Drugs Effective in the Therapy of the Epilepsies

The epilepsies are common and frequently devastating disorders, affecting approximately 2.5 million people in the United States alone. More than 40 distinct forms of epilepsy have been identified. 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 in that available drugs inhibit seizures, but neither effective prophylaxis nor cure is available. Compliance with medication is a major problem because of the need for long-term therapy together with unwanted effects of many drugs.

The mechanisms of action of antiseizure drugs fall into three major categories. Drugs effective against the most common forms of epileptic seizures, partial and secondarily generalized tonic-clonic seizures, appear to work by one of two mechanisms. One is to limit the sustained, repetitive firing of a neuron, an effect mediated by promoting the inactivated state of voltage-activated Na⁺ channels. A second mechanism appears to involve enhanced gamma-aminobutyric acid (GABA)mediated synaptic inhibition, an effect mediated by an action presynaptically for some drugs and postsynaptically for others. Drugs effective against a less common form of epileptic seizure, absence seizure, limit activation of a particular voltage-activated Ca²⁺ channel known as the T current.

Although many treatments are available, much effort is being devoted to novel approaches. Many of these approaches center on elucidating the genetic, cellular, and molecular mechanisms of the hyperexcitability, insights that promise to provide specific targets for novel therapies.

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 can be 'nonepileptic' when evoked in a normal brain by treatments such as electroshock or chemical convulsants or 'epileptic' when occurring without evident provocation. Pharmacological agents in current clinical use inhibit seizures, and thus are referred to as antiseizure drugs. Whether any of these agents has prophylactic value in preventing development of epilepsy (epileptogenesis) is uncertain.

Seizures are thought to arise from the cerebral cortex, and not from other central nervous system (CNS) structures such as thalamus, brainstem, or cerebellum. Epileptic seizures have been classified into partial seizures, those beginning focally in a cortical site, and generalized seizures, those that involve both hemispheres widely from the outset (Commission, 1981). 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 determines the drug selected for therapy. More detailed information is presented in Table 211.

Apart from this epileptic seizure classification, an additional classification specifies epileptic syndromes, which refer to a cluster of symptoms frequently occurring together and include seizure types, etiology, age of onset, and other factors (Commission, 1989). More than 40 distinct epileptic syndromes have been identified. The epileptic syndromes have been categorized into partial versus generalized epilepsies. The partial epilepsies may consist of any of the partial seizure types (Table 211) and 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, damage due to trauma or stroke, etc. Such lesions often are evident on brain imaging studies such as magnetic resonance imaging. Alternatively, the etiology may be genetic. The generalized epilepsies are characterized most commonly by one or more of the generalized seizure types listed in Table 211 and account for approximately 40% of all epilepsies. The etiology is usually genetic. The most common generalized epilepsy is referred to as juvenile myoclonic epilepsy, accounting for approximately 10% of all epileptic syndromes. The age of onset is in the early teens, and the condition is characterized typically by myoclonic and tonic-clonic and often absence seizures. 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; there is a familial clustering of cases, but the pattern of inheritance is not mendelian. To date, the classification of epileptic syndromes has had more of an impact on guiding clinical assessment and management than on selection of antiseizure drugs.

History

Phenobarbital was the first synthetic organic agent recognized as having antiseizure activity (Hauptmann, 1912); its sedative properties led investigators to test and demonstrate its effectiveness for suppressing seizures. In a landmark discovery, Merritt and Putnam (1938a) developed the electroshock seizure test in experimental animals to screen chemical agents for antiseizure effectiveness; in the course of screening a variety of drugs, they discovered that phenytoin suppressed seizures in the absence of sedative effects. The electroshock seizure test is extremely valuable, because drugs that are effective against tonic hindlimb extension induced by electroshock generally have proven to be effective against partial and tonic-clonic seizures in human beings. Another screening test, seizures induced by the chemoconvulsant pentylenetetrazol, is useful in identifying drugs that are effective against absence seizures in human beings. These screening tests remain useful even now. The chemical structures of most of the drugs introduced before 1965 were closely related to phenobarbital. These include the hydantoins, the oxazolidinediones, and the succinimides. The agents introduced after 1965 exhibit a diversity of chemical structures. These include benzodiazepines (clonazepam and clorazepate), an iminostilbene (carbamazepine), a branched-chain carboxylic acid (valproic acid), a phenyltriazine (lamotrigine), a cyclic analog of GABA (gabapentin), a sulfamate-substituted monosaccharide (topiramate), a nipecotic acid derivative (tiagabine), and a pyrrolidine derivative (levetiracetam).

Therapeutic Aspects

The ideal antiseizure drug would suppress all seizures without causing any unwanted effects. Unfortunately, the drugs used currently not only fail to control seizure activity in some patients, but they frequently cause unwanted effects that range in severity from minimal impairment of the CNS to death from aplastic anemia or hepatic failure. The physician who treats patients with epilepsy is thus faced with the task of selecting the appropriate drug or combination of drugs that best controls seizures in an individual patient at an acceptable level of untoward effects. It is generally held that complete control of seizures can be achieved in up to 50% of patients and that another 25% can be improved significantly. The degree of success varies as a function of seizure type, cause, and other factors.

To minimize toxicity, treatment with a single drug should be sought. If seizures are not controlled at adequate plasma concentrations of the initial agent, substitution of a second drug is preferred to the concurrent administration of another agent. However, multiple-drug therapy may be required, especially when two or more types of seizure occur in the same patient.

Measurement of drug concentrations in plasma facilitates optimizing antiseizure medication, especially when therapy is initiated, after dosage adjustments, in the event of therapeutic failure, when toxic effects appear, or when multiple-drug therapy is instituted. However, clinical effects of some drugs do not correlate well with their concentrations in plasma, and recommended concentrations are only guidelines for therapy. The ultimate therapeutic regimen must be determined by clinical assessment of effect and toxicity.

The general principles of the drug therapy of the epilepsies are summarized below, following discussion of the individual agents. Details of diagnosis and therapy can be found in the monographs and reviews listed at the end of the chapter.

Phenytoin

Phenytoin (diphenylhydantoin; DILANTIN DIPHENYLAN) is effective against all types of partial and tonic-clonic seizures but not absence seizures. Properties of other hydantoins (mephenytoin, ethotoin) are described in earlier editions of this book.

History

Phenytoin was first synthesized in 1908 by Biltz, but its anticonvulsant activity was not discovered until 1938 (Merritt and Putnam, 1938a,b). In contrast to the earlier accidental discovery of the antiseizure properties of bromide and phenobarbital, phenytoin was the product of a search among nonsedative structural relatives of phenobarbital for agents capable of suppressing electroshock convulsions in laboratory animals. It was introduced for the treatment of epilepsy in the same year. The discovery of phenytoin was a signal advance. Since this agent is not a sedative in ordinary doses, it established that antiseizure drugs need not induce drowsiness and encouraged the search for drugs with selective antiseizure action.

Structure-Activity Relationship

Phenytoin has the following structural formula:

A 5-phenyl or other aromatic substituent appears essential for activity against generalized tonic-clonic seizures. Alkyl substituents in position 5 contribute to sedation, a property absent in phenytoin. The position 5 carbon permits asymmetry, but there appears to be little difference in activity between isomers.

Pharmacological Effects

Central Nervous System

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.

The most significant effect of phenytoin is its ability to modify the pattern of maximal electroshock seizures. The characteristic tonic phase can be abolished completely, but the residual clonic seizure may be exaggerated and prolonged. This seizure-modifying action is observed with many other antiseizure drugs that are effective against generalized tonic-clonic seizures. By contrast, phenytoin does not inhibit clonic seizures evoked by pentylenetetrazol.

Mechanism of Action

Phenytoin limits the repetitive firing of action potentials evoked by a sustained depolarization of mouse spinal cord neurons maintained in vitro (McLean and Macdonald, 1983). 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. These effects of phenytoin are evident at concentrations in the range of therapeutic drug levels in cerebrospinal fluid (CSF) in human beings, concentrations that correlate with the free (or unbound) concentration of phenytoin in the serum. At these concentrations, the effects on Na⁺ channels are selective, in that 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, enhancement of responses to GABA, and others; these effects may underlie some of the unwanted toxicity associated with high levels of phenytoin.

Pharmacokinetic Properties

The pharmacokinetic characteristics of phenytoin are influenced markedly by its binding to serum proteins, by the nonlinearity of its elimination kinetics, and by its metabolism by the cytochrome P450 enzyme system. Phenytoin is extensively bound (about 90%) to serum proteins, mainly albumin. Small variations in the percentage of phenytoin that is bound dramatically affect the absolute amount of free (active) drug; increased proportions of free drug are evident in the neonate, in patients with hypoalbuminemia, and in uremic patients. Some agents, such as valproate, can compete with phenytoin for binding sites on plasma proteins; when combined with valproate-mediated inhibition of phenytoin metabolism, marked increases in free phenytoin can result. Measurement of free rather than total phenytoin permits direct assessment of this potential problem in patient management.

Phenytoin is one of the few drugs for which the rate of elimination varies as a function of its concentration (i.e., the rate is nonlinear). The plasma half-life of phenytoin ranges between 6 and 24 hours at plasma concentrations below 10 g/ml but 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 principally in the hepatic endoplasmic reticulum and mainly by the cytochrome P450 isoform CYP2C9/10 and to a lesser extent CYP2C19 (Table 212). The principal metabolite, a parahydroxyphenyl derivative, is inactive. Because its metabolism is saturable, other drugs that are metabolized by these enzymes can inhibit phenytoin's metabolism and produce a rise in phenytoin 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 hypoprothrombinemia. An alternative mechanism of drug interactions arises from phenytoin's ability to induce diverse cytochrome P450 enzymes; coadministration of phenytoin and medications metabolized by these enzymes can lead to an increased degradation of such medications. Of particular note in this regard are oral contraceptives, which are metabolized by the CYP3A4; treatment with phenytoin could enhance the metabolism of oral contraceptives and lead to unplanned pregnancy. The potential teratogenic effects of phenytoin underscore the importance of attention to this interaction. Carbamazepine, oxcarbazepine, phenobarbital, and primidone also can induce CYP3A4 and likewise might increase degradation of oral contraceptives.

The low aqueous solubility of phenytoin resulted in diverse problems for intravenous use and led to production of fosphenytoin, a water-soluble prodrug. Fosphenytoin (CEREBYX) is converted into phenytoin by phosphatases in liver and red blood cells with a half-life of 8 to 15 minutes. Fosphenytoin is useful for adults with partial or generalized seizures when parenteral administration is indicated.

Toxicity

The toxic effects of phenytoin depend upon 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. Although cardiac toxicity occurs more frequently in older patients and in those with known cardiac disease, it also can develop in young, healthy patients. These complications can be minimized by administering fosphenytoin at a rate of less than 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 medication also are primarily dose-related cerebellar-vestibular effects but include other CNS effects, behavioral changes, increased frequency of seizures, gastrointestinal symptoms, gingival hyperplasia, osteomalacia, and megaloblastic anemia. Hirsutism is an annoying untoward effect in young females. Usually, these phenomena can be made bearable by proper adjustment of dosage. Serious adverse effects, including those on the skin, bone marrow, and liver, probably are manifestations of drug allergy. Although rare, they necessitate withdrawal of the drug. Moderate elevation of the concentrations in plasma of enzymes that are used to assess hepatic function sometimes are observed; since these changes are transient and may result in part from induced synthesis of the enzymes, they do not necessitate withdrawal of the drug.

Electrophysiological evidence of peripheral neuropathy can occur in up to 30% of patients receiving phenytoin, but this phenomenon usually is not clinically significant. Gingival hyperplasia occurs in about 20% of all patients during chronic therapy and is probably the most common manifestation of phenytoin toxicity in children and young adolescents. It may be more frequent in those individuals who also develop coarsened facial features. The overgrowth of tissue appears to involve altered collagen metabolism. Toothless portions of the gums are not affected. The condition does not necessarily require withdrawal of medication, and it can be minimized by good oral hygiene.

A variety of endocrine effects have been reported. Inhibition of release of antidiuretic hormone (ADH) has been observed in patients with inappropriate ADH secretion. 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 inhibition of intestinal absorption of Ca²⁺. Phenytoin also increases the metabolism of vitamin K and reduces the concentration of vitamin Kdependent proteins that are important for normal Ca²⁺ metabolism in bone. This may explain why the osteomalacia is not always ameliorated by the administration of vitamin D.

Hypersensitivity reactions include morbilliform rash in 2% to 5% of patients and occasionally more serious skin reactions, including Stevens-Johnson syndrome. Systemic lupus erythematosus and potentially fatal hepatic necrosis have been reported rarely. Hematological reactions include neutropenia and leukopenia. A few instances of red-cell aplasia, agranulocytosis, and mild thrombocytopenia also have been reported. Lymphadenopathy, resembling Hodgkin's 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 the clinical effect. Thus, control of seizures generally is obtained with concentrations above 10 g/ml, while toxic effects such as nystagmus develop at concentrations around 20 g/ml.

Drug Interactions

Concurrent administration of any drug metabolized by the 2C9/10 isoform of cytochrome P450 can increase the plasma concentration of phenytoin by decreasing its rate of metabolism. Carbamazepine, which may enhance the metabolism of phenytoin, causes a well-documented decrease in phenytoin concentration. Conversely, phenytoin reduces the concentration of carbamazepine. Interaction between phenytoin and phenobarbital is variable.

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. The use of phenytoin and other agents in the therapy of epilepsies is discussed further at the end of this chapter. Various preparations of phenytoin differ significantly in both bioavailability and rate of absorption, and patients should thus be treated with the drug product of a single manufacturer.

Other Uses

Some cases of trigeminal and related neuralgias appear to respond to phenytoin, but carbamazepine may be preferable. The use of phenytoin in the treatment of cardiac arrhythmias is discussed in Chapter 35: Antiarrhythmic Drugs.

The pharmacology of the barbiturates as a class is considered in Chapter 17: Hypnotics and Sedatives; discussion in this chapter is limited to the two barbiturates used for therapy of the epilepsies. Although still marketed, a third barbiturate (metharbital) has virtually disappeared from therapeutic use.

Phenobarbital

Phenobarbital LUMINAL, others) was the first effective organic antiseizure agent (Hauptmann, 1912). It has relatively low toxicity, is inexpensive, and is still one of the more effective and widely used drugs for this purpose.

Structure-Activity Relationship

The structural formula of phenobarbital (5-phenyl-5-ethylbarbituric acid) is shown in Chapter 17: Hypnotics and Sedatives. The structure-activity relationship of the barbiturates has been studied extensively. Maximal antiseizure activity is obtained when one substituent at position 5 is a phenyl group. The 5,5-diphenyl derivative has less antiseizure potency than does phenobarbital, but it is virtually devoid of hypnotic activity. By contrast, 5,5-dibenzyl barbituric acid causes convulsions.

Antiseizure Properties

Most barbiturates have antiseizure properties. However, the capacity of some of these agents, such as phenobarbital, to exert maximal antiseizure action at doses below those required for hypnosis determines their clinical utility as antiseizure agents. Phenobarbital is active in most antiseizure tests in animals but is relatively nonselective. It inhibits tonic hindlimb extension in the maximal electroshock model, clonic seizures evoked by pentylenetetrazol, and kindled seizures.

Mechanism of Action

The mechanism by which phenobarbital inhibits seizures likely involves potentiation of synaptic inhibition through an action on the GABA_A receptor. Intracellular recordings of mouse cortical or spinal cord neurons demonstrated that phenobarbital enhances responses to iontophoretically applied GABA (Macdonald and Barker, 1979). These effects have been observed at therapeutically relevant concentrations of phenobarbital. Analyses of single channels in outside-out patches isolated from mouse spinal cord neurons demonstrated that phenobarbital increased the GABA receptormediated current by increasing the duration of bursts of GABA receptormediated currents without changing the frequency of bursts (Twyman et al., 1989). 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.

The mechanisms underlying the antiseizure as opposed to the sedative effects of the barbiturates have been enigmatic. That is, pentobarbital inhibits seizures, but at doses that produce marked sedation; by contrast, phenobarbital inhibits seizures at doses that cause minimal sedative effects. Both pentobarbital and phenobarbital enhance GABA_A receptormediated currents. Distinctive effects of pentobarbital and phenobarbital on GABA responses and voltage-activated Ca²⁺ channels may explain this enigma (ffrench-Mullen et al., 1993). The maximal effect of phenobarbital in enhancing GABA responses is only 40% of that of the active isomer of pentobarbital. Moreover, pentobarbital inhibits voltage-activated Ca²⁺ channels with greater potency than does phenobarbital (ffrench-Mullen et al., 1993); one consequence of inhibition of these Ca²⁺ channels could be blockade of Ca²⁺ entry into presynaptic nerve terminals and inhibition of release of neurotransmitters such as glutamate, resulting in net reduction of excitatory synaptic transmission. Thus the powerful sedative actions of pentobarbital could be due to greater maximal enhancement of GABA responses in conjunction with strong inhibition of Ca²⁺ current.

Pharmacokinetic Properties

Oral absorption of phenobarbital is complete but somewhat slow; peak concentrations in plasma occur several hours after a single dose. It is 40% to 60% bound to plasma proteins and bound to a similar extent in tissues, including brain. Up to 25% of a dose is eliminated by pH-dependent renal excretion of the unchanged drug; the remainder is inactivated by hepatic microsomal enzymes. The principal cytochrome P450 responsible is CYP2C9, with minor metabolism by CYP2C19 and 2E1. Phenobarbital induces uridine diphosphate glucuronosyl transferase (UGT) enzymes as well as CYP2C and 3A subfamilies of cytochrome P450. Drugs metabolized by these enzymes can be more rapidly degraded when coadministered with phenobarbital; importantly, oral contraceptives are metabolized by CYP3A4.

Toxicity

Sedation, the most frequent undesired effect of phenobarbital, is apparent to some extent in all patients upon initiation of therapy, but tolerance develops during chronic medication. Nystagmus and ataxia occur at excessive dosage. Phenobarbital sometimes produces 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% to 2% of patients. Exfoliative dermatitis is rare. Hypoprothrombinemia with hemorrhage has been observed in the newborn of mothers who have received phenobarbital during pregnancy; vitamin K is effective for treatment or prophylaxis. Megaloblastic anemia that responds to folate and osteomalacia that responds to high doses of vitamin D occur during chronic phenobarbital therapy of epilepsy, as they do during phenytoin medication. Other adverse effects of phenobarbital are discussed in Chapter 17: Hypnotics and Sedatives.

Plasma Drug Concentrations

During long-term therapy in adults, the plasma concentration of phenobarbital averages 10 g/ml per daily dose of 1 mg/kg; in children, the value is 5 to 7 g/ml per 1 mg/kg. Although a precise relationship between therapeutic results and concentration of drug in plasma does not exist, plasma concentrations of 10 to 35 g/ml are usually recommended for control of seizures; 15 g/ml is the minimum for prophylaxis against febrile convulsions.

The relationship between plasma concentration of phenobarbital and adverse effects varies with the development of tolerance. Sedation, nystagmus, and ataxia usually are absent at concentrations below 30 g/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 greater than 60 g/ml may be associated with marked intoxication in the nontolerant individual.

Since significant behavioral toxicity may be present despite the absence of overt signs of toxicity, the tendency to maintain patients, particularly children, on excessively high doses of phenobarbital should be resisted. The plasma phenobarbital concentration should be increased above 30 to 40 g/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 microsomal enzyme system by phenobarbital (see Chapters 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination and 17: Hypnotics and Sedatives). The variable interaction with phenytoin has been discussed above. Concentrations of phenobarbital in plasma may be elevated by as much as 40% during concurrent administration of valproic acid (see below).

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.

Mephobarbital MEBARAL) is N-methylphenobarbital. It is N-demethylated in the hepatic endoplasmic reticulum, and most of its activity during long-term therapy can be attributed to the accumulation of phenobarbital. Consequently, the pharmacological properties, toxicity, and clinical uses of mephobarbital are the same as those for phenobarbital.

Primidone

Primidone MYSOLINE) is effective against partial and tonic-clonic seizures.

Chemistry

Primidone may be viewed as a congener of phenobarbital in which the carbonyl oxygen of the urea moiety is replaced by two hydrogen atoms:

Antiseizure Properties

Primidone resembles phenobarbital in many laboratory antiseizure effects, but it is much less potent than phenobarbital in antagonizing seizures induced by pentylenetetrazol. The antiseizure effects of primidone are attributed to both the drug and its active metabolites, principally phenobarbital.

Pharmacokinetic Properties

Primidone is rapidly and almost completely absorbed after oral administration, although individual variability can be great. Peak concentrations in plasma usually are observed approximately 3 hours after ingestion. The plasma half-life of primidone is variable; mean values ranging from 5 to 15 hours have been reported.

Primidone is converted to two active metabolites, phenobarbital and phenylethylmalonamide (PEMA). Primidone and PEMA are bound to plasma proteins to only a small extent, whereas about half of phenobarbital is so bound. The half-life of PEMA in plasma is 16 hours; both it and phenobarbital accumulate during long-term therapy. The appearance of phenobarbital in plasma may be delayed several days upon initiation of therapy with primidone. Approximately 40% of the drug is excreted unchanged in the urine; unconjugated PEMA and, to a lesser extent, phenobarbital and its metabolites constitute the remainder.

Toxicity

The more common complaints are sedation, vertigo, dizziness, nausea, vomiting, ataxia, diplopia, and nystagmus. Patients also may experience an acute feeling of intoxication immediately following administration of primidone. This occurs before there is any significant metabolism of the drug. The relationship of adverse effects to dosage is complex, since they result from both the parent drug and its two active metabolites and since tolerance develops during long-term therapy. Side effects are occasionally quite severe when therapy is initiated.

Serious adverse effects are relatively uncommon, but maculopapular and morbilliform rash, leukopenia, thrombocytopenia, systemic lupus erythematosus, and lymphadenopathy have been reported. Acute psychotic reactions also have occurred. Hemorrhagic disease in the neonate, megaloblastic anemia, and osteomalacia similar to those discussed previously in connection with phenytoin and phenobarbital also have been described.

Plasma Drug Concentrations

The relationship between the dose of primidone and the concentration of the drug and its active metabolites in plasma shows marked individual variability. During long-term therapy, the plasma concentrations of primidone and phenobarbital average 1 g/ml and 2 g/ml, respectively, per daily dose of 1 mg/kg of primidone. The plasma concentration of PEMA usually is intermediate between those of primidone and phenobarbital. There is no clear relationship between the concentrations of primidone or its metabolites in plasma and therapeutic effect. As an initial guide, the dosage of primidone may be adjusted primarily with reference to the concentration of phenobarbital, as outlined previously for administered phenobarbital, and secondarily with reference to the concentration of the parent drug. Concentrations of primidone greater than 10 g/ml usually are associated with significant toxic side effects.

Drug Interactions

Phenytoin has been reported to increase the conversion of primidone to phenobarbital. Other drug interactions to be anticipated are those for phenobarbital.

Therapeutic Uses

Primidone is useful against generalized tonic-clonic and both simple and complex partial seizures. Its use in combination with phenobarbital is illogical. Primidone is ineffective against absence seizures but is sometimes useful against myoclonic seizures in young children.

Carbamazepine

Carbamazepine TEGRETOL, CARBATROL, others) was initially approved in the United States for use as an antiseizure agent in 1974. It has been employed since the 1960s for the treatment of trigeminal neuralgia. It is now considered to be a primary drug for the treatment of partial and tonic-clonic seizures.

Chemistry

Carbamazepine is related chemically to the tricyclic antidepressants. It is a derivative of iminostilbene with a carbamyl group at the 5 position; this moiety is essential for potent antiseizure activity. The structural formula of carbamazepine is as follows:

Pharmacological Effects

Although the effects of carbamazepine in animals and human beings resemble those of phenytoin in many ways, the two drugs differ in a number of potentially important ways. Carbamazepine has been found to produce therapeutic responses in manic-depressive patients, including some in whom lithium carbonate is not effective. Further, carbamazepine has antidiuretic effects that are sometimes associated with reduced concentrations of antidiuretic hormone (ADH) in plasma. The mechanisms responsible for these effects of carbamazepine are not clearly understood.

Mechanism of Action

Like phenytoin, carbamazepine limits the repetitive firing of action potentials evoked by a sustained depolarization of mouse spinal cord or cortical neurons maintained in vitro (McLean and Macdonald, 1986b). This appears to be mediated by a slowing of the rate of recovery of voltage-activated Na⁺ channels from inactivation. These effects of carbamazepine are evident at concentrations in the range of therapeutic drug levels in CSF in human beings. The effects of carbamazepine are selective at these concentrations, 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 pharmacokinetic characteristics of carbamazepine are complex. They are influenced by its limited aqueous solubility and by the ability of many antiseizure drugs, including carbamazepine itself, to increase their conversion to active metabolites by hepatic oxidative enzymes.

Carbamazepine is absorbed slowly and erratically after oral administration. Peak concentrations in plasma usually are observed 4 to 8 hours after oral ingestion, but may be delayed by as much as 24 hours, especially following the administration of a large dose. The drug distributes rapidly into all tissues. Binding to plasma proteins occurs to the extent of about 75%, and concentrations in the CSF appear to correspond to the concentration of free drug in plasma.

The predominant pathway of metabolism in human beings involves conversion to the 10,11-epoxide. This metabolite is as active as the parent compound in various animals, and 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, which are excreted in the urine principally as glucuronides. Carbamazepine also is inactivated by conjugation and hydroxylation. The hepatic cytochrome P450 isoform primarily responsible for biotransformation of carbamazepine is CYP3A4. Carbamazepine induces CYP2C and CYP3A and also UDP-glucuronosyltransferase, thus enhancing the metabolism of drugs degraded by these enzymes. Of particular importance in this regard are oral contraceptives, which are metabolized by CYP3A4.

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 (dermatitis, 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 enzymes in plasma in 5% to 10% of patients. A transient, mild leukopenia occurs in about 10% of patients during initiation of therapy and usually resolves within the first 4 months of continued treatment; transient thrombocytopenia also has been noted. In about 2% of patients, a persistent leukopenia may develop that requires withdrawal of the drug. The initial concern that aplastic anemia might be a frequent complication of long-term therapy with carbamazepine has not materialized. In the majority of cases, the administration of multiple drugs or the presence of another underlying disease has made it difficult to establish a causal relationship. In any event, the prevalence of aplastic anemia appears to be about 1 in 200,000 patients who are treated with the drug. It is not clear whether or not monitoring of hematological function can avert the development of irreversible aplastic anemia. Although carbamazepine is carcinogenic in rats, it is not known to be carcinogenic in human beings. The induction of fetal malformations during the treatment of pregnant women is discussed below.

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 to 12 g/ml, although considerable variation occurs. Side effects referable to the CNS are frequent at concentrations above 9 g/ml.

Drug Interactions

Phenobarbital, phenytoin, and valproate may increase the metabolism of carbamazepine by inducing CYP3A4; carbamazepine may enhance the biotransformation of phenytoin as well as the conversion of primidone to phenobarbital. Administration of carbamazepine may lower concentrations of valproate, lamotrigine, tiagabine, and topiramate given concurrently. 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. When it is used, renal and hepatic function and hematological parameters should be monitored. The therapeutic use of carbamazepine is discussed further at the end of this chapter.

Carbamazepine was introduced by Blom in the early 1960s and is now the primary agent for treatment of trigeminal and glossopharyngeal neuralgias. It is also effective for lightning tabetic pain. Most patients with neuralgia are benefited initially, but only 70% obtain continuing relief. Adverse effects have required discontinuation of medication in 5% to 20% of patients. The therapeutic range of plasma concentrations for antiseizure therapy serves as a guideline for its use in neuralgia. Carbamazepine also has found use in the treatment of bipolar affective disorders, a use that is discussed further in Chapter 20: Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania.

Oxcarbazepine

Oxcarbazepine TRILEPTAL) (10,11-dihydro-10-oxocarbamazepine) is a keto analog of carbamazepine. In human beings, oxcarbazepine functions as a prodrug, in that it 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 is carbamazepine, and substitution of oxcarbazepine for carbamazepine is associated with increased levels of phenytoin and valproic acid, presumably because of reduced induction of hepatic enzymes. There is no induction by oxcarbazepine of hepatic enzymes involved in its 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 has been approved for monotherapy or adjunct therapy for partial seizures in adults and as adjunctive therapy for partial seizures in children ages 4 to 16.

Ethosuximide

The succinimides evolved from a systematic search for effective agents less toxic than the oxazolidinediones for the treatment of absence seizures. Ethosuximide (ZARONTIN) is a primary agent for this type of epilepsy.

Structure-Activity Relationship

Ethosuximide has the following structural formula:

The structure-activity relationship of the succinimides is in accord with that for other antiseizure classes. Methsuximide (CELONTIN) and phensuximide (MILONTIN) have phenyl substituents and are more active against maximal electroshock seizures. Neither of these is now in common use. Discussion of their properties can be found in older editions of this book. Ethosuximide, with alkyl substituents, is the most active of the succinimides against seizures induced by pentylenetetrazol and is the most selective for absence seizures.

Pharmacological Effects

The most prominent characteristic of ethosuximide at nontoxic doses is protection against clonic motor seizures induced by pentylenetetrazol. By contrast, at nontoxic doses, ethosuximide does not inhibit tonic hindlimb extension of electroshock seizures or kindled seizures. This profile correlates with efficacy against absence seizures in human beings.

Mechanism of Action

Ethosuximide reduces low threshold Ca²⁺ currents (T currents) in thalamic neurons (Coulter et al., 1989). The thalamus plays an important role in generation of 3-Hz spike-wave rhythms typical of absence seizures (Coulter, 1998). Neurons in the thalamus exhibit a large amplitude T-current spike that underlies bursts of action potentials and likely plays an important role in thalamic oscillatory activity such as 3-Hz spike-and-wave activity. At clinically relevant concentrations, ethosuximide inhibits the T current, as evident in voltage-clamp recordings of acutely isolated, ventrobasal thalamic neurons from rats and guinea pigs. Ethosuximide reduces this current without modifying the voltage dependence of steady-state inactivation or the time course of recovery from inactivation. By contrast, succinimide derivatives with convulsant properties do not inhibit this current. Ethosuximide does not inhibit sustained repetitive firing or enhance GABA responses at clinically relevant concentrations. Current data are consistent with the idea that inhibition of T currents is the mechanism by which ethosuximide inhibits absence seizures.

Pharmacokinetic Properties

Absorption of ethosuximide appears to be complete, and peak concentrations occur in plasma within about 3 hours after a single oral dose. Ethosuximide is not significantly bound to plasma proteins; during long-term therapy, the concentration in the CSF is similar to that in plasma. The apparent volume of distribution averages 0.7 liter/kg.

In human beings, 25% of the drug is excreted unchanged in the urine. The remainder is metabolized by hepatic microsomal enzymes, but whether or not cytochrome P450 enzymes are responsible is unknown. The major metabolite, the hydroxyethyl derivative, accounts for about 40% of administered drug, is inactive, and is excreted as such and as the glucuronide in the urine. The plasma half-life of ethosuximide averages between 40 and 50 hours in adults and approximately 30 hours in children.

Toxicity

The most common dose-related side effects are gastrointestinal complaints (nausea, vomiting, and anorexia) and CNS effects (drowsiness, lethargy, euphoria, dizziness, headache, and hiccough). Some tolerance to these effects 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 syndromeas well as systemic lupus erythematosus, eosinophilia, leukopenia, thrombocytopenia, pancytopenia, and aplastic anemiaalso have been attributed to the drug. The leukopenia may be transient despite continuation of the drug, but several deaths have resulted from bone-marrow depression. Renal or hepatic toxicity has not been reported.

Plasma Drug Concentrations

During long-term therapy, the plasma concentration of ethosuximide averages about 2 g/ml per daily dose of 1 mg/kg. A plasma concentration of 40 to 100 g/ml is required for satisfactory control of absence seizures in most patients.

Therapeutic Uses

Ethosuximide is effective against absence seizures but not tonic-clonic seizures and has a lower risk of adverse effects than does trimethadione, a drug formerly used to treat absence seizures (its properties are discussed in earlier editions of this book). It is an important therapeutic agent for this type of epilepsy.

An initial daily dose of 250 mg in children (3 to 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 single daily dosage. 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 to 1000 mg in children. The use of ethosuximide and the other antiseizure agents is discussed further at the end of the chapter.

Valproic acid DEPAKENE, others) was approved for use in the United States in 1978. The antiseizure properties of valproate were discovered serendipitously when it was employed as a vehicle for other compounds that were being screened for antiseizure activity.

Chemistry

Valproic acid (n-dipropylacetic acid) is a simple branched-chain carboxylic acid; its structural formula is as follows:

Certain other branched-chain carboxylic acids have potencies similar to that of valproic acid in antagonizing pentylenetetrazol-induced convulsions. However, increasing the number of carbon atoms to nine introduces marked sedative properties. Straight-chain acids have little or no activity. The primary amide of valproic acid is about twice as potent as the parent compound.

Pharmacological Effects

Valproic acid is strikingly different from phenytoin or ethosuximide in that it is effective in inhibiting seizures in a variety of models. Like phenytoin and carbamazepine, valproate inhibits tonic hindlimb extension in maximal electroshock seizures and kindled seizures at doses without toxicity. Like ethosuximide, valproic acid inhibits clonic motor seizures induced by pentylenetetrazol at subtoxic doses. Its efficacy in diverse models parallels its efficacy against absence as well as partial and generalized tonic-clonic seizures in human beings.

Mechanism of Action

Valproic acid produces effects on isolated neurons similar to those of both phenytoin and ethosuximide. At therapeutically relevant concentrations, valproate inhibits sustained repetitive firing induced by depolarization of mouse cortical or spinal cord neurons (McLean and Macdonald, 1986a). The action is similar to that of both phenytoin and carbamazepine and appears to be mediated by a prolonged recovery of voltage-activated Na⁺ channels from inactivation. Valproic acid does not modify neuronal responses to iontophoretically applied GABA. In neurons isolated from a distinct region, the nodose ganglion, valproate also produces small reductions of the low-threshold (T) Ca²⁺ current (Kelly et al., 1990) at clinically relevant but slightly higher concentrations than limit sustained repetitive firing; this effect on T currents is similar to that of ethosuximide in thalamic neurons (Coulter et al., 1989). Together, these actions of limiting sustained repetitive firing and reducing T currents may contribute to the effectiveness of valproic acid against partial and tonic-clonic seizures and absence seizures, respectively.

Another potential mechanism that may contribute to valproate's antiseizure actions involves metabolism of GABA. Although valproate has no effect on responses to GABA, it does increase the amount of GABA that can be recovered from the brain after the drug is administered to animals. In vitro, valproate can stimulate the activity of the GABA synthetic enzyme, glutamic acid decarboxylase (Phillips and Fowler, 1982), and inhibit GABA degradative enzymes, GABA transaminase and succinic semialdehyde dehydrogenase (Chapman et al., 1982). Thus far it has been difficult to relate the increased GABA levels to the antiseizure activity of valproate.

Pharmacokinetic Properties

Valproic acid is absorbed rapidly and completely after oral administration. Peak concentration in plasma is observed in 1 to 4 hours, although this can be delayed for several hours if the drug is administered in enteric-coated tablets or is ingested with meals. The apparent volume of distribution for valproate is about 0.2 liter/kg. Its extent of binding to plasma proteins is usually about 90%, but the fraction bound is reduced as the total concentration of valproate is increased through the therapeutic range. Although concentrations of valproate in CSF suggest equilibration with free drug in the blood, there is evidence for carrier-mediated transport of valproate both into and out of the CSF.

The vast majority of valproate (95%) undergoes hepatic metabolism, with less than 5% excreted unchanged. Its hepatic metabolism occurs mainly by UGT enzymes and -oxidation. Valproate is a substrate for CYP2C9 and CYP2C19, but metabolism by these enzymes accounts for a relatively minor portion of its elimination. Some of the drug's metabolites, notably 2-propyl-2-pentenoic acid and 2-propyl-4-pentenoic acid, are nearly as potent antiseizure agents as the parent compound; however, only the former (2-en-valproic acid) accumulates in plasma and brain to a potentially significant extent (see above). The half-life of valproate is approximately 15 hours but is reduced in patients taking other antiepileptic drugs.

Toxicity

The most common side effects are transient gastrointestinal symptoms, including anorexia, nausea, and vomiting in about 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. Valproic acid has several effects on hepatic function. Elevation of hepatic enzymes in plasma is observed in up to 40% of patients and often occurs asymptomatically during the first several months of therapy. A rare complication is a fulminant hepatitis that is frequently fatal (see Dreifuss et al., 1989). Pathological examination reveals a microvesicular steatosis without evidence of inflammation or hypersensitivity reaction. Children below 2 years of age with other medical conditions who were given multiple antiseizure agents were especially likely to suffer fatal hepatic injury. At the other extreme, there were no deaths reported for patients over the age of 10 years who received only valproate. Acute pancreatitis and hyperammonemia also have been frequently associated with the use of valproic acid.

Plasma Drug Concentrations

The concentration of valproate in plasma that is associated with therapeutic effects is approximately 30 to 100 g/ml. However, the correlation between this concentration and efficacy is poor. There appears to be a threshold at about 30 to 50 g/ml; this is the concentration at which binding sites on plasma albumin begin to become saturated.

Drug Interactions

Valproate primarily inhibits drugs metabolized by 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 in the clinical setting result in valproate's displacing phenytoin and other drugs from albumin. With respect to phenytoin in particular, valproate's inhibition of the drug's metabolism is countered by displacement of phenytoin from albumin. The concurrent administration of valproate and clonazepam has been associated with the development of absence status epilepticus; however, this complication appears to be rare.

Therapeutic Uses

Valproate is effective in the treatment of absence, myoclonic, partial, and tonic-clonic seizures. The initial daily dose usually is 15 mg/kg, and this is increased at weekly intervals by 5 to 10 mg/kg per day to a maximum daily dose of 60 mg/kg. Divided doses should be given when the total daily dose exceeds 250 mg. The therapeutic uses of valproate in epilepsy are discussed further at the end of this chapter.

The benzodiazepines are employed clinically primarily as sedative-antianxiety drugs; their pharmacology is presented in detail in Chapters 17: Hypnotics and Sedatives and 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders. Discussion in this chapter is limited to consideration of their usefulness in the therapy of the epilepsies. A large number of benzodiazepines have broad antiseizure properties, but only clonazepam (KLONOPIN) and clorazepate (TRANXENE-SD; others) have been approved in the United States for the long-term treatment of certain types of seizures. Diazepam (VALIUM DIASTAT; others) and lorazepam (ATIVAN) have well-defined roles in the management of status epilepticus. The structures of the benzodiazepines are shown in Chapter 17: Hypnotics and Sedatives.

Antiseizure Properties

In animals, prevention of pentylenetetrazol-induced seizures by the benzodiazepines is much more prominent than is their modification of the maximal electroshock seizure pattern. Clonazepam is unusually potent in antagonizing the effects of pentylenetetrazol, but it is almost without action on seizures induced by maximal electroshock. Benzodiazepines, including clonazepam, suppress the spread of kindled seizures and generalized convulsions produced by stimulation of the amygdala, but do not abolish the abnormal discharge at the site of stimulation.

Mechanism of Action

The antiseizure actions of the benzodiazepines, as well as other effects that occur at nonsedating doses, result in large part from their ability to enhance GABA-mediated synaptic inhibition. Molecular cloning and study of recombinant receptors have demonstrated that the benzodiazepine receptor is an integral part of the GABA_A receptor (see Chapter 17: Hypnotics and Sedatives). At therapeutically relevant concentrations, benzodiazepines act at subsets of GABA_A receptors and increase the frequency, but not duration, of openings at GABA-activated chloride channels (Twyman et al., 1989). At higher 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 those 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, and concentrations in plasma are usually maximal within 1 to 4 hours. After intravenous administration, they are redistributed in a manner typical of that for highly lipid-soluble agents (see Chapter 1: Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, and Elimination). Central effects develop promptly, but wane rapidly as the drugs move to other tissues. Diazepam is redistributed especially rapidly, with a half-life of redistribution of about 1 hour. The extent of binding of benzodiazepines to plasma proteins correlates with lipid solubility, ranging from approximately 99% for diazepam to about 85% for clonazepam (see Appendix II).

The major metabolite of diazepam, N-desmethyl-diazepam, is somewhat less active than the parent drug and may behave as a partial agonist. This metabolite also is produced by the rapid decarboxylation of clorazepate following its ingestion. Both diazepam and N-desmethyl-diazepam are slowly hydroxylated to other active metabolites, such as oxazepam. The half-life of diazepam in plasma is between 1 and 2 days, while that of N-desmethyl-diazepam is about 60 hours. Clonazepam is metabolized principally by reduction of the nitro group to produce inactive 7-amino derivatives. Less than 1% of the drug is recovered unchanged in the urine. The half-life of clonazepam in plasma is about 1 day. Lorazepam is metabolized chiefly by conjugation with glucuronic acid; its half-life in plasma is about 14 hours.

Toxicity

The principal side effects of long-term oral therapy with clonazepam are drowsiness and lethargy. These occur in about 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 discontinuation of the drug. Other side effects include hypotonia, dysarthria, and dizziness. Behavioral disturbances, especially in children, can be very troublesome; these 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. Other aspects of the toxicity of the benzodiazepines are discussed in Chapter 17: Hypnotics and Sedatives. Cardiovascular and respiratory depression may occur after the intravenous administration of diazepam, clonazepam, or lorazepam, particularly if other antiseizure agents or central depressants have been administered previously.

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. However, tolerance to its antiseizure effects usually develops after 1 to 6 months of administration, after which some patients no longer will respond to clonazepam at any dosage. The initial dose of clonazepam for adults should not exceed 1.5 mg per day and for children is 0.01 to 0.03 mg/kg per day. The dose-dependent side effects are reduced if two or three divided doses are given each day. The dose may be increased every 3 days in amounts of 0.25 to 0.5 mg per day in children and 0.5 to 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.

While diazepam is an effective agent for treatment of status epilepticus, its short duration of action is a disadvantage, leading to the frequent use of intravenous phenytoin in combination with diazepam. Diazepam is administered intravenously and at a rate of no more than 5 mg per minute. The usual dose for adults is 5 to 10 mg, as required; this may be repeated at intervals of 10 to 15 minutes, up to a maximal dose of 30 mg. If necessary, this regimen can be repeated in 2 to 4 hours, but no more than 100 mg should be administered in a 24-hour period.

Although diazepam is not useful as an oral agent for the treatment of seizure disorders, clorazepate is effective in combination with certain other drugs in the treatment of partial seizures. The maximal inital dose of clorazepate is 22.5 mg per day in three portions for adults and 15 mg per day in two doses in children. Clorazepate is not recommended for children under the age of 9.

Gabapentin

Gabapentin NEURONTIN) is an antiseizure drug that was approved by the United States Food and Drug Administration in 1993. The chemical structure of gabapentin is a GABA molecule covalently bound to a lipophilic cyclohexane ring. Gabapentin was designed to be a centrally active GABA agonist, its high lipid solubility aimed at facilitating its transfer across the blood-brain barrier. The structure of gabapentin is shown below:

Pharmacological Effects and Mechanisms of Action

Gabapentin inhibits tonic hindlimb extension in the electroshock seizure model. Interestingly, gabapentin also inhibits clonic seizures induced by pentylenetetrazol. Its efficacy in both these tests parallels that of valproic acid and distinguishes it from phenytoin and carbamazepine. The anticonvulsant mechanism of action of gabapentin is unknown. Despite its design as a GABA agonist, gabapentin does not mimic GABA when iontophoretically applied to neurons in primary culture. Gabapentin may promote nonvesicular release of GABA through a poorly understood mechanism (Honmou et al., 1995). Gabapentin does bind a protein in cortical membranes with an amino acid sequence identical to that of the subunit of the L type of voltage-sensitive Ca²⁺ channel. Yet, gabapentin does not affect Ca²⁺ currents of the T, N, or L types of Ca²⁺ channels in dorsal root ganglion cells (Macdonald and Greenfield, 1997). Gabapentin has not been found consistently to reduce sustained repetitive firing of action potentials (Macdonald and Kelly, 1993).

Pharmacokinetics

Gabapentin is absorbed after oral administration and is not metabolized in human beings. It is excreted unchanged, mainly in the urine. Its half-life, when it is used as monotherapy, is 5 to 9 hours. Concurrent administration of gabapentin does not affect the plasma concentrations of phenytoin, carbamazepine, phenobarbital, or valproate.

Therapeutic Uses

Gabapentin is approved by the FDA for treating partial seizures, with and without secondary generalization, in adults when used in addition to other antiseizure drugs. Double-blind, placebo-controlled trials of patients with refractory partial seizures demonstrated that addition of gabapentin to other antiseizure drugs was superior to placebo. The median seizure decrease induced by gabapentin was approximately 27% compared with 12% for placebo. A double-blind study of gabapentin (900 or 1800 mg/day) monotherapy disclosed that gabapentin was similar in efficacy to carbamazepine (600 mg/day). Gabapentin also is being used for migraine, chronic pain, and bipolar disorder.

Gabapentin usually is effective in doses of 900 to 1800 mg daily in three doses. Therapy usually is begun with a low dose (300 mg once on the first day), and the dose is increased in daily increments of 300 mg until an effective dose is reached.

Toxicity

The most common adverse effects of gabapentin are somnolence, dizziness, ataxia, and fatigue. These effects usually are mild to moderate in severity but resolve within two weeks of onset during continued treatment. Overall, gabapentin is well tolerated.

Lamotrigine

Lamotrigine LAMICTAL) is a phenyltriazine derivative initially developed as an antifolate agent based upon the incorrect idea that reducing folate would effectively combat seizures. Structure-activity studies indicate that its effectiveness as an antiseizure drug is unrelated to its antifolate properties (Macdonald and Greenfield, 1997). It was approved by the Food and Drug Administration in 1994. Its chemical structure is:

Pharmacological Effects and Mechanisms of Action

Lamotrigine suppresses tonic hindlimb extension in the maximal electroshock model and partial and secondarily generalized seizures in the kindling model but does not inhibit clonic motor seizures induced by pentylenetetrazol. 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 (Xie et al., 1995). This may well explain lamotrigine's actions on partial and secondarily generalized seizures. However, as mentioned below, 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 are incompletely understood. One possibility involves lamotrigine's inhibition of glutamate release in rat cortical slices treated with veratridine, a Na⁺ channel activator, raising the possibility that lamotrigine inhibits synaptic release of glutamate by acting at Na⁺ channels themselves.

Pharmacokinetics

Lamotrigine is completely absorbed from the gastrointestinal tract and is metabolized primarily by glucuronidation. The plasma half-life of a single dose is 24 to 35 hours. Administration of phenytoin, carbamazepine, phenobarbital, or primidone reduces the half-life of lamotrigine to approximately 15 hours and reduces plasma concentrations of lamotrigine. Conversely, 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 approximately 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 in some patients.

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. A double-blind comparison of lamotrigine and carbamazepine monotherapy in newly diagnosed partial or generalized tonic-clonic seizures disclosed similar efficacy for the two drugs, but lamotrigine was better tolerated (Brodie et al., 1995). A double-blind, placebo-controlled trial of addition of lamotrigine to existing antiseizure drugs demonstrated effectiveness of lamotrigine against tonic-clonic seizures and drop attacks in children with the Lennox-Gastaut syndrome (Motte et al., 1997). Lennox-Gastaut syndrome is a disorder of childhood characterized by multiple seizure types, mental retardation, and refractoriness to antiseizure medication. There also is emerging evidence that lamotrigine is effective against juvenile myoclonic epilepsy and absence epilepsy. Patients who already are 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 per 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 to 500 mg/day divided into two 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 to 50 mg/day every 1 to 2 weeks up to a maintenance dose of 100 to 150 mg/day divided into two 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.

Acetazolamide

Acetazolamide, the prototype for the carbonic anhydrase inhibitors, is discussed in Chapter 29: Diuretics. Its antiseizure actions are discussed in previous editions of this textbook. Although it is sometimes effective against absence seizures, its usefulness is limited by the rapid development of tolerance. Adverse effects are minimal when it is used in moderate dosage for limited periods.

Felbamate

Felbamate FELBATOL) is a dicarbamate which was approved by the Food and Drug Administration for partial seizures in 1993. An association between felbamate and aplastic anemia in at least ten cases resulted in a recommendation by the Food and Drug Administration and the manufacturer for the immediate withdrawal of most patients from treatment with this drug. The structure of felbamate is shown below:

Felbamate is effective in both the maximal electroshock and pentylenetetrazol seizure models. Clinically relevant concentrations of felbamate inhibit NMDA-evoked responses and potentiate GABA-evoked responses in whole-cell, voltage-clamp recordings of cultured rat hippocampal neurons (Rho et al., 1994). This dual action on excitatory and inhibitory transmitter responses may contribute to the wide spectrum of action of the drug in seizure models.

An active control, randomized, double-blind protocol demonstrated the efficacy of felbamate in patients with poorly controlled partial and secondarily generalized seizures (Sachdeo et al., 1992). Felbamate also was found to be efficacious against seizures in patients with Lennox-Gastaut syndrome (The Felbamate Study Group in Lennox-Gastaut Syndrome, 1993). The clinical efficacy of this compound, which inhibited responses to NMDA and potentiated those to GABA, underscores the potential value of additional antiseizure agents with similar mechanisms of action.

Levetiracetam

Levetiracetam KEPPRA) is a pyrrolidine, the racemically pure S-enantiomer of -ethyl-2-oxo-1-pyrrolidineacetamide, which was approved by the Food and Drug Administration in 1999 for treating partial seizures in adults when used in addition to other drugs. Its structure is:

Pharmacological Effects and Mechanism of Action

Levetiracetam exhibits a novel pharmacological profile insofar as it inhibits partial and secondarily generalized tonic-clonic seizures in the kindling model yet is ineffective against maximum electroshock- and pentylenetetrazol-induced seizures, findings consistent with effectiveness against partial and secondarily generalized tonic-clonic seizures clinically. The mechanism by which levetiracetam exerts these antiseizure effects is unknown. No evidence for an action on voltage-gated Na⁺ channels or either GABA-or glutamate-mediated synaptic transmission has emerged. A stereoselective binding site has been identified in rat brain membranes, but the molecular identity of this site remains obscure.

Pharmacokinetics

Levetiracetam is rapidly and almost completely absorbed after oral administration. Ninety-five percent of the drug and its metabolite are excreted in the urine, 65% of which is unchanged drug; 24% of the drug is metabolized by hydrolysis of the acetamide group. It neither induces nor is a high-affinity substrate for cytochrome P450 isoforms or glucuronidation enzymes and thus is devoid of known interactions with other antiseizure drugs, oral contraceptives, or anticoagulants.

Therapeutic Use

A double-blind, placebo-controlled trial of adults with refractory partial seizures demonstrated that addition of levetiracetam to other antiseizure medications was superior to placebo. Its efficacy for monotherapy is being investigated.

Toxicity

The drug is well tolerated. The most frequently reported adverse effects are somnolence, asthenia, and dizziness.

Tiagabine

Tiagabine GABITRIL) is a derivative of nipecotic acid that was approved by the Food and Drug Administration in 1998 for treating partial seizures in adults when used in addition to other drugs. Its structure is as follows:

Pharmacological Effects and Mechanism of Action

Tiagabine inhibits the GABA transporter, GAT-1, and thereby reduces GABA uptake into neurons and glia. In CA1 neurons of the hippocampus, tiagabine increases the duration of inhibitory synaptic currents, findings consistent with prolonging the effect of GABA at inhibitory synapses through reducing its reuptake by GAT-1. Tiagabine inhibits maximum electroshock seizures and both limbic and secondarily generalized tonic-clonic seizures in the kindling model, results suggestive of efficacy against partial and tonic-clonic seizures clinically.

Pharmacokinetics

Tiagabine is rapidly absorbed after oral administration, extensively bound to proteins, and metabolized mainly in the liver and predominantly by CYP3A. Its half-life is about 8 hours but is shortened by 2 to 3 hours when coadministered with hepatic enzyme-inducing drugs such as phenobarbital, phenytoin, or carbamazepine.

Therapeutic Use

Double-blind, placebo-controlled trials have established tiagabine's efficacy as add-on therapy of refractory partial seizures with or without secondary generalization. Its efficacy for monotherapy for this indication has not yet been established.

Toxicity

The principal adverse effects include dizziness, somnolence, and tremor; they appear to be mild to moderate in severity, and appear shortly after drug initiation. The fact that tiagabine and other drugs thought to enhance effects of synaptically released GABA can facilitate spike-and-wave discharges in animal models of absence seizures raises the possibility that tiagabine may be contraindicated in patients with generalized absence epilepsy.

Topiramate

Topiramate TOPAMAX) is a sulfamate-substituted monosaccharide that was approved by the Food and Drug Administration in 1996 for partial seizures in adults when used in addition to other drugs. Its structure is as follows:

Pharmacological Effects and Mechanisms of Action

Topiramate reduces voltage-gated Na⁺ currents in cerebellar granule cells and may act on the inactivated state of the channel in a manner similar to that of phenytoin. In addition, topiramate enhances postsynaptic GABA_A-receptor currents and also limits activation of the AMPA-kainate-subtype(s) of glutamate receptor. Topiramate also is a weak carbonic anhydrase inhibitor. Topiramate inhibits maximal electroshock and pentylenetetrazol-induced seizures as well as partial and secondarily generalized tonic-clonic seizures in the kindling model, findings predictive of a broad spectrum of antiseizure actions clinically.

Pharmacokinetics

Topiramate is rapidly absorbed after oral administration and is mainly excreted unchanged in the urine. The remainder undergoes metabolism by hydroxylation, hydrolysis, and glucuronidation with no one metabolite accounting for more than 5% of an oral dose. Its half-life is about a day. Reduced estradiol plasma concentrations occur with concurrent topiramate, suggesting the need for higher doses of oral contraceptives when coadministered with topiramate.

Therapeutic Use

Double-blind, placebo-controlled studies established the efficacy of topiramate in both adults and children with refractory partial seizures with or without secondary generalized tonic-clonic seizures. Topiramate also was found to be significantly more effective than placebo against both drop attacks and tonic-clonic seizures in patients with Lennox-Gastaut syndrome and against tonic-clonic and myoclonic seizures in adults and children with primary generalized epilepsy. A pilot study suggests that topiramate may be effective against infantile spasms.

Toxicity

Topiramate is well tolerated. The most common adverse effects are somnolence, fatigue, weight loss, and nervousness.

Zonisamide

Zonisamide ZONEGRAN) is a sulfonamide derivative that was approved by the Food and Drug Administration in 2000 for partial seizures in adults when used in addition to other drugs. Its structure is as follows:

Pharmacological Effects and Mechanism of Action

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. Zonisamide inhibits tonic hindlimb extension evoked by maximal electroshock and inhibits both partial and secondarily generalized seizures in the kindling model, results predictive of clinical effectiveness against partial and secondarily generalized tonic-clonic seizures. Zonisamide does not inhibit minimal clonic seizures induced by pentylenetetrazol, suggesting that the drug will not be effective clinically against myoclonic seizures. Zonisamide's inhibition of T-type Ca²⁺ currents suggests that it may be effective against absence seizures, yet its effects in absence models such as the lethargic mouse or the absence epileptic rat of Strasbourg have not been reported.

Pharmacokinetics

Zonisamide is almost completely absorbed after oral administration, has a long half-life (about 63 hours), and is about 40% bound to plasma protein. Approximately 85% of an oral dose is excreted in the urine, principally as unmetabolized zonisamide and a glucuronide of sulfamoylacetyl phenol, which is a product of metabolism by CYP3A4. Phenobarbital, phenytoin, and carbamazepine decrease the plasma concentration/dose ratio of zonisamide, whereas lamotrigine increases this ratio. Conversely, zonisamide has little effect on the plasma concentrations of other antiseizure drugs.

Therapeutic Use

Double-blind, placebo-controlled studies of patients with refractory partial seizures demonstrated that addition of zonisamide to other drugs was superior to placebo. Additional studies of zonisamide have been initiated in absence seizures, infantile spasms, and Lennox-Gastaut syndrome, but only largely anecdotal data are currently available.

Toxicity

Overall, zonisamide is well tolerated. The most common adverse effects include somnolence, ataxia, anorexia, nervousness, and fatigue. Approximately 1% of individuals develop renal calculi during treatment with zonisamide; the mechanism of this effect is obscure.

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 efficacy of antiseizure drugs has been assessed in clinical trials on the basis of seizure type, not epilepsy syndrome type, and thus seizure type determines drug selection. The drugs commonly used for distinct seizure types are listed in Table 211. The efficacy combined with the unwanted effects of a given drug determine which particular drug is optimal for a given patient.

The first issue that arises is whether or not and when to initiate treatment. For example, it may not be necessary to initiate antiseizure therapy after an isolated tonic-clonic seizure in a healthy young adult who lacks a family history of epilepsy and who has a normal neurological exam, a normal EEG, and a normal brain magnetic resonance imaging (MRI) scan. That is, the odds of seizure recurrence in the next year (15%) approximate the risk of a drug reaction sufficiently severe to warrant discontinuation of medication (Bazil and Pedley, 1998). Alternatively, a similar seizure occurring in an individual with a positive family history of epilepsy, an abnormal neurological exam, an abnormal EEG, and an abnormal MRI carries a risk of recurrence approximating 60%, odds that favor initiation of therapy.

Unless extenuating circumstances such as status epilepticus exist, medication should be initiated with a single drug. Initial dosage usually is that expected to provide a plasma drug concentration during the plateau state at least in the lower portion of the range associated with clinical efficacy. To minimize dose-related adverse effects, therapy with many drugs is initiated at reduced dosage. Dosage is increased at appropriate intervals, as required for control of seizures or as limited by toxicity, and such adjustment is preferably assisted by monitoring of drug concentrations in plasma. Compliance with a properly selected, single drug in maximal tolerated dosage results in complete control of seizures in approximately 50% of patients. If a seizure occurs despite optimal drug levels, the physician should assess the presence of potential precipitating factors such as sleep deprivation, a concurrent febrile illness, or drugs; drugs might consist of large amounts of caffeine or even over-the-counter medications, which can include drugs that can lower the seizure threshold.

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 when a drug is being discontinued to minimize risk of seizure recurrence. In the case of partial seizures in adults, the diversity of available drugs permits selection of a second drug that acts by a distinct mechanism. Smith et al. (1987) found that 55% of such patients could be managed satisfactorily on a second single drug, yet others report that only 9% to 11% of patients with complex partial seizures failing an initial drug achieve complete seizure control with a second single drug (Schmidt and Richter, 1986; Dasheiff et al., 1986).

In the event that therapy with a second single drug also is inadequate, many physicians resort to treatment with two drugs simultaneously. This decision should not be taken lightly, because most patients obtain optimal seizure control with fewest unwanted effects when taking a single drug. Nonetheless, some patients will not be controlled adequately without the use of two or more antiseizure agents simultaneously. No properly controlled studies have compared systematically one particular drug combination with another. It seems wise to select two drugs that act by distinct mechanisms (e.g., one that promotes Na⁺ channel inactivation and another that enhances GABA-mediated synaptic inhibition). Additional issues that warrant careful consideration are the unwanted effects of each drug and the potential drug interactions. As specified in Table 212, many of these drugs induce expression of cytochrome P450 enzymes and thereby impact the metabolism of themselves and/or other drugs. Overall, the more recently developed antiseizure drugs present fewer problems with respect to drug interactions. If a patient fails two drugs in monotherapy, the odds that polytherapy will provide complete control are small. Alternative measures such as epilepsy surgery should be considered.

Essential to optimal management of epilepsy is the filling out of a seizure chart by the patient or a relative. Frequent visits to the physician or seizure clinic may be necessary early in the period of treatment, since hematological and other possible side effects may require consideration of a change in medication. Long-term follow-up with neurological examinations and possibly EEG and neuroimaging studies is appropriate. Most crucial for successful management is regularity of medication, since faulty compliance is the most frequent cause for failure of therapy with antiseizure drugs.

Measurement of plasma drug concentration at appropriate intervals greatly facilitates the initial adjustment of dosage for individual differences in drug elimination and the subsequent adjustment of dosage to minimize dose-related adverse effects without sacrifice of seizure control. Periodic monitoring during maintenance therapy can detect failure of the patient to take the medication as prescribed. Knowledge of plasma drug concentration can be especially helpful during multiple-drug therapy. If toxicity occurs, monitoring helps to identify the particular drug(s) responsible, and if pharmacokinetic drug interaction occurs, monitoring can guide readjustment of dosage.

Duration of Therapy

In an attempt to provide guidelines for withdrawal of antiseizure drugs, Shinnar et al. (1994) prospectively studied 264 children in whom antiseizure drugs were discontinued after a mean seizure-free interval of 2.9 years. Children were followed for a mean of 58 months to assess seizure recurrence. Seizures recurred in 36% of children. Factors associated with an increased risk of recurrence included a positive family history of epilepsy, presence of slowing on EEG prior to withdrawal, onset of epilepsy after age 12 (compared with younger ages), atypical febrile seizures, and certain epileptic syndromes such as juvenile myoclonic epilepsy.

In a prospective study, the treatment of patients with generalized or partial seizures was stopped after 2 seizure-free years; only patients who had been treated with a single drug (phenytoin, carbamazepine, or valproate) were included (Callaghan et al., 1988). The overall rate of relapse (within 3 years) was approximately 33% in both children and adults. Although only 92 patients were studied, the risk of relapse was apparently greatest for patients with complex partial seizures or those who had a persistently abnormal EEG.

Although these and other results are encouraging, it is not yet possible to provide clear guidelines for the selection of patients for withdrawal from therapy. Such decisions must be made on an individual basis, weighing both the medical and psychosocial consequences of recurrence of seizures against the potential toxicity associated with prolonged therapy.

If a decision to withdraw antiseizure drugs is made, such withdrawal should be done gradually over a period of months. The risk of status epilepticus is increased with abrupt cessation of therapy.

Simple and Complex Partial and Secondarily Generalized Tonic-Clonic Seizures

The efficacy and toxicity of carbamazepine, phenobarbital, phenytoin, and primidone for treatment of partial and secondarily generalized tonic-clonic seizures in adults have been examined in a double-blind prospective study (Mattson et al., 1985). A subsequent double-blind prospective study compared carbamazepine with valproate (Mattson et al., 1992). Carbamazepine and phenytoin were the most effective overall for single-drug therapy of partial or generalized tonic-clonic seizures. The choice between carbamazepine and phenytoin required assessment of toxic effects of drugs. Primidone was associated with greater incidence of toxicity early in the course of therapy, including nausea, dizziness, ataxia, and somnolence. Decreased libido and impotence were associated with all four drugs (carbamazepine 13%, phenobarbital 16%, phenytoin 11%, and primidone 22%), but significantly more commonly with primidone. The study comparing carbamazepine with valproate revealed that carbamazepine provided superior control of complex partial seizures. With respect to adverse effects, carbamazepine was more commonly associated with skin rash, but valproate was more commonly associated with tremor and weight gain. Overall, the data demonstrated that carbamazepine and phenytoin are preferable for treatment of partial seizures, but phenobarbital, valproic acid, and primidone are efficacious. A double-blind comparison of lamotrigine and carbamazepine disclosed similar efficacy of the two drugs, but lamotrigine was better tolerated (Brodie et al., 1995). Lamotrigine is used for monotherapy of partial and secondarily generalized tonic-clonic seizures. Multiple drugs recently were approved for add-on therapy of these seizures, including gabapentin, levetiracetam, tiagabine, topiramate, and zonisamide.

Control of secondarily generalized tonic-clonic seizures did not differ significantly with carbamazepine, phenobarbital, phenytoin, or primidone (Mattson et al., 1985). Valproate was as effective as carbamazepine for control of secondarily generalized tonic-clonic seizures (Mattson et al., 1992). Since secondarily generalized tonic-clonic seizures usually coexist with partial seizures, carbamazepine, phenytoin, and lamotrigine are the first-line drugs for these conditions.

Absence Seizures

The best current data indicate that ethosuximide and valproate are equally effective in the treatment of absence seizures (see Mikati and Browne, 1988). Between 50% and 75% of newly diagnosed patients can be rendered free of seizures. In the event that tonic-clonic seizures are present or emerge during therapy, valproate is the agent of first choice. Emerging evidence suggests that lamotrigine is effective for absence seizures (Bazil and Pedley, 1998).

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 also absence seizures. Monotherapy with lamotrigine may be effective in some patients with juvenile myoclonic epilepsy in whom valproic acid proves unsatisfactory (Bazil and Pedley, 1998).

Febrile Convulsions

Two percent to 4% of children experience a convulsion associated with a febrile illness. From 25% to 33% of these children will have another febrile convulsion. Only 2% to 3% become epileptic in later years. This is a sixfold increase in risk compared with the general population. 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 more than 15 minutes, 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 only 10%.

Concern regarding the increased risk of developing epilepsy or other neurological sequelae led many physicians to prescribe antiseizure drugs prophylactically after a febrile seizure. Uncertainties regarding the efficacy of prophylaxis for reducing epilepsy combined with substantial side effects of phenobarbital prophylaxis (Farwell et al., 1990) argue against the use of chronic therapy for prophylactic purposes (Freeman, 1992). 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 the adrenocorticosteroids are commonly used. A randomized study found vigabatrin (-vinyl GABA) to be efficacious in comparison to placebo (Appleton et al., 1999). Constriction of visual fields has been reported in some adults treated with vigabatrin (Miller et al., 1999). The drug has not been approved by the U.S. Food and Drug Administration but is available in other countries.

The 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. Addition of lamotrigine to other antiseizure drugs resulted in improved seizure control in comparison to placebo in a double-blind trial (Motte et al., 1997), demonstrating lamotrigine to be an effective and well-tolerated drug for this treatment-resistant form of epilepsy. Felbamate also was found to be effective for seizures in this syndrome, but the occasional occurrence of aplastic anemia has limited its use.

Status Epilepticus and Other Convulsive Emergencies

Status epilepticus is a neurological emergency. Mortality for adults approximates 20% (Lowenstein and Alldredge, 1998). The goal of treatment is rapid termination of behavioral and electrical seizure activity; the longer the episode of status epilepticus is untreated, the more difficult it is to control and the risk of permanent brain damage increases. Critical to the management is a clear plan, prompt treatment with effective drugs in adequate doses, and attention to hypoventilation and hypotension. Since hypoventilation may result from high doses of drugs used for treatment, it may be necessary to assist respiration temporarily. Drugs should be administered by intravenous route only. Because of slow and unreliable absorption, the intramuscular route has no place in treatment of status epilepticus. To assess the optimal initial drug regimen, a double-blind, multicenter trial compared four intravenous treatments: diazepam followed by phenytoin; lorazepam; phenobarbital; and phenytoin alone (Treiman et al., 1998). The treatments were shown to have similar efficacies, in that success rates ranged from 44% to 65%, but lorazepam alone was significantly better than phenytoin alone. No significant differences were found with respect to recurrences or adverse reactions.

Antiseizure Therapy and Pregnancy

Use of antiseizure drugs has diverse implications of great importance for the health of women, issues considered in guidelines articulated by the American Academy of Neurology (Morrell, 1998). These issues include interactions with oral contraceptives, potential teratogenic effects, and effects on vitamin K metabolism in pregnant women.

The effectiveness of oral contraceptives appears to be reduced by concomitant use of antiseizure drugs. The failure rate of oral contraceptives is 3.1/100 years in women receiving antiseizure drugs compared to a rate of 0.7/100 years in nonepileptic women. One attractive explanation of the increased failure rate is the increased rate of oral contraceptive metabolism caused by antiseizure drugs that induce hepatic enzymes (see Table 212); particular caution is needed with any antiseizure drug that induces CYP3A4. The apparent teratogenic effects of antiseizure drugs add to the deleterious consequences of oral contraceptive failure.

Epidemiological evidence suggests that antiseizure drugs have teratogenic effects. Infants of epileptic mothers are at twofold greater risk of major congenital malformations than offspring of nonepileptic mothers (4% to 8% compared to 2% to 4%). These malformations include congenital heart defects, neural tube defects, and others. Inferring causality from the associations found in large epidemiological studies with many uncontrolled variables can be hazardous, but a causal role for antiseizure drugs is suggested by association of congenital defects with higher concentrations of a drug or with polytherapy compared to monotherapy. Phenytoin, carbamazepine, valproate, and phenobarbital all have been associated with teratogenic effects. Whether or not the recently developed antiseizure drugs also will be associated with teratogenic effects awaits clinical experience with these agents. 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) has been recommended by the United States Public Health Service for all women of childbearing age to reduce the likelihood of neural tube defects, and this is appropriate for epileptic women as well.

Antiseizure drugs that induce cytochrome P450 enzymes have been associated with vitamin K deficiency in the newborn, which can result in a coagulopathy and intracerebral hemorrhage in the neonate. Treatment with vitamin K₁, 10 mg/day during the last month of gestation, has been recommended for prophylaxis.

Improved therapies for epilepsy are likely to emerge from several lines of investigation over the next decade: (1) Clinical experience and additional clinical trials with the recently approved antiseizure drugs should optimize their utilization for diverse forms of epilepsy. (2) Increased insight into genetic, cellular, and molecular mechanisms of epilepsy emerging from basic investigations should lead to the development of drugs acting by mechanisms distinct from currently available medications. (3) Insight into cellular and molecular mechanisms of epileptogenesis emerging from studies of animal models should lead to pharmacological prophylaxis of individuals at high risk of developing epilepsy. (4) Pharmacogenomic investigations should optimize selection of antiseizure drugs efficacious in a given individual and permit identification of individuals at high risk for devastating, idiosyncratic drug effects.

For further discussion of the epilepsies and convulsive disorders, see Chapter 348 in Harrison's Principles of Internal Medicine, 16th ed., McGraw-Hill, New York, 2005.