Second-Generation Anticonvulsant Drugs

Anticonvulsant drugs are pharmacological agents used for seizure control and/or to prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action, including ion-channel (Na+, calcium) blocking and inhibition of GABA reuptake. Second-generation anticonvulsants exert their effects via these mechanisms and are associated with good efficacy, fewer toxic effects, and better tolerability, and generally do not require blood level monitoring. Medications in this class include felbamate, gabapentin, pregabalin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, zonisamide, and lacosamide. Anticonvulsant drugs are indicated for focal seizures, generalized tonic-clonic seizures, myoclonic seizures, and Lennox-Gastaut syndrome. Some anticonvulsants are also indicated in conditions unrelated to seizures (e.g., bipolar disorder). The most common adverse effects include dizziness, headache, and somnolence.

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Overview

Definitions

Antiseizure drugs (ASDs) are used to suppress abnormal electrical activity in the brain through various mechanisms.

  • Seizures are episodes of neurologic dysfunction caused by uncontrolled, abnormal neuronal activity in the brain and are characterized by sudden changes in senses, perception, motor activity, or behavior.
  • Epilepsy is a condition with an enduring risk of recurrent unprovoked seizures (at least 2 or more episodes occurring > 24 hours apart).

Pathophysiology of seizures

The hyperexcitable state of neurons results from 3 steps:

  • Paroxysmal depolarization shifts:
    • ↑ Excitatory synaptic neurotransmission
    • Glutamate is the most abundant excitatory neurotransmitter.
      • ↑ Na+ and calcium (Ca2+) influx through glutamate-gated channels (and in the process, K+ goes out of the cell)
      • Other receptors trigger the release of intracellular Ca2+ stores → increase in intracellular Ca2+
      • Generation of repetitive action potentials
  • Increased excitation of surrounding neurons:
    • Repeated depolarization → ↑ extracellular K+
    • Elevated K+ drives the depolarization of surrounding neurons.
  • Failure to inhibit excitatory feedback circuit:
    • Excess glutamate stimulation
    • Loss of refractory period occurs (where neurons are unable to generate action potentials).
    • Decreased activity of GABA:
      • Main inhibitory neurotransmitter in the brain
      • Defects in GABA activation or inhibition → seizures

Second-generation antiseizure drugs

  • Newer drugs with good efficacy, fewer toxic effects, better tolerability; no blood-level monitoring required
  • Can have a combination of mechanisms of action
  • Some of these drugs may also be used as monotherapy or adjunctive therapy.
  • As with 1st-generation ASDs, the use of newer medications has been associated with increased suicidal ideation.
  • Medications in this class:
    • Felbamate
    • Gabapentin
    • Pregabalin
    • Lacosamide
    • Lamotrigine
    • Levetiracetam
    • Oxcarbazepine
    • Perampanel
    • Tiagabine
    • Topiramate
    • Vigabatrin
    • Zonisamide

Felbamate

Chemistry and pharmacodynamics

  • Dicarbamate derivative
  • Mechanism of action: blocks the channel at the N-methyl-D-aspartate (NMDA) excitatory receptor (a binding site for glutamate)
Felbamate

Chemical structure of felbamate

Image: “Felbamate” by Harbin. License: Public Domain

Pharmacokinetics

  • Oral, with rapid and almost complete absorption
  • Food does not affect absorption.
  • Half-life: 20–23 hours
  • Hepatic metabolism (cytochrome P450 (CYP) system: primarily CYP3A4)
  • Excretion: urine (50% excreted unchanged)

Indications

  • Partial seizures
  • Lennox-Gastaut syndrome

Adverse effects and contraindications

  • Adverse effects:
    • Aplastic anemia
    • Hepatic failure
    • Anorexia, nausea, vomiting
    • Drowsiness, headache, irritability
  • Contraindications:
    • Hypersensitivity to the drug
    • Blood dyscrasias
    • Hepatic dysfunction
  • Precautions:
    • Not the 1st-line therapy for seizures
    • Indicated only for individuals showing inadequate response to alternative ASDs

Gabapentin and Pregabalin

Chemistry and pharmacodynamics

  • Gabapentin: structurally similar to GABA, bound to a lipophilic cyclohexane ring
  • Pregabalin:
    • Chemically related to GABA
    • GABA molecule bound to isobutane
  • Mechanism of action:
    • ↓ Excitatory transmission by acting on the voltage-gated Ca2+ channels (𝜶2𝜹 subunit) presynaptically
    • No binding to GABA receptors
Chemical structure of pregabalin

Chemical structure of pregabalin

Image: “Pregabalin” by Harbin. License: Public Domain

Pharmacokinetics and indications

Table: Gabapentin and pregabalin pharmacokinetics and indications
DrugPharmacokineticsIndications
Gabapentin
  • Oral
  • Not bound to plasma proteins
  • Half-life: approximately 6 hours
  • Not metabolized
  • Excreted unchanged in urine
  • Focal (partial) seizures
  • Postherpetic neuralgia
Pregabalin
  • Focal (partial) seizures
  • Others:
    • Fibromyalgia
    • Neuropathic pain
    • Postherpetic neuralgia

Adverse effects and contraindications

  • Adverse effects:
    • Somnolence, dizziness, ataxia
    • Edema
    • Angioedema, anaphylaxis
    • Infection
    • Gabapentin may exacerbate myasthenia gravis.
  • Contraindications:
    • Drug hypersensitivity
    • Both drugs are pregnancy category C.

Lacosamide

Chemistry and pharmacodynamics

  • Amino acid (L-serine) derivative
  • Mechanism of action: enhances slow inactivation of voltage-dependent Na+ channels without affecting the fast inactivation phases
Chemical structure of lacosamide

Chemical structure of lacosamide

Image: “Lacosamide” by Fvasconcellos. License: Public Domain

Pharmacokinetics

  • Oral, with complete absorption; IV
  • Half-life: approximately 13 hours
  • Hepatic metabolism (CYP)
  • Excretion: urine

Indications

  • Focal (partial) seizures
  • Primary generalized tonic-clonic seizures

Adverse effects and contraindications

  • Adverse effects:
    • Prolonged PR interval, cardiac arrhythmias
    • Blurred vision, diplopia
    • Dizziness, drowsiness, headache
    • Nausea
  • Contraindications:
    • Hypersensitivity to the drug
    • 2nd- or 3rd-degree atrioventricular block

Lamotrigine

Chemistry and pharmacodynamics

  • Phenyltriazine derivative
  • Mechanisms of action:
    • Inhibition of voltage-sensitive Na+ channels
    • Inhibition of glutamate release
Chemical structure of lamotrigine

Chemical structure of lamotrigine

Image: “Lamotrigine” by Harbin. License: Public Domain

Pharmacokinetics

  • Oral, almost completely absorbed (90%)
  • Half-life: up to 33 hours
  • 55% bound to plasma proteins
  • Hepatic metabolism
  • Excretion: urine

Indications

  • Focal (partial)-onset seizures
  • Generalized-onset seizures
  • Lennox-Gestaut syndrome
  • Bipolar disorder (as maintenance therapy)

Adverse effects and contraindications

  • Adverse effects:
    • Dizziness, headache
    • Nausea, vomiting
    • Blurred vision, diplopia
    • Rash (with potential to escalate to Stevens–Johnson syndrome)
    • Aseptic meningitis
    • Blood dyscrasias
    • Arrhythmias
  • Contraindications: hypersensitivity to the drug
  • Precautions in:
    • Cardiac conduction disorders
    • Structural cardiac disease

Levetiracetam and Brivaracetam

Chemistry and pharmacodynamics

  • Chemistry:
    • Levetiracetam: pyrrolidine derivative
    • Brivaracetam: levetiracetam analog
  • Mechanism of action: binds the synaptic protein SV2A, affecting neuronal excitability (↓ SV2A → ↓ action potential-dependent neurotransmission)
Chemical structure of levetiracetam

Chemical structure of levetiracetam

Image: “Levetiracetam” by Harbin. License: Public Domain

Pharmacokinetics and indications

Table: Pharmacokinetics and indications for levetiracetam vs brivaracetam
DrugPharmacokineticsIndications
Levetiracetam
  • Oral, almost complete absorption
  • Half-life: 6–8 hours
  • Not bound to plasma proteins
  • Minimal metabolism by hydrolysis to an inactive metabolite
  • Excretion: approximately 66% excreted unchanged in urine
  • Focal (partial) seizures
  • Generalized-onset juvenile myoclonic epilepsy
  • Generalized tonic-clonic seizures
Brivaracetam
  • Oral, almost complete absorption
  • Half-life: 9 hours
  • Metabolism by hydrolysis to an inactive metabolite
  • Excretion: urine
Focal (partial) seizures

Adverse effects and contraindications

  • Adverse effects:
    • Fatigue
    • Dizziness, somnolence
    • Hypertension
    • Upper respiratory infection
    • Vomiting
    • Brivaracetam: psychiatric symptoms (e.g., psychosis), leukopenia
  • Contraindications: hypersensitivity to the drug

Oxcarbazepine

Chemistry and pharmacodynamics

  • Chemically related to carbamazepine
  • Effects are from the drug as well as the monohydroxy metabolite.
  • Mechanisms of action:
    • Blocking of voltage-sensitive Na+ channels
    • Also known to ↑ K+ conductance and modulate high-voltage Ca+2-channel activity

Pharmacokinetics

  • Oral, with complete absorption
  • Half-life: 8–10 hours
  • Extensive hepatic metabolism (to its active metabolite)
  • Excretion: urine

Indications

Oxcarbazepine is indicated in focal (partial)-onset seizures.

Adverse effects and contraindications

  • Adverse effects:
    • Blood dyscrasias
    • ↓ Bone mineral density (osteopenia, osteoporosis)
    • Cognitive symptoms, somnolence, dizziness
    • Hepatic dysfunction
    • Hyponatremia
    • Hypothyroidism
    • Hypersensitivity reactions
    • Vomiting
  • Contraindication: hypersensitivity to the drug

Perampanel

Chemistry and pharmacodynamics

  • Pyridone derivative
  • Mechanism of action: noncompetitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor
Chemical structure of perampanel

Chemical structure of perampanel

Image: “Perampanel” by Meodipt. License: Public Domain

Pharmacokinetics

  • Oral, with complete absorption
  • Half-life: approximately 105 hours
  • Hepatic metabolism via CYP3A
  • Excretion: feces > urine

Indications

  • Focal (partial) seizures
  • Primary generalized tonic-clonic seizures

Adverse effects and contraindications

  • Adverse effects:
    • Severe psychiatric or behavioral changes (e.g., homicidal ideation, aggression, irritability, hostility)
    • Dizziness, fatigue
    • Rash
    • Weight gain, edema
    • Nausea, vomiting
  • Contraindications: hypersensitivity to the drug

Rufinamide

Chemistry and pharmacodynamics

  • Triazole derivative
  • Not related to other ASDs
  • Mechanism of action:
    • Modulating Na+-channel activity (prolonging or enhancing slow inactivation), reducing repetitive firing
    • Increasing the inactive state of channels
Chemical structure of rufinamide

Chemical structure of rufinamide

Image: “Rufinamide” by Vaccinationist. License: Public Domain

Pharmacokinetics

  • Oral, with slow absorption
  • Half-life: 6–10 hours
  • Metabolized by hydrolysis to an inactive metabolite (independent of CYPs)
  • Excretion: urine

Indications

Rufinamide is indicated in the adjunctive treatment of Lennox-Gestaut syndrome.

Adverse effects and contraindications

  • Adverse effects:
    • Shortened QT interval
    • Headache
    • Cognitive symptoms, coordination abnormalities
    • Rash
    • Vomiting
  • Contraindications:
    • Familial short QT syndrome or history of short QT
    • Hypersensitivity to the drug

Stiripentol

Chemistry and pharmacodynamics

  • Aromatic alcohol
  • Unrelated to other ASDs
  • Mechanism of action:
    • Modulates GABA-A receptor, enhancing inhibitory neurotransmission
    • Inhibitory effect on CYP enzymes, reducing the metabolism of other ASDs

Pharmacokinetics

  • Oral, well absorbed
  • Half-life: 13 hours
  • Hepatic metabolism
  • Excretion: urine

Indications

Stiripentol is indicated in the management of Dravet syndrome (previously known as severe myoclonic epilepsy in infancy).

Adverse effects and contraindications

  • Adverse effects:
    • Drowsiness
    • Behavioral changes, suicidal ideation
    • Anorexia, weight loss
  • Contraindication: hypersensitivity to the drug

Tiagabine

Chemistry and pharmacodynamics

  • Lipophilic analog of nipecotic acid
  • Mechanism of action: enhances GABA activity by inhibiting GABA reuptake
Chemical structure of tiagabine

Chemical structure of tiagabine

Image: “Tiagabine” by Fvasconcellos. License: Public Domain

Pharmacokinetics

  • Oral, rapid absorption
  • Half-life: 7–9 hours
  • Hepatic metabolism (CYP system)
  • Excretion: mostly feces

Indications

Tiagabine is indicated for the adjunctive treatment of focal (partial) seizures.

Adverse effects and contraindications

  • Adverse effects:
    • Dizziness, somnolence
    • Fatigue
    • Abdominal pain
    • Dermatologic reactions
  • Contraindication: hypersensitivity to the drug

Topiramate

Chemistry and pharmacodynamics

  • Topiramate: a monosaccharide structure containing sulfamate
  • Mechanism of action:
    • Blocks the voltage-dependent Na+ channels in neurons
    • Amplifies GABA-A activity
    • Antagonizes NMDA-glutamate receptors
    • Inhibits carbonic anhydrase (↑ hydrogen ions in the cell + ↓ pH leading to the extracellular shift of K+ → hyperpolarization and ↑ seizure threshold)
Chemical structure of topiramate

Chemical structure of topiramate

Image: “Topiramate” by UnicornFightCluba. License: Public Domain

Pharmacokinetics

  • Oral, rapid absorption
  • Half-life: up to 23 hours
  • Minimal hepatic metabolism
  • Excretion: urine

Indications

  • Focal (partial) seizures
  • Primary generalized tonic-clonic seizures
  • Adjunctive therapy for Lennox-Gastaut syndrome
  • Migraine prophylaxis

Adverse effects and contraindications

  • Adverse effects:
    • Kidney stones
    • Hepatic impairment
    • Cognitive impairment, sedation, dizziness
    • Depression and mood-related effects
    • Weight loss
  • Contraindications:
    • Hypersensitivity to the drug
    • Pregnancy

Vigabatrin

Chemistry and pharmacodynamics

  • Structural analog of GABA (but does not bind to GABA receptors)
  • Mechanism of action: inhibits GABA transaminase irreversibly (GABA uptake inhibitor)

Pharmacokinetics

  • Oral, completely absorbed
  • Half-life: approximately 11 hours
  • Minimal metabolism
  • Excretion: urine

Indications

  • Infantile spasms
  • Refractory complex partial seizures

Adverse effects and contraindications

  • Adverse effects:
    • Permanent vision loss
    • Dizziness, drowsiness
    • Peripheral neuropathy
    • Anemia
    • Rash
    • Constipation, vomiting
  • Contraindication:
    • Hypersensitivity to the drug
    • Pregnancy

Zonisamide

Chemistry and pharmacodynamics

  • Sulfonamide derivative
  • Mechanism of action: decreases high-frequency firing by blocking the voltage-gated Na+ channels and T-type Ca+2 channels
Chemical structure of zonisamide

Chemical structure of zonisamide

Image: “Zonisamide” by Fvasconcellos. License: Public Domain

Pharmacokinetics

  • Oral, complete absorption
  • Half-life: 1–3 days
  • Hepatic metabolism
  • Excretion: mostly urine

Indications

Zonisamide is indicated for the adjunctive therapy of focal (partial) seizures.

Adverse effects and contraindications

  • Adverse effects:
    • Cognitive and behavioral changes
    • ↑ Ammonia, encephalopathy
    • Metabolic acidosis
  • Contraindication: hypersensitivity to the drug

Comparison of 2nd-Generation Antiseizure Drugs

Antiseizure drugs and mechanisms

Table: Antiseizure drugs and mechanisms
Site/factor affectedMain mechanism of actionDrugs
Na+ channelsInhibition of voltage-sensitive Na+ channels
  • Lamotrigine*
  • Oxcarbazepine
  • Topiramate*
  • Zonisamide*
Enhancement of slow inactivation
  • Lacosamide
  • Rufinamide
Calcium channelsBlocking of T-type calcium channelsZonisamide*
Modulation of calcium channels (α2δ subunit)
  • Gabapentin
  • Pregabalin
GABAGABA reuptake inhibitors
  • Tiagabine
  • Vigabatrin
Stimulation of GABA receptors
  • Stiripentol
  • Topiramate*
GlutamateGlutamate receptor antagonists
  • Felbamate
  • Perampanel
  • Topiramate*
↓ Glutamate releaseLamotrigine*
Neurotransmitter releaseSynaptic vesicle 2A modulators
  • Levetiracetam
  • Brivaracetam
*Mixed mechanisms

Second-generation antiseizure drugs and indications

Table: Second-generation antiseizure drugs and indications
IndicationsSpecific conditionsDrugs
Seizure relatedFocal (partial) seizures
  • Brivaracetam
  • Felbamate
  • Gabapentin
  • Lacosamide
  • Lamotrigine
  • Levetiracetam
  • Oxcarbazepine
  • Perampanel
  • Pregabalin
  • Tiagabine
  • Topiramate
  • Zonisamide
Primary generalized tonic-clonic seizures
  • Lacosamide
  • Lamotrigine
  • Levetiracetam
  • Perampanel
  • Topiramate
Lennox-Gastaut syndrome
  • Felbamate
  • Lamotrigine
  • Rufinamide
  • Topiramate
Juvenile myoclonic epilepsyLevetiracetam
Infantile spasms and refractory complex partial seizuresVigabatrin
Dravet syndromeStiripentol
Seizure unrelated
  • Fibromyalgia
  • Neuropathic pain
Pregabalin
Postherpetic neuralgia
  • Gabapentin
  • Pregabalin
Bipolar disorderLamotrigine
Migraine prophylaxisTopiramate

References

  1. Kim, K.S., et al. (2015). Antiepileptic drugs: Second-generation/Newer agents. In Cohen, H. (Ed.), Casebook in Clinical Pharmacokinetics and Drug dosing, 1st ed., Vol. 1. pp 43-53. McGraw-Hill Education.
  2. Ochoa, J.G. (2020). Antiseizure drugs. In Benbadis, S.R., et al. (Ed.), Medscape. Retrieved September 22, 2021, from https://emedicine.medscape.com/article/1187334
  3. Porter, R.J., Rogawski, M.A. (2018). Antiseizure drugs. In Katzung, B.G. et al. (Ed.), Basic and Clinical Pharmacology, 14th ed., Vol. 1. pp. 409-437. McGraw Hill.
  4. Schachter, S.C. (2021). Antiseizure medications: Mechanism of action, pharmacology, and adverse effects. In Garcia, P. et al. (Ed.), UpToDate. Retrieved October 11, 2021, from https://www.uptodate.com/contents/antiseizure-medications-mechanism-of-action-pharmacology-and-adverse-effects
  5. Smith, M.D., Metcalf, C.S., Wilcox, K.S. (2017). Pharmacotherapy of the epilepsies. In Brunton, L.L., & Hilal-Dandan, R., & Knollmann, B.C.(Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=170106435
  6. UpToDate, Inc. (2021) Felbamate: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/felbamate-drug-information
  7. UpToDate, Inc. (2021). Gabapentin: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/gabapentin-drug-information
  8. UpToDate, Inc. (2021). Pregabalin: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/pregabalin-drug-information
  9. UpToDate, Inc. (2021). Lacosamide: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/lacosamide-drug-information
  10. UpToDate, Inc. (2021). Lamotrigine: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/lamotrigine-drug-information
  11. UpToDate, Inc. (2021). Levetiracetam: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/levetiracetam-drug-information
  12. UpToDate, Inc. (2021). Brivaracetam: Drug information. UpToDate. Retrieved Oct 10, 2021, from https://www.uptodate.com/contents/brivaracetam-drug-information
  13. UpToDate, Inc. (2021). Oxcarbazepine: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/oxcarbazepine-drug-information
  14. UpToDate, Inc. (2021). Perampanel: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/perampanel-drug-information
  15. UpToDate, Inc. (2021). Stiripentol: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/stiripentol-drug-information
  16. UpToDate, Inc. (2021). Tiagabine: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/tiagabine-drug-information
  17. UpToDate, Inc. (2021). Topiramate: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/topiramate-drug-information
  18.  UpToDate, Inc. (2021). Vigabatrin: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/vigabatrin-drug-information
  19. UpToDate, Inc. (2021). Zonisamide: Drug information. UpToDate. Retrieved Oct 11, 2021, from https://www.uptodate.com/contents/zonisamide-drug-information

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