Antiseizure Medications

Epilepsy Overview

• Epilepsy is a chronic brain disorder characterized by recurrent, unpredictable seizures.
• Affects approximately 1% of the world's population; fourth most common neurological disorder.
• Seizures are transient alterations in behavior, sensation, or consciousness due to abnormal, synchronized electrical discharges in the brain.
• Etiology:
  • Symptomatic: Resulting from brain damage (traumatic brain injury, stroke, infections), tumors, or developmental lesions.
  • Genetic: Complex inheritance (oligogenic or polygenic), rarely a single gene defect.
  • Idiopathic: Genetic epilepsies with seizures as the only clinical manifestation and no identifiable structural or metabolic abnormality.
• Idiopathic Generalized Epilepsy (IGE):
  • Formerly used for generalized epilepsies with bilateral EEG discharges (childhood absence epilepsy, juvenile myoclonic epilepsy, etc.).
  • Now categorized as Genetic Generalized Epilepsy (GGE), but the term IGE may still be used.
• Developmental and Epileptic Encephalopathies (DEEs):
  • Severe, intractable epilepsy forms with developmental and intellectual disabilities.
  • Can be acquired (hypoxic-ischemic encephalopathy, perinatal stroke, infections, trauma) or part of a genetic syndrome (tuberous sclerosis complex).
  • Examples: Lennox-Gastaut syndrome, Dravet syndrome (mutations in SCN1A gene), CDKL5 deficiency disorder (mutations in CDKL5 gene), PCDH19 clustering epilepsy (mutations in PCDH19 gene), GLUT1 deficiency syndrome (mutations in SLC2A glucose transporter gene), infantile spasms (West syndrome).

Use of Antiseizure Medications

• Typically used chronically to prevent seizures in people with epilepsy.
• Also used in people without epilepsy to prevent seizures during acute illnesses (meningitis) or after neurosurgery/traumatic brain injury.
• Used to manage acute repetitive seizures (seizure clusters) or to terminate ongoing seizures (status epilepticus, prolonged febrile seizures, neonatal seizures, exposure to nerve toxins).
• Seizures can be caused by acute toxic or metabolic disorders (hypocalcemia), requiring specific abnormality correction.

Classification of Seizures

• Epileptic seizures are classified into two main categories:
  • Focal Onset Seizures: Begin in a local cortical site.
  • Generalized Onset Seizures: Involve both brain hemispheres from the onset.
• Focal seizures can transition to bilateral tonic-clonic seizures (formerly called “secondarily generalized”).
• Focal Aware Seizures: Preservation of consciousness.
• Focal Impaired Awareness Seizures: Impaired consciousness.
• Tonic-Clonic Convulsions: Loss of consciousness, falls, stiffens (tonic phase), jerks (clonic phase), followed by confusion and tiredness (postictal period).
• Generalized Tonic-Clonic Seizures: Involve both hemispheres from the onset; occur in patients with idiopathic (genetic) generalized epilepsies.
• Generalized Absence Seizures: Brief episodes of unconsciousness (4–20 seconds) with no warning and immediate resumption of consciousness.
• Epileptic Spasms: Sudden flexion, extension, or mixed extension-flexion of predominantly proximal and truncal muscles.
• Myoclonic Seizures: Sudden, brief (<100 milliseconds), involuntary contractions of muscles or muscle groups.
• Atypical Absences: Occur in DEEs (Lennox-Gastaut syndrome); loss of awareness begins and ends less abruptly than in typical absence seizures.
• Atonic Seizures: Sudden loss of muscle tone, often causing a forward fall (mainly occur in the Lennox-Gastaut syndrome).

$\text{Table 24-1: International League Against Epilepsy classification of seizure types}$

Treatment of Epilepsy

• Antiseizure medications are administered orally to prevent seizures.
• Medication choice depends on the type of seizures or the patient’s syndromic classification.
• Appropriately chosen medications provide adequate seizure control in about two-thirds of patients.
• Monotherapy is preferred to minimize adverse effects.
• Multiple medications are used simultaneously for hard-to-control seizures.
• Pharmacoresistance: Failure to achieve seizure control following adequate trials with two or more appropriate medications.
• DEEs (Lennox-Gastaut syndrome, early infantile developmental and epileptic encephalopathy (EIDEE), infantile spasms, Dravet syndrome) are difficult to treat with medications.
• Focal seizures may also be refractory to medications.
• Surgery:
  • Epilepsy can be cured by surgical resection of the affected brain region (temporal lobe resection for mesial temporal lobe epilepsy).
  • Lesionectomy may be curative when seizures arise from cortical injury, malformation, tumor, or a vascular lesion.
• Electrical Stimulation:
  • Vagus Nerve Stimulator (VNS): Implanted pulse generator that stimulates the left vagus nerve; for drug-refractory focal seizures and symptomatic generalized epilepsies of the Lennox-Gastaut type.
  • Responsive Neurostimulator (RNS): Implanted closed-loop system that detects abnormal electrical activity and delivers electrical stimulation to prevent seizure occurrence.
  • Deep Brain Stimulation (DBS): Bilateral open-loop stimulation to the anterior nuclei of the thalamus; for focal seizures with or without secondary generalization.
• Dietary Therapies:
  • Ketogenic diets (high in fat, low in carbohydrate, controlled protein intake) are effective in refractory epilepsy.
  • Beneficial in myoclonic epilepsies, infantile spasms, Dravet syndrome, seizures associated with tuberous sclerosis complex, and GLUT1 deficiency syndrome (De Vivo disease).
  • Most commonly used in children, but adults can also benefit.

Mechanisms of Action of Antiseizure Medications

• Protect against seizures by interacting with molecular targets in the brain.
• Inhibit the local generation of seizure discharges by:
  • Reducing the ability of neurons to fire action potentials at a high rate.
  • Reducing neuronal synchronization.
• Inhibit the spread of epileptic activity by:
  • Strengthening the inhibitory surround mediated by GABAergic interneurons.
  • Reducing glutamate-mediated excitatory neurotransmission.
• Specific actions:
  • Modulation of voltage-gated sodium, calcium, or potassium channels.
  • Enhancement of fast GABA-mediated synaptic inhibition.
  • Modification of synaptic release processes.
  • Diminution of fast glutamate-mediated excitation.
• Imbalance favoring excitation over inhibition leads to seizure generation.
• Treatments inhibit excitation (sodium channel blockers, modification of glutamate release, AMPA receptor antagonists) or enhance inhibition (positive allosteric modulators of GABAA receptors, increased availability of GABA, Kv7 channel openers).
• Targeting disease pathology is a more specific approach (successful in tuberous sclerosis complex with everolimus).

$\text{Table 24-2: Molecular targets of antiseizure drugs}$

Pharmacokinetics of Antiseizure Medications

• Adequate drug exposure must be continuously maintained due to the life-threatening nature of seizures.
• Narrow therapeutic window necessitates careful dosing to avoid toxicity.
• Understanding pharmacokinetic properties is essential.
• Considerations:
  • Nonlinear relationships between dose and drug exposure.
  • Influence of hepatic or renal impairment on clearance.
  • Drug-drug interactions (common due to combination therapy).
• Hepatic Enzymes:
  • Many antiseizure medications are metabolized by hepatic enzymes.
  • Some (carbamazepine, oxcarbazepine, eslicarbazepine acetate, phenobarbital, phenytoin, primidone) are strong inducers of hepatic cytochrome P450 and glucuronyl transferase enzymes.
• Drug Interactions:
  • Addition of a new drug can affect the clearance of the current drug.
  • Current drug may necessitate selection of a different dosing regimen for the new drug.
  • New drug may increase the concentration of an existing drug by inhibiting its metabolism or reduce it by inducing its metabolism.
• Renal Excretion: Some antiseizure medications are excreted in the kidney and are less susceptible to drug-drug interactions.
• Active Metabolites: Oxcarbazepine, carbamazepine, primidone, mephenytoin, and clobazam have active metabolites; conversion extent can be affected by other drugs.
• Protein Binding:
  • Phenytoin, tiagabine, valproate, diazepam, perampanel, stiripentol, and ganaxolone are highly (>90%) bound to plasma proteins.
  • Displacement from plasma proteins by other protein-bound drugs can cause transient toxicity.
• Levetiracetam, gabapentin, and pregabalin have minimal drug interactions.
• Antiseizure drugs can affect other medications; oral contraceptive levels may be reduced by strong inducers.
• Bioavailability and CNS Penetration:
  • Antiseizure medications must have reasonable oral bioavailability and enter the central nervous system.
  • Predominantly distributed into total body water.
• Plasma clearance is relatively slow; many are medium to long acting (administered two or three times a day).
• Extended-release preparations are available for drugs with short half-lives to improve compliance.
• Next sections will review widely used antiseizure medications, categorized by their effectiveness for focal seizures, generalized onset seizures, and certain epilepsy syndromes.

$\text{Figure 24-1: Molecular targets for antiseizure medications}$

Medications Used for Focal (Partial Onset) Seizures

• Carbamazepine is a prototype, also indicated for tonic-clonic (grand mal) seizures.
• Carbamazepine can exacerbate certain seizure types in idiopathic (genetic) generalized epilepsies.
• Other popular medications include lamotrigine, lacosamide, and oxcarbazepine; levetiracetam is also frequently used.
• Phenobarbital is useful if cost is an issue.
• Vigabatrin and felbamate are third-line drugs due to the risk of toxicity.

CARBAMAZEPINE

• One of the most widely used antiseizure medications, primarily for focal (partial onset) and focal-to-bilateral tonic-clonic seizures.
• Also used for trigeminal neuralgia (first-choice medication) and as a mood stabilizer for bipolar disorder.
• Chemistry: Iminostilbene (dibenzazepine)—a tricyclic compound similar structurally to tricyclic antidepressants.

Mechanism of Action

• Prototypical sodium channel-blocking antiseizure medication.
• Interacts with voltage-gated sodium channels (Nav1) responsible for the rising phase of neuronal action potentials.
• Sodium channels cycle through resting, open, and inactivated states.
• Carbamazepine and other sodium channel-blocking medications bind preferentially to the channel when it is in the inactivated state, stabilizing it.
• Use-dependent blocking action: High-frequency trains of action potentials are more effectively inhibited than individual action potentials.
• Voltage dependence: A greater fraction of sodium channels exist in the inactivated state at depolarized potentials.
• Preferentially inhibits action potentials during seizure discharges without greatly interfering with ordinary ongoing action potential firing.
• Reduces transmitter output at synapses.
• Carbamazepine has activity in the rodent maximal electroshock (MES) but not in the pentylenetetrazol (PTZ) test.

Clinical Uses

• Effective for focal and focal-to-bilateral tonic-clonic seizures.
• May be effective in the treatment of generalized tonic-clonic seizures in idiopathic (genetic) generalized epilepsies, but use with caution as it can exacerbate absence and myoclonic seizures.
• Also effective for trigeminal and glossopharyngeal neuralgia and mania in bipolar disorder.

Pharmacokinetics

• Nearly 100% oral bioavailability, but the rate of absorption varies widely among patients.
• Peak levels are usually achieved 6–8 hours after administration.
• Distribution is slow, and the volume of distribution is approximately 1 L/kg.
• Plasma protein binding is approximately 70%.
• Very low systemic clearance of approximately 1 L/kg/d at the start of therapy.
• Induces its own metabolism, causing serum concentrations to fall after a few weeks of treatment.
• Half-life decreases from 36 hours after an initial single dose to 8–12 hours in subjects receiving continuous therapy.
• Metabolized in the liver, primarily by CYP3A4, to carbamazepine-10,11-epoxide (has antiseizure activity).

Dosage Recommendations & Therapeutic Levels

• Available in immediate-release tablets and suspensions, and extended-release forms.
• Effective in children (15–25 mg/kg/d).
• Typical daily maintenance dose in adults is 800–1200 mg/d, with a maximum recommended dose of 1600 mg/d (rarely, 2400 mg/d).
• Therapeutic concentrations (trough level) are usually 4–8 mcg/mL.
• Initiation of therapy should be slow, with gradual increases in dose.

Drug Interactions

• Stimulates the transcriptional up-regulation of CYP3A4 and CYP2B6, leading to reduced carbamazepine concentrations and increased metabolism of concomitant antiseizure medications.
• Valproate may inhibit carbamazepine clearance and increase steady-state blood levels.
• Phenytoin and phenobarbital may decrease steady-state concentrations of carbamazepine through enzyme induction.
• No clinically significant protein-binding interactions have been reported.

Adverse Effects

• Dose-dependent mild gastrointestinal discomfort, dizziness, blurred vision, diplopia, or ataxia; sedation occurs only at high doses.
• Benign leukopenia occurs in many patients; intervention is needed if the neutrophil count falls below 1000/mm3.
• Rash and hyponatremia are the most common reasons for discontinuation.
• Stevens-Johnson syndrome is rare, but the risk is significantly higher in patients with the HLA-B∗1502 allele (Asians are recommended to be tested before starting therapy).

OXCARBAZEPINE

• 10-keto analog of carbamazepine; cannot form an epoxide metabolite.
• Hypothesized that oxcarbazepine is better tolerated, but little evidence is available to document this claim.
• Rapidly and almost completely (>95%) absorbed; quickly converted to active 10-hydroxy metabolites, S(+)- and R(–)-licarbazepine.

ESLICARBAZEPINE ACETATE

• A prodrug of S(+)-licarbazepine, provides an alternative to oxcarbazepine, with some minor differences.
• Like oxcarbazepine, eslicarbazepine acetate is converted to eslicarbazepine but the conversion occurs more rapidly and it is nearly completely to the S(+) form, with only a small amount of the R(−) isomer (5%) formed by chiral inversion.
• Administered at a dosage of 400–1600 mg/d; titration is typically required for the higher doses.

LACOSAMIDE

• A sodium channel-blocking antiseizure medication approved for the treatment of focal seizures.
• Has favorable pharmacokinetic properties and good tolerability.

Mechanism of Action

• Early studies suggested that lacosamide enhances a poorly understood type of sodium channel inactivation called slow inactivation.
• Recent studies, however, contradict this view and indicate that the drug binds selectively to the fast inactivated state of sodium channels—as is the case for other sodium channel-blocking antiseizure medications, except that the binding is much slower.

Clinical Uses

• Lacosamide is approved for the treatment of focal onset seizures in patients age 17 years and older.
• In clinical trials with more than 1300 patients, lacosamide was effective at doses of 200 mg/d and had greater and roughly similar overall efficacy at 400 and 600 mg/d, respectively.

Pharmacokinetics

• Oral lacosamide is rapidly and completely absorbed in adults, with no food effect. Bioavailability is nearly 100%.
• Peak concentrations occur from 1 to 4 hours after oral dosing, with an elimination half-life of 13 hours.

PHENYTOIN

• First identified to have antiseizure activity in 1938, is the oldest nonsedating medication used in the treatment of epilepsy.
• It is prescribed for the prevention of focal seizures and generalized tonic-clonic seizures and for the acute treatment of status epilepticus.

Mechanism of Action

• Phenytoin is a sodium channel-blocking antiseizure medication that acts in a similar fashion to carbamazepine and other agents in the class.

Clinical Uses

• Phenytoin is effective in preventing focal onset seizures and also tonic-clonic seizures, whether they are focal-to-bilateral tonic-clonic (secondarily generalized) or occurring in the setting of an idiopathic (genetic) generalized epilepsy syndrome.

Pharmacokinetics & Drug Interactions

• Absorption of phenytoin is highly dependent on the formula- tion. Particle size and pharmaceutical additives affect both the rate and the extent of absorption.

MEPHENYTOIN, ETHOTOIN, & PHENACEMIDE

• Many analogs of phenytoin have been synthesized, but only three have been marketed in the USA, with none currently com-mercially available.
• Of the three, mephenytoin and ethotoin are hydantoins, whereas phenacemide (phenacetylurea) is a ring-opened analog of phenytoin.

GABAPENTIN & PREGABALIN

• Gabapentin [1-(aminomethyl)cyclohexaneacetic acid] and pregabalin [(S)-3-(aminomethyl)-5-methylhexanoic acid], known as “gabapentinoids,” are amino acid-like molecules that were origi-nally synthesized as analogs of GABA but are now known not to act through GABA mechanisms.
• They are used in the treatment of focal seizures and various nonepilepsy indications, such as neuro-pathic pain, restless legs syndrome, and anxiety disorders. 576 THE PHARMACOLOGICAL BASIS OF THERAPEUTICS

Mechanism of Action

• Despite their close structural resemblance to GABA, gabapentin and pregabalin do not act through effects on GABA receptors or any other mechanism related to GABA-mediated neurotransmis-sion.
• Rather, gabapentinoids bind avidly to α2δ proteins, specifi-cally α2δ-1 and α2δ-2.

Clinical Uses

• Gabapentin and pregabalin are effective in the treatment of focal seizures; there is no evidence that they are efficacious in gener-alized epilepsies.

Pharmacokinetics

• Gabapentin and pregabalin are not metabolized and do not induce hepatic enzymes; they are eliminated unchanged in the urine.
• Both medications are absorbed by the L-amino acid trans-port system, which is found only in the upper small intestine.

TIAGABINE

• Tiagabine, a selective inhibitor of the GAT-1 GABA transporter, is a second-line treatment for focal seizures.
• It is contraindicated in generalized onset epilepsies.

Mechanism of Action

• Tiagabine is a lipophilic, blood-brain barrier-permeant analog of nipecotic acid, a GABA uptake inhibitor that is not active sys-temically.

Clinical Uses

• Tiagabine is indicated for the adjunctive treatment of focal sei-zures, with or without secondary generalization (focal-to-bilateraltonic-clonic).

Pharmacokinetics

• Tiagabine is 90–100% bioavailable, has linear kinetics, and is highly protein bound.

RETIGABINE (EZOGABINE)

• Retigabine (US Adopted Name: ezogabine), a potassium channel opener, is indicated for the treatment of focal seizures.
• Because retigabine causes pigment discoloration of the skin and eye, it had limited use and its sale was discontinued.

Mechanism of Action

• Retigabine is an allosteric opener of KCNQ2-5 (Kv7.2-Kv7.5) voltage-gated potassium channels, which are localized, in part, in axons and nerve terminals.

Clinical Use

• Doses of retigabine range from 600 to 1200 mg/d, with 900 mg/dexpected to be the most common.

CENOBAMATE

• Cenobamate is a tetrazole alkyl monocarbamate used in the treatment of focal seizures.
• It has broad-spectrum antiseizure activity in animal models, but a clinical assessment of its efficacy in the treatment of generalized seizures has not yet been completed.

Clinical Uses

• The usual maintenance dose of cenobamate is 200 mg once daily.
• A dose of 400 mg once daily was studied in a clinical trial and had efficacy only modestly greater than the 200-mg dose.

Pharmacokinetics

• Cenobamate is well absorbed following oral administration (>88%) and reaches peak levels within 1–4 hours.

Medications Effective for Focal Seizures & Certain Generalized Onset Seizure Types

LAMOTRIGINE

• Lamotrigine is considered a sodium channel-blocking antisei- zure medication; it is effective for the treatment of focal sei-zures, as are other medications in this category.

Chemistry

• Lamotrigine was developed when investigators thought that the antifolate effects of certain antiseizure medications such as phe-nytoin might contribute to their effectiveness.

Mechanism of Action

• The action of lamotrigine on voltage-gated sodium channels is similar to that of carbamazepine.

Clinical Uses

• Although most controlled studies have evaluated lamotrigine as add-on therapy, the medication is effective as monotherapy for focal seizures, and lamotrigine is now widely prescribed for this indication because of its excellent tolerability.

Pharmacokinetics

• Lamotrigine is almost completely absorbed and has a volume of distribution of 1–1.4 L/kg.

LEVETIRACETAM

• Levetiracetam is a broad-spectrum antiseizure agent and one of the most commonly prescribed drugs for epilepsy, primarily because of its perceived favorable adverse effect profile, broad therapeutic window, favorable pharmacokinetic properties, and lack of drug-drug interactions.

Mechanism of Action

• Levetiracetam is an analog of piracetam, which is purported to be a cognition enhancer.

Clinical Uses

• Levetiracetam is effective in the treatment of focal seizures in adults and children, primary generalized tonic-clonic seizures, and the myoclonic seizures of juvenile myoclonic epilepsy.

Pharmacokinetics

• Oral absorption of levetiracetam is rapid and nearly complete, with peak plasma concentrations in 1.3 hours.

BRIVARACETAM

• Brivaracetam, the 4-n-propyl analog of levetiracetam, is a high-affinity SV2A ligand recently approved for the treatment of focal (partial) onset seizures.
• There is no evidence that brivaracetam has superior efficacy to levetiracetam for this indication.
• As is the case with leve-tiracetam, brivaracetam use has been associated with psychiatric adverse effects including depression, insomnia, irritability, aggression, belligerence, anger, and anxiety.
• There is some evidence that patients experiencing such behavioral adverse effects during treatment with levetiracetam will benefit from a switch to brivaracetam.
• However, there is also evidence that levetiracetam may have reduced propensity for other adverse effects such as dizziness.