Basic and Clinical Pharmacology, 13th Ed.

Antiseizure Drugs

Roger J. Porter, MD, & Brian S. Meldrum, MB, PhD


A 23-year-old woman presents to the office for consultation regarding her antiseizure medications. Seven years ago, this otherwise healthy young woman had a generalized tonic-clonic seizure (GTCS) at home. She was rushed to the emergency department, at which time she was alert but complained of headache. A consulting neurologist placed her on levetiracetam, 500 mg bid. Four days later, EEG showed rare right temporal sharp waves. MRI was normal. One year after this episode, a repeat EEG was unchanged, and levetiracetam was gradually increased to 1000 mg bid. The patient had no significant adverse effects from this dosage. At age 21, she had a second GTCS while in college; further discussion with her roommate at that time revealed a history of two recent episodes of 1–2 minutes of altered consciousness with lip smacking (complex partial seizures). A repeat EEG showed occasional right temporal spikes. What is one possible strategy for controlling her present symptoms?

Approximately 1% of the world’s population has epilepsy, the third most common neurologic disorder after dementia and stroke. Although standard therapy permits control of seizures in 80% of these patients, millions (500,000 people in the USA alone) have uncontrolled epilepsy. Epilepsy is a heterogeneous symptom complex—a chronic disorder characterized by recurrent seizures. Seizures are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons. The causes of seizures are many and include the full range of neurologic diseases—from infection to neoplasm and head injury. In some subgroups, heredity has proved to be a predominant factor. Single gene defects, usually of an autosomal dominant nature involving genes coding voltage-gated ion channels or GABAA receptors, have been shown to account for a small number of familial generalized epilepsies. Commonly, one family shows multiple epilepsy syndromes including, for example, febrile seizures, absence attacks, and juvenile myoclonic epilepsy.

The antiseizure drugs described in this chapter are also used in patients with febrile seizures or with seizures occurring as part of an acute illness such as meningitis. The term “epilepsy” is not usually applied to such patients unless chronic seizures develop later. Seizures are occasionally caused by an acute underlying toxic or metabolic disorder, in which case appropriate therapy should be directed toward the specific abnormality, eg, hypocalcemia. In most cases of epilepsy, however, the choice of medication depends on the empiric seizure classification.


For a long time it was assumed that a single antiepileptic drug (AED) could be developed for the treatment of all forms of epilepsy. However, the causes of epilepsy are extremely diverse, encompassing genetic and developmental defects and infective, traumatic, neoplastic, and degenerative disease processes. Drug therapy to date shows little evidence of etiologic specificity. There is some specificity according to seizure type (Table 24–1), which is most clearly seen with generalized seizures of the absence type. These are typically seen with 2–3 Hz spike-and-wave discharges on the electroencephalogram, which respond to ethosuximide and valproate but can be exacerbated by phenytoin and carbamazepine. Drugs acting selectively on absence seizures can be identified by animal screens, using either threshold pentylenetetrazol clonic seizures in mice or rats or mutant mice showing absence-like episodes (so-called lethargic, star-gazer, or tottering mutants). In contrast, the maximal electroshock (MES) test, with suppression of the tonic extensor phase, identifies drugs such as phenytoin, carbamazepine, and lamotrigine, which are active against generalized tonic-clonic seizures and complex partial seizures. The maximal electroshock test as the major initial screen for new drugs led predominantly to the early identification of drugs with a mechanism of action involving prolonged inactivation of the voltage-gated Na+channel (see Chapter 14). Limbic seizures induced in rats by the process of electrical kindling (involving repeated episodes of focal electrical stimulation) probably provide a better screen for predicting efficacy in complex partial seizures.

TABLE 24–1 Classification of seizure types.


Existing antiseizure drugs provide adequate seizure control in about two thirds of patients. So-called “drug resistance” may be observed from the onset of attempted therapy or may develop after a period of relatively successful therapy. Explanations are being sought in terms of impaired access of the drugs to target sites or insensitivity of target molecules to them. In children, some severe seizure syndromes associated with progressive brain damage are very difficult to treat. In adults, some focal seizures are refractory to medications. Some, particularly in the temporal lobe, are amenable to surgical resection. Some of the drug-resistant population may respond to vagus nerve stimulation (VNS), a nonpharmacologic treatment for epilepsy now widely approved for treatment of patients with partial seizures. Another device approved in the USA for the treatment of medically refractory partial epilepsy is the responsive neurostimulator (RNS) system. The RNS neurostimulator is designed to detect abnormal electrical activity in the brain and deliver electrical brain stimulation to normalize activity before the patient experiences seizures. Other devices, using various paradigms of electrical stimulation, are in clinical development. One of these, a deep brain stimulation device, has been approved in Canada and in Europe, but not in the USA.

New antiseizure drugs are being sought not only by the screening tests noted above but also by more focused approaches. Compounds are sought that act by one of three mechanisms: (1) enhancement of GABAergic (inhibitory) transmission, (2) diminution of excitatory (usually glutamatergic) transmission, or (3) modification of ionic conductances. Presynaptic effects on transmitter release appear particularly important, and some molecular targets are known, eg, SV2A (see Figure 24–2).

Although it is widely recognized that current antiseizure drugs are palliative rather than curative, successful strategies for identifying drugs that are either disease modifying or that prevent epileptogenesis have proved elusive. Neuronal targets for current and potential antiseizure drugs include both excitatory and inhibitory synapses. Figure 24–1 represents a glutamatergic (excitatory) synapse, and Figure 24–2indicates targets in a GABAergic (inhibitory) synapse.


FIGURE 24–1 Molecular targets for antiseizure drugs at the excitatory, glutamatergic synapse. Presynaptic targets diminishing glutamate release include 1, voltage-gated (VG) Na+ channels (phenytoin, carbamazepine, lamotrigine, and lacosamide); 2, VG-Ca2+ channels (ethosuximide, lamotrigine, gabapentin, and pregabalin); 3, K+ channels (retigabine); synaptic vesicle proteins, 4, SV2A (levetiracetam); and 5, CRMP-2, collapsin-response mediator protein-2. Postsynaptic targets include 6, AMPA receptors (blocked by phenobarbital, topiramate, lamotrigine, and perampanel) and 7, NMDA receptors (blocked by felbamate). EAAT, excitatory amino acid transporter; NTFs, neurotrophic factors; SV2A, synaptic vesicular proteins. Red dots represent glutamate.


FIGURE 24–2 Molecular targets for antiseizure drugs at the inhibitory, GABAergic synapse. These include “specific” targets: 1, GABA transporters (especially GAT-1, tiagabine); 2, GABA-transaminase (GABA-T, vigabatrin); 3, GABAA receptors (benzodiazepines); potentially, 4, GABAB receptors; and 5, synaptic vesicular proteins (SV2A). Effects may also be mediated by “nonspecific” targets such as by voltage-gated (VG) ion channels and synaptic proteins. IPSP, inhibitory postsynaptic potential. Blue dots represent GABA.



Until 1990, approximately 16 antiseizure drugs were available, and 13 of them can be classified into five very similar chemical groups: barbiturates, hydantoins, oxazolidinediones, succinimides, and acetylureas. These groups have in common a similar heterocyclic ring structure with a variety of substituents (Figure 24–3). For drugs with this basic structure, the substituents on the heterocyclic ring determine the pharmacologic class, either anti-MES or antipentylenetetrazol. Very small changes in structure can dramatically alter the mechanism of action and clinical properties of the compound. The remaining drugs in this older group—carbamazepine, valproic acid, and the benzodiazepines—are structurally dissimilar, as are the newer compounds marketed since 1990, ie, eslicarbazepine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.


FIGURE 24–3 Antiseizure heterocyclic ring structure. The X varies as follows: hydantoin derivatives, –N–; barbiturates, –C–N–; oxazolidinediones, –O–; succinimides, –C–; acetylureas, –NH2 (N connected to C2). R1, R2, and R3vary within each subgroup.


The antiseizure drugs exhibit many similar pharmacokinetic properties—even those whose structural and chemical properties are quite diverse—because most have been selected for oral activity and all must enter the central nervous system. Although many of these compounds are only slightly soluble, absorption is usually good, with 80–100% of the dose reaching the circulation. Most antiseizure drugs (other than phenytoin, tiagabine, and valproic acid) are not highly bound to plasma proteins.

Antiseizure drugs are cleared chiefly by hepatic mechanisms, although they have low extraction ratios (see Chapter 3). Many are converted to active metabolites that are also cleared by the liver. These drugs are predominantly distributed into total body water. Plasma clearance is relatively slow; many antiseizure drugs are therefore considered to be medium to long acting. Some have half-lives longer than 12 hours. Many of the older antiseizure drugs are potent inducers of hepatic microsomal enzyme activity. Compliance is better with less frequent administration; thus extended-release formulations permitting once- or twice-daily administration may offer an advantage.


The classic major drugs for partial and generalized tonic-clonic seizures are phenytoin (and congeners), carbamazepine, valproate, and the barbiturates. However, the availability of newer drugs—eslicarbazepine, lamotrigine, levetiracetam, gabapentin, oxcarbazepine, pregabalin, retigabine, topiramate, vigabatrin, lacosamide, and zonisamide—is altering clinical practice in countries where these compounds are available. The next section of the chapter is a description of major drugs from a historical and structural perspective. Factors involved in the clinical choice of drugs are described in the last section of the chapter.


Phenytoin is the oldest nonsedative antiseizure drug, introduced in 1938 after a systematic evaluation of compounds such as phenobarbital that altered electrically induced seizures in laboratory animals. It was known for decades as diphenylhydantoin.


Phenytoin is a diphenyl-substituted hydantoin with the structure shown. It has much lower sedative properties than compounds with alkyl substituents at the 5 position. A more soluble prodrug of phenytoin, fosphenytoin, is available for parenteral use; this phosphate ester compound is rapidly converted to phenytoin in the plasma.


Mechanism of Action

Phenytoin has major effects on several physiologic systems. It alters Na+, K+, and Ca2+ conductance, membrane potentials, and the concentrations of amino acids and the neurotransmitters norepinephrine, acetylcholine, and γ-aminobutyric acid (GABA). Studies with neurons in cell culture show that phenytoin blocks sustained high-frequency repetitive firing of action potentials (Figure 24–4). This effect is seen at therapeutically relevant concentrations. It is a use-dependent effect (see Chapter 14) on Na+ conductance, arising from preferential binding to—and prolongation of—the inactivated state of the Na+ channel. This effect is also seen with therapeutically relevant concentrations of carbamazepine, lamotrigine, and valproate and probably contributes to their antiseizure action in the electroshock model and in partial seizures. Phenytoin also blocks the persistent Na+ current, as do several other AEDs including valproate, topiramate, and ethosuximide.


FIGURE 24–4 Effects of three antiseizure drugs on sustained high-frequency firing of action potentials by cultured neurons. Intracellular recordings were made from neurons while depolarizing current pulses, approximately 0.75 s in duration, were applied (on-off step changes indicated by arrows). In the absence of drug, a series of high-frequency repetitive action potentials filled the entire duration of the current pulse. Phenytoin, carbamazepine, and sodium valproate all markedly reduced the number of action potentials elicited by the current pulses. (Adapted, with permission, from Macdonald RL, Meldrum BS: Principles of anti-epileptic drug action. In: Levy RH et al [editors]: Antiepileptic Drugs, 4th ed. Raven Press, 1995.)

In addition, phenytoin paradoxically causes excitation in some cerebral neurons. A reduction of calcium permeability, with inhibition of calcium influx across the cell membrane, may explain the ability of phenytoin to inhibit a variety of calcium-induced secretory processes, including release of hormones and neurotransmitters. Recording of excitatory and inhibitory postsynaptic potentials show that phenytoin decreases the synaptic release of glutamate and enhances the release of GABA. The mechanism of phenytoin’s action probably involves a combination of actions at several levels. At therapeutic concentrations, the major action of phenytoin is to block Na+ channels and inhibit the generation of rapidly repetitive action potentials. Presynaptic actions on glutamate and GABA release probably arise from actions other than those on voltage-gated Na+ channels.

Clinical Uses

Phenytoin is effective against partial seizures and generalized tonic-clonic seizures. In the latter, it appears to be effective against attacks that are either primary or secondary to another seizure type.


Absorption of phenytoin is highly dependent on the formulation of the dosage form. Particle size and pharmaceutical additives affect both the rate and the extent of absorption. Absorption of phenytoin sodium from the gastrointestinal tract is nearly complete in most patients, although the time to peak may range from 3 to 12 hours. Absorption after intramuscular injection is unpredictable, and some drug precipitation in the muscle occurs; this route of administration is not recommended for phenytoin. In contrast, fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well absorbed after intramuscular administration.

Phenytoin is highly bound to plasma proteins. The total plasma level decreases when the percentage that is bound decreases, as in uremia or hypoalbuminemia, but correlation of free levels with clinical states remains uncertain. Drug concentration in cerebrospinal fluid is proportionate to the free plasma level. Phenytoin accumulates in brain, liver, muscle, and fat.

Phenytoin is metabolized to inactive metabolites that are excreted in the urine. Only a very small proportion of the dose is excreted unchanged.

The elimination of phenytoin is dose-dependent. At very low blood levels, phenytoin metabolism follows first-order kinetics. However, as blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize phenytoin is approached. Further increases in dosage, though relatively small, may produce very large changes in phenytoin concentrations (Figure 24–5). In such cases, the half-life of the drug increases markedly, steady state is not achieved in routine fashion (since the plasma level continues to rise), and patients quickly develop symptoms of toxicity.


FIGURE 24–5 Nonlinear relationship of phenytoin dosage and plasma concentrations. Five patients (identified by different symbols) received increasing dosages of phenytoin by mouth, and the steady-state serum concentration was measured at each dosage. The curves are not linear since, as the dosage increases, the metabolism is saturable. Note also the marked variation among patients in the serum levels achieved at any dosage. (Adapted, with permission, from Jusko WJ: Bioavailability and disposition kinetics of phenytoin in man. In: Kellaway P, Petersen I [editors]: Quantitative Analytic Studies in Epilepsy. Raven Press, 1977.)

The half-life of phenytoin varies from 12 to 36 hours, with an average of 24 hours for most patients in the low to mid therapeutic range. Much longer half-lives are observed at higher concentrations. At low blood levels, it takes 5–7 days to reach steady-state blood levels after every dosage change; at higher levels, it may be 4–6 weeks before blood levels are stable.

Therapeutic Levels & Dosage

The therapeutic plasma level of phenytoin for most patients is between 10 and 20 mcg/mL. A loading dose can be given either orally or intravenously; the latter, using fosphenytoin, is the method of choice for convulsive status epilepticus (discussed later). When oral therapy is started, it is common to begin adults at a dosage of 300 mg/d, regardless of body weight. This may be acceptable in some patients, but it frequently yields steady-state blood levels below 10 mcg/mL, which is the minimum therapeutic level for most patients. If seizures continue, higher doses are usually necessary to achieve plasma levels in the upper therapeutic range. Because of its dose-dependent kinetics, some toxicity may occur with only small increments in dosage. The phenytoin dosage should be increased each time by only 25–30 mg in adults, and ample time should be allowed for the new steady state to be achieved before further increasing the dosage. A common clinical error is to increase the dosage directly from 300 mg/d to 400 mg/d; toxicity frequently occurs at a variable time thereafter. In children, a dosage of 5 mg/kg/d should be followed by readjustment after steady-state plasma levels are obtained.

Two types of oral phenytoin sodium are currently available in the USA, differing in their respective rates of dissolution; one is absorbed rapidly and one more slowly. Only the slow-release extended-action formulation can be given in a single daily dosage, and care must be used when changing brands (see Preparations Available). Although a few patients being given phenytoin on a long-term basis have been proved to have low blood levels from poor absorption or rapid metabolism, the most common cause of low levels is poor compliance. Fosphenytoin sodium is available for intravenous or intramuscular use and replaces intravenous phenytoin sodium, a much less soluble form of the drug.

Drug Interactions & Interference with Laboratory Tests

Drug interactions involving phenytoin are primarily related to protein binding or to metabolism. Since phenytoin is 90% bound to plasma proteins, other highly bound drugs, such as phenylbutazone and sulfonamides, can displace phenytoin from its binding site. In theory, such displacement may cause a transient increase in free drug. A decrease in protein binding—eg, from hypoalbuminemia—results in a decrease in the total plasma concentration of drug but not the free concentration. Intoxication may occur if efforts are made to maintain total drug levels in the therapeutic range by increasing the dose. The protein binding of phenytoin is decreased in the presence of renal disease. The drug has an affinity for thyroid-binding globulin, which confuses some tests of thyroid function; the most reliable screening test of thyroid function in patients taking phenytoin appears to be measurement of thyroid-stimulating hormone (TSH).

Phenytoin has been shown to induce microsomal enzymes responsible for the metabolism of a number of drugs. Autostimulation of its own metabolism, however, appears to be insignificant.


Dose-related adverse effects caused by phenytoin are often similar to those caused by other antiseizure drugs in this group, making differentiation difficult in patients receiving multiple drugs. Nystagmus occurs early, as does loss of smooth extraocular pursuit movements, but neither is an indication for decreasing the dose. Diplopia and ataxia are the most common dose-related adverse effects requiring dosage adjustment; sedation usually occurs only at considerably higher levels. Gingival hyperplasia and hirsutism occur to some degree in most patients; the latter can be especially unpleasant in women. Long-term use is associated in some patients with coarsening of facial features and with mild peripheral neuropathy, usually manifested by diminished deep tendon reflexes in the lower extremities. Long-term use may also result in abnormalities of vitamin D metabolism, leading to osteomalacia. Low folate levels and megaloblastic anemia have been reported, but the clinical importance of these observations is unknown.

Idiosyncratic reactions to phenytoin are relatively rare. A skin rash may indicate hypersensitivity of the patient to the drug. Fever may also occur, and in rare cases the skin lesions may be severe and exfoliative. Lymphadenopathy may be difficult to distinguish from malignant lymphoma, and although some studies suggest a causal relationship between phenytoin and Hodgkin’s disease, the data are far from conclusive. Hematologic complications are exceedingly rare, although agranulocytosis has been reported in combination with fever and rash.


Many congeners of phenytoin have been synthesized, but only three have been marketed in the USA, and one of these (phenacemide) has been withdrawn. The other two congeners, mephenytoin and ethotoin, like phenytoin, appear to be most effective against generalized tonic-clonic seizures and partial seizures. No well-controlled clinical trials have documented their effectiveness. The incidence of severe reactions such as dermatitis, agranulocytosis, or hepatitis is higher for mephenytoin than for phenytoin.

Ethotoin may be recommended for patients who are hypersensitive to phenytoin, but larger doses are required. The adverse effects and toxicity are generally less severe than those associated with phenytoin, but the drug appears to be less effective.

Both ethotoin and mephenytoin share with phenytoin the property of saturable metabolism within the therapeutic dosage range. Careful monitoring of the patient during dosage alterations with either drug is essential. Mephenytoin is metabolized to 5,5-ethylphenylhydantoin via demethylation. This metabolite, nirvanol, contributes most of the antiseizure activity of mephenytoin. Both mephenytoin and nirvanol are hydroxylated and undergo subsequent conjugation and excretion. Therapeutic levels for mephenytoin range from 5 to 16 mcg/mL, and levels above 20 mcg/mL are considered toxic.

Therapeutic blood levels of nirvanol are between 25 and 40 mcg/mL. A therapeutic range for ethotoin has not been established.


Closely related to imipramine and other antidepressants, carbamazepine is a tricyclic compound effective in treatment of bipolar depression. It was initially marketed for the treatment of trigeminal neuralgia but has proved useful for epilepsy as well.


Although not obvious from a two-dimensional representation of its structure, carbamazepine has many similarities to phenytoin. The ureide moiety (–N–CO–NH2) in the heterocyclic ring of most antiseizure drugs is also present in carbamazepine. Three-dimensional structural studies indicate that its spatial conformation is similar to that of phenytoin.


Mechanism of Action

The mechanism of action of carbamazepine appears to be similar to that of phenytoin. Like phenytoin, carbamazepine shows activity against maximal electroshock seizures. Carbamazepine, like phenytoin, blocks Na+ channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons in culture (Figure 24–4). It also acts presynaptically to decrease synaptic transmission. Potentiation of a voltage-gated K+ current has also been described. These effects probably account for the anticonvulsant action of carbamazepine. Binding studies show that carbamazepine interacts with adenosine receptors, but the functional significance of this observation is not known.

Clinical Uses

Although carbamazepine has long been considered a drug of choice for both partial seizures and generalized tonic-clonic seizures, some of the newer antiseizure drugs are beginning to displace it from this role. Carbamazepine is not sedative in its usual therapeutic range. The drug is also very effective in some patients with trigeminal neuralgia, although older patients may tolerate higher doses poorly, with ataxia and unsteadiness. Carbamazepine is also useful for controlling mania in some patients with bipolar disorder.


The rate of absorption of carbamazepine varies widely among patients, although almost complete absorption apparently occurs in all. Peak levels are usually achieved 6–8 hours after administration. Slowing absorption by giving the drug after meals helps the patient tolerate larger total daily doses.

Distribution is slow, and the volume of distribution is roughly 1 L/kg. The drug is approximately 70% bound to plasma proteins; no displacement of other drugs from protein binding sites has been observed.

Carbamazepine has a very low systemic clearance of approximately 1 L/kg/d at the start of therapy. The drug has a notable ability to induce microsomal enzymes. Typically, the half-life of 36 hours observed in subjects after an initial single dose decreases to as little as 8–12 hours in subjects receiving continuous therapy. Considerable dosage adjustments are thus to be expected during the first weeks of therapy. Carbamazepine also alters the clearance of other drugs (see below).

Carbamazepine is completely metabolized in humans to several derivatives. One of these, carbamazepine-10,11-epoxide, has been shown to have anticonvulsant activity. The contribution of this and other metabolites to the clinical activity of carbamazepine is unknown.

Therapeutic Levels & Dosage

Carbamazepine is available only in oral form. The drug is effective in children, in whom a dosage of 15–25 mg/kg/d is appropriate. In adults, daily doses of 1 g or even 2 g are tolerated. Higher dosage is achieved by giving multiple divided doses daily. Extended-release preparations permit twice-daily dosing for most patients. In patients in whom the blood is drawn just before the morning dose (trough level), the therapeutic level is usually 4–8 mcg/mL. Although many patients complain of diplopia at drug levels above 7 mcg/mL, others can tolerate levels above 10 mcg/mL, especially with monotherapy. Extended-release formulations that overcome some of these issues are now available.

Drug Interactions

Drug interactions involving carbamazepine are almost exclusively related to the drug’s enzyme-inducing properties. As noted previously, the increased metabolic capacity of the hepatic enzymes may cause a reduction in steady-state carbamazepine concentrations and an increased rate of metabolism of other drugs, eg, primidone, phenytoin, ethosuximide, valproic acid, and clonazepam. Other drugs such as valproic acid may inhibit carbamazepine clearance and increase steady-state carbamazepine blood levels. Other anticonvulsants, however, such as phenytoin and phenobarbital, may decrease steady-state concentrations of carbamazepine through enzyme induction. No clinically significant protein-binding interactions have been reported.


The most common dose-related adverse effects of carbamazepine are diplopia and ataxia. The diplopia often occurs first and may last less than an hour during a particular time of day. Rearrangement of the divided daily dose can often remedy this complaint. Other dose-related complaints include mild gastrointestinal upsets, unsteadiness, and, at much higher doses, drowsiness. Hyponatremia and water intoxication have occasionally occurred and may be dose related.

Considerable concern exists regarding the occurrence of idiosyncratic blood dyscrasias with carbamazepine, including fatal cases of aplastic anemia and agranulocytosis. Most of these have been in elderly patients with trigeminal neuralgia, and most have occurred within the first 4 months of treatment. The mild and persistent leukopenia seen in some patients is not necessarily an indication to stop treatment but requires careful monitoring. The most common idiosyncratic reaction is an erythematous skin rash; other responses such as hepatic dysfunction are unusual.


Oxcarbazepine is closely related to carbamazepine and is useful in the same seizure types, but it may have an improved toxicity profile. Oxcarbazepine has a half-life of only 1–2 hours. Its activity, therefore, resides almost exclusively in the 10-hydroxy metabolite (especially the S(+) enantiomer, eslicarbazepine), to which it is rapidly converted and which has a half-life similar to that of carbamazepine, ie, 8–12 hours. The drug is mostly excreted as the glucuronide of the 10-hydroxy metabolite.


Oxcarbazepine is less potent than carbamazepine, both in animal models of epilepsy and in epileptic patients; clinical doses of oxcarbazepine may need to be 50% higher than those of carbamazepine to obtain equivalent seizure control. Some studies report fewer hypersensitivity reactions to oxcarbazepine, and cross-reactivity with carbamazepine does not always occur. Furthermore, the drug appears to induce hepatic enzymes to a lesser extent than carbamazepine, minimizing drug interactions. Although hyponatremia may occur more commonly with oxcarbazepine than with carbamazepine, most adverse effects that occur with oxcarbazepine are similar in character to reactions reported with carbamazepine.


Eslicarbazepine acetate (ESL) is a prodrug that has been approved as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization. ESL is more rapidly converted to S(+)-licarbazine (eslicarbazine) than is oxcarbazepine; clearly both prodrugs have the same metabolite as active product. The mechanism of action of carbamazepine, oxcarbazepine, and ESL appears to be the same, ie, blocking of voltage-gated Na+channels. The R(−) enantiomer has some activity, but much less than its counterpart.

Clinically, the drug is similar to carbamazepine and oxcarbazepine in its spectrum of action, but it is less well studied in other possible indications. A possible advantage of ESL is its once-daily dosing regimen. The measured half-life of the S(+) enantiomer is 9–11 hours. The drug is administered at a dosage of 400–1200 mg/d; titration is typically required for the higher doses.

Minimal drug level effects are observed with co-administration of carbamazepine, levetiracetam, lamotrigine, topiramate, and valproate. Oral contraceptives may be less effective with concomitant ESL administration.


Aside from the bromides, phenobarbital is the oldest of the currently available antiseizure drugs. Although it has long been considered one of the safest of the antiseizure agents, the use of other medications with lesser sedative effects has been urged. Many consider the barbiturates the drugs of choice for seizures only in infants.


The four derivatives of barbituric acid clinically useful as antiseizure drugs are phenobarbital, mephobarbital, metharbital, and primidone. The first three are so similar that they are considered together. Metharbital is methylated barbital, and mephobarbital is methylated phenobarbital; both are demethylated in vivo. The pKas of these three weak acid compounds range from 7.3 to 7.9. Slight changes in the normal acid-base balance, therefore, can cause significant fluctuation in the ratio of the ionized to the nonionized species. This is particularly important for phenobarbital, the most commonly used barbiturate, whose pKa is similar to the plasma pH of 7.4.

The three-dimensional conformations of the phenobarbital and N-methylphenobarbital molecules are similar to that of phenytoin. Both compounds possess a phenyl ring and are active against partial seizures.

Mechanism of Action

The exact mechanism of action of phenobarbital is unknown, but enhancement of inhibitory processes and diminution of excitatory transmission probably contribute significantly. Recent data indicate that phenobarbital may selectively suppress abnormal neurons. Like phenytoin, phenobarbital suppresses high-frequency repetitive firing in neurons in culture through an action on Na+ conductance, but only at high concentrations. Also at high concentrations, barbiturates block some Ca2+ currents (L-type and N-type). Phenobarbital binds to an allosteric regulatory site on the GABAA receptor, and it enhances the GABA receptor-mediated current by prolonging the openings of the Cl channels (see Chapter 22). Phenobarbital can also decrease excitatory responses. An effect on glutamate release is probably more significant than blockade of AMPA responses (see Chapter 21). Both the enhancement of GABA-mediated inhibition and the reduction of glutamate-mediated excitation are seen with therapeutically relevant concentrations of phenobarbital.

Clinical Uses

Phenobarbital is useful in the treatment of partial seizures and generalized tonic-clonic seizures, although the drug is often tried for virtually every seizure type, especially when attacks are difficult to control. There is little evidence for its effectiveness in generalized seizures such as absence, atonic attacks, and infantile spasms; it may worsen certain patients with these seizure types.

Some physicians prefer either metharbital (no longer readily available) or mephobarbital (especially the latter) to phenobarbital because of supposed decreased adverse effects. Only anecdotal data are available to support such comparisons.

Pharmacokinetics, Therapeutic Levels, & Dosage

For pharmacokinetics, drug interactions, and toxicity of phenobarbital, see Chapter 22.

The therapeutic levels of phenobarbital in most patients range from 10 mcg/mL to 40 mcg/mL. Documentation of effectiveness is best in febrile seizures, and levels below 15 mcg/mL appear ineffective for prevention of febrile seizure recurrence. The upper end of the therapeutic range is more difficult to define because many patients appear to tolerate chronic levels above 40 mcg/mL.


Primidone, or 2-desoxyphenobarbital (Figure 24–6), was first marketed in the early 1950s. It was later reported that primidone was metabolized to phenobarbital and phenylethylmalonamide (PEMA). All three compounds are active anticonvulsants.


FIGURE 24–6 Primidone and its active metabolites.

Mechanism of Action

Although primidone is converted to phenobarbital, the mechanism of action of primidone itself may be more like that of phenytoin.

Clinical Uses

Primidone, like its metabolites, is effective against partial seizures and generalized tonic-clonic seizures and may be more effective than phenobarbital. It was previously considered to be the drug of choice for complex partial seizures, but later studies of partial seizures in adults strongly suggest that carbamazepine and phenytoin are superior to primidone. Attempts to determine the relative potencies of the parent drug and its two metabolites have been conducted in newborn infants, in whom drug-metabolizing enzyme systems are very immature and in whom primidone is only slowly metabolized. Primidone has been shown to be effective in controlling seizures in this group and in older patients beginning treatment with primidone; older patients show seizure control before phenobarbital concentrations reach the therapeutic range. Finally, studies of maximal electroshock seizures in animals suggest that primidone has an anticonvulsant action independent of its conversion to phenobarbital and PEMA (the latter is relatively weak).


Primidone is completely absorbed, usually reaching peak concentrations about 3 hours after oral administration, although considerable variation has been reported. Primidone is generally distributed in total body water, with a volume of distribution of 0.6 L/kg. It is not highly bound to plasma proteins; approximately 70% circulates as unbound drug.

Primidone is metabolized by oxidation to phenobarbital, which accumulates very slowly, and by scission of the heterocyclic ring to form PEMA (Figure 24–6). Both primidone and phenobarbital also undergo subsequent conjugation and excretion.

Primidone has a larger clearance than most other antiseizure drugs (2 L/kg/d), corresponding to a half-life of 6–8 hours. PEMA clearance is approximately half that of primidone, but phenobarbital has a very low clearance (see Table 3–1). The appearance of phenobarbital corresponds to the disappearance of primidone. Phenobarbital therefore accumulates very slowly but eventually reaches therapeutic concentrations in most patients when therapeutic doses of primidone are administered. During chronic therapy, phenobarbital levels derived from primidone are usually two to three times higher than primidone levels.

Therapeutic Levels & Dosage

Primidone is most efficacious when plasma levels are in the range of 8–12 mcg/mL. Concomitant levels of its metabolite, phenobarbital, at steady state usually vary from 15 to 30 mcg/mL. Dosages of 10–20 mg/kg/d are necessary to obtain these levels. It is very important, however, to start primidone at low doses and gradually increase over days to a few weeks to avoid prominent sedation and gastrointestinal complaints. When adjusting doses of the drug, it is important to remember that the parent drug reaches steady state rapidly (30–40 hours), but the active metabolites phenobarbital (20 days) and PEMA (3–4 days) reach steady state much more slowly.


The dose-related adverse effects of primidone are similar to those of its metabolite, phenobarbital, except that drowsiness occurs early in treatment and may be prominent if the initial dose is too large. Gradual increments are indicated when starting the drug in either children or adults.


Felbamate has been approved and marketed in the USA and in some European countries. Although it is effective in some patients with partial seizures, the drug causes aplastic anemia and severe hepatitis at unexpectedly high rates and has been relegated to the status of a third-line drug for refractory cases.

Felbamate appears to have multiple mechanisms of action. It produces a use-dependent block of the NMDA receptor, with selectivity for the NR1-2B subtype. It also produces a barbiturate-like potentiation of GABAA receptor responses. Felbamate has a half-life of 20 hours (somewhat shorter when administered with either phenytoin or carbamazepine) and is metabolized by hydroxylation and conjugation; a significant percentage of the drug is excreted unchanged in the urine. When added to treatment with other antiseizure drugs, felbamate increases plasma phenytoin and valproic acid levels but decreases levels of carbamazepine.


In spite of the seriousness of the adverse effects, thousands of patients worldwide utilize this medication. Usual dosages are 2000–4000 mg/d in adults, and effective plasma levels range from 30 mcg/mL to 100 mcg/mL. In addition to its usefulness in partial seizures, felbamate has proved effective against the seizures that occur in Lennox-Gastaut syndrome.


Gabapentin is an amino acid, an analog of GABA, that is effective against partial seizures. Originally planned as a spasmolytic, it was found to be more effective as an antiseizure drug. Pregabalin is another GABA analog, closely related to gabapentin, and has been approved for both antiseizure activity and for its analgesic properties.


Mechanism of Action

In spite of their close structural resemblance to GABA, gabapentin and pregabalin do not act directly on GABA receptors. They may, however, modify the synaptic or nonsynaptic release of GABA. An increase in brain GABA concentration is observed in patients receiving gabapentin. Gabapentin is transported into the brain by the L-amino acid transporter. Gabapentin and pregabalin bind avidly to the α2δ subunit of voltage-gated N-type Ca2+ channels. This appears to underlie the main mechanism of action, which is decreasing Ca2+ entry, with a predominant effect on presynaptic channels. A decrease in the synaptic release of glutamate provides the antiepileptic effect.

Clinical Uses

Gabapentin is effective as an adjunct against partial seizures and generalized tonic-clonic seizures at dosages that range up to 2400 mg/d in controlled clinical trials. Open follow-up studies permitted dosages up to 4800 mg/d, but data are inconclusive on the effectiveness or tolerability of such doses. Monotherapy studies also document some efficacy. Some clinicians have found that very high dosages are needed to achieve improvement in seizure control. Effectiveness in other seizure types has not been well demonstrated. Gabapentin has also been promoted for the treatment of neuropathic pain and is now indicated for postherpetic neuralgia in adults at doses of 1800 mg and above. The most common adverse effects are somnolence, dizziness, ataxia, headache, and tremor.

Pregabalin is approved for the adjunctive treatment of partial seizures, with or without secondary generalization; controlled clinical trials have documented its effectiveness. It is available only in oral form, and the dosage ranges from 150 to 600 mg/d, usually in two or three divided doses. Pregabalin is also approved for use in neuropathic pain, including painful diabetic peripheral neuropathy and postherpetic neuralgia. It is the first drug in the USA approved for fibromyalgia. In Europe it is also approved for generalized anxiety disorder.


Gabapentin is not metabolized and does not induce hepatic enzymes. Absorption is nonlinear and dose-dependent at very high doses, but the elimination kinetics are linear. The drug is not bound to plasma proteins. Drug-drug interactions are negligible. Elimination is via renal mechanisms; the drug is excreted unchanged. The half-life is relatively short, ranging from 5 to 8 hours; the drug is typically administered two or three times per day.

Pregabalin, like gabapentin, is not metabolized and is almost entirely excreted unchanged in the urine. It is not bound to plasma proteins and has virtually no drug-drug interactions, again resembling the characteristics of gabapentin. Likewise, other drugs do not affect the pharmacokinetics of pregabalin. The half-life of pregabalin ranges from about 4.5 hours to 7.0 hours, thus requiring more than once-daily dosing in most patients.


Lacosamide is an amino acid-related compound that has been studied in both pain syndromes and partial seizures. The drug was approved in Europe and the USA in 2008 for the treatment of partial seizures.

Mechanism of Action

Activity resides in the R(−) enantiomer. It does not act directly on GABA or glutamate receptors. Lacosamide enhances slow inactivation of voltage-gated Na+ channels (in contrast to the prolongation of fast inactivation shown by other AEDs). Slow inactivation (with a half-time of around 100 msec) does not result in complete blockade of Na+ channels. Nevertheless, the antiseizure effects (and the CNS side effects) of lacosamide are additive to those of established AEDs acting by prolonging inactivation of the Na+ channel. Although lacosamide was previously thought to bind to the collapsin-response mediator protein, CRMP-2, thereby blocking the effect of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) on axonal and dendritic growth, recent evidence suggests that such binding does not occur.

Clinical Uses

Lacosamide is approved as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization in patients with epilepsy who are age 16–17 years and older. Clinical trials include three multicenter, randomized placebo-controlled studies with more than 1300 patients. Treatment was effective at both 200 and 400 mg/d. Adverse effects were dizziness, headache, nausea, and diplopia. In the open-label follow-up study, at dosages ranging from 100 to 800 mg/d, many patients continued lacosamide treatment for 24–30 months. The drug is typically administered twice daily, beginning with 50 mg doses and increasing by 100 mg increments weekly. An intravenous formulation provides short-term replacement for the oral drug. The oral solution is a source of phenylalanine.


Oral lacosamide is rapidly and completely absorbed in adults, with no food effect. Bioavailability is nearly 100%. The plasma concentrations are proportional to dosage up to 800 mg orally. Peak concentrations occur from 1 to 4 hours after oral dosing, with an elimination half-life of 13 hours. There are no active metabolites and protein binding is minimal. Lacosamide does not induce or inhibit cytochrome P450 isoenzymes, so drug interactions are negligible.


Lamotrigine was developed when some investigators thought that the antifolate effects of certain antiseizure drugs (eg, phenytoin) might contribute to their effectiveness. Several phenyltriazines were developed, and though their antifolate properties were weak, some were active in seizure screening tests.


Mechanism of Action

Lamotrigine, like phenytoin, suppresses sustained rapid firing of neurons and produces a voltage- and use-dependent blockade of Na+ channels. This action probably explains lamotrigine’s efficacy in focal epilepsy. It appears likely that lamotrigine also inhibits voltage-gated Ca2+ channels, particularly the N- and P/Q-type channels, which would account for its efficacy in primary generalized seizures in childhood, including absence attacks. Lamotrigine also decreases the synaptic release of glutamate.

Clinical Uses

Although most controlled studies have evaluated lamotrigine as add-on therapy, it is generally agreed that the drug is effective as monotherapy for partial seizures, and lamotrigine is now widely prescribed for this indication. The drug is also active against absence and myoclonic seizures in children and is approved for seizure control in the Lennox-Gastaut syndrome. Lamotrigine is also effective for bipolar disorder. Adverse effects include dizziness, headache, diplopia, nausea, somnolence, and skin rash. The rash is considered a typical hypersensitivity reaction. Although the risk of rash may be diminished by introducing the drug slowly, pediatric patients are at greatest risk, some studies suggest that a potentially life-threatening dermatitis will develop in 1–2% of pediatric patients.


Lamotrigine is almost completely absorbed and has a volume of distribution in the range of 1–1.4 L/kg. Protein binding is only about 55%. The drug has linear kinetics and is metabolized primarily by glucuronidation to the 2-N-glucuronide, which is excreted in the urine. Lamotrigine has a half-life of approximately 24 hours in normal volunteers; this decreases to 13–15 hours in patients taking enzyme-inducing drugs. Lamotrigine is effective against partial seizures in adults at dosages typically between 100 and 300 mg/d and with a therapeutic blood level near 3 mcg/mL. Valproate causes a twofold increase in the drug’s half-life; in patients receiving valproate, the initial dosage of lamotrigine must be reduced to 25 mg every other day.


Levetiracetam is a piracetam analog that is ineffective against seizures induced by maximum electroshock or pentylenetetrazol but has prominent activity in the kindling model. This is the first major drug with this unusual preclinical profile that is effective against partial seizures. Brivaracetam, an analog of levetiracetam, is in clinical trials.


Mechanism of Action

Levetiracetam binds selectively to the synaptic vesicular protein SV2A. The function of this protein is not understood but it is likely that levetiracetam modifies the synaptic release of glutamate and GABA through an action on vesicular function. In addition, levetiracetam inhibits N-type calcium channels and inhibits calcium release from intracellular stores.

Clinical Uses

Levetiracetam is marketed for the adjunctive treatment of partial seizures in adults and children for primary generalized tonic-clonic seizures and for the myoclonic seizures of juvenile myoclonic epilepsy. Adult dosing can begin with 500 or 1000 mg/d. The dosage can be increased every 2–4 weeks by 1000 mg to a maximum dosage of 3000 mg/d. The drug is dosed twice daily. Adverse effects include somnolence, asthenia, ataxia, and dizziness. Less common but more serious are mood and behavioral changes; psychotic reactions are rare. Drug interactions are minimal; levetiracetam is not metabolized by cytochrome P450. Oral formulations include extended-release tablets; an intravenous preparation is also available.


Oral absorption of levetiracetam is nearly complete; it is rapid and unaffected by food, with peak plasma concentrations in 1.3 hours. Kinetics are linear. Protein binding is less than 10%. The plasma half-life is 6–8 hours, but may be longer in the elderly. Two thirds of the drug is excreted unchanged in the urine; the drug has no known active metabolites.


Perampanel is an orally active AMPA antagonist approved for the treatment of partial seizures.

Mechanism of Action

Perampanel acts selectively at postsynaptic AMPA receptors (Figure 24–1). It binds to an allosteric site on the glutamate-gated Na+/K+ AMPA channel and is therefore noncompetitive in its action. Whereas blockade of the NMDA receptor shortens the duration of repetitive discharge in model neuronal systems, blockade of AMPA receptors appears to prevent such discharge.

Clinical Uses

Perampanel is approved for the adjunctive treatment of partial seizures with or without secondary generalization in patients 12 years of age or older. Three phase 3 studies, including 1480 patients, confirmed the effectiveness of the drug using once-daily administration. Effective doses ranged from 4 to 12 mg/d. Although the drug was generally well tolerated, a small number of patients experienced serious or life-threating behavioral adverse reactions including aggression, hostility, irritability, and anger, with or without a previous history of psychiatric disorders. More common adverse effects were dizziness, somnolence, and headache. Falls were more common at higher doses. Although a rash occurred in 1–2% of patients, all had benign outcomes when the drug was discontinued.


Perampanel has a long half-life, typically ranging from 70 to 110 hours, which permits once-daily dosing. Steady state is not achieved for 2–3 weeks, which has substantial implications for dosage changes. The kinetics are linear in the dose range of 2–12 mg/d. The half-life is prolonged in moderate hepatic failure. Absorption is rapid and the drug is fully bioavailable. Although food slows the rate of absorption, the extent (AUC) is not affected. Perampanel is 95% bound to plasma proteins. The drug is extensively metabolized via initial oxidation and subsequent glucuronidation. Although oxidative metabolism appears to be primarily mediated by CYP3A4 and CYP3A5, these may not be the only pathways involved.

Drug Interactions

The most significant drug interactions with perampanel are with potent CYP3A inducer antiseizure drugs such as carbamazepine, oxcarbazepine, and phenytoin. Interactions are also significant with alcohol and with oral contraceptives containing levonorgestrel. Potent CYP3A inducers may increase the clearance of perampanel by 50–70%, requiring careful consideration when using these drugs concomitantly. When perampanel was administered with carbamazepine, the half-life decreased from 105 hours to 25 hours. Of somewhat lesser concern is the potential for strong P450 inhibitors to increase the levels of perampanel.


Retigabine (ezogabine in the USA) is approved for the adjunctive treatment of partial-onset seizures in adults. It is a potassium-channel facilitator and unique in its mechanism of action. Absorption is not affected by food and kinetics are linear; drug interactions are minimal. Doses range from 600 to 1200 mg/d, with 900 mg/day expected to be the median. The current dosage form requires three-times-per-day administration, and the dose must be titrated in most patients. Most adverse effects are dose-related and include dizziness, somnolence, blurred vision, confusion, and dysarthria. Bladder dysfunction, mostly mild and related to the drug’s mechanism of action, was observed in 8-9% of patients in the clinical trials. In 2013, reports began to appear of blue pigmentation, primarily on the skin and lips; the problem is rather common, occurring in about one third of patients on long-term therapy. Retinal pigment abnormalities are less common but may occur independent of skin changes. Decreased visual acuity has been reported, but documentation is lacking. Nevertheless, any of the above symptoms are reasons to consider the discontinuation of retigabine. Regulatory agencies have recommended use of retigabine only in cases where other antiseizure drugs are not adequate or not tolerated. The FDA recently announced changes in the labeling of ezogabine to warn about the risks of retinal abnormalities, possible vision loss, and bluish skin discoloration, all of which could be permanent. More information is available at


Rufinamide is a triazole derivative with little similarity to other antiseizure drugs.


Mechanism of Action

Rufinamide is protective in the maximal electroshock and pentylenetetrazol tests in rats and mice. It decreases sustained high-frequency firing of neurons in vitro and is thought to prolong the inactive state of the Na+ channel. Significant interactions with GABA systems or metabotropic glutamate receptors have not been seen.

Clinical Uses

Rufinamide is approved in the USA for adjunctive treatment of seizures associated with the Lennox-Gastaut syndrome in patients age 4 years and older. The drug is effective against all seizure types in this syndrome, especially against tonic-atonic seizures. Recent data also suggest it may be effective against partial seizures. Treatment in children is typically started at 10 mg/kg/d in two equally divided doses and gradually increased to 45 mg/kg/d or 3200 mg/d, whichever is lower. Adults can begin with 400–800 mg/d in two equally divided doses up to a maximum of 3200 mg/d as tolerated. The drug should be given with food. The most common adverse events are somnolence, vomiting, pyrexia, and diarrhea.


Rufinamide is well absorbed, but plasma concentrations peak between 4 and 6 hours. The half-life is 6–10 hours, and minimal plasma protein binding is observed. Although cytochrome P450 enzymes are not involved, the drug is extensively metabolized to inactive products. Most of the drug is excreted in the urine; an acid metabolite accounts for about two thirds of the dose. In one study, rufinamide did not appear to significantly affect the plasma concentrations of other drugs used for the Lennox-Gastaut syndrome such as topiramate, lamotrigine, or valproic acid, but conflicting data suggest more robust interactions with other AEDs, including effects on rufinamide levels, especially in children.


Stiripentol, though not a new molecule, was approved in Europe in 2007 for a very specific type of epilepsy. The drug is used with clobazam and valproate in the adjunctive therapy of refractory generalized tonic-clonic seizures in patients with severe myoclonic epilepsy of infancy (SMEI, Dravet’s syndrome) whose seizures are not adequately controlled with clobazam and valproate. The drug is legally imported into the USA on a compassionate use basis. The mechanism of action of stiripentol is not well understood but it has been shown to enhance GABAergic transmission in the brain, partly through a barbiturate-like effect, ie, prolonged opening of the Cl channels in GABAAreceptors. It also increases GABA levels in the brain. It can increase the effect of other AEDs by slowing their inactivation by cytochrome P450.

Stiripentol is a potent inhibitor of CYP3A4, CYP1A2, and CYP2C19. Adverse effects of stiripentol itself are few, but the drug can dramatically increase the levels of valproate, clobazam, and the active metabolite of the latter, norclobazam. These drugs must be used cautiously together to avoid adverse effects. Dosing is complex, typically beginning with a reduction of the concomitant medication; stiripentol is then started at 10 mg/kg/d and is increased gradually to tolerability or to much higher doses. The kinetics of stiripentol are nonlinear.


Tiagabine is a derivative of nipecotic acid and was “rationally designed” as an inhibitor of GABA uptake (as opposed to discovery through random screening).


Mechanism of Action

Tiagabine is an inhibitor of GABA uptake in both neurons and glia. It preferentially inhibits the transporter isoform 1 (GAT-1) rather than GAT-2 or GAT-3 and increases extracellular GABA levels in the forebrain and hippocampus where GAT-1 is preferentially expressed. It prolongs the inhibitory action of synaptically released GABA, but its most significant effect may be potentiation of tonic inhibition. In rodents, it is potent against kindled seizures but weak against the maximal electroshock model, consistent with its predominant action in the forebrain and hippocampus.

Clinical Uses

Tiagabine is indicated for the adjunctive treatment of partial seizures and is effective in doses ranging from 16 to 56 mg/d. Divided doses as often as four times daily are sometimes required. Minor adverse events are dose related and include nervousness, dizziness, tremor, difficulty in concentrating, and depression. Excessive confusion, somnolence, or ataxia may require discontinuation. Psychosis occurs rarely. The drug can cause seizures in some patients, notably those taking the drug for other indications. Rash is an uncommon idiosyncratic adverse effect.


Tiagabine is 90–100% bioavailable, has linear kinetics, and is highly protein bound. The half-life is 5–8 hours and decreases in the presence of enzyme-inducing drugs. Food decreases the peak plasma concentration but not the area under the concentration curve (see Chapter 3). Hepatic impairment causes a slight decrease in clearance and may necessitate a lower dose. The drug is oxidized in the liver by CYP3A. Elimination is primarily in the feces (60–65%) and urine (25%).


Topiramate is a substituted monosaccharide that is structurally different from all other antiseizure drugs.


Mechanism of Action

Topiramate blocks repetitive firing of cultured spinal cord neurons, as do phenytoin and carbamazepine. Its mechanism of action, therefore, is likely to involve blocking of voltage-gated Na+ channels. It also acts on high-voltage activated (L-type) Ca2+ channels. Topiramate potentiates the inhibitory effect of GABA, acting at a site different from the benzodiazepine or barbiturate sites. Topiramate also depresses the excitatory action of kainate on glutamate receptors. The multiple effects of topiramate may arise through a primary action on kinases altering the phosphorylation of voltage-gated and ligand-gated ion channels.

Clinical Uses

Clinical trials of topiramate as monotherapy demonstrated efficacy against partial and generalized tonic-clonic seizures. The drug is also approved for the Lennox-Gastaut syndrome, and may be effective in infantile spasms and even absence seizures. Topiramate is also approved for the treatment of migraine headaches. The use of the drug in psychiatric disorders is controversial; convincing controlled data are lacking. Dosages typically range from 200 to 600 mg/d, with a few patients tolerating dosages higher than 1000 mg/d. Most clinicians begin at a low dose (50 mg/d) and increase slowly to prevent adverse effects. Several studies have used topiramate in monotherapy with encouraging results. Although no idiosyncratic reactions have been noted, dose-related adverse effects occur most frequently in the first 4 weeks and include somnolence, fatigue, dizziness, cognitive slowing, paresthesias, nervousness, and confusion. Acute myopia and glaucoma may require prompt drug withdrawal. Urolithiasis has also been reported. The drug is teratogenic in animal models, and hypospadias has been reported in male infants exposed in utero to topiramate; no causal relationship, however, could be established.


Topiramate is rapidly absorbed (about 2 hours) and is 80% bioavailable. There is no food effect on absorption, minimal (15%) plasma protein binding, and only moderate (20–50%) metabolism; no active metabolites are formed. The drug is primarily excreted unchanged in the urine. The half-life is 20–30 hours. An extended-release formulation is available, which is promoted for once-daily administration. Although increased levels are seen with renal failure and hepatic impairment, there is no age or gender effect, no autoinduction, no inhibition of metabolism, and kinetics are linear. Drug interactions do occur and can be complex, but the major effect is on topiramate levels rather than on the levels of other antiseizure drugs. Birth control pills may be less effective in the presence of topiramate, and higher estrogen doses may be required.


Current investigations that seek drugs to enhance the effects of GABA include efforts to find GABA agonists and prodrugs, GABA transaminase inhibitors, and GABA uptake inhibitors. Vigabatrin is one such drug.


Mechanism of Action

Vigabatrin is an irreversible inhibitor of GABA aminotransferase (GABA-T), the enzyme responsible for the degradation of GABA. It may also inhibit the vesicular GABA transporter. Vigabatrin produces a sustained increase in the extracellular concentration of GABA in the brain. This leads to some desensitization of synaptic GABAA receptors but prolonged activation of nonsynaptic GABAA receptors that provide tonic inhibition. A decrease in brain glutamine synthetase activity is probably secondary to the increased GABA concentrations. It is effective in a wide range of seizure models. Vigabatrin is marketed as a racemate; the S(+) enantiomer is active and the R(−) enantiomer appears to be inactive.

Clinical Uses

Vigabatrin is useful in the treatment of partial seizures and infantile spasms. The half-life is approximately 6–8 hours, but considerable evidence suggests that the pharmacodynamic activity of the drug is more prolonged and not well correlated with the plasma half-life. In infants, the dosage is 50–150 mg/d. In adults, vigabatrin should be started at an oral dosage of 500 mg twice daily; a total of 2–3 g (rarely more) daily may be required for full effectiveness.

Typical toxicities include drowsiness, dizziness, and weight gain. Less common but more troublesome adverse reactions are agitation, confusion, and psychosis; preexisting mental illness is a relative contraindication. The drug was delayed in its worldwide introduction by the appearance in rats and dogs of a reversible intramyelinic edema. This phenomenon has now been detected in infants taking the drug; the clinical significance is unknown. In addition, long-term therapy with vigabatrin has been associated with development of peripheral visual field defects in 30–50% of patients. The lesions are located in the retina, increase with drug exposure, and are usually not reversible. Newer techniques such as optical coherence tomography may better define the defect, which has proved difficult to quantify. Vigabatrin is usually reserved for use in patients with infantile spasms or with complex partial seizures refractory to other treatments.


Zonisamide is a sulfonamide derivative. Its primary site of action appears to be the Na+ channel; it also acts on T-type voltage-gated Ca2+ channels. The drug is effective against partial and generalized tonic-clonic seizures and may also be useful against infantile spasms and certain myoclonias. It has good bioavailability, linear kinetics, low protein-binding, renal excretion, and a half-life of 1–3 days. Dosages range from 100 to 600 mg/d in adults and from 4 to 12 mg/d in children. Adverse effects include drowsiness, cognitive impairment, and potentially serious skin rashes. Zonisamide does not interact with other antiseizure drugs.



Ethosuximide was introduced in 1960 as the third of three marketed succinimides in the USA. Ethosuximide has very little activity against maximal electroshock but considerable efficacy against pentylenetetrazol seizures; it was introduced as a “pure petit mal” drug.


Ethosuximide is the last antiseizure drug to be marketed whose origin is in the cyclic ureide structure. The three antiseizure succinimides marketed in the USA are ethosuximide, phensuximide, and methsuximide. Methsuximide and phensuximide have phenyl substituents, whereas ethosuximide is 2-ethyl-2-methylsuccinimide.


Mechanism of Action

Ethosuximide has an important effect on Ca2+ currents, reducing the low-threshold (T-type) current. This effect is seen at therapeutically relevant concentrations in thalamic neurons. The T-type Ca2+ currents are thought to provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack. Inhibition of this current could therefore account for the specific therapeutic action of ethosuximide. A recently described effect on inwardly rectifying K+ channels may also be significant.

Clinical Uses

As predicted from its activity in laboratory models, ethosuximide is particularly effective against absence seizures, but has a very narrow spectrum of clinical activity. Documentation of its effectiveness in human absence seizures was achieved with long-term electroencephalographic recording techniques. Data continue to show that ethosuximide and valproate are the drugs of choice for absence seizures and are more effective than lamotrigine.


Absorption is complete following administration of the oral dosage forms. Peak levels are observed 3–7 hours after oral administration of the capsules. Ethosuximide is not protein-bound. The drug is completely metabolized, principally by hydroxylation, to inactive metabolites. Ethosuximide has a very low total body clearance (0.25 L/kg/d). This corresponds to a half-life of approximately 40 hours, although values from 18 to 72 hours have been reported.

Therapeutic Levels & Dosage

Therapeutic levels of 60–100 mcg/mL can be achieved in adults with dosages of 750–1500 mg/d, although lower or higher dosages and blood levels (up to 125 mcg/mL) may be necessary and tolerated in some patients. Ethosuximide has a linear relationship between dose and steady-state plasma levels. The drug might be administered as a single daily dose were it not for its adverse gastrointestinal effects; twice-a-day dosage is common.

Drug Interactions & Toxicity

Administration of ethosuximide with valproic acid results in a decrease in ethosuximide clearance and higher steady-state concentrations owing to inhibition of metabolism. No other important drug interactions have been reported for the succinimides. The most common dose-related adverse effect of ethosuximide is gastric distress, including pain, nausea, and vomiting. When an adverse effect does occur, temporary dosage reductions may allow adaptation. Other dose-related adverse effects are transient lethargy or fatigue and, much less commonly, headache, dizziness, hiccup, and euphoria. Behavioral changes are usually in the direction of improvement. Non-dose-related or idiosyncratic adverse effects of ethosuximide are extremely uncommon.


Phensuximide (no longer readily available) and methsuximide are phenylsuccinimides that were developed and marketed before ethosuximide. They are used primarily as anti-absence drugs. Methsuximide is generally considered more toxic, and phensuximide less effective, than ethosuximide. Unlike ethosuximide, these two compounds have some activity against maximal electroshock seizures, and methsuximide has been used for partial seizures by some investigators.


Sodium valproate, also used as the free acid, valproic acid, was found to have antiseizure properties when used as a solvent in the search for other drugs effective against seizures. It was marketed in France in 1969 but was not licensed in the USA until 1978. Valproic acid is fully ionized at body pH, and for that reason the active form of the drug may be assumed to be the valproate ion regardless of whether valproic acid or a salt of the acid is administered.


Valproic acid is one of a series of fatty carboxylic acids that have antiseizure activity; this activity appears to be greatest for carbon chain lengths of five to eight atoms. The amides and esters of valproic acid are also active antiseizure agents.


Mechanism of Action

The time course of valproate’s anticonvulsant activity appears to be poorly correlated with blood or tissue levels of the parent drug, an observation giving rise to considerable speculation regarding both the active species and the mechanism of action of valproic acid. Valproate is active against both pentylenetetrazol and maximal electroshock seizures. Like phenytoin and carbamazepine, valproate blocks sustained high-frequency repetitive firing of neurons in culture at therapeutically relevant concentrations. Its action against partial seizures may be a consequence of this effect on Na+ currents. Blockade of NMDA receptor-mediated excitation may also be important. Much attention has been paid to the effects of valproate on GABA. Several studies have shown increased levels of GABA in the brain after administration of valproate, although the mechanism for this increase remains unclear. An effect of valproate to facilitate glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, has been described. An inhibitory effect on the GABA transporter GAT-1 may contribute. At very high concentrations, valproate inhibits GABA transaminase in the brain, thus blocking degradation of GABA. However, at the relatively low doses of valproate needed to abolish pentylenetetrazol seizures, brain GABA levels may remain unchanged. Valproate produces a reduction in the aspartate content of rodent brain, but the relevance of this effect to its anticonvulsant action is not known.

Valproic acid is a potent inhibitor of histone deacetylase and through this mechanism changes the transcription of many genes. A similar effect, but to a lesser degree, is shown by some other antiseizure drugs (topiramate, carbamazepine, and a metabolite of levetiracetam).

Clinical Uses

Valproate is very effective against absence seizures and is often preferred to ethosuximide when the patient has concomitant generalized tonic-clonic attacks. Valproate is unique in its ability to control certain types of myoclonic seizures; in some cases the effect is very dramatic. The drug is effective in tonic-clonic seizures, especially those that are primarily generalized. A few patients with atonic attacks may also respond, and some evidence suggests that the drug is effective in partial seizures. Its use in epilepsy is at least as broad as that of any other drug. Intravenous formulations are occasionally used to treat status epilepticus.

Other uses of valproate include management of bipolar disorder and migraine prophylaxis.


Valproate is well absorbed after an oral dose, with bioavailability greater than 80%. Peak blood levels are observed within 2 hours. Food may delay absorption, and decreased toxicity may result if the drug is given after meals.

Valproic acid is 90% bound to plasma proteins, although the fraction bound is somewhat reduced at blood levels greater than 150 mcg/mL. Since valproate is both highly ionized and highly protein-bound, its distribution is essentially confined to extracellular water, with a volume of distribution of approximately 0.15 L/kg. At higher doses, there is an increased free fraction of valproate, resulting in lower total drug levels than expected. It may be clinically useful, therefore, to measure both total and free drug levels. Clearance for valproate is low and dose dependent; its half-life varies from 9 to 18 hours. Approximately 20% of the drug is excreted as a direct conjugate of valproate.

The sodium salt of valproate is marketed in Europe as a tablet and is quite hygroscopic. In Central and South America, the magnesium salt is available, which is considerably less hygroscopic. The free acid of valproate was first marketed in the USA in a capsule containing corn oil; the sodium salt is also available in syrup, primarily for pediatric use. An enteric-coated tablet of divalproex sodium is also marketed in the USA. This improved product, a 1:1 coordination compound of valproic acid and sodium valproate, is as bioavailable as the capsule but is absorbed much more slowly and is preferred by many patients. Peak concentrations following administration of the enteric-coated tablets are seen in 3–4 hours. Various extended-release preparations are available; not all are bioequivalent and may require dosage adjustment.

Therapeutic Levels & Dosage

Dosages of 25–30 mg/kg/d may be adequate in some patients, but others may require 60 mg/kg/d or even more. Therapeutic levels of valproate range from 50 to 100 mcg/mL.

Drug Interactions

Valproate displaces phenytoin from plasma proteins. In addition to binding interactions, valproate inhibits the metabolism of several drugs, including phenobarbital, phenytoin, and carbamazepine, leading to higher steady-state concentrations of these agents. The inhibition of phenobarbital metabolism, for example, may cause levels of the barbiturate to rise steeply, causing stupor or coma. Valproate can dramatically decrease the clearance of lamotrigine.


The most common dose-related adverse effects of valproate are nausea, vomiting, and other gastrointestinal complaints such as abdominal pain and heartburn. The drug should be started gradually to avoid these symptoms. Sedation is uncommon with valproate alone but may be striking when valproate is added to phenobarbital. A fine tremor is frequently seen at higher levels. Other reversible adverse effects, seen in a small number of patients, include weight gain, increased appetite, and hair loss.

The idiosyncratic toxicity of valproate is largely limited to hepatotoxicity, but this may be severe; there seems little doubt that the hepatotoxicity of valproate has been responsible for more than 50 fatalities in the USA alone. The risk is greatest for patients under 2 years of age and for those taking multiple medications. Initial aspartate aminotransferase values may not be elevated in susceptible patients, although these levels do eventually become abnormal. Most fatalities have occurred within 4 months after initiation of therapy. Some clinicians recommend treatment with oral or intravenous L-carnitine as soon as severe hepatotoxicity is suspected. Careful monitoring of liver function is recommended when starting the drug; the hepatotoxicity is reversible in some cases if the drug is withdrawn. The other observed idiosyncratic response with valproate is thrombocytopenia, although documented cases of abnormal bleeding are lacking. It should be noted that valproate is an effective and popular antiseizure drug and that only a very small number of patients have had severe toxic effects from its use.

Several epidemiologic studies of valproate have confirmed a substantial increase in the incidence of spina bifida in the offspring of women who took valproate during pregnancy. In addition, an increased incidence of cardiovascular, orofacial, and digital abnormalities has been reported. These observations must be strongly considered in the choice of drugs during pregnancy.


Trimethadione, the first oxazolidinedione (Figure 24–3), was introduced as an antiseizure drug in 1945 and remained the drug of choice for absence seizures until the introduction of succinimides in the 1950s. Use of the oxazolidinediones—trimethadione, paramethadione, and dimethadione—is now very limited; the latter two are not readily available.

These compounds are active against pentylenetetrazol-induced seizures. Trimethadione raises the threshold for seizure discharges after repetitive thalamic stimulation. It—or, more notably, its active metabolite dimethadione—has the same effect on thalamic Ca2+ currents as ethosuximide (reducing the T-type Ca2+ current). Thus, suppression of absence seizures is likely to depend on inhibiting the pacemaker action of thalamic neurons.

Trimethadione is rapidly absorbed, with peak levels reached within 1 hour after drug administration. It is not bound to plasma proteins. Trimethadione is completely metabolized in the liver by demethylation to dimethadione, which may exert the major antiseizure activity. Dimethadione has an extremely long half-life (240 hours). The therapeutic plasma level range for trimethadione has never been established, although trimethadione blood levels higher than 20 mcg/mL and dimethadione levels higher than 700 mcg/mL have been suggested. A dosage of 30 mg/kg/d of trimethadione is necessary to achieve these levels in adults.

The most common and bothersome dose-related adverse effect of the oxazolidinediones is sedation. Trimethadione has been associated with many other toxic adverse effects, some of which are severe. These drugs should not be used during pregnancy.


Some drugs not classifiable by application to seizure type are discussed in this section.


Six benzodiazepines play prominent roles in the therapy of epilepsy (see also Chapter 22). Although many benzodiazepines are similar chemically, subtle structural alterations result in differences in activity and pharmacokinetics. They have two mechanisms of antiseizure action, which are shown to different degrees by the six compounds. This is evident from the fact that diazepam is relatively more potent against electroshock and clonazepam against pentylenetetrazol (the latter effect correlating with an action at the GABA-benzodiazepine allosteric receptor sites). Possible mechanisms of action are discussed in Chapter 22.

Diazepam given intravenously or rectally is highly effective for stopping continuous seizure activity, especially generalized tonic-clonic status epilepticus (see below). The drug is occasionally given orally on a long-term basis, although it is not considered very effective in this application, probably because of the rapid development of tolerance. A rectal gel is available for refractory patients who need acute control of bouts of seizure activity. Lorazepamappears in some studies to be more effective and longer acting than diazepam in the treatment of status epilepticus and is preferred by some experts.

Clonazepam is a long-acting drug with documented efficacy against absence seizures; on a milligram basis, it is one of the most potent antiseizure agents known. It is also effective in some cases of myoclonic seizures and has been tried in infantile spasms. Sedation is prominent, especially on initiation of therapy; starting doses should be small. Maximal tolerated doses are usually in the range of 0.1–0.2 mg/kg, but many weeks of gradually increasing daily doses may be needed to achieve these dosages in some patients. Nitrazepam is not marketed in the USA but is used in many other countries, especially for infantile spasms and myoclonic seizures. It is less potent than clonazepam, and superiority to that drug has not been documented.

Clorazepate dipotassium is approved in the USA as an adjunct to treatment of complex partial seizures in adults. Drowsiness and lethargy are common adverse effects, but as long as the drug is increased gradually, dosages as high as 45 mg/d can be given.

Clobazam is widely used in a variety of seizure types. It is a 1,5-benzodiazepine (other marketed benzodiazepines are 1,4-benzodiazepines) and reportedly has less sedative potential. Whether the drug has significant clinical advantages is not clear. It has a half-life of 18 hours and is effective at dosages of 0.5–1 mg/kg/d. It does interact with some other antiseizure drugs and causes adverse effects typical of the benzodiazepines; efficacy, in some patients, is limited by the development of tolerance. It has an active metabolite, norclobazam. The drug is approved in the USA for treatment of Lennox-Gastaut syndrome.


See Chapter 22.


Two prominent aspects of benzodiazepines limit their usefulness. The first is their pronounced sedative effect, which is unfortunate both in the treatment of status epilepticus and in chronic therapy. Children may manifest a paradoxical hyperactivity, as with barbiturates. The second problem is tolerance, in which seizures may respond initially but recur within a few months. The remarkable antiseizure potency of these compounds often cannot be realized because of these limiting factors.


Acetazolamide is a diuretic whose main action is the inhibition of carbonic anhydrase (see Chapter 15). Mild acidosis in the brain may be the mechanism by which the drug exerts its antiseizure activity; alternatively, the depolarizing action of bicarbonate ions moving out of neurons via GABA receptor ion channels may be diminished by carbonic anhydrase inhibition. Acetazolamide has been used for all types of seizures but is severely limited by the rapid development of tolerance, with return of seizures usually within a few weeks. The drug may have a special role in epileptic women who experience seizure exacerbations at the time of menses; seizure control may be improved and tolerance may not develop because the drug is not administered continuously. The usual dosage is approximately 10 mg/kg/d to a maximum of 1000 mg/d.

Another carbonic anhydrase inhibitor, sulthiame, was not found to be effective as an anticonvulsant in clinical trials in the USA. It is marketed in a number of other countries.



In general, the type of medication used for epilepsy depends on the empiric nature of the seizure. For this reason, considerable effort has been expended to classify seizures so that clinicians will be able to make a “seizure diagnosis” and on that basis prescribe appropriate therapy. Errors in seizure diagnosis cause use of the wrong drugs, and an unpleasant cycle ensues in which poor seizure control is followed by increasing drug doses and medication toxicity. As noted, seizures are divided into two groups: partial and generalized. Drugs used for partial seizures are more or less the same for all subtypes of partial seizures, but drugs used for generalized seizures are determined by the individual seizure subtype. A summary of the most widely used international classification of epileptic seizures is presented in Table 24–1.

Partial (Focal) Seizures

Partial seizures are those in which a localized onset of the attack can be ascertained, either by clinical observation or by electroencephalographic recording; the attack begins in a specific locus in the brain. There are three types of partial seizures, determined to some extent by the degree of brain involvement by the abnormal discharge.

The least complicated partial seizure is the simple partial seizure, characterized by minimal spread of the abnormal discharge such that normal consciousness and awareness are preserved. For example, the patient may have a sudden onset of clonic jerking of an extremity lasting 60–90 seconds; residual weakness may last for 15–30 minutes after the attack. The patient is completely aware of the attack and can describe it in detail. The electroencephalogram may show an abnormal discharge highly localized to the involved portion of the brain.

The complex partial seizure also has a localized onset, but the discharge becomes more widespread (usually bilateral) and almost always involves the limbic system. Most complex partial seizures arise from one of the temporal lobes, possibly because of the susceptibility of this area of the brain to insults such as hypoxia or infection. Clinically, the patient may have a brief warning followed by an alteration of consciousness during which some patients stare and others stagger or even fall. Most, however, demonstrate fragments of integrated motor behavior called automatisms for which the patient has no memory. Typical automatisms are lip smacking, swallowing, fumbling, scratching, and even walking about. After 30–120 seconds, the patient makes a gradual recovery to normal consciousness but may feel tired or ill for several hours after the attack.

The last type of partial seizure is the secondarily generalized attack, in which a partial seizure immediately precedes a generalized tonic-clonic (grand mal) seizure. This seizure type is described in the text that follows.

Generalized Seizures

Generalized seizures are those in which there is no evidence of localized onset. The group is quite heterogeneous.

Generalized tonic-clonic (grand mal) seizures are the most dramatic of all epileptic seizures and are characterized by tonic rigidity of all extremities, followed in 15–30 seconds by a tremor that is actually an interruption of the tonus by relaxation. As the relaxation phases become longer, the attack enters the clonic phase, with massive jerking of the body. The clonic jerking slows over 60–120 seconds, and the patient is usually left in a stuporous state. The tongue or cheek may be bitten, and urinary incontinence is common. Primary generalized tonic-clonic seizures begin without evidence of localized onset, whereas secondary generalized tonic-clonic seizures are preceded by another seizure type, usually a partial seizure. The medical treatment of both primary and secondary generalized tonic-clonic seizures is the same and uses drugs appropriate for partial seizures.

The absence (petit mal) seizure is characterized by both sudden onset and abrupt cessation. Its duration is usually less than 10 seconds and rarely more than 45 seconds. Consciousness is altered; the attack may also be associated with mild clonic jerking of the eyelids or extremities, with postural tone changes, autonomic phenomena, and automatisms. The occurrence of automatisms can complicate the clinical differentiation from complex partial seizures in some patients. Absence attacks begin in childhood or adolescence and may occur up to hundreds of times a day. The electroencephalogram during the seizure shows a highly characteristic 2.5–3.5 Hz spike-and-wave pattern. Atypical absence patients have seizures with postural changes that are more abrupt, and such patients are often mentally retarded; the electroencephalogram may show a slower spike-and-wave discharge, and the seizures may be more refractory to therapy.

Myoclonic jerking is seen, to a greater or lesser extent, in a wide variety of seizures, including generalized tonic-clonic seizures, partial seizures, absence seizures, and infantile spasms. Treatment of seizures that include myoclonic jerking should be directed at the primary seizure type rather than at the myoclonus. Some patients, however, have myoclonic jerking as the major seizure type, and some have frequent myoclonic jerking and occasional generalized tonic-clonic seizures without overt signs of neurologic deficit. Many kinds of myoclonus exist, and much effort has gone into attempts to classify this entity.

Atonic seizures are those in which the patient has sudden loss of postural tone. If standing, the patient falls suddenly to the floor and may be injured. If seated, the head and torso may suddenly drop forward. Although most often seen in children, this seizure type is not unusual in adults. Many patients with atonic seizures wear helmets to prevent head injury. Momentary increased tone may be observed in some patients, hence the use of the term “tonic-atonic seizure.”

Infantile spasms are an epileptic syndrome and not a seizure type. The attacks, though sometimes fragmentary, are most often bilateral and are included for pragmatic purposes with the generalized seizures. These attacks are most often characterized clinically by brief, recurrent myoclonic jerks of the body with sudden flexion or extension of the body and limbs; the forms of infantile spasms are, however, quite heterogeneous. Ninety percent of affected patients have their first attack before the age of 1 year. Most patients are intellectually delayed, presumably from the same cause as the spasms. The cause is unknown in many patients, but such widely disparate disorders as infection, kernicterus, tuberous sclerosis, and hypoglycemia have been implicated. In some cases, the electroencephalogram is characteristic. Drugs used to treat infantile spasms are effective only in some patients; there is little evidence that the cognitive retardation is alleviated by therapy, even when the attacks disappear.


In designing a therapeutic strategy, the use of a single drug is preferred, especially in patients who are not severely affected and who can benefit from the advantage of fewer adverse effects using monotherapy. For patients with hard-to-control seizures, multiple drugs are usually utilized simultaneously.

For most of the older antiseizure drugs, relationships between blood levels and therapeutic effects have been characterized to a high degree. The same is true for the pharmacokinetics of these drugs. These relationships provide significant advantages in the development of therapeutic strategies for the treatment of epilepsy. The therapeutic index for most antiseizure drugs is low, and toxicity is not uncommon. Thus, effective treatment of seizures often requires an awareness of the therapeutic levels and pharmacokinetic properties as well as the characteristic toxicities of each agent. Measurements of antiseizure drug plasma levels can be very useful when combined with clinical observations and pharmacokinetic data (Table 24–2). The relationship between seizure control and plasma drug levels is variable and often less clear for the drugs marketed since 1990.

TABLE 24–2 Serum concentrations reference ranges for some antiseizure drugs.




For many years, the choice of drugs for partial and tonic-clonic seizures was usually limited to phenytoin, carbamazepine, or barbiturates. There was a strong tendency to limit the use of sedative antiseizure drugs such as barbiturates and benzodiazepines to patients who could not tolerate other medications; this trend led, in the 1980s, to increased use of carbamazepine. Although carbamazepine and phenytoin remain widely used, most newer drugs (marketed after 1990) are effective against these same seizure types. With the older drugs, efficacy and long-term adverse effects are well established; this creates a confidence level in spite of questionable tolerability. Most newer drugs have a broader spectrum of activity, and many are well tolerated; therefore, the newer drugs are often preferred to the older ones. Although some data suggest that most of these newer drugs confer an increased risk of nontraumatic fractures, choosing a drug on this basis is not yet practical.


The issues (described above) related to choosing between old and new drugs apply to the generalized group of seizures as well.

The drugs used for generalized tonic-clonic seizures are the same as for partial seizures; in addition, valproate is clearly useful.

At least three drugs are effective against absence seizures. Two are nonsedating and therefore preferred: ethosuximide and valproate. Clonazepam is also highly effective but has disadvantages of dose-related adverse effects and development of tolerance. Lamotrigine and topiramate may also be useful.

Specific myoclonic syndromes are usually treated with valproate; an intravenous formulation can be used acutely if needed. It is nonsedating and can be dramatically effective. Other patients respond to clonazepam, nitrazepam, or other benzodiazepines, although high doses may be necessary, with accompanying drowsiness. Zonisamide and levetiracetam may be useful. Another specific myoclonic syndrome, juvenile myoclonic epilepsy, can be aggravated by phenytoin or carbamazepine; valproate is the drug of choice followed by lamotrigine and topiramate.

Atonic seizures are often refractory to all available medications, although some reports suggest that valproate may be beneficial, as may lamotrigine. Benzodiazepines have been reported to improve seizure control in some of these patients but may worsen the attacks in others. Felbamate has been demonstrated to be effective in some patients, although the drug’s idiosyncratic toxicity limits its use. If the loss of tone appears to be part of another seizure type (eg, absence or complex partial seizures), every effort should be made to treat the other seizure type vigorously, hoping for simultaneous alleviation of the atonic component of the seizure. The ketogenic (high fat) diet may also be useful.


The treatment of infantile spasms is unfortunately limited to improvement of control of the seizures rather than other features of the disorder, such as retardation. Most patients receive a course of intramuscular corticotropin, although some clinicians note that prednisone may be equally effective and can be given orally. Clinical trials have been unable to settle the matter. In either case, therapy must often be discontinued because of adverse effects. If seizures recur, repeat courses of corticotropin or corticosteroids can be given, or other drugs may be tried. A repository corticotropin for injection is now approved in the USA for the treatment of infantile spasms, either of cryptogenic or symptomatic etiology. Other drugs widely used are the benzodiazepines such as clonazepam or nitrazepam; their efficacy in this heterogeneous syndrome may be nearly as good as that of corticosteroids. Vigabatrin is effective and is considered the drug of choice by many pediatric neurologists. The mechanism of action of corticosteroids or corticotropin in the treatment of infantile spasms is unknown but may involve reduction in inflammatory processes.


There are many forms of status epilepticus. The most common, generalized tonic-clonic status epilepticus, is a life-threatening emergency, requiring immediate cardiovascular, respiratory, and metabolic management as well as pharmacologic therapy. The latter virtually always requires intravenous administration of antiseizure medications. Diazepam is the most effective drug in most patients for stopping the attacks and is given directly by intravenous push to a maximum total dose of 20–30 mg in adults. Intravenous diazepam may depress respiration (less frequently, cardiovascular function), and facilities for resuscitation must be immediately at hand during its administration. The effect of diazepam is not lasting, but the 30- to 40-minute seizure-free interval allows more definitive therapy to be initiated. Some physicians prefer lorazepam, which is equivalent to diazepam in effect and perhaps somewhat longer acting. For patients who are not actually in the throes of a seizure, diazepam therapy can be omitted and the patient treated at once with a long-acting drug such as phenytoin.

Until the introduction of fosphenytoin, the mainstay of continuing therapy for status epilepticus was intravenous phenytoin, which is effective and nonsedating. It can be given as a loading dose of 13–18 mg/kg in adults; the usual error is to give too little. Administration should be at a maximum rate of 50 mg/min. It is safest to give the drug directly by intravenous push, but it can also be diluted in saline; it precipitates rapidly in the presence of glucose. Careful monitoring of cardiac rhythm and blood pressure is necessary, especially in elderly people. At least part of the cardiotoxicity is from the propylene glycol in which the phenytoin is dissolved. Fosphenytoin, which is freely soluble in intravenous solutions without the need for propylene glycol or other solubilizing agents, is a safer parenteral agent. Because of its greater molecular weight, this prodrug is two thirds to three quarters as potent as phenytoin on a milligram basis.

In previously treated epileptic patients, the administration of a large loading dose of phenytoin may cause some dose-related toxicity such as ataxia. This is usually a relatively minor problem during the acute status episode and is easily alleviated by later adjustment of plasma levels.

For patients who do not respond to phenytoin, phenobarbital can be given in large doses: 100–200 mg intravenously to a total of 400–800 mg. Respiratory depression is a common complication, especially if benzodiazepines have already been given, and there should be no hesitation in instituting intubation and ventilation.

Although other drugs such as lidocaine have been recommended for the treatment of generalized tonic-clonic status epilepticus, general anesthesia is usually necessary in highly resistant cases.

For patients in absence status, benzodiazepines are still drugs of first choice. Rarely, intravenous valproate may be required.



The potential teratogenicity of antiseizure drugs is controversial and important. It is important because teratogenicity resulting from long-term drug treatment of millions of people throughout the world may have a profound effect even if the effect occurs in only a small percentage of cases. It is controversial because both epilepsy and antiseizure drugs are heterogeneous, and few epileptic patients who are not receiving these drugs are available for study. Furthermore, patients with severe epilepsy, in whom genetic factors rather than drug factors may be of greater importance in the occurrence of fetal malformations, are often receiving multiple antiseizure drugs in high doses.

In spite of these limitations, it appears—from whatever cause—that children born to mothers taking antiseizure drugs have an increased risk, perhaps twofold, of congenital malformations. Phenytoin has been implicated in a specific syndrome called fetal hydantoin syndrome, although not all investigators are convinced of its existence and a similar syndrome has been attributed both to phenobarbital and to carbamazepine. Valproate, as noted above, has also been implicated in a specific malformation, spina bifida. It is estimated that a pregnant woman taking valproic acid or sodium valproate has a 1–2% risk of having a child with spina bifida. Topiramate has shown some teratogenicity in animal testing and, as noted earlier, in the human male fetus.

In dealing with the clinical problem of a pregnant woman with epilepsy, most epileptologists agree that although it is important to minimize exposure to antiseizure drugs, both in numbers and dosages, it is also important not to allow maternal seizures to go unchecked.


Withdrawal of antiseizure drugs, whether by accident or by design, can cause increased seizure frequency and severity. The two factors to consider are the effects of the withdrawal itself and the need for continued drug suppression of seizures in the individual patient. In many patients, both factors must be considered. It is important to note, however, that the abrupt discontinuance of antiseizure drugs ordinarily does not cause seizures in nonepileptic patients, provided that the drug levels are not above the usual therapeutic range when the drug is stopped.

Some drugs are more easily withdrawn than others. In general, withdrawal of anti-absence drugs is easier than withdrawal of drugs needed for partial or generalized tonic-clonic seizures. Barbiturates and benzodiazepines are the most difficult to discontinue; weeks or months may be required, with very gradual dosage decrements, to accomplish their complete outpatient removal.

Because of the heterogeneity of epilepsy, complete discontinuance of antiseizure drug administration is an especially difficult problem. If a patient is seizure-free for 3 or 4 years, a trial of gradual discontinuance is often warranted.


Antiseizure drugs are central nervous system depressants but are rarely lethal. Very high blood levels are usually necessary before overdoses can be considered life-threatening. The most dangerous effect of antiseizure drugs after large overdoses is respiratory depression, which may be potentiated by other agents, such as alcohol. Treatment of antiseizure drug overdose is supportive; stimulants should not be used. Efforts to hasten removal of antiseizure drugs, such as alkalinization of the urine (phenytoin is a weak acid), are usually ineffective.


An FDA analysis of suicidal behavior during clinical trials of antiseizure drugs was carried out in 2008. The presence of either suicidal behavior or suicidal ideation was 0.37% in patients taking active drugs and 0.24% in patients taking placebo. This, according to one analyst, represents an additional 2 of 1000 patients with such thoughts or behaviors. It is noteworthy that, although the entire class may receive some changes in labeling, the odds ratios for carbamazepine and for valproate were less than 1, and no data were available for phenytoin. Whether this effect is real or inextricably associated with this serious, debilitating disorder—with its inherently high rate of suicidality—is unclear.


Three potential new antiseizure drugs are in phase 2 or phase 3 development; these are brivaracitam, YKP3089, and ganaxolone. Other drugs are less advanced but can be found on the epilepsy website at

SUMMARY Antiseizure Drugs







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Lamotrigine was gradually added to the regimen to a dosage of 200 mg bid. Since then, the patient has been seizure-free for almost 2 years but now comes to the office for a medication review. Gradual discontinuation of levetiracetam is planned if the patient continues to do well for another year, although risk of recurrent seizures is always present when medications are withdrawn.