported. Restlessness, agitation, anxiety, aggressiveness, inability to concentrate, and other behavioral effects have occurred primarily in patients with a prior history of psychiatric disturbance. Urticaria and other skin reactions, including Stevens-Johnson syndrome, as well as systemic lupus erythematosus, eosinophilia, leukopenia, thrombocytopenia, pancytopenia, and aplastic anemia also have been attributed to the drug.

THERAPEUTIC USES AND PLASMA DRUG CONCENTRATIONS. Ethosuximide is effective against absence seizures but not tonic-clonic seizures. An initial daily dose of 250 mg in children (3-6 years old) and 500 mg in older children and adults is increased by 250-mg increments at weekly intervals until seizures are adequately controlled or toxicity intervenes. Divided dosage is required occasionally to prevent nausea or drowsiness associated with once-daily dosing. The usual maintenance dose is 20 mg/kg per day. Increased caution is required if the daily dose exceeds 1500 mg in adults or 750-1000 mg in children. The plasma concentration of ethosuximide averages ~2 μg/mL per daily dose of 1 mg/kg. A plasma concentration of 40-100 μg/mL usually is required for satisfactory control of absence seizures.

VALPROIC ACID

Valproic acid (DEPAKENE, others) produces effects on isolated neurons similar to those of phenytoin and ethosuximide (see Table 21–2). At therapeutically relevant concentrations, valproate inhibits sustained repetitive firing induced by depolarization of cortical or spinal cord neurons. The action appears to be mediated by a prolonged recovery of voltage-activated Na+ channels from inactivation. Valproate also produces small reductions of T-type Ca2+ currents. These actions of limiting sustained repetitive firing and reducing T-type currents may contribute to the effectiveness of valproic acid against partial and tonic-clonic seizures and absence seizures, respectively. In vitro, valproate can stimulate GABA synthesis and inhibit GABA degradation.

PHARMACOKINETIC PROPERTIES. Valproic acid is absorbed rapidly and completely after oral administration. Peak concentration in plasma is observed in 1-4 h (delayed by several hours if the drug is ingested with food or taken as enteric-coated tablets). Its extent of binding to plasma proteins is ~90%, but the fraction bound is reduced as the total concentration of valproate is increased through the therapeutic range. The majority of valproate (95%) is cleared by hepatic metabolism, mainly by UGTs and β-oxidation. Two of the drug’s metabolites, 2-propyl-2-pentenoic acid and 2-propyl-4-pentenoic acid, are nearly as potent antiseizure agents as the parent molecule. The t1/2 of valproate is ~15 h but is reduced in patients taking other antiepileptic drugs.

TOXICITY. The most common side effects are transient GI symptoms, including anorexia, nausea, and vomiting in ~16% of patients. Effects on the CNS include sedation, ataxia, and tremor; these symptoms occur infrequently and usually respond to a decrease in dosage. Rash, alopecia, and stimulation of appetite have been observed occasionally; weight gain has been seen with chronic valproic acid treatment in some patients. Elevation of hepatic transaminases in plasma is observed in up to 40% of patients. A rare complication is a fulminant hepatitis that is frequently fatal. Children < 2 years of age with other medical conditions who were given multiple antiseizure agents were especially likely to suffer fatal hepatic injury. Acute pancreatitis and hyperammonemia also have been frequently associated with the use of valproic acid. Valproic acid can also produce teratogenic effects.

DRUG INTERACTIONS. Valproate inhibits the metabolism of drugs that are substrates for CYP2C9, including phenytoin and phenobarbital. Valproate also inhibits UGT and thus inhibits the metabolism of lamotrigine and lorazepam. A high proportion of valproate is bound to albumin, and the high molar concentrations of valproate result in valproate’s displacing phenytoin and other drugs from albumin.

THERAPEUTIC USES AND PLASMA DRUG CONCENTRATIONS. Valproate is a broad-spectrum antiseizure drug effective in the treatment of absence, myoclonic, partial, and tonic-clonic seizures. The initial daily dose usually is 15 mg/kg, increased at weekly intervals by 5-10 mg/kg/day to a maximum daily dose of 60 mg/kg. Plasma concentrations associated with therapeutic effects are ~30-100 μg/mL, with a threshold at ~30-50 μg/mL. However, there is a poor correlation between the plasma concentration and efficacy.

BENZODIAZEPINES

The benzodiazepines are used primarily as sedative-antianxiety drugs; their pharmacology is described in Chapters 14 and 17. A large number of benzodiazepines have broad antiseizure properties, but only clonazepam (KLONOPIN, others) and clorazepate (TRANXENE, others) have been approved in the U.S. for the long-term treatment of certain seizures. Midazolam was designated an orphan drug for intermittent treatment of bouts of increased seizure activity in refractory patients with epilepsy who are on stable regimens of antiseizure drugs. Diazepam (VALIUM, DIASTAT; others) and lorazepam (ATIVAN, others) have well-defined roles in the management of status epilepticus.

MECHANISM OF ACTION. The antiseizure actions of the benzodiazepines result in large part from their ability to enhance GABA-mediated synaptic inhibition. The benzodiazepine receptor is an integral part of the GABAA receptor (see Figure 14–6). Benzodiazepines act at subsets of GABAA receptors and increase the frequency, but not duration, of openings at GABA-activated Cl channels. At high concentrations, diazepam and many other benzodiazepines can reduce sustained high-frequency firing of neurons, similar to the effects of phenytoin, carbamazepine, and valproate. Although these concentrations correspond to concentrations achieved in patients during treatment of status epilepticus with diazepam, they are considerably higher than those associated with antiseizure or anxiolytic effects in ambulatory patients.

PHARMACOKINETIC PROPERTIES. Benzodiazepines are well absorbed after oral administration. Concentrations in plasma peak within 1-4 h. After intravenous administration, central effects develop promptly but wane rapidly as the drugs redistribute to other tissues. Diazepam has a t1/2 of redistribution of ~1 h. The extent of binding of benzodiazepines to plasma proteins correlates with lipid solubility, ranging from ~99% for diazepam to ~85% for clonazepam. The major metabolite of diazepam, N-desmethyl-diazepam, is somewhat less active than the parent drug and may behave as a partial agonist. Thet1/2 of diazepam in plasma is between 1 and 2 days, while that of N-desmethyl-diazepam is ~60 h. Clonazepam is metabolized to produce inactive 7 amino derivatives. Less than 1% of the drug is recovered unchanged in the urine. The t1/2 of clonazepam in plasma is ~23 h. Lorazepam is metabolized chiefly by conjugation with glucuronic acid; its t1/2 in plasma is ~14 h.

TOXICITY. The principal side effects of long-term oral therapy with clonazepam are drowsiness and lethargy. These occur in ~50% of patients initially, but tolerance often develops with continued administration. Muscular incoordination and ataxia are less frequent. Although these symptoms usually can be kept to tolerable levels by reducing the dosage or the rate at which it is increased, they sometimes force drug discontinuation. Other side effects include hypotonia, dysarthria, and dizziness. Behavioral disturbances, especially in children, may include aggression, hyperactivity, irritability, and difficulty in concentration. Both anorexia and hyperphagia have been reported. Increased salivary and bronchial secretions may cause difficulties in children. Seizures are sometimes exacerbated, and status epilepticus may be precipitated if the drug is discontinued abruptly. Cardiovascular and respiratory depression may occur after the intravenous administration of diazepam, clonazepam, or lorazepam, particularly if administered after other antiseizure agents or central depressants.

PLASMA DRUG CONCENTRATIONS. Because tolerance affects the relationship between drug concentration and drug antiseizure effect, plasma concentrations of benzodiazepines are of limited value.

THERAPEUTIC USES. Clonazepam is useful in the therapy of absence seizures as well as myoclonic seizures in children. Tolerance to its antiseizure effects usually develops after 1-6 months of administration, after which some patients will no longer respond to clonazepam at any dosage. The initial dose of clonazepam for adults should not exceed 1.5 mg per day and for children 0.01-0.03 mg/kg per day. The dose-dependent side effects are reduced if 2 or 3 divided doses are given each day. The dose may be increased every 3 days in amounts of 0.25-0.5 mg per day in children and 0.5-1 mg per day in adults. The maximal recommended dose is 20 mg per day for adults and 0.2 mg/kg per day for children. Clonazepam intranasal spray is designated as an orphan drug for recurrent acute repetitive seizures.

While diazepam is an effective agent for treatment of status epilepticus, its short duration of action is a disadvantage, leading to the more frequent use of lorazepam. Clorazepate is effective in combination with certain other drugs in the treatment of partial seizures. The maximal initial dose of clorazepate is 22.5 mg per day in 3 portions for adults and children > 12 years and 15 mg per day in 2 divided doses in children 9-12 years of age. Clorazepate is not recommended for children < 9 years. Clobazam (ONFI, others) is recently FDA-approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children > 2 years of age. Starting dose is 5 mg in children < 30 kg in body weight, maximal dose is 20 mg. Starting dose for > 30 kg body weight is 10 mg and maximal dose is 40 mg.

OTHER ANTISEIZURE DRUGS

GABAPENTIN AND PREGABALIN

Gabapentin (NEURONTIN, others) and pregabalin (LYRICA) are antiseizure drugs that consist of a GABA molecule covalently bound to a lipophilic cyclohexane ring or isobutane, respectively. Gabapentin was designed to be a centrally active GABA agonist, with its high lipid solubility aimed at facilitating its transfer across the blood-brain barrier.

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MECHANISMS OF ACTION. Gabapentin inhibits tonic hind-limb extension in the electroshock seizure model and clonic seizures induced by pentylenetetrazol. Its efficacy in both these tests parallels that of valproic acid and distinguishes it from phenytoin and carbamazepine. Despite their design as GABA agonists, neither gabapentin nor pregabalin mimics GABA when applied to neurons in primary culture. These compounds bind with high affinity to a protein in cortical membranes with an amino acid sequence identical to that of the Ca2+ channel subunit α2δ-1 but their molecular mechanism of action remains unknown, providing job security for researchers in this area. These compounds also have analgesic properties; the analgesic efficacy of pregabalin is eliminated in mice carrying a mutation in the α2δ-1 protein.

PHARMACOKINETICS. Gabapentin and pregabalin are absorbed after oral administration and are not metabolized in humans. These compounds are not bound to plasma proteins and are excreted unchanged in the urine. Their half-lives approximate 6 h. These compounds have no known interactions with other antiseizure drugs.

THERAPEUTIC USES AND TOXICITY. Gabapentin and pregabalin are effective for partial seizures, with and without secondary generalization, when used in addition to other antiseizure drugs. Pregabalin is approved for treatment of neuropathic pain associated with spinal cord injury. Gabapentin also is used for the treatment of migraine, chronic pain, bipolar disorder, and restless leg syndrome. Gabapentin usually is effective in doses of 900-1800 mg daily in 3 doses, although 3600 mg may be required in some patients. Therapy usually is begun with a low dose (300 mg/day), which is increased by 300 mg/day until an effective dose is reached. Gabapentin is well tolerated. Common adverse effects include mild to moderate somnolence, dizziness, ataxia, and fatigue that resolve within 2 weeks of onset during continued treatment. Gabapentin and pregabalin are listed in pregnancy category C.

LAMOTRIGINE

Lamotrigine (LAMICTAL, others) is a phenyltriazine derivative initially developed as an antifolate agent but the drug’s effectiveness as an antiseizure medication is unrelated to its antifolate properties.

MECHANISMS OF ACTION. Lamotrigine blocks sustained repetitive firing of mouse spinal cord neurons and delays the recovery from inactivation of recombinant Na+ channels, mechanisms similar to those of phenytoin and carbamazepine. Lamotrigine is effective against a broader spectrum of seizures than phenytoin and carbamazepine, suggesting that lamotrigine may have actions in addition to regulating recovery from inactivation of Na+ channels. The mechanisms underlying its broad spectrum of actions may involve inhibiting synaptic release of glutamate.

PHARMACOKINETICS. Lamotrigine is completely absorbed from the GI tract and is metabolized primarily by glucuronidation. The plasma t1/2 of a single dose is 24-30 h. Administration of phenytoin, carbamazepine, or phenobarbital reduces the t1/2 and plasma concentrations of lamotrigine. Addition of valproate markedly increases plasma concentrations of lamotrigine, likely by inhibiting glucuronidation. Addition of lamotrigine to valproic acid produces a reduction of valproate concentrations by ~25% over a few weeks. Concurrent use of lamotrigine and carbamazepine is associated with increases of the 10,11-epoxide of carbamazepine and clinical toxicity.

THERAPEUTIC USE. Lamotrigine is useful for monotherapy and add-on therapy of partial and secondarily generalized tonic-clonic seizures in adults and Lennox-Gastaut syndrome in both children and adults. Patients already taking a hepatic enzyme–inducing antiseizure drug (such as carbamazepine, phenytoin, phenobarbital, or primidone, but not valproate) should be given lamotrigine initially at 50 mg/day for 2 weeks. The dose is increased to 50 mg twice per day for 2 weeks and then increased in increments of 100 mg/day each week up to a maintenance dose of 300-500 mg/day divided into 2 doses. For patients taking valproate in addition to an enzyme-inducing antiseizure drug, the initial dose should be 25 mg every other day for 2 weeks, followed by an increase to 25 mg/day for 2 weeks; the dose then can be increased by 25-50 mg/day every 1-2 weeks up to a maintenance dose of 100-150 mg/day divided into 2 doses.

TOXICITY. The most common adverse effects are dizziness, ataxia, blurred or double vision, nausea, vomiting, and rash when lamotrigine was added to another antiseizure drug. A few cases of Stevens-Johnson syndrome and disseminated intravascular coagulation have been reported. The incidence of serious rash in pediatric patients (~0.8%) is higher than in the adult population (0.3%).

LEVETIRACETAM

Levetiracetam (KEPPRA, others) is FDA-approved for adjunctive therapy for myoclonic, partial-onset, and primary generalized tonic-clonic seizures in adults and children as young as 4 years old. The mechanism by which levetiracetam exerts these antiseizure effects is unknown.

PHARMACOKINETICS. Levetiracetam is rapidly and almost completely absorbed after oral administration and is not bound to plasma proteins. Ninety-five percent of the drug and its inactive metabolite are excreted in the urine, 65% as unchanged drug; the main metabolite results from hydrolysis of the acetamide group. Levetiracetam is devoid of known interactions with other antiseizure drugs, oral contraceptives, or anticoagulants.

THERAPEUTIC USE AND TOXICITY. In clinical trials, levetiracetam given in addition to other antiseizure medications in adults with either refractory partial seizures or uncontrolled generalized tonic-clonic seizures was superior to placebo. Levetiracetam also has efficacy as adjunctive therapy for refractory generalized myoclonic seizures. Insufficient evidence is available about its use as monotherapy for partial or generalized epilepsy. Levetiracetam is well tolerated. Adverse effects include somnolence, asthenia, and dizziness.

TIAGABINE

Tiagabine (GABITRIL) is used for partial seizures in adults. Tiagabine inhibits the GABA transporter, GAT-1, and thereby reduces GABA uptake into neurons and glia, thereby prolonging the dwell time of GABA at inhibitory synapses.

PHARMACOKINETICS. Tiagabine is rapidly absorbed after oral administration, extensively bound to serum or plasma proteins, and metabolized mainly by hepatic CYP3A. Its t1/2 of ~8 h is shortened by 2-3 h when coadministered with hepatic enzyme–inducing drugs such as phenobarbital, phenytoin, or carbamazepine.

THERAPEUTIC USE AND TOXICITY. Tiagabine is effective as add-on therapy of refractory partial seizures with or without secondary generalization. Its efficacy as monotherapy for newly diagnosed or refractory partial and generalized epilepsy has not been established. Adverse effects include dizziness, somnolence, and tremor that are mild to moderate in severity and appear shortly after initiation of therapy. Tiagabine-enhanced effects of synaptically released GABA can facilitate spike-and-wave discharges in animal models of absence seizures. Case reports suggest that tiagabine treatment of patients with a history of spike-and-wave discharges causes exacerbations of their EEG abnormalities. Thus, tiagabine may be contraindicated in patients with generalized absence epilepsy. Paradoxically, tiagabine has been associated with the occurrence of seizures in patients without epilepsy and off-label use of the drug is discouraged.

TOPIRAMATE

Topiramate (TOPAMAX, others) is FDA-approved as initial monotherapy (in patients at least 10 years old) and as adjunctive therapy (for patients as young as 2 years of age) for partial-onset or primary generalized tonic-clonic seizures, for Lennox-Gastaut syndrome in patients 2 years of age and older, and for migraine headache prophylaxis in adults.

MECHANISMS OF ACTION. Topiramate reduces voltage-gated Na+ currents in cerebellar granule cells and may act on the inactivated state of the channel similar to phenytoin. In addition, topiramate activates a hyperpolarizing K+ current, enhances postsynaptic GABAA receptor currents, and limits activation of AMPA-kainate receptors (see Table 14–1 and Figures 14–614–7, and 14–8). Topiramate is a weak carbonic anhydrase inhibitor.

PHARMACOKINETICS. Topiramate is rapidly absorbed after oral administration, exhibits little (10-20%) binding to plasma proteins, and is mainly excreted unchanged in the urine. The remainder undergoes metabolism by hydroxylation, hydrolysis, and glucuronidation with no single metabolite accounting for > 5% of an oral dose. Its t1/2 is ~1 day. Reduced estradiol plasma concentrations occur with concurrent topiramate, suggesting the need for higher doses of oral contraceptives when coadministered with topiramate.

THERAPEUTIC USE AND TOXICITY. Topiramate is equivalent to valproate and carbamazepine in children and adults with newly diagnosed partial and primary generalized epilepsy. It is effective as monotherapy for refractory partial epilepsy and refractory generalized tonic-clonic seizures. Topiramate is also effective as adjunctive therapy (against both drop attacks and tonic-clonic seizures in patients with Lennox-Gastaut syndrome, and for migraine headache prophylaxis in adults). Topiramate is well tolerated. Common adverse effects are somnolence, fatigue, weight loss, and nervousness. It can precipitate renal calculi, which is most likely due to inhibition of carbonic anhydrase. Topiramate has been associated with cognitive impairment and patients may complain about a change in the taste of carbonated beverages.

ZONISAMIDE

Zonisamide (ZONEGRAN, others) is a sulfonamide derivative used as adjunctive therapy of partial seizures in adults. Zonisamide inhibits the T-type Ca2+ currents. In addition, zonisamide inhibits the sustained, repetitive firing of spinal cord neurons, presumably by prolonging the inactivated state of voltage-gated Na+ channels in a manner similar to actions of phenytoin and carbamazepine.

PHARMACOKINETICS. Zonisamide is almost completely absorbed after oral administration, has a long t1/2 (~63 h), and is ~40% bound to plasma protein. Approximately 85% of an oral dose is excreted in the urine, principally as unmetabolized zonisamide and a glucuronide of a metabolite formed by CYP3A4. Phenobarbital, phenytoin, and carbamazepine decrease the plasma concentration/dose ratio of zonisamide, whereas lamotrigine increases this ratio. Zonisamide has little effect on the plasma concentrations of other antiseizure drugs.

THERAPEUTIC USE AND TOXICITY. In clinical trials, the addition of zonisamide to other drugs in patients with refractory partial seizures was superior to placebo. There is insufficient evidence for its efficacy as monotherapy for newly diagnosed or refractory epilepsy. Zonisamide is well tolerated. Common adverse effects include somnolence, ataxia, anorexia, nervousness, and fatigue. Approximately 1% of individuals develop renal calculi, which may relate to its ability to inhibit carbonic anhydrase. Zonisamide can cause metabolic acidosis, which is more frequent in younger patients. Patients with predisposing conditions (e.g., renal disease, severe respiratory disorders, diarrhea, surgery, ketogenic diet) may be at greater risk. Measurement of serum bicarbonate prior to initiating therapy and periodically thereafter is recommended.

LACOSAMIDE

Lacosamide (VIMPAT) is approved as adjunctive therapy for partial-onset seizures in patients 17 years of age and older.

Lacosamide enhances slow inactivation of voltage-gated Na+ channels and limits sustained repetitive firing, the neuronal firing pattern characteristic of partial seizures. Lacosamide also binds collapsin response mediator protein 2 (crmp-2), a phosphoprotein involved in neuronal differentiation and axon outgrowth. Its antiseizure mechanism of action is more likely mediated by its enhancing slow inactivation of Na+ channels. Clinical studies of adults with refractory partial seizures demonstrated that addition of lacosamide to other drugs was superior to placebo.

RUFINAMIDE

Rufinamide (BANZEL) is a triazole derivative approved for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome. Rufinamide enhances slow inactivation of voltage-gated Na+ channels and limits sustained repetitive firing, the firing pattern characteristic of partial seizures. Whether this is the mechanism by which rufinamide suppresses seizures is presently unclear.

VIGABATRIN

Vigabatrin (SABRIL) is used as adjunctive therapy of refractory partial complex seizures in adults. In addition, vigabatrin is designated as an orphan drug for treatment of infantile spasms. Due to progressive and permanent bilateral vision loss, vigabatrin must be reserved for patients who have failed several alternative therapies.

Vigabatrin is a structural analog of GABA that irreversibly inhibits GABA degradation, thereby leading to increased concentrations of GABA in the brain. A 2-week, randomized, clinical trial of vigabatrin for infantile spasms in children < 2 years old revealed time- and dose-dependent increases in responders, evident as freedom from spasms for 7 consecutive days. The subset of children in whom infantile spasms were caused by tuberous sclerosis was particularly responsive to vigabatrin.

EZOGABINE

Ezogabine (POTIGA) is a carbamate ethyl ester and K+- channel activator approved by the FDA for the treatment of partial-onset seizures.

Ezogabine is administered orally. Starting dose is 100 mg 3 times daily that is increased gradually to a maximal dose of 1200 mg/day. Ezogabine is metabolized primarily via glucuronidation and eliminated mainly through renal excretion. Its t1/2 is ~8-11 h. Serious adverse effects are dose related and include difficulty in urination, hallucination, suicidal thoughts, and QT prolongation. Less serious side effects include drowsiness, dizziness, fatigue, blurred vision, tremor, memory impairment, asthenia, gait disturbance and balance disorder, and slurred speech.

PERAMPANEL

Perampanel (FYCOMPA) is a selective noncompetitive antagonist of the AMPA glutamate receptor. It is approved for the treatment of partial-onset seizures with or without secondarily generalized seizures.

Recommended starting oral dose is 2 mg once daily titrated to a maximal dose of 4-12 mg once daily taken at bedtime. The drug is rapidly absorbed after oral administration. The t1/2 is ~105 h. It is 95% bound to plasma protein, mainly albumin. It is metabolized by oxidation followed by glucuronidation. Adverse effects include aggressive behavior, suicidal thoughts, sleepiness, vertigo, dizziness, nausea, problems with walking and muscle coordination, and weight gain.

ACETAZOLAMIDE

Acetazolamide, the prototype for the carbonic anhydrase inhibitors (see Chapter 25), is sometimes effective against absence seizures but its usefulness is limited by the rapid development of tolerance.

FELBAMATE

Felbamate (FELBATOL) is a dicarbamate. An association between felbamate and aplastic anemia resulted in the withdrawal of most patients from treatment with this drug. Postmarketing experience revealed an association between felbamate exposure and liver failure.

GENERAL PRINCIPLES AND CHOICE OF DRUGS FOR THE THERAPY OF THE EPILEPSIES

Early diagnosis and treatment of seizure disorders with a single appropriate agent offers the best prospect of achieving prolonged seizure-free periods with the lowest risk of toxicity. An attempt should be made to determine the cause of the epilepsy with the hope of discovering a correctable lesion, either structural or metabolic. The drugs commonly used for distinct seizure types are listed in Table 21–1. The efficacy combined with the unwanted effects of a given drug determine which particular drug is optimal for a given patient.

In the absence of extenuating circumstances such as status epilepticus, only monotherapy should be initiated. Initial dosing should be low and should target steady-state plasma drug concentrations within the lower range associated with clinical efficacy. Dosage is increased and monitored at appropriate intervals as required for control of seizures or as limited by toxicity. Compliance with a properly selected, single drug in maximal tolerated dosage results in complete control of seizures in ~50% of patients. If compliance has been confirmed yet seizures persist, another drug should be substituted. Unless serious adverse effects of the drug dictate otherwise, dosage always should be reduced gradually to minimize risk of seizure recurrence. The literature suggests that among previously untreated patients, 47% become seizure-free with the first drug and an additional 14% become seizure-free with a second or third agent. If therapy with a second single drug is inadequate, combination therapy is warranted; the decision to use combination therapy should not be made lightly, because most patients obtain optimal seizure control with fewest unwanted effects when taking a single drug. In choosing a combination, it seems wise to select 2 drugs that act by distinct mechanisms (e.g., one that promotes Na+ channel inactivation and another that enhances GABA-mediated synaptic inhibition) (see Table 21–2). Side effects of each drug and the potential drug interactions also should be considered.

DURATION OF THERAPY

Antiseizure drugs are typically continued for at least 2 years. Tapering and discontinuing therapy should be considered, if the patient is seizure-free after 2 years. Factors associated with high risk for recurrent seizures following discontinuation of therapy include EEG abnormalities, known structural lesions, abnormalities on neurological exam, and history of frequent seizures or medically refractory seizures prior to control. Conversely, factors associated with low risk for recurrent seizures include idiopathic epilepsy, normal EEG, onset in childhood, and seizures easily controlled with a single drug. Typically, 80% of recurrences will occur within 4 months of discontinuing therapy. Clinician and patient must weigh the risk of recurrent seizure and the associated potential deleterious consequences (e.g., loss of driving privileges) against the various implications of continuing medication including cost, unwanted effects, implications of diagnosis of epilepsy, etc. Medications should be tapered slowly over a period of several months.

SIMPLE AND COMPLEX PARTIAL AND SECONDARILY GENERALIZED TONIC-CLONIC SEIZURES

The efficacy and toxicity of carbamazepine, phenobarbital, and phenytoin for treatment of partial and secondarily generalized tonic-clonic seizures in adults have been compared. Carbamazepine and phenytoin were the most effective agents.

ABSENCE SEIZURES

Ethosuximide and valproate are considered equally effective in the treatment of absence seizures. Between 50% and 75% of newly diagnosed patients are free of seizures following therapy with either drug. If tonic-clonic seizures are present or emerge during therapy, valproate is the agent of first choice. Lamotrigine is also effective for newly diagnosed absence epilepsy although it is not FDA-approved for this indication.

MYOCLONIC SEIZURES

Valproic acid is the drug of choice for myoclonic seizures in the syndrome of juvenile myoclonic epilepsy, in which myoclonic seizures often coexist with tonic-clonic and absence seizures. Levetiracetam also has demonstrated efficacy as adjunctive therapy for refractory generalized myoclonic seizures.

FEBRILE CONVULSIONS

Two to 4% of children experience a convulsion associated with a febrile illness. From 25-33% of these children will have another febrile convulsion. Only 2-3% become epileptic in later years. Several factors are associated with an increased risk of developing epilepsy: preexisting neurological disorder or developmental delay, a family history of epilepsy, or a complicated febrile seizure (i.e., the febrile seizure lasted > 15 min, was one-sided, or was followed by a second seizure in the same day). If all of these risk factors are present, the risk of developing epilepsy is ~10%. Uncertainties regarding the efficacy of prophylaxis for reducing epilepsy combined with substantial side effects of phenobarbital prophylaxis argue against the use of chronic therapy for prophylactic purposes in these cases. For children at high risk of developing recurrent febrile seizures and epilepsy, rectally administered diazepam at the time of fever may prevent recurrent seizures and avoid side effects of chronic therapy.

SEIZURES IN INFANTS AND YOUNG CHILDREN

Infantile spasms with hypsarrhythmia are refractory to the usual antiseizure agents. Corticotropin or glucocorticoids are commonly used. Vigabatrin (γ-vinyl GABA; SABRIL) is efficacious in comparison to placebo. The potential for progressive and permanent vision loss has resulted in vigabatrin being labeled with a black box warning and marketed under a restrictive distribution program. The drug has an orphan drug status for the treatment of infantile spasms. Lennox-Gastaut syndrome is a severe form of epilepsy, which usually begins in childhood and is characterized by cognitive impairments and multiple types of seizures including tonic-clonic, tonic, atonic, myoclonic, and atypical absence seizures. Lamotrigine is an effective and well-tolerated additive drug for this treatment-resistant form of epilepsy. Felbamate also is effective for seizures in this syndrome, but the occasional occurrence of aplastic anemia and hepatic failure have limited its use. Topiramate has also been demonstrated to be effective.

STATUS EPILEPTICUS AND OTHER CONVULSIVE EMERGENCIES

Status epilepticus is a neurological emergency. Mortality for adults approximates 20%. The goal of treatment is rapid termination of behavioral and electrical seizure activity due to the risk of permanent brain damage. Prompt treatment is essential with effective drugs in adequate doses, and attention to hypoventilation and hypotension. Because hypoventilation may result from high doses of drugs used, it may be necessary to assist respiration temporarily. Drugs should be administered by the IV route only. Four IV treatments: diazepam followed by phenytoin; lorazepam; phenobarbital; and phenytoin alone seem to have similar efficacies, with success rates ranging from 44-65%. Lorazepam alone was found to be significantly better than phenytoin alone. No significant differences were found with respect to recurrences or adverse reactions.

ANTISEIZURE THERAPY AND PREGNANCY

The effectiveness of oral contraceptives appears to be reduced by concomitant use of antiseizure drugs. This may be caused by the increased rate of oral contraceptive metabolism by antiseizure drugs that induce CYPs (see Table 21–3). Antiseizure drugs that induce CYPs have been associated with vitamin K deficiency in the newborn, which can result in a coagulopathy and intracerebral hemorrhage. Treatment with vitamin K1, 10 mg/day during the last month of gestation, has been recommended for prophylaxis.

TERATOGENICITY. Antiseizure drugs have teratogenic effects. The malformations include congenital heart defects, neural tube defects, cleft lip, cleft palate, and others. Phenytoin, carbamazepine, valproate, lamotrigine, and phenobarbital all have been associated with teratogenic effects. One consideration for a woman with epilepsy who wishes to become pregnant is a trial free of antiseizure drug; monotherapy with careful attention to drug levels is another alternative. Polytherapy with toxic levels should be avoided. Folate supplementation (0.4 mg/day) is recommended for all women of childbearing age to reduce the likelihood of neural tube defects.