First-Generation Anticonvulsant Drugs

Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca2+) blocking and GABA reuptake inhibition. Phenobarbital, phenytoin, carbamazepine, valproic acid, and ethosuximide are the 1st-generation antiseizure drugs. Anticonvulsant drugs generally have complicated pharmacokinetics, multiple drug interactions, and narrow therapeutic ranges compared with new-generation drugs.

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Overview

Definitions

Anticonvulsant drugs 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 disease with an enduring risk of recurrent unprovoked seizures (> 2 episodes occurring > 24 hours apart).

Pathophysiology of seizures

The hyperexcitable state of neurons results via the following 3 steps:

  • Paroxysmal depolarization shifts:
    • ↑ Excitatory synaptic neurotransmission
    • Glutamate is the most abundant excitatory neurotransmitter.
      • ↑ Na+ and calcium (Ca2+) influx through glutamate-gated channels (K+ efflux occurs during this process.)
      • Other receptors trigger the release of intracellular Ca2+ stores → increase in intracellular Ca2+
      • Generation of repetitive action potentials
  • Increased excitation of the surrounding neurons:
    • Repeated depolarizations → ↑ extracellular K+
    • Elevated K+ drives depolarization of the surrounding neurons.
  • Failure to inhibit excitatory feedback circuit:
    • Stimulation by excess glutamate
    • Loss of refractory period (neurons unable to generate action potential)
    • Decreased activity of GABA:
      • The main inhibitory neurotransmitter in the brain
      • Defects in GABA activation or inhibition → seizures

General mechanisms of first-generation antiseizure drugs

  • Na+ channel blockers:
    • Phenytoin
    • Carbamazepine
    • Valproic acid
  • Promotion of GABA-related inhibition:
    • Benzodiazepines
    • Phenobarbital
    • Valproic acid
  • Ca2+ channel blocker:
    • Ethosuximide

Phenobarbital

Chemistry and Pharmacodynamics

  • Barbiturates, to which phenobarbital belongs, are sedative-hypnotic agents. Only a few are effective antiseizure drugs (effective below the hypnotic dose).
    • Phenobarbital:
      • 5-Ethyl-5-phenylbarbituric acid
      • Low toxicity, inexpensive
    • Primidone is a less used barbiturate:
      • Largely replaced by new-generation anticonvulsants
      • Converted into phenobarbital and phenylethylmalonamide (PEMA)
  • Mechanism of action:
    • Binds to GABA-A receptor, potentiating synaptic inhibition
    • Leads to neuronal hyperpolarization by extending the duration of chloride channel opening
chemical structure of phenobarbital 1st generation anticonvulsant drugs

Chemical structure of phenobarbital

Image: “Phenobarbital” by Harbinary. License: Public Domain

Pharmacokinetics

  • Absorption:
    • IV, IM, or oral administration (with varying levels of absorption)
    • Peak concentrations are achieved several hours after the dose.
  • Distribution: 40%–60% is bound to plasma proteins.
  • Metabolism: hepatic metabolism via hepatic microsomal enzymes or the cytochrome P450 (CYP) system (primarily CYP2C9)
  • Excretion: renal (up to 25% excreted unchanged in urine)

Indications

  • Generalized and focal tonic-clonic seizures
  • Partial seizures
  • First-line treatment in neonatal seizures
  • Off-label: treatment of symptoms of alcohol withdrawal

Drug-drug interactions

  • Induces uridine 5′-diphosphoglucuronyltransferase (UGT) and CYP:
    • When coadministered with phenobarbital, drugs metabolized by UGT and CYP are more rapidly degraded.
    • Oral contraceptives (metabolized by CYP3A4) have decreased efficacy.
  • CNS-depressant effect of alcohol is enhanced.

Adverse effects and contraindications

  • Adverse effects:
    • Sedation (can lead to coma, respiratory depression)
    • Bradycardia, hypotension
    • Ataxia, nystagmus (with high dosage)
    • Constipation, nausea, vomiting
    • Stevens-Johnson syndrome (SJS) (rare)
  • Warnings:
    • Risk of respiratory depression and death with high doses or when coadministered with other depressants (e.g., narcotics, benzodiazepines)
    • ↑ Risk of psychological and physical dependence
    • Seizures occur with abrupt cessation.
  • Contraindications:
    • Hypersensitivity to barbiturates
    • Hepatic impairment
    • Dyspnea or airway obstruction
    • Porphyria
  • Pregnancy considerations:
    • Associated with fetal abnormalities
    • When used in the 3rd trimester → ↑ risk of neonatal withdrawal symptoms (seizures, hyperirritability)

Phenytoin

Chemistry and pharmacodynamics

  • Phenytoin:
    • 5,5-Diphenylhydantoin
    • Antiseizure activity, generally without CNS depression
  • Fosphenytoin is a related antiseizure drug:
    • Phenytoin prodrug (water soluble)
    • Administered IV or IM
  • Mechanism of action:
    • Protects against seizures by blocking voltage-gated Na+ channels
    • Blocks sustained, high-frequency, repetitive firing of action potentials
Chemical Structure of phenytoin 1st generation anticonvulsant drugs

Chemical structure of phenytoin

Image: “Phenytoin structure” by Harbin. License: Public Domain

Pharmacokinetics

  • Absorption:
    • 2 oral formulations: rapid-release and extended-release forms. Once-daily dosing is possible with extended-release phenytoin.
    • Generic and brand-name phenytoin may differ in phenytoin content:
      • Affects phenytoin levels
      • Checking levels is important when changing routes and preparations.
  • Distribution:
    • Extensively bound to plasma proteins (90%)
    • Unbound (free) phenytoin exerts biological effects.
    • Populations such as neonates, the elderly, and individuals with hypoalbuminemia may exhibit toxicity even if drug levels in serum are normal.
  • Metabolism:
    • Hepatic metabolism with > 90% metabolized by microsomal enzymes (particularly CYP2C9)
    • The inactive metabolite is excreted in the bile.
  • Excretion:
    • Metabolite is reabsorbed in the GI tract and excreted in urine.
    • <5% of phenytoin is excreted unchanged by the kidneys.

Indications

  • Treatment of generalized and focal seizures
  • Mixed seizures (myoclonic and tonic clonic)
  • Status epilepticus
  • Seizure prophylaxis (for craniotomy)

Drug-drug interactions

  • Induces CYP and UGT:
    • Phenytoin can affect warfarin in different ways, thus monitoring is needed:
      • ↑ INR: When phenytoin is initiated, it displaces warfarin from the protein-binding sites.
      • ↓ INR: observed in long-term phenytoin use, as phenytoin is a CYP inducer
    • Phenytoin can decrease the effects of:
      • Oral contraceptives
      • Carbamazepine
  • Notable interactions that increase phenytoin effects:
    • Alcohol
    • Amiodarone
    • Cimetidine
    • Chlordiazepoxide
    • Diazepam
    • Ethosuximide
    • Sulfamethoxazole
    • Valproic acid
  • Notable interactions that may decrease phenytoin effects:
    • Carbamazepine
    • Sucralfate

Adverse effects and contraindications

  • Adverse effects:
    • Nausea, abdominal pain
    • Anorexia
    • Incoordination
    • Nystagmus
    • ↑ Risk of suicidal risk/behavior
    • Hepatic injury
    • Hypertrichosis
    • Gingival hypertrophy
    • Folic acid depletion
    • ↓ Bone density
    • SJS and toxic epidermal necrolysis (TEN)
  • Warnings:
    • Narrow therapeutic index
    • Abrupt withdrawal of phenytoin may result in seizures.
    • Rapid IV infusion can lead to cardiac arrhythmias and hypotension.
    • Hepatotoxicity: Obtain baseline and periodic hepatic function tests.
  • Contraindications:
    • Hypersensitivity to the drug or its components
    • Sinus bradycardia
    • Atrioventricular block
    • Adams-Stokes syndrome
  • Pregnancy considerations: associated with teratogenesis (e.g., neural tube defects, cleft palate, microcephaly, and mental defects)

Carbamazepine

Chemistry and pharmacodynamics

  • Carbamazepine:
    • Iminostilbene derivative (with a carbamyl group at position 5)
    • Chemically related to tricyclic antidepressants
  • Oxcarbazepine is a related antiseizure drug:
    • Carbamazepine analog
    • Similar mechanism as that of carbamazepine but a less potent enzyme inducer (minimal effect on the CYP system)
  • Mechanism of action:
    • Na+ channel blocker
    • Binds to voltage-gated Na+ channels in its inactive conformation, limiting the repetitive and sustained firing of action potentials
Chemical structure of carbamazepine

Chemical structure of carbamazepine

Image: “Carbamazepine structural formulae” by Jü. License: Public Domain

Pharmacokinetics

  • Absorption:
    • Slow absorption after an oral dose
    • Peak concentrations are achieved after up to 8 hours of ingestion.
  • Distribution:
    • 70% protein bound
    • Distribution in all tissues, drug concentration in CSF is similar to that of the free drug in plasma
  • Metabolism:
    • Metabolized in the liver via hepatic CYP3A4
    • Potent and broad-spectrum CYP inducer
  • Excretion: renal

Indications

  • Seizure disorder (focal and generalized)
  • Neuropathic pain (e.g., trigeminal neuralgia)
  • Bipolar disorder

Drug-drug interactions

  • Carbamazepine is a potent inducer of CYP and UGT (may reduce plasma concentrations of concurrently administered medications by inducing their metabolism):
    • Clonazepam
    • Topiramate
    • Valproic acid
    • Zonisamide
    • Nonnucleoside reverse-transcriptase inhibitors
  • Drugs/foods that increase carbamazepine effects:
    • Brivaracetam
    • Felbamate
    • Levetiracetam
    • Lamotrigine
    • Grapefruit
  • Drugs that decrease carbamazepine effects:
    • Clonazepam
    • Phenytoin

Adverse effects and contraindications

  • Adverse effects:
    • Dizziness
    • Ataxia
    • Blurred vision
    • Nausea, vomiting
    • Hepatic injury
    • Hyponatremia
    • Hematological toxicity (aplastic anemia, agranulocytosis)
    • Hypersensitivity reactions
    • SIADH
  • Warnings:
    • ↑ Risk of SJS and TEN in individuals with the HLA-B*1502 allele (often seen in individuals of Asian ancestry)
    • Obtain hematologic studies because of the risk of hematologic toxicity:
      • Monitor if a reduction in platelet and WBC counts is noted.
      • Discontinue if bone marrow suppression occurs.
    • Hepatotoxicity: Obtain baseline and periodic hepatic function tests.
    • As SIADH can occur, monitor electrolytes especially in individuals at risk of hyponatremia (e.g., individuals on diuretic therapy).
  • Contraindications:
    • Hypersensitivity to carbamazepine or its components
    • Bone marrow suppression
    • Concomitant use of delavirdine, nefazodone, or other nonnucleoside reverse-transcriptase inhibitors that are CYP3A4 substrates
    • Hepatic disease
    • Porphyria
  • Pregnancy considerations: associated with teratogenic effects (e.g., spina bifida, craniofacial and cardiovascular malformations)

Valproic acid

Chemistry and pharmacodynamics

  • Valproic acid:
    • N-dipropylacetic acid
    • Inhibits several types of seizures
  • Divalproex is a related antiseizure drug:
    • Valproic acid derivative
    • Contains the sodium salt of valproic acid and valproic acid
  • Mechanism of action:
    • Blocks voltage-dependent Na+ channels → suppresses repetitive neuronal firing
    • Inhibits GABA transaminase → ↑ GABA levels
    • Decreases T-type Ca2+ currents
Chemical structure of valproic acid

Chemical structure of valproic acid

Image: “Valproic acid” by Harbin. License: Public Domain

Pharmacokinetics

  • Absorption:
    • Generally absorbed rapidly after oral ingestion
    • Delay in absorption noted in enteric-coated formulations or if ingested with meals
  • Distribution: 90% bound to plasma proteins
  • Metabolism:
    • Hepatic metabolism
    • Moderately inhibits CYP and UGT glucuronidation
  • Excretion: renal (<5% unchanged in the urine)

Indications

  • Generalized and focal seizures
  • Absence seizures
  • Prophylaxis of migraine headaches
  • Bipolar disorder

Drug-drug interactions

  • Valproic acid inhibits CYP and UGT and can increase the effects of the following drugs:
    • Carbamazepine
    • Ethosuximide
    • Phenytoin
    • Phenobarbital
    • Lamotrigine
  • Valproic acid can decrease the effects of:
    • Felbamate (unknown mechanism)
    • Oxcarbazepine (↑ metabolism)
  • The following drugs can decrease the efficacy of valproic acid:
    • Carbamazepine
    • Ethosuximide

Adverse effects and contraindications

  • Adverse effects:
    • Nausea, vomiting
    • Hair loss
    • Tremors
    • Weight gain, obesity, and metabolic syndrome
    • Hepatic injury
    • Thrombocytopenia and other coagulation disturbances
  • Warnings:
    • Hepatotoxicity:
      • ↑ Risk of acute liver failure (especially in neurometabolic syndromes from mitochondrial DNA polymerase gamma (POLG) gene mutations)
      • Baseline and periodic hepatic function tests
    • Acute pancreatitis (medical evaluation required if individuals present with abdominal pain and symptoms indicative of pancreatitis)
  • Contraindications:
    • Known hypersensitivity to valproic acid
    • Liver disease
    • Mitochondrial disorders (Alpers-Huttenlocher syndrome)
    • Urea cycle disorders (valproic acid inhibits urea synthesis → ↑ ammonia levels)
  • Pregnancy considerations:
    • Teratogenic
    • Fetal abnormalities (valproate syndrome) include:
      • Neural tube defects such as spina bifida
      • Developmental delay
      • Cleft lip/palate
      • Congenital heart defects
      • Limb abnormalities

Ethosuximide

Chemistry and pharmacodynamics

  • Ethosuximide:
    • α-Ethyl-α-methylsuccinimide
    • Effective in absence seizures (when not accompanied by other types of seizures)
  • Mechanism of action: reduces T-type Ca2+ channels of the thalamic neurons
Chemical structure of ethosuximide

Chemical structure of ethosuximide

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

Pharmacokinetics

  • Absorption:
    • Bioavailability is 93% after an oral dose.
    • Peak drug concentration in the blood is attained between 3 and 4 hours.
  • Distribution:
    • Little or no protein binding
    • Drug distribution in CSF is similar to that in plasma.
  • Metabolism: hepatic microsomal enzymes (particularly CYP3A)
  • Excretion: renal (25% unchanged)

Indications

Treatment of absence seizures

Drug-drug interactions

  • CNS-depressant effects can be exacerbated by other drugs and lead to drowsiness.
  • Orlistat may decrease ethosuximide levels.

Adverse effects and contraindications

  • Adverse effects:
    • Nausea, vomiting, anorexia
    • Drowsiness, lethargy, euphoria, dizziness, headache
    • Parkinson’s disease-like symptoms
    • Photophobia
    • Hypersensitivity reactions
  • Warnings:
    • Exercise caution when performing tasks (can cause drowsiness).
    • Monitor CBC as ethosuximide can cause blood dyscrasias.
    • Exercise caution in individuals with renal and hepatic impairment.
  • Contraindications: hypersensitivity to ethosuximide or its ingredients
  • Pregnancy considerations: associated with birth defects

Comparison of Medications

Table: Pharmacokinetics of drugs used to treat essential tremors
MedicationsMechanism of actionMajor adverse effectsInteractionsIndications
Barbiturates (phenobarbital)Binds to GABA receptor subunits → ↑ GABA inhibitory activity
  • Sedation
  • Cardiorespiratory depression
Induces CYP and UGTGeneralized and focal seizures
PhenytoinBlocks voltage-gated Na+ channels
  • Gingival hypertrophy
  • ↑ Body hair
  • ↓ Bone density
  • Rash
  • Ataxia
  • Nystagmus
  • Hepatotoxicity
Induces CYP and UGT
  • Generalized and focal seizures
  • Mixed seizures
  • Prevention of seizures during neurosurgery
CarbamazepineBlocks Na+ channels
  • GI symptoms
  • Rash
  • Hyponatremia
  • SJS, TEN
  • Bone marrow suppression
Induces CYP and UGT
  • Generalized and focal seizures
  • Neuropathic pain
Valproic acid
  • Blocks Na+ channels
  • ↑ GABA transaminase → ↑ GABA
  • Nausea, vomiting
  • Metabolic syndrome
  • Hepatotoxicity
  • ↓ Platelet count
  • Coagulation problems
Inhibits CYP and UGT
  • Generalized and focal seizures
  • Absence seizures
  • Migraine prophylaxis
  • Bipolar disorder
Ethosuximide↓ T-type Ca2+ channel currentsDrowsiness (CNS depression)↑ Phenytoin effectsAbsence seizures
Abbreviations:
UGT: uridine 5′-diphosphoglucuronyltransferase
CYP: cytochrome P450
SJS: Stevens-Johnson syndrome
TEN: toxic epidermal necrolysis

References

  1. Al Khalili, Y., Sekhon, S., Jain, S. (2021). Carbamazepine toxicity. StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK507852/
  2. Bialer, M. (2012). How did phenobarbital’s chemical structure affect the development of subsequent antiepileptic drugs (AEDs)? Epilepsia, 53, 3-11. https://doi.org/10.1111/epi.12024
  3. Crader, M., Johns, T. (2021). Warfarin drug interactions. StatPearls. Retrieved Aug 29, 2021, from https://www.statpearls.com/ArticleLibrary/viewarticle/31296
  4. Lowenstein, D.H. (2018). Seizures and epilepsy. Jameson, J., Fauci, A.S., Kasper, D.L., Hauser, S.L., Longo, D.L., Loscalzo, J. (Eds.), Harrison’s Principles of Internal Medicine, 20e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192531797
  5. Miller, C. (2020). Phenytoin toxicity. Medscape. Retrieved Aug 29, 2021, from https://emedicine.medscape.com/article/816447-overview
  6. Ropper, A.H., Samuels, M.A., Klein, J.P., Prasad, S. (Eds.) (2019). Epilepsy and other seizure disorders. Adams and Victor’s Principles of Neurology, 11e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=1477&sectionid=138318583
  7. Schachter, S. (2021). Anti-seizure medications. UpToDate. Retrieved Aug 28, 2021, from https://www.uptodate.com/contents/antiseizure-medications-mechanism-of-action-pharmacology-and-adverse-effects
  8. Shakkottai, V.G., Lomen-Hoerth, C. (2019). Nervous system disorders. Hammer, G.D., McPhee, S.J. (Eds.), Pathophysiology of Disease: An Introduction to Clinical Medicine, 8e. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2468&sectionid=198220873
  9. Smith, M.D., Metcalf, C.S., Wilcox, K.S. (2017). Pharmacotherapy of the epilepsies. 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
  10. UpToDate. (2021). Carbamazepine: Drug information. UpToDate. Retrieved Aug 29, 2021, from https://www.uptodate.com/contents/carbamazepine-drug-information
  11. UpToDate. (2021) Ethosuximide: Drug information. UpToDate. Retrieved Aug 29, 2021, from https://www.uptodate.com/contents/ethosuximide-drug-information
  12. UpToDate. (2021). Phenobarbital: Drug information. UpToDate. Retrieved Aug 29, 2021, from https://www.uptodate.com/contents/phenobarbital-drug-information
  13. UpToDate. (2021). Phenytoin: Drug information. UpToDate. Retrieved Aug 29, 2021, from https://www.uptodate.com/contents/phenytoin-drug-information
  14. UpToDate. (2021). Valproate: Drug information. UpToDate. Retrieved Aug 29, 2021, from https://www.uptodate.com/contents/valproate-drug-information

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