CNS Pharmacology: Antiepileptic Drugs

Introduction/Overview

Epilepsy remains one of the most common neurological disorders worldwide, affecting approximately 50 million individuals across all ages. Antiepileptic drugs (AEDs) constitute the cornerstone of therapeutic intervention, providing seizure control and improving quality of life for patients. The pharmacologic landscape of AEDs has expanded considerably over the past few decades, encompassing a broad spectrum of agents with diverse mechanisms of action, pharmacokinetic profiles, and therapeutic indications. Understanding the intricacies of AED pharmacology is essential for clinicians and pharmacists alike, given the complex interactions with comorbid conditions, concomitant medications, and patient-specific factors such as age, renal function, and pregnancy status.

Learning objectives for this chapter include:

• Identification of the major classes of AEDs and their chemical characteristics.
• Explanation of the principal mechanisms through which AEDs exert anticonvulsant effects.
• Interpretation of pharmacokinetic parameters relevant to dosing strategies.
• Recognition of approved and off‑label indications for contemporary AEDs.
• Recognition of common and serious adverse effect profiles, as well as potential drug interactions.
• Application of special considerations for vulnerable patient populations.

Classification

Drug Classes and Categories

AEDs can be grouped into several broad categories based on structural origin, mechanism of action, or clinical use. Historically, the first generation of AEDs comprised phenobarbital, phenytoin, and carbamazepine, which were largely sodium‑channel blockers. Subsequent generations introduced agents with distinct pharmacologic targets, such as valproic acid (a broad‑spectrum agent affecting sodium, calcium, and GABAergic pathways) and levetiracetam (a synaptic vesicle protein ligand). The most recent agents include lacosamide (enhancer of slow inactivation of sodium channels) and perampanel (antagonist of AMPA glutamate receptors). The classification can also be organized by chemical class: phenols, phenylbutyrates, sulfonamides, amino acid derivatives, among others.

Chemical Classification

From a chemical standpoint, AEDs are diverse. Phenobarbital and phenytoin are barbiturates and phenols, respectively; carbamazepine is a dibenzazepine; valproic acid is a short‑chain fatty acid; levetiracetam is a pyrrolidine derivative; lacosamide is a benzamide; perampanel is a thienopyridone. This heterogeneity underlines the importance of understanding individual drug properties when selecting therapy.

Mechanism of Action

Detailed Pharmacodynamics

Antiepileptic drugs achieve seizure suppression through modulation of neuronal excitability. Sodium‑channel blockers, such as phenytoin, carbamazepine, and lacosamide, stabilize the inactivated state of voltage‑gated Na⁺ channels, thereby reducing repetitive firing. Phenytoin and carbamazepine preferentially inhibit the fast inactivation pathway, whereas lacosamide targets the slow inactivation component, offering a distinct therapeutic profile.

Valproic acid exerts multi‑faceted effects: it increases gamma‑aminobutyric acid (GABA) levels by inhibiting GABA transaminase, inhibits voltage‑gated Na⁺ and Ca²⁺ channels, and modulates histone deacetylase activity, thereby influencing gene expression. GABAergic potentiation is central to valproic acid’s broad-spectrum efficacy.

Levetiracetam binds to synaptic vesicle protein 2A (SV2A), modulating neurotransmitter release without affecting classical ion channels. This unique mechanism accounts for its favorable side‑effect profile and low propensity for pharmacokinetic interactions.

Perampanel functions as a non‑competitive antagonist of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor, thereby attenuating excitatory synaptic transmission. This action distinguishes perampanel from other AEDs that act via ion channel modulation.

Receptor Interactions

In addition to sodium‑channel blockade, AEDs interact with various receptors and transporters. Carbamazepine and phenytoin antagonize the NMDA receptor indirectly by reducing intracellular calcium. Gabapentin and pregabalin bind to the α2δ subunit of voltage‑gated calcium channels, decreasing calcium influx and subsequent neurotransmitter release. While not classic AEDs, these agents are often employed adjunctively for partial seizures.

Molecular/Cellular Mechanisms

Beyond ion channel modulation, AEDs influence intracellular signaling pathways. Valproic acid’s inhibition of histone deacetylase leads to altered transcription of genes involved in neuronal plasticity and seizure threshold. Lacosamide’s enhancement of slow Na⁺ channel inactivation involves allosteric modulation of the channel’s S4 voltage sensor, providing a distinct temporal profile of action. These molecular insights support the development of novel AEDs with targeted mechanisms.

Pharmacokinetics

Absorption, Distribution, Metabolism, Excretion

Oral bioavailability varies widely among AEDs. Phenobarbital and carbamazepine exhibit high oral absorption (>80 %), whereas levetiracetam demonstrates near‑complete absorption (~100 %). Food intake can influence absorption; for instance, phenytoin’s absorption is reduced when taken with high‑fat meals, potentially necessitating dose adjustments.

Distribution is governed by plasma protein binding. Phenytoin and carbamazepine are highly protein‑bound (>90 %), which predisposes them to competitive displacement interactions. Valproic acid binds to albumin and α1‑acid glycoprotein, with binding rates of 70–90 %. Levetiracetam and lacosamide have modest protein binding (<10 %), reducing interaction risk.

Metabolic pathways differ among agents. Phenytoin, carbamazepine, and valproic acid undergo hepatic cytochrome P450 (CYP) oxidation, leading to the formation of reactive metabolites. Phenytoin is metabolized primarily by CYP2C9 and CYP2C19, whereas carbamazepine is primarily CYP3A4/5. Valproic acid is metabolized via glucuronidation and beta‑oxidation, with minimal CYP involvement. Levetiracetam and lacosamide are largely excreted unchanged by the kidneys, with minimal hepatic metabolism.

Elimination routes vary accordingly. Renal excretion predominates for levetiracetam, lacosamide, and perampanel, whereas hepatic metabolism is central for phenobarbital, phenytoin, carbamazepine, and valproic acid. Dose adjustments may be necessary in renal or hepatic impairment, depending on the drug’s primary elimination pathway.

Half‑Life and Dosing Considerations

Therapeutic plasma concentrations are maintained by careful dosing that accounts for variable half‑lives. Phenytoin’s half‑life ranges from 8 to 20 hours and displays non‑linear kinetics; small dose changes can lead to disproportionate concentration alterations. Carbamazepine’s half‑life spans 12 to 30 hours and shows auto‑induction of metabolism, necessitating dose escalation over time. Valproic acid has a half‑life of approximately 9–16 hours, with dose‑dependent saturation of metabolic pathways, particularly in hepatic impairment.

Levetiracetam’s half‑life is 3–4 hours, allowing flexible twice‑daily dosing. Lacosamide’s half‑life averages 10 hours, facilitating once‑daily dosing. Perampanel’s half‑life is notably prolonged (~105 hours), permitting once‑weekly dosing in some regimens. Dosing schedules must also consider the therapeutic window and seizure type; for example, generalized tonic‑clonic seizures may require higher peak concentrations than partial seizures.

Therapeutic Uses/Clinical Applications

Approved Indications

Antiepileptic drugs are approved for a spectrum of seizure types. Carbamazepine, phenytoin, and lacosamide are indicated primarily for focal seizures. Valproic acid serves as a first‑line agent for generalized tonic‑clonic, absence, and myoclonic seizures. Phenobarbital remains a mainstay for neonatal seizures and refractory status epilepticus. Levetiracetam and gabapentin are frequently employed as adjunctive therapy for partial seizures. Perampanel is approved for focal seizures with or without secondarily generalized seizures. Lacosamide is indicated for focal seizures in adults and adolescents.

Off‑Label Uses

Several AEDs are widely used off‑label. Lamotrigine, though primarily indicated for partial and generalized seizures, is commonly prescribed for bipolar disorder. Topiramate, originally approved for focal seizures, is utilized for migraine prophylaxis and weight loss. Oxcarbazepine, a derivative of carbamazepine, is employed for partial seizures with reduced adverse effect profile. Additionally, clonazepam and diazepam, benzodiazepines with anticonvulsant properties, are routinely used for status epilepticus despite not being classified as first‑line AEDs.

Adverse Effects

Common Side Effects

Phenytoin frequently causes ataxia, nystagmus, and cognitive impairment. Carbamazepine may induce dizziness, hyponatremia, and rash. Valproic acid is associated with hepatotoxicity, thrombocytopenia, and weight gain. Phenobarbital commonly leads to sedation, respiratory depression, and paradoxical agitation. Levetiracetam’s side effects are typically mild, including dizziness, somnolence, and irritability. Lacosamide may produce dizziness, peripheral edema, and, rarely, bradycardia. Perampanel is known for dizziness, somnolence, and behavioral disturbances such as irritability or aggression.

Serious/ Rare Adverse Reactions

Severe cutaneous adverse reactions, such as Stevens‑Johnson syndrome, have been reported with carbamazepine and phenytoin, particularly in patients with certain HLA alleles. Valproic acid may precipitate fatal hepatotoxicity, especially in children under two years. Phenobarbital can cause respiratory depression in overdose scenarios. Lacosamide is associated with a small risk of serious cardiac conduction abnormalities, including atrioventricular block. Perampanel’s behavioral side effects may lead to suicidal ideation in susceptible individuals.

Black Box Warnings

Valproic acid carries a black‑box warning for hepatotoxicity in children and teratogenicity resulting in neural tube defects. Carbamazepine and phenytoin also carry warnings for serious skin reactions. Phenobarbital’s black‑box warning addresses the risk of respiratory depression in overdose. Lacosamide’s black‑box warning highlights potential cardiac conduction abnormalities. Perampanel’s warning pertains to the risk of serious psychiatric adverse events, including suicidal ideation and aggression.

Drug Interactions

Major Drug‑Drug Interactions

Phenytoin and carbamazepine act as strong inducers of hepatic CYP3A4, potentially reducing plasma concentrations of concomitant medications such as oral contraceptives, clopidogrel, and certain antiretrovirals. Valproic acid inhibits multiple CYP enzymes, leading to increased levels of drugs like phenytoin, carbamazepine, and selective serotonin reuptake inhibitors (SSRIs). Phenobarbital, a potent inducer of CYP2C9 and CYP2C19, can lower concentrations of warfarin and anticoagulants.

Levetiracetam’s minimal CYP involvement reduces interaction potential; however, it may induce serum concentrations of lamotrigine by enhancing glucuronidation. Lacosamide is a moderate inducer of CYP3A4, potentially lowering levels of drugs such as statins and oral contraceptives. Perampanel is metabolized by CYP3A4; induction of CYP3A4 by drugs like rifampin may lower perampanel exposure, whereas inhibition may increase it.

Contraindications

Patients with severe hepatic dysfunction are generally contraindicated for phenobarbital, phenytoin, carbamazepine, and valproic acid due to the risk of exacerbated hepatic injury. Severe renal impairment may contraindicate levetiracetam, lacosamide, and perampanel, as dosing adjustments are required. Certain antipsychotics with high sedative properties should be avoided concurrently with CNS‑depressant AEDs to mitigate additive respiratory depression.

Special Considerations

Use in Pregnancy/Lactation

Valproic acid is strongly teratogenic, with a high incidence of neural tube defects and cognitive impairment in exposed infants; its use is generally avoided when possible. Carbamazepine and phenytoin pose a moderate teratogenic risk, primarily associated with cleft palate and neural tube defects. Phenobarbital’s teratogenic potential is lower but still significant. Levetiracetam and lacosamide are considered comparatively safer, with limited teratogenic data but no strong evidence of fetal harm. During lactation, all AEDs cross the breast milk barrier; however, levetiracetam and lacosamide have lower infant exposure relative to older agents.

Pediatric/Geriatric Considerations

In children, the risk of developmental toxicity necessitates careful selection of AEDs, favoring levetiracetam, lacosamide, or lamotrigine when appropriate. Dosing in pediatrics often requires weight‑based calculations and frequent therapeutic drug monitoring. Geriatric patients are more susceptible to drug accumulation, particularly for agents with renal elimination; dose reductions and therapeutic monitoring are imperative. Age‑related changes in hepatic metabolism may also influence drug clearance.

Renal/Hepatic Impairment

For renal impairment, levetiracetam, lacosamide, and perampanel require dose adjustments proportional to creatinine clearance. Valproic acid and carbamazepine are partially renally excreted but are primarily metabolized hepatically; however, hepatic impairment may lead to accumulation and increased risk of hepatotoxicity. Phenobarbital’s hepatic metabolism is markedly reduced in hepatic dysfunction, necessitating cautious titration.

Summary/Key Points

• Antiepileptic drugs exhibit diverse mechanisms, including sodium‑channel blockade, GABAergic potentiation, and glutamate receptor antagonism.
• Pharmacokinetic profiles vary; careful consideration of absorption, protein binding, metabolism, and elimination informs dosing strategies.
• Approved indications span focal, generalized, and refractory seizures; off‑label uses extend to psychiatric and metabolic disorders.
• Adverse effect profiles range from mild sedation to serious hepatotoxicity; black‑box warnings exist for several agents.
• Drug interactions hinge largely on CYP induction or inhibition; therapeutic drug monitoring is essential for agents with narrow therapeutic windows.
• Special populations—including pregnant women, children, elderly, and patients with organ dysfunction—require individualized dosing and monitoring.
• Clinical decision‑making should balance seizure control efficacy against potential toxicities, tailoring therapy to the patient’s unique clinical context.

References

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