eMedicine Specialties > Neurology > Seizures and Epilepsy

Antiepileptic Drugs

Juan G Ochoa, MD, Associate Professor of Neurology, Director, EEG Lab/Epilepsy Monitoring Unit, Department of Neurology, Neuroscience Institute, University of Florida at Jacksonville
Willise Riche, MD, Epilepsy Program Coordinator, Department of Neurology, Shands Hospital; Educator, Department of Neurology, University of Phoenix at Jacksonville

Updated: Apr 17, 2009

Introduction

Modern treatment of seizures started in 1850 with the introduction of bromides, based on the theory that epilepsy was caused by an excessive sex drive. In 1910, phenobarbital, which then was used to induce sleep, was found to have antiseizure activity and became the drug of choice for many years. A number of medications similar to phenobarbital were developed, including primidone. Houston Merrit and Tracy Putnam introduced animal models for screening multiple compounds for antiepileptic activity, published in Journal of the American Medical Association in 1938. In 1940, phenytoin (PHT) was found to be an effective drug for the treatment of epilepsy, and since then it has become a major first-line antiepileptic drug (AED) in the treatment of partial and secondarily generalized seizures.

In 1968, carbamazepine (CBZ) was approved, initially for the treatment of trigeminal neuralgia; later, in 1974, it was approved for partial seizures. Ethosuximide has been used since 1958 as a first-choice drug for the treatment of absence seizures without generalized tonic-clonic seizures. Valproate was licensed in Europe in 1960 and in the United States in 1978, and now is widely available throughout the world. It became the drug of choice in primary generalized epilepsies and in the mid 1990s was approved for treatment of partial seizures. These anticonvulsants were the mainstays of seizure treatment until the 1990s, when newer AEDs with good efficacy, fewer toxic effects, better tolerability, and no need for blood level monitoring were developed. The new AEDs have been approved in the United States as add-on therapy only, with the exception of topiramate and oxcarbazepine; lamotrigine is approved for conversion to monotherapy.

For information on seizures and epilepsy, see eMedicine's article Seizures and Epilepsy, Overview and Classification.

Treatment of epilepsy

Understanding the mechanism of action and pharmacokinetics of AEDs is important in clinical practice so that they can be used effectively, especially in multidrug regimens (see Media file 1).

Pearls of antiepileptic drug use and management.

The dynamic target of seizure control in the management of epilepsy is achieving balance between the factors that influence the excitatory postsynaptic potential (EPSP) and those that influence inhibitory postsynaptic potential (IPSP).

The AEDs can be grouped according to their main mechanism of action, although many of them have several actions and others have unknown mechanisms of action. The main groups include sodium channel blockers, calcium current inhibitors, gamma-aminobutyric acid (GABA) enhancers, glutamate blockers, carbonic anhydrase inhibitors, hormones, and drugs with unknown mechanisms of action (see Media file 3).

Antiepileptic drugs can be grouped according to their major mechanism of action. Some antiepileptic drugs work by acting on a combination of channels and/or some unknown mechanism of action.

The firing of an action potential by an axon is accomplished through sodium channels. Each sodium channel dynamically exists in 3 states, which are as follows:

• A resting state during which the channel allows passage of sodium into the cell
• An active state in which the channel allows increased influx of sodium into the cell
• An inactive state in which the channel does not allow passage of sodium into the cell

During an action potential, these channels exist in the active state and allow influx of sodium ions. Once the activation or stimulus is terminated, a percentage of these sodium channels become inactive for a period of time known as the refractory period. With constant stimulus or rapid firing, many of these channels exist in the inactive state, rendering the axon incapable of propagating the action potential. AEDs that target these sodium channels prevent the return of these channels to the active state by stabilizing the inactive form of these channels. In doing so, repetitive firing of the axons is prevented (see Media file 4).

Some antiepileptic drugs stabilize the inactive configuration of the sodium (Na+) channel, preventing high-frequency neuronal firing.

Calcium channels exist in 3 known forms in the human brain: L, N, and T. These channels are small and are inactivated quickly. The influx of calcium currents in the resting state produces a partial depolarization of the membrane, facilitating the development of an action potential after rapid depolarization of the cell. They function as the "pacemakers" of normal rhythmic brain activity. This is true particularly of the thalamus. T-calcium channels have been known to play a role in the 3 per second spike-and-wave discharges of absence seizures. AEDs that inhibit these T-calcium channels are particularly useful for controlling absence seizures (see Media file 5).

Low-voltage calcium (Ca2+) currents (T-type) are responsible for the rhythmic thalamocortical spike and wave patterns of generalized absence seizures. Some antiepileptic drugs lock these channels, inhibiting the underlying slow depolarizations necessary to generate spike-wave bursts.

When GABA binds to a GABA-A receptor, the passage of chloride, a negatively charged ion, into the cell is facilitated via chloride channels. This influx of chloride increases the negativity of the cell (ie, a more negative resting membrane potential). This causes the cell to have greater difficulty reaching the action potential. GABA is produced by decarboxylation of glutamate mediated by the enzyme glutamic acid decarboxylase (GAD). Some drugs may act as modulators of this enzyme, enhancing the production of GABA and down-regulating glutamate.

Some AEDs function as an agonist to this mode of chloride conductance by blocking the reuptake of GABA (ie, tiagabine) or by inhibiting its metabolism mediated by GABA transaminase (ie, vigabatrin), resulting in increased accumulation of GABA at the postsynaptic receptors (see Media file 6).

The GABA-A receptor mediates chloride (Cl-) influx, leading to hyperpolarization of the cell and inhibition. Antiepileptic drugs may act to enhance Cl- influx or decrease GABA metabolism.

Glutamate receptors bind glutamate, an excitatory amino acid neurotransmitter. Upon binding glutamate, the receptors facilitate the flow of both sodium and calcium ions into the cell, while potassium ions flow out of the cell, resulting in excitation. The glutamate receptor has 5 potential binding sites and causes different responses depending on the stimulated or blocked site. These sites are the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) site, the kainate site, the N -methyl-D-aspartate (NMDA) site, the glycine site, and the metabotropic site that has 7 subunits (GluR 1-7). AEDs that modify these receptors are antagonistic to glutamate (see Media files 7-8).

Glutamate, the main excitatory neurotransmitter in the CNS, binds to multiple receptor sites that differ in activation and inactivation time courses, desensitization kinetics, conductance, and ion permeability. The 3 main glutamate receptor subtypes are N-methyl-D-aspartate (NMDA), metabotropic, and non-NMDA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA] and kainate receptors). Antiepileptic drugs known to possess this mechanism of action are listed.

Schematic representation of the N-methyl-D-aspartate (NMDA) receptor.

Sex hormones

Progesterone is a natural anticonvulsant that acts by increasing chloride conductance at GABA-A receptors and attenuates glutamate excitatory response. It also alters messenger RNA for GAD and GABA-A receptor subunits. On the other hand, estrogen acts as a proconvulsant by reducing chloride conductance and acting as an agonist at NMDA receptors in the CA1 region of the hippocampus.

Carbonic anhydrase inhibition

Inhibition of the enzyme carbonic anhydrase increases the concentration of hydrogen ions intracellularly and decreases the pH. The potassium ions shift to the extracellular compartment to buffer the acid-base status. This event results in hyperpolarization and an increase in seizure threshold of the cells. Acetazolamide has been used as an adjunctive therapy in refractory seizures with catamenial pattern (ie, seizure clustering around menstrual period). Topiramate and zonisamide also are weak inhibitors of this enzyme; however, this is not believed to be an important mechanism for their antiseizure efficacy.

Synaptic vesicle protein 2A binding

SV2A is ubiquitously expressed in the brain, but its function has not been clearly defined. SV2A appear to be important for the availability of calcium-dependent neurotransmitter vesicles ready to release their content.¹ The lack of SV2A results in decreased action potential-dependent neurotransmission, while action potential-independent neurotransmission remains normal.^2,3 The role in epilepsy is confirmed by the finding of SV2A knock-out mice developing strong seizure phenotype a few weeks after birth.^2,3 The anticonvulsant potency of SV2A ligands is correlated with their binding affinity in the audiogenic seizure-prone mice.^4,5 Levetiracetam binds the SV2A.

Sodium Channel Blockers

Sodium channel blockade is the most common and the most well-characterized mechanism of currently available AEDs. AEDs that target these sodium channels prevent the return of the channels to the active state by stabilizing the inactive form. In doing so, repetitive firing of the axons is prevented. The presynaptic and postsynaptic blockade of sodium channels of the axons causes stabilization of the neuronal membranes, blocks and prevents posttetanic potentiation, limits the development of maximal seizure activity, and reduces the spread of seizures.

Carbamazepine

CBZ is a major first-line AED for partial seizures and generalized tonic-clonic seizures. It is a tricyclic compound and initially was used primarily for the treatment of trigeminal neuralgia, but its value in the treatment of epilepsy was discovered quite by chance. The main mode of action of CBZ is to block sodium channels during rapid, repetitive, sustained neuronal firing and to prevent posttetanic potentiation. It has been approved in the United States for the treatment of epilepsy since 1974. However, it has been used for epilepsy since 1968.

Pharmacokinetics

CBZ is a crystalline substance that is insoluble in water, which limits the route to oral administration. Because it is an unstable substance, care must be taken to protect it from hot or humid conditions, which decrease its bioavailability by 50%. Approximately 75-85% of the drug is plasma protein bound, and it has a free fraction of 20-24% of the total plasma concentration. The cerebrospinal fluid (CSF) levels ranges between 17% and 31%. It is metabolized extensively in the liver and induces its own metabolism. The major metabolic pathway is epoxidation to CBZ 10,11-epoxide and hydrolysis to CBZ 10,11-trans -dihydrodiol.

Because CBZ induces its own metabolism, causing an increase in clearance and a decrease in levels, the serum half-life decreases by 50% during the first few weeks of treatment. The elimination half-life ranges from 5-26 hours following repeated treatment in healthy volunteers and patients with epilepsy. In children, the half-life ranges from 3-32 hours. Its induction of hepatic cytochrome P-450 system activity also increases the metabolism of other AEDs. Peak levels of the drug are present in the blood for 4-8 hours. Formulations that are available include suspension, syrup, tablets (100 mg, 200 mg, 400 mg), chewable tablets (100 mg, 200 mg), extended release capsules (Tegretol XR; 100 mg, 200 mg, 400 mg), Carbatrol (200 mg, 300 mg), and rectal suppositories.

Antiepileptic effect and clinical use

CBZ is one of the most widely used AEDs in the world. It is highly effective for partial onset seizures, including cryptogenic and symptomatic partial seizures. It also has demonstrated good efficacy in the treatment of generalized tonic-clonic seizures. The drug is highly effective and well tolerated. The major disadvantages of this drug are transient adverse dose-related effects when initiating therapy and occasional toxicity.

Side effects and toxicity

CBZ can produce dose-related adverse effects, which include dizziness, diplopia, nausea, ataxia, and blurred vision. Rare idiosyncratic adverse effects include aplastic anemia, agranulocytosis, thrombocytopenia, and Stevens-Johnson syndrome. Asymptomatic elevation of liver enzymes is observed commonly during the course of therapy in 5-10% of patients. Rarely, severe hepatotoxic effects can occur.

Drug interactions

Several drugs, such as macrolide antibiotics (erythromycin and clarithromycin), isoniazid, chloramphenicol, calcium channel blockers, cimetidine, and propoxyphene, inhibit the hepatic enzyme cytochrome P-4503A4 (CYP3A4), which is responsible for the metabolic breakdown of CBZ, thereby raising its levels. Phenobarbital, phenytoin, felbamate, and primidone also lower its levels through CYP3A4. Toxic symptoms or breakthrough seizures may occur if the dose of CBZ is not adjusted. Grapefruit juice and St. John's wort are inducers of CYP3A4 and can decrease CBZ levels.

CBZ induces the metabolism of tricyclic antidepressants, oral contraceptives, cyclosporin A, and warfarin. Any drug that is metabolized by the hepatic enzyme CYP3A4 will have reduced levels since CBZ induces this enzyme.

Summary

CBZ still is one of the most widely used AEDs. The extended-release preparations, Tegretol XR (Novartis) and Carbatrol (Shire), are better tolerated than the immediate-release preparations.

Phenytoin

Since its introduction in 1938, PHT has been a major first-line AED in the treatment of partial and secondary generalized seizures in the United States. It blocks movements of ions through the sodium channels during propagation of the action potential, and therefore blocks and prevents posttetanic potentiation, limits development of maximal seizure activity, and reduces the spread of seizures. It also demonstrates an inhibiting effect on calcium channels and the sequestration of calcium ions in nerve terminals, thereby inhibiting voltage-dependent neurotransmission at the level of the synapse. An antiepileptic effect also is seen on calmodulin and other secondary messenger systems, the mechanisms of which are unclear. The adverse-effect profile (eg, gingival hyperplasia and coarsening of the facial features in women) makes its use less desirable than CBZ in some patients.

Pharmacokinetics

PHT is a lipid-soluble crystalline powder that is a weak acid and has a pKa in the range of 8.3-9.2, making it soluble in alkaline solutions. Usually, it is administered to patients as a sodium salt. It is not absorbed in the stomach because of the low pH of the gastric juices but is absorbed rather slowly in the small intestines, the juices of which have a higher pH. Food and diseases of the small intestines alter PHT absorption. Oral bioavailability is approximately 95%, and peak level after oral administration is reached in approximately 4-12 hours. It is 70-95% bound to plasma protein, and the volume of distribution is 0.5-0.8 L/kg. The brain-plasma ratio is between 1 and 2.

PHT is metabolized in the liver by the hepatic P-450 mixed oxidase system and follows zero-order kinetics. A number of minor metabolites are formed, none of which are active (ie, have no antiepileptic properties). Excretion is through the kidneys. Elimination half-life is 7-42 hours. The drug is available as capsules (25 mg, 50 mg, 100 mg, 200 mg), chewable tablets (50 mg), suspension (30 mg/5 mL, 125 mg/5 mL), and injection (250 mg/5 mL). Administration frequency is 1-2 times a day.

Antiepileptic effect and clinical use

PHT is one of the most commonly used first-line or adjunctive treatments for partial and generalized seizures, Lennox-Gastaut syndrome, status epilepticus, and childhood epileptic syndromes. It is not indicated for myoclonus and absence seizures. This drug is highly effective and economical for the patient; however, tolerability of the drug is still in dispute.

Adverse effects and toxicity

One disadvantage of this drug is that it causes CNS and systemic adverse effects. The long-term use of PHT has been associated with osteoporosis; therefore, it must be used with caution in susceptible populations and routine screening must be performed to detect the condition early. CNS effects occur particularly in the cerebellum and the vestibular system, causing ataxia and nystagmus. It is not a generalized CNS depressant; however, some degree of drowsiness and lethargy is present, without progressing to hypnosis. Nausea and vomiting, rash, blood dyscrasias, headaches, vitamin K and folate deficiencies, loss of libido, hormonal dysfunction, and bone marrow hypoplasia are among the most common adverse effects. When given during pregnancy, PHT, like other AEDs, can cause cleft palate, cleft lip, congenital heart disease, slowed growth rate, and mental deficiency in the offspring.

Drug interactions

Among all AEDs, PHT has one of the most problematic drug interaction profiles. The 2 major reasons are its highly protein-bound (>90%) nature and its use of the P-450 enzymes for metabolism. CBZ and phenobarbital have variable and unpredictable effects (ie, increase or decrease) on PHT levels since they both induce and compete for hepatic enzymes. Valproate raises levels of PHT by displacing PHT from its protein-binding site and inhibiting its metabolism.

Other drugs that significantly increase PHT levels are isoniazid, cimetidine, chloramphenicol, dicumarol, and sulfonamides. Drugs that lower PHT levels are vigabatrin and amiodarone. PHT itself is a strong inducer of hepatic enzymes and alters levels of other drugs. It decreases levels of CBZ, ethosuximide, felbamate, primidone, tiagabine, and phenobarbital. It inhibits dicumarol, warfarin, and corticosteroids; clotting factors and immunosuppression must be monitored and doses adjusted accordingly. Other drugs whose levels are reduced by PHT and require monitoring and adjustment include furosemide, cyclosporin, folate, and praziquantel. levels of chloramphenicol and quinidine are elevated by PHT.

Summary

Epileptologists, in general, try to avoid prescribing PHT because of the poor side-effect profile. Despite the difficult pharmacokinetics and the adverse effects, this drug is used widely. The once-a-day dosing, good efficacy, many years of experience, possibility of monitoring the plasma levels, and availability of a parenteral preparation make it suitable for use by the primary care physician.

Fosphenytoin

Fosphenytoin sodium injection is a prodrug intended for parenteral administration. Its active metabolite is PHT. It is safer and better tolerated than PHT and can be infused 3 times faster than intravenous (IV) PHT.

Pharmacokinetics

When administered by IV infusion, maximum plasma fosphenytoin concentration is achieved at the end of the infusion. Fosphenytoin is completely bioavailable following intramuscular (IM) administration. Peak concentration occurs at 30 minutes after administration. The half-life is 15 minutes, and the drug is presumed to be metabolized completely by phosphatases to PHT. Fosphenytoin is not excreted in the urine.

Antiepileptic effect and clinical use

The antiepileptic effect of fosphenytoin is attributable to PHT. It is clearly better tolerated than PHT. One double-blind controlled study compared the infusion tolerance of fosphenytoin at 150 mg PE/min and PHT 50 mg/min. Local intolerance was reported in 9% of patients after fosphenytoin loading; 21% had infusion disrupted, and the infusion time was 13 minutes. Patients who received PHT, on the other hand, reported 90% local intolerance, 67% had infusion disrupted, and infusion time averaged 44 minutes. Fosphenytoin is indicated for treatment of status epilepticus and for short-term parenteral administration when other routes are not available or inappropriate.

Adverse effects and toxicity

Cardiovascular depression and hypotension may occur but to a lesser extent than with PHT. These adverse effects usually are related to the rate of infusion. Slower infusion is recommended in susceptible patients. Severe burning, itching, and/or paresthesia, mainly in the groin area, have been associated with rapid infusion. The discomfort may be improved by lowering the infusion rate or temporary discontinuation. Hepatic or hemopoietic adverse reactions, like those seen with PHT, also may occur.

Summary

Fosphenytoin is a better IV preparation than PHT, mainly because of tolerability and safety. It also may allow faster achievement of therapeutic serum PHT levels. However, fosphenytoin is much more expensive than PHT.

Oxcarbazepine

Oxcarbazepine (OXC) is a recently developed analog of CBZ. OXC was developed in an attempt to hold on to the benefits of CBZ while avoiding its auto-induction and drug interaction properties. Licensed in over 50 countries, including the United States, OXC now is considered one of the first-line therapies in some countries. OXC does not produce the epoxide metabolite, which is largely responsible for the adverse effects reported with CBZ. Like CBZ, OXC blocks the neuronal sodium channel during sustained rapid repetitive firing.

Pharmacokinetics

OXC is absorbed almost completely on oral administration and can be taken with food. It metabolizes to the active 10-monohydroxy metabolite (MHD), 10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide. MHD is the active compound that is responsible for the pharmacologic effects of OXC. Volume of distribution is 0.3-0.8 L/kg. Protein binding is 38%. It readily crosses the blood-brain barrier. Metabolism takes place in the liver; no epoxide is formed, accounting for the better tolerability of this drug than of CBZ. It induces some cytochrome P-450 enzymes, including CYP3A4, CYP3A5, and CYP2C19, but other cytochrome enzymes appear to be unaffected. Excretion is via the kidneys; peak levels are reached in 4 hours. The half-life is 8-10 hours.

Drug interactions

OXC interacts with oral contraceptives, thereby reducing their efficacy. It does not increase the metabolism of warfarin, cimetidine, erythromycin, verapamil, or dextropropoxyphene.

Antiepileptic effects and clinical use

OXC is approved for monotherapy or adjunctive therapy in partial and secondary generalized seizures. Four randomized, double-blind trials of this agent as monotherapy demonstrated effectiveness superior to that of placebo in patients with refractory epilepsy and in candidates for epilepsy surgery. OXC is better tolerated and has fewer drug interactions than CBZ. Retrospective studies have reported worsening of seizures caused by oxcarbazepine in juvenile idiopathic generalized epilepsies. Substitution for CBZ can be made abruptly with an OXC-to-CBZ ratio of 300:200. Available formulations are tablets (150 mg, 300 mg, 600 mg), and the recommended frequency of administration is twice a day. The initial dose in children is 10 mg/kg/d, with titration up to a maximum of 30 mg/kg. In adults, the dose is 600 mg/d up to a maximum of 2400 mg/d.

Adverse effects and toxicity

Somnolence, headache, dizziness, rash, hyponatremia, weight gain, GI disturbances, and alopecia are the most commonly reported adverse effects. The allergic rash is similar to the one caused by CBZ. Dose-related adverse effects include fatigue, headache, dizziness, and ataxia. Hyponatremia is mild and can be corrected by fluid restriction. Hyponatremia is uncommon in children younger than 17 years, but it occurs in 2.5% of adults and 7.4% of the elderly. Idiosyncratic reactions appear to be less common than with CBZ.

Summary

Some patients require low starting doses (300 mg/d) and slower titration for better tolerability. Comparison studies of tolerability between slow-release CBZ and OXC are not available. OXC is an effective drug for partial seizures but may aggravate myoclonic or absence seizures.

Lamotrigine

Lamotrigine (LTG) is a triazine compound that is chemically unrelated to any of the other AEDs. It was developed as an antifolate agent based on a theory that the mechanism of some AEDs is related to their antifolate property. It was approved in the United States in 1994. Its major mechanism of action is blocking voltage-dependent sodium-channel conductance. It has been found to inhibit depolarization of the glutaminergic presynaptic membrane, thus inhibiting release of glutamate. It has a weak antifolate effect that is unrelated to its antiseizure efficacy.

Pharmacokinetics

On oral administration, LTG has a bioavailability close to 100%, reaching peak levels within 1-3 hours and achieving a volume of distribution of 0.9-1.3 L/kg. Its solubility is poor in both ethanol and water; therefore, it is not available in parenteral form. Protein binding is 55% and the elimination half-life is 24-41 hours. It is metabolized by the liver and excreted through the kidneys. It produces auto-induction at higher doses and has no active metabolites.

Drug interactions

LTG levels increase with concomitant use of valproate to 70 hours. It does not induce or inhibit hepatic enzymes; therefore, it does not affect the metabolism of lipid-soluble drugs such as warfarin and oral contraceptives. Conversely, drugs that induce hepatic enzymes may reduce the half-life of LTG from 23 hours to 14-16 hours. LTG levels must be adjusted accordingly.

Antiepileptic effect and clinical use

LTGs significant effect on seizures as compared to placebo was demonstrated in 9 of 10 placebo-controlled trials in which LTG was administered as add-on therapy. LTG resulted in a 17-59% reduction in seizures, with most trials showing 25-30% median reduction in seizures. It is effective in partial onset and secondarily generalized tonic-clonic seizures, primary generalized seizures (ie, absence seizures and primary generalized tonic-clonic seizures), atypical absence seizures, tonic/atonic seizures, and Lennox-Gastaut syndrome. It is sometimes effective for myoclonic seizures, but can cause worsening of myoclonic seizures in some patients with juvenile myoclonic epilepsy or myoclonic epilepsy of infancy. It currently is approved in the United States for adjunctive therapy for partial onset and secondarily generalized tonic-clonic seizures, crossover to monotherapy, and Lennox-Gastaut syndrome.

The dose regimen and titration schedule depends on coadministration of other AEDs, the titration rate being slower with enzyme-inhibiting AEDs such as valproate than with enzyme-inhibiting AEDs such as PHT and CBZ. Preset packages are available with the recommended doses of LTG, with and without valproate. In children on valproate, the starting dose of LTG is 0.15 mg/kg, with increments every 1-2 weeks up to a maximum of 1-5 mg/kg. In patients taking concomitant enzyme inducers, the starting dose is 0.6 mg/kg, up to a maximum of 5-15 mg/kg. It is available in tablets (25 mg, 50 mg, 100 mg, 150 mg, and 200 mg) and chewable tablets (5 mg, 25 mg, and 100 mg); it is administered twice a day.

Adverse effects and toxicity

Different from most AEDs, LTG produces few CNS side effects. Rash is the main concern associated with this drug. It occurs in 5% of patients and is associated with rapid titration. Severe rash (more common in children taking valproate) may develop and lead to Stevens-Johnson syndrome, which may be fatal, but this is rare (0.1%). Other commonly reported adverse reactions are headache, blood dyscrasias, ataxia, diplopia, GI disturbance, psychosis, tremor, hypersensitivity reactions, somnolence, and insomnia.

Lamotrigine is the only AED with more than 500 documented pregnancy exposures. The International Lamotrigine Pregnancy Registry Update reported 414 monotherapy exposures, giving a risk of 2.9% (12 of 414; 95% confidence interval [CI], 1.6-5.1%). The North American AED Pregnancy Registry found no overall risk of major malformations (2.3%, RR = 1.4 [1.4–10.0]) in 684 infants exposed to lamotrigine monotherapy, but an increased risk of orofacial clefts (7.3 of 1,000). In contrast, the EUROCAT congenital anomaly registers, which cover more than one quarter of births in Europe, did not find an increased risk of orofacial clefts for 40 children exposed to lamotrigine monotherapy (OR: 0.67, 95% CI: 0.82–1.72).⁶   

Summary

LTG is a very effective and well-tolerated drug. Combination therapy with valproate enhances the antiepileptic effect; however, it also increases the chances of developing allergic skin reactions. Very slow titration is important for better tolerability. The excellent side-effect profile and lack of significant CNS toxicity make this drug one of the preferred choices in treating elderly patients. The reported low incidence of congenital malformations when exposed to pregnant patients makes this drug one of the preferred treatments during pregnancy.

Zonisamide

Zonisamide (ZNS) was synthesized as a benzisoxazole in 1974. It is chemically unrelated to any of the other AEDs. It is a small-ringed structure related to sulfonamide antibiotics with pH-dependent solubility in water. Although ZNS was approved by the US Food and Drug Administration (FDA) in March 2000 for the indication of partial seizures in patients older than 12 years as adjunctive therapy to other AEDs, it has been approved and studied in Japan for more than 10 years. The major mechanism of action of ZNS is reduction of neuronal repetitive firing by blocking sodium channels and preventing neurotransmitter release. It also exerts influence on T-type calcium channels and prevents influx of calcium. ZNS also exhibits neuroprotective effects through free radical scavenging.

Pharmacokinetics

ZNS is absorbed quickly and completely when administered orally, reaching peak levels in 2-4 hours. It has a relatively long half-life of 60 hours. It has a high affinity for binding to RBCs and a 40% protein-binding capacity, exhibiting a linear dose/plasma concentration at doses of 100-400 mg. Partially metabolized by the liver (70%), it uses the cytochrome P-450 system, followed by glucuronidation. Although it uses the cytochrome P-450 system, it is not an inducer of the system. Metabolites of this drug are not biologically active, and 35% of the drug is excreted unchanged in the urine.

Antiepileptic effect and clinical use

ZNS has been approved for adjunctive therapy for patients with partial seizures who are 12 years or older. It is preferred clinically because of the ease of patient tolerance, degree of seizure reduction, long half-life, and lack of drug interactions with other AEDs. ZNS provides dose-dependent, effective, and generally well-tolerated adjunctive therapy in patients with partial seizures. Retrospective studies have shown that ZNS is a very effective treatment for myoclonus, especially in juvenile myoclonic epilepsy. In small series of women of childbearing years, spontaneous abortions and congenital abnormalities in human fetuses have been reported at a rate of 7%, which is twofold greater than the rate in the general population (2-3%). However, many of these women were treated with polytherapy.

Adverse effects and toxicity

The most commonly reported adverse reactions to ZNS are dizziness, anorexia, headache, ataxia, confusion, speech abnormalities, mental slowing, irritability, tremor, and weight gain. Gradual titration of the drug appears to reduce the manifestations of adverse reactions. Somnolence and fatigue have been reported frequently. ZNS is associated with renal stones in 1.5% of patients; therefore, the risk in patients with a history of renal stones needs to be weighed against the therapeutic benefits of the medication. Oligohidrosis has been reported in children, mainly due to the effect on carbonic anhydrase. Idiosyncratic skin reactions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported in Japan at a rate of 46 per million patient-years of exposure. This drug should not be used in patients who are allergic to sulfonamides.

Drug interactions

PHT, CBZ, phenobarbital, and valproic acid decrease the half-life from 63 hours to 27-46 hours, thereby reducing levels of ZNS; however, ZNS does not affect the levels of these drugs.

Summary

ZNS is a good alternative for patients with compliance problems because of its long half-life; it can be used once daily without significant fluctuation of blood levels. In addition, it does not have the cosmetic and pharmacokinetic problems of PHT. Its mechanism of action, inhibiting thalamic T-calcium currents, may make it effective in absence epilepsy and juvenile myoclonic epilepsy.

GABA Receptor Agonists

A seizure reflects an imbalance between excitatory and inhibitory activity in the brain, with an increment of excitation over inhibition. The most important inhibitory neurotransmitter in the brain is GABA. For a summary of the AEDs with effects on GABA, see Media file 9.

GABA drugs and their known sites of action.

The GABA system can be enhanced by direct binding to GABA-A receptors, by blocking presynaptic GABA uptake, by inhibiting the metabolism of GABA by GABA transaminase, and by increasing the synthesis of GABA (see Media file 8).

Schematic representation of the N-methyl-D-aspartate (NMDA) receptor.

The benzodiazepines most commonly used for treatment of epilepsy are lorazepam, diazepam, clonazepam, and clobazam. The first 2 drugs are used mainly for emergency treatment of seizures because of their quick onset of action, availability of IV forms, and strong anticonvulsant effects. Their use for long-term treatment is limited because of the development of tolerance.

The two barbiturates mostly commonly used in the treatment of epilepsy are phenobarbital and primidone. They bind to a barbiturate-binding site of the benzodiazepine receptor to affect the duration of chloride channel opening. They have been used widely throughout the world. They are very potent anticonvulsants, but they have significant adverse effects that limit their use. With the development of new drugs, the barbiturates now are used as second-line drugs for the treatment of chronic seizures.

Clobazam

This benzodiazepine has a 1,5 substitution instead of the usual 1,4-diazepine. This change results in an 80% reduction in its anxiolytic activity and a 10-fold decrease in its sedative effects. It has been licensed in Europe since 1975 but is not available in the United States. In addition to its agonist action at the GABA-A receptor, clobazam may affect voltage-sensitive conductance of calcium ions and the function of sodium channels.

Pharmacokinetics

Clobazam is relatively insoluble in water; therefore, no IV or IM preparations are available. Its oral bioavailability is about 90%. Time to peak plasma concentrations (T_max) is 1-4 hours. Absorption rate is decreased when taken with meals, but total absorption is not affected. Plasma protein binding of clobazam is approximately 83% with the proportion of bound to unbound drug independent of clobazam concentration. Very low plasma protein levels are associated with increases in the unbound (ie, free) fraction, for example, in renal or hepatic disease. Brain and saliva concentrations are proportional to the unbound fraction. A good correlation exists between dosage and plasma levels; significant interindividual variations exist.

Clobazam is metabolized by oxidation in the liver to norclobazam (N -desmethylclobazam). This metabolite has a very long half-life (ie, 50 h), but it has a low affinity for the benzodiazepine receptor, and its antiepileptic effect is unclear. The elimination half-life usually is in the range of 10-50 hours. Norclobazam is conjugated in the liver and excreted in the bile as glucuronate and in the urine as sulfate. The clobazam plasma level is 20-350 ng/mL. Norclobazam levels typically are 10 times higher than clobazam levels at usual clinical dosage.

Drug interactions

No significant clinical interactions are reported. Minor interactions are common.

Antiepileptic effect and clinical use

Clobazam is a potent anticonvulsant for partial epilepsy. No double-blind, controlled studies have been reported, but the trials performed showed a striking benefit. In one study, the mean reduction of seizures was 50% in more than 50% of patients. These patients had partial epilepsy and were taking other AEDs. In one Canadian study in drug-naive children, clobazam monotherapy was found to be as effective as CBZ or PHT.

The major clinical problem of this drug is the development of tolerance; sedation tolerance is more evident than antiepileptic tolerance. No clear correlation between plasma levels and seizure control has been found. No measures have been effective against the development of tolerance. The anxiolytic effect (mild) may be beneficial for some patients. It is effective in a wide range of epilepsies and should be considered as adjunctive therapy. It can be used in patients with Lennox-Gastaut syndrome or primary or secondarily generalized seizures. Clobazam is administered orally at a dose 10-20 mg/d, taken at night or twice daily. No parenteral preparations are available.

Adverse effects and toxicity

Essentially, the adverse effects are similar to those of other benzodiazepines. The most common effect is sedation. Other adverse effects include dizziness, ataxia, blurred vision, diplopia, irritability, depression, muscle fatigue, and weakness. Idiosyncratic reactions are very rare and no fatal reactions have been reported so far.

Summary

Clobazam is useful in intermittent treatments (eg, catamenial epilepsy) and as prophylaxis for some situations, such as traveling, celebrations, and other occasions.

Clonazepam

Clonazepam, a 1,4-substituted benzodiazepine, is one of the first benzodiazepines used for epilepsy. Clonazepam has higher affinity for the GABA-A receptor site than diazepam and binds to GABA-A receptors that do not bind with other benzodiazepines. It may have some action on sodium-channel conductance.

Pharmacokinetics

Clonazepam has an oral bioavailability of 80%. T_max is 1-4 hours, but it could be delayed for as long as 8 hours. Plasma protein binding is 86% with a volume of distribution of 1.5- 4.4 L/kg. It is highly lipid soluble and can cross the blood-brain barrier rapidly. Plasma levels and antiepileptic effects are not correlated. Clonazepam is acetylated in the liver; therefore, the metabolic rate depends on the genetic acetylator function. The metabolites of clonazepam have no clinical relevance. The elimination half-life ranges from 20-80 hours, and it has a very low clearance (approximately 100 mL/min in adults). Less than 0.5% is excreted in the urine.

Drug interactions

Clonazepam levels are decreased by coadministration of enzyme-inducing drugs. No significant clinical interactions have been reported.

Antiepileptic effect and clinical use

Clonazepam is a potent AED and the drug of choice for myoclonic seizures and subcortical myoclonus. It also is effective in generalized convulsions and, to a lesser extent, in partial epilepsies. It rarely is used as adjunctive treatment of refractory epilepsy because of its sedative effect and tolerance, which are similar to those of other benzodiazepines. It is very effective in the emergency treatment of status epilepticus, like diazepam, and can be given IV or rectally. Withdrawal from clonazepam may induce status epilepticus or exacerbation of seizures. Psychiatric withdrawal also may occur, manifested as insomnia, anxiety, psychosis, and tremor. Clonazepam is available as 0.5 mg, 1 mg, and 2 mg tablets, and as an IV solution. Usual starting dose is 0.25-4 mg/d once or twice daily. Slow titration is recommended.

Adverse effects and toxicity

The major adverse effect is sedation, even at low doses. Children can tolerate this medication much better than adults; therefore, pediatricians use it most often. Clonazepam has the typical adverse effects of benzodiazepines (eg, ataxia, hyperactivity, restlessness, irritability, depression, cardiovascular or respiratory depression). Children and infants may have hypersalivation. Occasionally, tonic seizures may be exacerbated. Idiosyncratic reactions are rare and include marked leukopenia.

Summary

Clonazepam is used for all types of myoclonus, and is useful in patients with concomitant anxiety disorder.

Phenobarbital

This is the most commonly prescribed AED of the 20th century. It is a very potent anticonvulsant with a broad spectrum of action. Currently, its use is limited because of its adverse effects. It is a free acid, relatively insoluble in water. The sodium salt is soluble in water but unstable in solution. It has a direct action on GABA-A receptors by binding to the barbiturate-binding site that prolongs the duration of chloride channel opening. It also reduces sodium and potassium conductance and calcium influx and depresses glutamate excitability.

Pharmacokinetics

Phenobarbital (PHB) is a powerful inducer of the hepatic microsomal enzymes. It has an oral or IM bioavailability of 80-100% in adults. Time to peak plasma level is 1-3 hours, but it may be delayed after oral administration in patients with poor GI motility. The serum peak levels after IM injection are achieved in 4 hours. Ethanol increases the rate of PHB absorption. It is absorbed mainly in the small intestine. Plasma protein binding is 40-60%. The concentration in breast milk is approximately 40% of the serum concentration. The volume of distribution ranges from 0.42-0.75 L/kg. Change in pH causes shift of the drug between compartments; therefore, acidosis increases the concentration of PHB in the tissue compartment.

After IV administration, PHB is distributed quickly to highly vascular organs, except the brain, and then it is distributed evenly. After 6-12 minutes, it penetrates the brain, but the brain penetration is much faster during status epilepticus because of increased blood flow and acidosis.

PHB has a very long elimination half-life (ie, 75-120 h); in infants, the half-life is much longer, up to 400 hours. In individuals older than 6 months, the half-life falls to 20-75 hours. PHB is metabolized in the liver. The major metabolite is p-hydroxyphenobarbital, which is excreted as a glucuronide conjugate. PHB has extensive urinary resorption, which is enhanced by acidification of the urine.

Drug interactions

Metabolism of PHB is inhibited by PHT, valproate, felbamate, and dextropropoxyphene. Enzyme inducers, such as rifampin, decrease PHB levels. Because of the potent induction of the hepatic enzymes, PHB increases the metabolism of estrogen, steroids, warfarin, CBZ, diazepam, clonazepam, and valproate. Its effect on PHT is unpredictable.

Antiepileptic effect and clinical use

In a multicenter double-blind study, PHB was found to be as effective as PHT and CBZ in the treatment of partial and secondarily generalized seizures. The Veterans Administration (VA) cooperative study, however, comparing PHB, primidone, PHT, and CBZ, showed a significantly lower retention in patients on PHB or primidone despite their similar efficacy, because of poorer tolerability. No statistical difference was reported between PHT and CBZ. PHB is effective in a wide variety of seizures and is currently the cheaper AED. Although PHB effectiveness is not questioned, it is a second-line drug because of its adverse effects such as sedation and cognitive slowing.

PHB is available in tablets of 15 mg, 30 mg, 50 mg, 60 mg, and 100 mg; elixirs (15 mg/mL); and injections (200 mg/mL). Usual starting dose is 30-60 mg once a day. The dose can be titrated up to 240 mg/d. Slow titration is better tolerated. Therapeutic blood levels are 15-40 mg/L. Physical dependence and withdrawal seizures occur with long-term use. Therefore, very slow withdrawal over several weeks to months is recommended.

Adverse effects and toxicity

The most important adverse effects are cognitive and behavior alterations. Children are more likely than adults to exhibit behavioral changes (ie, paradoxical hyperkinesis). Sedation is prominent, particularly at the beginning of therapy, and usually subsides. Psychomotor slowing, poor concentration, depression, irritability, ataxia, and decreased libido are other effects. Long-term use of PHB may be associated with coarsening of facial features, osteomalacia, and Dupuytren contractures. Folate deficiency, megaloblastic anemia, and idiosyncratic skin reaction are rare. Vitamin supplementation is warranted. Hepatitis has been reported secondary to an immune-mediated process.

Summary

PHB still is a first-line drug for treatment of status epilepticus. However, because of its adverse-effect profile, it is a second-line agent in the treatment of partial onset and secondarily generalized tonic-clonic seizures. In developing countries, it is used widely because of its low cost.

Primidone

This drug is metabolized to PHB and phenylethylmalonamide (PEMA). The main action is through the derived PHB. The real clinical effect of primidone or PEMA is unknown and controversial.

Pharmacokinetics

Primidone is absorbed orally. Bioavailability is close to 100%, with a peak level after 3 hours. Plasma protein binding is only 25%. Elimination half-life is 5-18 hours but that of its derivative PHB is 75-120 hours. Primidone is metabolized by the cytochrome oxidase system; therefore, it is affected by enzyme inducers, including PHB itself. The levels of primidone seldom are useful for monitoring efficacy, and range from 5-12 mg/L. PHB level is the same as the level when PHB is administered directly (15-40 mg/L).

Antiepileptic effect and clinical use

Primidone has the same indications as PHB. It is available in tablets of 50 mg and 250 mg and suspension of 250 mg/5 mL; 250 mg of primidone is equivalent to 60 mg of PHB. The average therapeutic doses range from 500-1500 mg.

Adverse effects and toxicity

The major adverse effects are intense sedation, dizziness, and nausea at the onset of treatment, most likely secondary to administration of the parental drug. These effects usually clear after 1 week of treatment. Very low dose is recommended at the onset of treatment. Other effects are the same as those of PHB.

Summary

Primidone can be used for partial onset and secondarily generalized seizures. However, it is a second-line agent because of its side-effect profile, which is similar to that of PHB. It has been useful in the treatment of essential tremor at low doses.

GABA Reuptake Inhibitors

At least 4 specific GABA-transporting compounds help in the reuptake of GABA; these carry GABA from the synaptic space into neurons and glial cells, where it is metabolized. Nipecotic acid and tiagabine are inhibitors of these transporters; this inhibition makes increased amounts of GABA available in the synaptic cleft. GABA prolongs inhibitory postsynaptic potentials (IPSPs).

Tiagabine

Tiagabine (TGB) is a derivative of the GABA uptake inhibitor nipecotic acid. It acts by inhibition of the GABA transporter-1 (GAT-1). This inhibitory effect is reversible. TGB is lipid soluble and thus is able to cross the blood-brain barrier. It was introduced into clinical practice in 1998. Measurements in human and experimental models have confirmed that extracellular GABA concentrations increase after administration of TGB. Studies have shown little or no effect at other receptor systems.

Pharmacokinetics

The oral bioavailability of the drug is approximately 96%. The time to peak concentrations is approximately 1 hour after oral intake. A second peak of the plasma concentration of TGB is seen 12 hours after ingestion, probably caused by enterohepatic circulation. Food decreases absorption 2- or 3-fold; however, the total amount absorbed is unchanged by food administration. The volume of distribution is 1 L/kg, and the drug is bound extensively (ie, 96%) to human plasma proteins. It is metabolized extensively in the liver by the P-450 system. None of the TGB metabolites has any antiepileptic action, and less than 3% of the drug appears unchanged in the urine.

The plasma half-life of TGB has been found to range from 4.5-8.1 hours in healthy volunteers, and this is reduced to 3.8-4.9 hours in patients with epilepsy who are co-medicated with enzyme-inducing drugs. The clearance of TGB is greater in children. The elimination of the drug is reduced in patients with mild to moderately severe liver impairment.

Drug interactions

TGB causes a small decrease in valproate. It has no significant effects on plasma concentrations of progesterone, estradiol, follicle-stimulating hormone, or luteinizing hormone.

Hepatic-inducing drugs increase the clearance of TGB by two thirds. TGB plasma concentrations are not affected by valproate, cimetidine, or erythromycin.

Antiepileptic effect and clinical use

TGB has been studied as adjunctive therapy in 5 double-blind, placebo-controlled studies, which demonstrated its efficacy. It is available for use as second-line add-on therapy in patients with partial or secondarily generalized seizures refractory to treatment.

Besides the 5 studies already mentioned, TGB has been the subject of a series of other clinical trials designed to demonstrate efficacy, including 3 trials (1 open and 2 double-blinded) in monotherapy and 6 open long-term studies. In a meta-analysis comparing these results with placebo-controlled, randomized trials of other drugs, no significant differences in efficacy were demonstrated among TGB, gabapentin, LTG, topiramate, vigabatrin, or ZNS. In the long-term extension studies, 772 patients were treated with TGB ( <80 mg/d), with reduction in seizure frequency by 50% or more in about 30-40% of patients treated for 3-6 months. This effect was maintained for 12 months in patients with partial seizures but not in patients with secondarily generalized seizures. The drug is available for use as second-line add-on therapy in patients with partial or secondarily generalized seizures that are refractory to treatment.

In the United States, the recommended dosage is 4 mg/d with a titration of 4-8 mg/d each week, and the usual maintenance dose is 32-56 mg/d. In Europe, the recommended dose is 15 mg/d followed by weekly incremental increases of 5-15 mg up to a maximum of 15-30 mg/d. In patients on concomitant enzyme inducers, the dose could be increased gradually to 45 mg/d.

Adverse effects and toxicity

The most troublesome adverse effects include dizziness, asthenia, nervousness, tremor, depressed mood, and emotional lability. Diarrhea also was significantly more frequent among TGB-treated patients than placebo-treated patients. Other adverse effects included somnolence, headaches, abnormal thinking, abdominal pain, pharyngitis, ataxia, confusion, psychosis, and skin rash. No changes in biochemical or hematological parameters were reported. Serious idiosyncratic adverse effects were recorded as commonly in patients on placebo as in those on TGB.

A few clinical trials have reported the occurrence of convulsive and nonconvulsive status epilepticus with TGB. In the author's experience, one case of nonconvulsive status was caused by accidental overdose. TGB therapy should be used cautiously in patients with a history of status epilepticus.

TGB is contraindicated in severe hepatic impairment, pregnancy, and lactation.

Summary

Use of TGB is limited to adjunctive therapy in refractory partial epilepsy. It should not be used in absence epilepsy or in partial epilepsies with generalized spike wave, since it can worsen seizure control or cause status epilepticus.

GABA Transaminase Inhibitor

GABA is metabolized by transamination in the extracellular compartment by GABA-transaminase (GABA-T). Inhibition of this enzymatic process leads to an increase in the extracellular concentration of GABA. Vigabatrin (VGB) inhibits the enzyme GABA-T.

Vigabatrin

In the 1970s, GABA was recognized as an important inhibitory neurotransmitter in the CNS. Favoring the balance toward the GABA system was a major target of drug research, and soon VGB was developed. The drug was licensed worldwide, except in the United States because of its toxicity. It is a close structural analog of GABA, binding irreversibly to the active site of GABA-T. Newly synthesized enzymes take 4-6 days to normalize the enzymatic activity. In vivo studies in human and animal subjects have shown that VGB significantly increases extracellular GABA concentrations in the brain. VGB has no other known action.

Pharmacokinetics

VGB is highly water soluble but only slightly soluble in ethanol. It is absorbed rapidly following oral ingestion, with an oral bioavailability of 100%. Time to peak concentration is approximately 2 hours, and the volume of distribution of the drug is 0.8 L/kg. About 10% of the plasma concentration is found in CSF. Only a small fraction crosses the placenta. VGB is excreted in urine (up to 95%) with a half-life of 4-7 hours. In elderly patients, clearance is reduced and the half-life may double. VGB does not induce the activity of hepatic enzymes. Correlation between plasma levels and clinical effect is poor.

Drug interactions

VGB can reduce plasma concentration of PHT by 25%. This probably is mediated by decreased absorption; however, the exact mechanism is unknown. No other pharmacokinetic or pharmacodynamic interactions are present.

Antiepileptic effect and clinical use

VGB has been studied exhaustively in 9 double-blind controlled trials. These trials reported that 40-50% patients with refractory partial seizures had a reduction in seizure frequency of more than 50%, and as many as 10% of patients became seizure free. Many patients continued the drug after completion of the trial. The dose of VGB ranged from 1000-4000 mg/d. It is less effective against primarily generalized tonic-clonic seizures and also may worsen myoclonic seizures or generalized absence seizures. Like TGB, VGB has been reported to cause absence status. Patients with myoclonus or Lennox-Gastaut syndrome do not respond well to VGB. In placebo-controlled trials in patients with refractory epilepsy, 20% of children and 5% of adults showed an increase in seizures. VGB is very effective in the treatment of infantile spasms; therefore, it is the drug of choice for this indication in many countries.

The usual starting dose for adults is 500 mg twice daily, and is increased by 250-500 mg every 1-2 weeks to a maximum dose of 4000 mg/d. In children, 40 mg/kg/d is the usual starting dose, with maintenance doses of 80-100 mg/kg.

Adverse effects and toxicity

The most common adverse effect is drowsiness. Other important adverse effects include neuropsychiatric symptoms, such as depression (5%), agitation (7%), confusion and, rarely, psychosis. Minor adverse effects, usually at the onset of therapy, include fatigue, headache, dizziness, increase in weight, tremor, double vision, and abnormal vision. VGB has little effect on cognitive function.

VGB causes widespread intramyelinic vacuolization throughout the brains of rats and dogs; however, studies in primates and human subjects failed to demonstrate such changes. The drug also affected the retina in some rodent species, and recent studies in human subjects showed visual field changes, characterized by nasal constriction and then concentric constriction, with preservation of central vision. In one series, visual field disturbances were found in more than 50% of cases. The mechanism of this effect is unknown and the risk factors are unclear. In some cases, this appears to be irreversible.

Acute hypersensitivity or idiosyncratic immunological adverse effects are extremely rare.

Summary

VGB is a very potent drug. It is useful in infantile spasms, particularly in patients with tuberous sclerosis. Unfortunately, because of this drug's toxicity, its use is restricted. It has not been approved by the US Food and Drug Administration (FDA) because of its adverse visual effects.

AEDs With a Potential GABA Mechanism of Action

The enzyme GAD converts glutamate into GABA. Currently, valproate and gabapentin are known to have some effects on this enzyme to enhance the synthesis of GABA in addition to other potential mechanisms of action. Valproate also blocks the neuronal sodium channel during rapid sustained repetitive firing. Gabapentin has a weak competitive inhibition of the enzyme GABA-T. As with other AEDs, whether these mechanisms of action alone are responsible for the antiseizure efficacy of these drugs is unclear.

Gabapentin

Gabapentin (GBP) was developed to have a structure similar to that of GABA; however, experimental evidence showed that GBP has, in fact, little or no action on the GABA receptor. It is highly soluble in water. It enhances the enzyme GAD, but does so weakly. It binds with the alpha₂ delta subunit of calcium channels in the cerebral neocortex, hippocampus, and spinal cord; this mechanism of action may be important for its efficacy in pain.

At this time, the exact mechanism by which GBP increases the intracellular concentration of GABA is unknown. In vivo MR spectroscopy studies have shown that GBP increases brain levels of GABA and its metabolites homocarnosine and pyrrolidinone. It also may reduce monoamines and affect serotonin release.

GBP is a competitive inhibitor of the enzyme branched chain amino acid transferase, which metabolizes the branch chain amino acids (l-leucine, l-isoleucine, and l-valine) to glutamate. Through this mechanism, GBP may reduce brain glutamate levels.

Pharmacokinetics

GBP has a bioavailability of less than 60%; bioavailability is affected mainly by variable absorption, which depends on an L-amino acid transporter. Absorption may be impaired in some clinical situations in which active transport usually is compromised. In addition, single doses of GBP greater than 1200 mg decrease the bioavailability to 35%. Once absorbed, the drug readily crosses the blood-brain barrier and achieves a plasma-to-CSF ratio of approximately 1:10. Peak serum levels are achieved within 2-4 hours of oral administration. The volume of distribution in adults is about 0.64-1.04 L/kg at steady state.

GBP is not bound to plasma proteins and is not metabolized. It does not induce hepatic enzymes. It is excreted entirely in an unchanged form. The renal clearance of 120-130 mL/min is correlated linearly with creatinine clearance. The elimination half-life of the drug is 5-9 hours. Steady-state levels are achieved within a few days, and the half-life does not change with chronic administration, nor is it influenced by concomitant medications. Few data on the correlation between serum level and effectiveness are reported. In patients with renal disorders, the dose should be adjusted according to creatinine clearance; it is removed during hemodialysis.

Drug interactions

GBP has no pharmacokinetic drug interactions. However, antacids can reduce the bioavailability of GBP.

Antiepileptic effect and clinical use

Several open and double-blind trials have been conducted with GBP. In the United States, patients were randomized to receive 600 mg, 1200 mg, or 1800 mg of GBP or placebo. The percentage of patients who had a reduction of seizures of 50% or more was 18-26% with GBP and 8% with placebo. A large multicenter study carried out in the UK randomized patients to receive add-on therapy with either GBP 1200 mg or placebo and showed a reduction in partial seizures of 50% or more in 28% of the patients taking GBP and 9.8% of patients taking placebo.

A double-blind study in children with partial epilepsy showed response rates of 17% on GBP and 7% on placebo, whereas in other double-blind, placebo-controlled studies, GBP had no effect in childhood absence seizures. These trials were performed at a relatively low dose, and a better response was obtained in trials using a higher dose; however, the latest trials were not double blind. In clinical practice, higher doses often are used. GBP is useful in the treatment of partial and secondarily generalized tonic-clonic seizures but is ineffective in myoclonus and in most generalized seizure disorders. The drug appears to have only a modest efficacy, particularly at lower doses.

GBP is available as capsules of 100 mg, 300 mg, 400 mg, and 600 mg and tablets of 800 mg. Rapid titration is well tolerated in some patients, but usually the drug is titrated at weekly intervals to a maximum of 3600-4800 mg/d.

Its lack of drug interactions, lack of plasma protein binding, and renal excretion make GBP particularly useful in patients with renal or hepatic disease and in patients on complex drug regimens. Patients with coexistent migraine headache or neuropathic pain may benefit from this drug.

Adverse effects and toxicity

GBP is relatively well tolerated, although it does have some adverse effects, particularly in high doses, but these usually are relatively minor. No significant serious idiosyncratic or systemic adverse effects have been reported. The incidence of rash is 0.5% and of neutropenia, 0.2%. EEG changes and/or angina were found in 0.05%. No cases of hepatotoxicity have been recorded.

In the early double-blind studies, 44% of patients reported adverse effects with 900 mg of GBP. Similar adverse effects were recorded in later studies with 1200 mg. In a US study of patients taking 1800 mg/d, somnolence was recorded in 36% of patients, dizziness in 24%, ataxia in 26%, nystagmus in 17%, headache in 9%, tremor in 15%, fatigue in 11%, diplopia in 11%, rhinitis in 11%, and nausea or vomiting in 6%. Most of these effects were mild.

Pregabalin

Pregabalin is well absorbed after oral administration. Following oral administration under fasting conditions, the peak plasma concentration is 1.5 hours; however, the rate of pregabalin absorption is decreased when given with food, resulting in a decrease in C_max of approximately 25-30% and an increase in T_max to approximately 3 hours. Oral bioavailability is 90% and it is independent of dose and presence of food. Steady state is achieved within 24-48 hours.

Pregabalin does not bind to plasma proteins. The apparent volume of distribution following oral administration is approximately 0.5 L/kg. Pregabalin crosses the blood-brain barrier in animals and has been shown to cross the placenta in rats and is present in the milk of lactating rats.

After oral administration, approximately 90% is recovered in the urine as unchanged pregabalin. Only about 0.9% is found in urine as the N-methylated derivative.

Pregabalin is eliminated primarily by renal excretion with a mean elimination half-life of 6.3 hours in patients with normal renal function. Pregabalin elimination is nearly proportional to creatinine clearance (CrCl). Dosage reduction in patients with renal failure is necessary. Pregabalin is effectively removed from plasma by hemodialysis (50% after 4 h of hemodialysis).

The most common side effects of pregabalin are dizziness and drowsiness. Other important side effects include dry mouth, edema, blurred vision, weight gain, and difficulty concentrating. Pregabalin has rarely been associated with angioedema (swelling of the face, tongue, lips, and gums, throat, and larynx).

Summary

Pregabalin is a more potent version of gabapentin with better bioavailability and similar side effect profile. Efficacy has been demonstrated as add-on treatment for partial onset seizures. It has the advantage of being easily removed by hemodialysis in renal patients in contrast to gabapentin. Anxiolytic and analgesic properties could be useful in treating patients with comorbidities.

Valproate

Valproate (VPA) is the drug of choice for primary generalized epilepsies, and is also approved for the treatment of partial seizures. It was discovered by accident; first synthesized in 1882, its antiepileptic properties were recognized when it was used as a solvent for the experimental screening of new antiepileptic compounds. It was licensed in Europe in the early 1960s, where its use became extensive. It has been used in different forms, including divalproex sodium, magnesium or calcium salt, or valpromide. These forms do not differ significantly.

The mechanism of action is uncertain. VPA enhances GABA function, but this effect is observed only at high concentrations. It may increase the synthesis of GABA by stimulating GAD. It also produces selective modulation of voltage-gated sodium currents during sustained, rapid, repetitive neuronal firing.

Pharmacokinetics

VPA is a simple molecule, similar to endogenous fatty acids. It is slightly soluble in water and highly soluble in organic solvents. The sodium salt is highly water soluble, whereas the calcium and magnesium salts are insoluble. VPA is absorbed rapidly and nearly completely, with a bioavailability close to 100%. The peak plasma level after oral administration is reached in 13 minutes to 2 hours. The acid form takes a longer time to reach peak plasma concentration (3-4 h), and divalproex sodium reaches peak plasma concentration slightly faster. The enteric-coated divalproex sodium reaches peak concentration in approximately 3-8 hours. The sprinkle form peaks in 4 hours.

VPA is 85-95% bound to plasma proteins. Protein binding decreases at higher levels (ie, >100 mg/mL), in renal and hepatic diseases, and during pregnancy. Some other drugs (eg, aspirin, phenylbutazone) displace VPA, but other AEDs do not. Total serum VPA levels affect protein binding such that at serum concentrations less than 75 mcg/mL, the unbound fraction ranges from 7-9%. At serum concentrations of 100 mc/mL, the free fraction increased to 15%. The volume of distribution is 0.1-0.4 L/kg. VPA reaches the brain by an active transport process that is saturable. It is metabolized in the liver (96%) mainly by beta-oxidation and then glucuronidation. Less than 4% is excreted unchanged in urine. Some metabolites may be responsible for adverse effects, particularly the 4-ene metabolite that may cause hepatic toxicity. The plasma half-life is 16 hours. When used with enzyme-inducing AEDs, the half-life is reduced to 9 hours.

An IV form of VPA (DEPACON, Abbott Pharmaceuticals) is available. It is well tolerated, with only 2% of patients discontinuing treatment because of adverse effects, and has no significant effect on the cardiovascular system. Bioavailability is similar to that of the oral preparation. The T_max after IV VPA is at the end of 1-hour infusion, and thus the drug should be administered every 6 hours.

Drug interactions

VPA is a potent inhibitor of both oxidation and glucuronidation. It increases plasma levels of free fractions of PHT, PHB, CBZ epoxide, and LTG. It decreases total PHT level. The levels of VPA are decreased by enzyme-inducing drugs and are increased by felbamate and clobazam.

Antiepileptic effect and clinical use

VPA is a potent AED, effective against a wide range of seizure types. It is the drug of choice in idiopathic generalized epilepsy. Open and comparative studies have shown excellent control rates in patients with newly diagnosed typical absence seizure. It is the drug of choice for juvenile myoclonic epilepsy and can be used in other types of myoclonus. Also, it is a first-line drug in photosensitive epilepsy and Lennox-Gastaut syndrome. It is a second choice in the treatment of infantile spasms. In focal epilepsy, VPA has been shown to be as effective as other first-line agents. VPA is one of the most commonly used AEDs around the world.

The usual starting dose is 250 mg/d with a maintenance dose of 500-1500 mg/d. In the author's opinion, 3 times per day dosing is better tolerated, but twice-daily dosage is usual. Rapid titration usually is well tolerated. In children, the usual dose is 20 mg/kg/d and the maintenance dose is 40 mg/kg. Serum level has poor correlation with clinical effect and has significant daily fluctuations. IV VPA should be administered as a 60-minute infusion with a rate not exceeding 20 mg/min. It is available as 125 mg, 250 mg, and 500 mg delayed-release tablets; 125 mg and 250 mg sprinkle capsules; 500 mg extended-release tablets; 250 mg/5 mL syrup; and parenteral preparation for IV injection.

In utero exposure

Even though VPA has been used for many years, large controlled and blinded studies to determine the frequency of adverse effects have not been conducted. Based on clinical experience, dose-related adverse effects include nausea, vomiting (mainly during initiation of therapy and improved by administration of enteric-coated preparations), tremor, sedation, confusion or irritability, and weight gain. Metabolic effects from interference in mitochondrial metabolism include hypocarnitinemia, hyperglycinemia, and hyperammonemia. Severe sedation or even coma may result from hyperammonemia, typically with normal liver function tests. Patients with an underlying urea cycle enzyme defect may become encephalopathic from acute hyperammonemia, which may be fatal occasionally.

Hair loss or curling of hair may occur, which in the author's patients has improved when the patients used baby shampoo and a multivitamin supplement. VPA has adverse endocrine effects, including insulin resistance and change in sex hormone levels causing anovulatory cycles, amenorrhea, and polycystic ovary syndrome. Bone marrow suppression with neutropenia and allergic rashes are rare. Acute pancreatitis is rare but potentially fatal and usually reverses after withdrawal of VPA.

The most serious idiosyncratic adverse effect is hepatotoxicity. This is observed mainly in patients younger than 2 years and with polytherapy.

Summary

VPA is a very potent AED, but because of its adverse-effect profile, it is being replaced by newer AEDs. The new extended-release preparation may decrease dose-related adverse effects and may be better tolerated. It may be useful in patients with concomitant migraine headache. Hepatic failure from VPA is extremely rare in adulthood. VPA should be used with caution in women of reproductive age. The inhibition of kindling in experimental models suggests a potential use as a prophylactic agent for seizures; however, no clinical studies support this hypothesis. IV VPA is useful in patients when oral administration is not possible and when rapid IV loading is necessary. It is also helpful in patients with poorly controlled repetitive seizures that require a rapid IV load. Unlike PHT or PHB, IV VPA is not associated with hemodynamic changes.

Glutamate Blockers

Glutamate and aspartate are the most two important excitatory neurotransmitters in the brain. The glutamate system is a complex system with macromolecular receptors with different binding sites (ie, AMPA, kainate, NMDA, glycine, metabotropic site). The AMPA and the kainate sites open a channel through the receptor, allowing sodium and small amounts of calcium to enter. The NMDA site opens a channel that allows large amounts of calcium to enter along with the sodium ions. This channel is blocked by magnesium in the resting state.

The glycine site facilitates the opening of the NMDA receptor channel. The metabotropic site is regulated by complex reactions and its response is mediated by second messengers. NMDA antagonists have a limited use because they produce psychosis and hallucinations. In addition to these adverse effects, learning and memory may be impaired by blocking these receptors, because NMDA receptors are associated with learning processes and long-term potentiation (see Media file 8).

Schematic representation of the N-methyl-D-aspartate (NMDA) receptor.

Felbamate

Felbamate is a potent anticonvulsant, very effective against multiple seizure types. Unfortunately, after the occurrence of aplastic anemia and hepatic failure, approval for general use was withdrawn. It is now available in the United States only for a very limited use, principally by neurologists in patients for whom potential benefit outweighs the risk. It blocks the NMDA receptors and voltage-gated calcium channels and also modulates sodium-channel conductance, but has no effect on GABA receptors.

In addition to its activity against seizures, felbamate has been shown to have a neuroprotective effect on models of hypoxic-ischemic injuries. Wallis and Panizzon reported neuroprotection after treatment with felbamate in the rat hippocampal slice model following hypoxic exposure.¹⁹ Wasterlain et al also demonstrated the neuroprotective effect of felbamate after bilateral carotid ligation in rat pups with a window of opportunity for neuroprotection of 1-4 hours after the ligation.²⁰

Pharmacokinetics

After oral administration, felbamate is well absorbed, with a time to peak plasma concentration of 1-4 hours after the dose. It is distributed rapidly throughout the body, including the brain. Lipid-mediated blood-brain barrier penetration of felbamate is similar to that of PHT and PHB. It is 20-25% bound to plasma proteins (mainly albumin). The liver, via hydroxylation and conjugation, extensively metabolizes felbamate. The major identified metabolites of felbamate are p-hydroxy-felbamate, 2-hydroxy-felbamate, a monocarbonate, and a 3-carbamoyl oxy-2-phenylpropionic acid. Approximately 40-49% of felbamate doses are recovered in the urine as the parent compound. The elimination half-life of felbamate ranges from 13-30 hours when administered as monotherapy.

Concomitant enzyme inducers decrease the half-life to 13-14 hours, and the concentration of felbamate is significantly higher than expected in the presence of VPA. Felbamate also increases PHT levels and reduces CBZ levels with increments in CBZ-epoxide levels.

Antiepileptic effect and clinical use

Because of its potentially fatal toxic effects, use of felbamate is restricted to patients with severe partial epilepsy or Lennox-Gastaut syndrome who do not respond to other medications. This limited usage is because of the small but definitive risk of aplastic anemia and hepatic failure. The reported therapeutic serum level ranges from 30-100 mg/L. Initial dose of 1200 mg/d in 3 or 4 divided doses, with titration of 600 mg/wk up to a maximum of 2400-3600 mg/d, is recommended. Reducing the dosage of concomitant AEDs can eliminate most adverse effects. In children, recommended starting dose is 15 mg/kg/d, with weekly increments as high as 45 mg/kg/d. Again, concomitant AEDs should be reduced by 20% or more upon initiation of treatment and reduced further on the basis of symptoms and blood levels. Felbamate is available as 400 mg and 600 mg tablets and 600 mg/5 mL suspension.

Adverse effects and toxicity

Felbamate usually is well tolerated. Common adverse effects include insomnia, weight loss, nausea, decreased appetite, dizziness, fatigue, ataxia, and lethargy. Polytherapy is associated with increases in adverse effects. Clinical trials have shown that approximately 12% of patients discontinue the drug because of adverse effects. Fatal hepatic failure has been reported in 14 of 110,000 treated patients. Besides polytherapy, no other risk factor has been found. Most of the deaths occurred within 6 months of initiation of therapy.

Summary

Use of felbamate is restricted to patients with severe refractory epilepsy or Lennox-Gastaut syndrome.

Topiramate

Topiramate is a very potent anticonvulsant. It is structurally different from other AEDs. It is derived from D-fructose and initially was developed as an antidiabetic drug. In animal models, it was found to have potent antiepileptic effects. Topiramate has multiple mechanisms of action. It exerts an inhibitory effect on sodium conductance, decreasing the duration of spontaneous bursts and the frequency of generated action potentials, enhances GABA by unknown mechanisms, inhibits the AMPA subtype glutamate receptor, and is a weak inhibitor of carbonic anhydrase.

Pharmacokinetics

Topiramate is absorbed rapidly after oral administration and has a bioavailability close to 100%. When administered at regular doses, food delays but does not affect the extent of absorption. The time to peak blood levels is about 2 hours. The volume of distribution ranges from 0.6-1.0 L/kg. Plasma protein binding is approximately 15%. Only 15% of topiramate is metabolized in the liver by the P-450 microsomal enzyme system. None of the metabolites has antiepileptic action, and the majority of the drug (ie, 85%) is excreted unchanged in the urine. However, metabolism is much more extensive in patients on polytherapy, presumably as a result of enzyme induction. In patients with renal failure, doses may need to be reduced. The elimination half-life ranges from 18-23 hours and is independent of dose over the normal clinical range. In experimental settings, no tolerance to topiramate has been recorded.

Drug interactions

Enzyme-inducing drugs, such as PHT or CBZ, decrease serum topiramate concentrations by approximately 50%. Topiramate generally does not affect the steady-state concentrations of the other drugs given in polytherapy, although PHT levels may rise occasionally. Topiramate reduces ethyl estradiol levels by 30% and may inactivate the low-dose contraceptive pill. It may cause a mild reduction in digoxin levels.

Antiepileptic effect and clinical use

Topiramate has a marked antiepileptic effect, as demonstrated in 6 double-blind, parallel group, placebo-controlled, add-on trials and in a variety of open studies. As many as 5% of the patients became seizure free in some trials, 44% had reduction in seizure frequency of greater than 50% (compared to 12% of patients on placebo), and 21% had reduction in seizure frequency of more than 75%. Meta-analysis of placebo-controlled parallel group studies of topiramate and the other new AEDs has shown greater effects from topiramate than any of the other drugs compared to placebo. It also has been effective in drug-resistant generalized epilepsies as adjunctive therapy, including juvenile myoclonic epilepsy, absence and generalized tonic-clonic seizures, and Lennox-Gastaut syndrome. In the United States, it currently is approved for (1) partial onset and secondarily generalized tonic-clonic seizures, (2) primary generalized tonic-clonic seizures, and (3) Lennox Gastaut syndrome.

Topiramate is available as 25 mg, 50 mg, 100 mg, and 200 mg tablets and as 15 mg and 25 mg sprinkle formulations. A parenteral form is not available. It should be started at a low dose and titrated slowly to prevent adverse effects. Recommended starting dose is 25 mg/d; this is increased in weekly or biweekly increments of 25-50 mg. Maintenance dose is 200-600 mg/d in 2 divided doses. In children, the usual starting dose is 0.5-1 mg/kg/d with increments of 0.5-1 mg/kg/d every 2 weeks. In clinical trials, pediatric dosing in the range of 9-11 mg/kg/d produced optimal seizure control.

Adverse effects and toxicity

The most common adverse effects of topiramate include ataxia, impairment of concentration, confusion, dizziness, fatigue, paresthesia in the extremities, somnolence, disturbance of memory, depression, agitation, and slowness of speech. If the drug is continued, many adverse effects subside within a few weeks.

The most common adverse effects in children are somnolence, anorexia, fatigue, and nervousness. The drug causes weight loss in many patients, sometimes more than 10 kg, an effect that may lead to discontinuation. The weight loss appears to be related to appetite suppression. As the drug is a carbonic anhydrase inhibitor, it also has a propensity to cause renal calculi; therefore, patients should be encouraged to drink plenty of fluids.

No idiosyncratic severe reactions or allergic rashes have been reported; however, in the author's experience, several cases of pruritus have occurred, always associated with previous history of allergic rash to other medications. No hepatotoxicity, hematologic toxicity, serious GI toxicity, or cardiotoxicity have been documented. Recently, acute myopia with angle-closure glaucoma has been reported as a rare adverse event associated with topiramate.

Summary

Most physicians agree that topiramate is a highly effective AED. The adverse cognitive effects occur more frequently at higher doses and with a rapid titration rate. These cognitive adverse effects can be reduced by using a slow titration rate of 25 mg every week, until 200 mg/d is reached. Subsequently the dose can be increased in weekly increments of 25-50 mg/d to a target dose of 400-600 mg/d. In the author's experience, very slow titration, occasionally by increments of 25 mg/d biweekly, has improved tolerability in sensitive patients. Obese patients with epilepsy may benefit from this drug because of its weight-loss–inducing effect. Topiramate is also indicated as a prophylactic agent in patients with migraine headaches.

AEDs With Other Mechanisms of Action

Levetiracetam

Levetiracetam (LEV) is a piracetam (S-enantiomer pyrrolidone) derivative. It was developed in the 1980s to enhance cognitive functions and for anxiolysis. It is a unique AED in that it is ineffective in classic seizure models that screen potential compounds for antiseizure efficacy such as maximal electroshock and pentylenetetrazol in rats and mice. During preclinical evaluations, it was found to be effective in several models of seizures, including tonic and clonic audiogenic seizures in mice, tonic seizures in the maximum electroshock-seizure test in mice, and tonic seizures induced in rodents by chemoconvulsants.

Interestingly, LEV inhibits the development of pentylenetetrazol-induced amygdala kindling in mice, a situation in which other drugs such as PHT and CBZ are inactive. The mechanism of action is possibly related to a brain-specific stereo-selective binding site, the synaptic vesicle protein 2A (SV2A). The SV2A appear to be important for the availability of calcium-dependent neurotransmitter vesicles ready to release their content.¹ The lack of SV2A results in decreased action potential-dependent neurotransmission, while action potential-independent neurotransmission remains normal.^2,3  In addition, it reduces bicuculline-induced hyperexcitability in rat hippocampal CA3 neurons, suggesting a non-GABAergic mechanism. LEV inhibits Ca²⁺ release from the IP3-sensitive stores without reducing Ca²⁺ storage, which could explain some of LEV's antiepileptic properties.

Pharmacokinetics

LEV is absorbed rapidly following oral administration, with an oral bioavailability of approximately 100%. The peak concentration is reached approximately 0.6-1.3 hours after ingestion and the rate of absorption is slowed by food. It does not bind to plasma proteins. The volume of distribution is approximately 0.5-0.7 L/kg. It is minimally metabolized (approximately 27%), mainly by hydrolysis of the acetamide group. It does not involve the enzymes of the cytochrome P-450 system. The clinical relevance of the metabolites is likely to be negligible.

Approximately 66% is excreted unchanged in urine. LEV is cleared 48 hours after oral administration by glomerular filtration with partial tubular reabsorption. Although its elimination half-life is only 6-8 hours, its pharmacodynamic half-life is likely to be longer. In patients with renal insufficiency, the half-life may be increased up to 24 hours. The drug is removed during hemodialysis. LEV crosses the placenta, and fetal concentrations are similar to maternal levels.

Drug interactions

No significant drug interactions have been identified. Levetiracetam does not inhibit CYP450 isoenzymes, epoxide hydrolase, or UDP-glucuronidation.

Antiepileptic effect and clinical use

LEV is a potent AED. A multicenter, double-blind, responder-selected study evaluating LEV as monotherapy in patients with refractory partial epilepsy showed a 73.8% reduction of seizure frequency in 59.2% of the patients, and 18% of the monotherapy group remained seizure free. Tolerability studies have demonstrated that LEV is very well tolerated. In the EEG model, this drug induced a decrease in the number of frequent epileptiform discharges in most patients. An open-label study reported that 6 of 9 patients with juvenile myoclonic epilepsy refractory to VPA and/or LTG became seizure free on LEV.

These results suggest that LEV might have a significant effect in generalized epilepsies. In March, 2007 it was approved by the FDA as adjunctive treatment for primary generalized tonic-clonic seizures in adults and children aged 6 years and older.

Adult dose

The starting adult dose is 500 mg twice a day, with weekly increments of 500-1000 mg/d to 3000 mg, if required. A slower titration rate of 250 mg twice a day with subsequent weekly dose increases by 500 mg is tolerated better.

Pediatric dose

Tonic-clonic seizures:

<6 years: Not established

6-15 years: 10 mg/kg PO bid; may increase daily dose by 20-mg/kg increments q2wk, not to exceed 30 mg/kg bid

>16 years: Administer as in adults

Partial onset seizures:

<4 years: Not established

4-15 years: 20 mg/kg/d PO divided bid; may increase by 20 mg/kg/d increments q2wk; not to exceed 60 mg/kg/d; use oral solution if weight £20 kg

>16 years: Administer as in adults

Myoclonic seizures:

<12 years: Not established

>12 years: Administer as in adults

The drug is best given twice a day. LEV is available in tablets of 250 mg, 500 mg, 750 mg, and 1000 mg. Intravenous and oral solutions are also available.

Adverse effects and toxicity

LEV is well tolerated. The most significant adverse effects are somnolence, asthenia, and dizziness. A number of patients reported infection, usually related to upper respiratory tract; however, none of these patients discontinued the drug, and it was not associated with changes in WBC count. In phase II and the open extension studies that represent exposure to LEV of approximately 2258 patient-years, adverse effects were reported in more than 10% of cases. They included headache (25%), accidental injury (25%), convulsion (23%), infection (23%), asthenia (22%), somnolence (22%), dizziness (18%), pain (15%), pharyngitis (11%), and a flu-like syndrome (10%).

No serious acute idiosyncratic reactions have been reported, and no evidence of visual field disturbance has been reported. LEV has no strong tendency to exacerbate seizures, unlike this paradoxical effect recorded in some patients treated with other AEDs.

Summary

LEV is very useful in patients with hepatic or renal insufficiency and patients on concomitant medications, because it has no drug interactions. Current data support a good safety profile and efficacy in different patient populations, causing LEV to become one of the preferred AEDs in elderly patients. IV preparation is available and a good alternative to treat seizures in the acute setting. Efficacy in status epilepticus has not been established. The antiepileptogenic effect observed in kindling models makes it a potential agent for the prevention of epilepsy in conditions such as traumatic brain injury. However, no clinical studies have been performed to confirm this hypothesis.

Multimedia

Media file 1: Pearls of antiepileptic drug use and management.

Media file 2: The dynamic target of seizure control in the management of epilepsy is achieving balance between the factors that influence the excitatory postsynaptic potential (EPSP) and those that influence inhibitory postsynaptic potential (IPSP).

Media file 3: Antiepileptic drugs can be grouped according to their major mechanism of action. Some antiepileptic drugs work by acting on a combination of channels and/or some unknown mechanism of action.

Media file 4: Some antiepileptic drugs stabilize the inactive configuration of the sodium (Na+) channel, preventing high-frequency neuronal firing.

Media file 5: Low-voltage calcium (Ca2+) currents (T-type) are responsible for the rhythmic thalamocortical spike and wave patterns of generalized absence seizures. Some antiepileptic drugs lock these channels, inhibiting the underlying slow depolarizations necessary to generate spike-wave bursts.

Media file 6: The GABA-A receptor mediates chloride (Cl-) influx, leading to hyperpolarization of the cell and inhibition. Antiepileptic drugs may act to enhance Cl- influx or decrease GABA metabolism.

Media file 7: Glutamate, the main excitatory neurotransmitter in the CNS, binds to multiple receptor sites that differ in activation and inactivation time courses, desensitization kinetics, conductance, and ion permeability. The 3 main glutamate receptor subtypes are N-methyl-D-aspartate (NMDA), metabotropic, and non-NMDA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA] and kainate receptors). Antiepileptic drugs known to possess this mechanism of action are listed.

Media file 8: Schematic representation of the N-methyl-D-aspartate (NMDA) receptor.

Media file 9: GABA drugs and their known sites of action.

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Keywords

antiepileptic drug, AED, seizures, epilepsy, seizure treatment, epilepsy treatment, anticonvulsants, antiseizure drugs, epilepsy drugs, seizure, carbamazepine, CBZ, phenytoin, PHT, fosphenytoin, oxcarbazepine, OXC, lamotrigine, LTG, zonisamide, ZNS, clobazam, clonazepam, phenobarbital, PHB, primidone, tiagabine, TGB, vigabatrin, VGB, gabapentin, GBP, valproate, VPA, felbamate, topiramate, levetiracetam, LEV, pregabalin, antiepileptic drugs, antiepileptic medications

Contributor Information and Disclosures

Author

Juan G Ochoa, MD, Associate Professor of Neurology, Director, EEG Lab/Epilepsy Monitoring Unit, Department of Neurology, Neuroscience Institute, University of Florida at Jacksonville
Juan G Ochoa, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, and American Epilepsy Society
Disclosure: Pfizer None Speaking and teaching; Glaxo Honoraria Speaking and teaching; UCB Pharma Honoraria Speaking and teaching

Coauthor(s)

Willise Riche, MD, Epilepsy Program Coordinator, Department of Neurology, Shands Hospital; Educator, Department of Neurology, University of Phoenix at Jacksonville
Disclosure: Nothing to disclose.

Medical Editor

Erasmo A Passaro, MD, Director, Comprehensive Epilepsy Program/Clinical Neurophysiology Lab, Bayfront Medical Center Florida Center for Neurology
Erasmo A Passaro, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association, and American Society of Neuroimaging
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; Takeda Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Jose E Cavazos, MD, PhD, FAAN, Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, University of Texas Health Science Center at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center; Director of the Epilepsy Center, Audie L Murphy Veterans Affairs Medical Center
Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and Society for Neuroscience
Disclosure: Glaxo-SmithKline Honoraria Consulting; Ortho-McNeil Neurologics Honoraria Consulting; UCB Pharma Honoraria Consulting

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

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