Introduction

• Revolutionized Treatment:
  • Introduced in the early 1960s.
  • Significant impact on the treatment of generalized epilepsies.
• Chemical Composition:
  • Valproic acid: 2-propyl pentanoic acid, 2-propyl valeric acid.
  • Initially used as an organic solvent before discovering its antiepileptic activity in 1963.
• Forms of Valproate:
  • Includes sodium valproate, magnesium valproate, and sodium divalproex.

Authorized Indications

• UK-SmPC:

  • Treatment of generalized, partial, or other epilepsy.

• FDA-PI:

  • Monotherapy and adjunctive therapy for complex partial seizures.
  • Sole and adjunctive therapy for simple and complex absence seizures.
  • Adjunctive therapy for multiple seizure types, including absence seizures.

• Definitions:

  • Simple Absence: Brief loss of consciousness with generalized epileptic discharges.
  • Complex Absence: Includes additional clinical signs.

• Intravenous Use:

  • Valproate sodium injection for patients unable to take oral valproate temporarily.

Clinical Applications

• Effectiveness:
  • Broad-spectrum AED effective for various seizures and epilepsies.
  • Superior efficacy in generalized seizures and idiopathic generalized epilepsy (IGE).
  • Effective for photosensitive epilepsy.
• Limitations:
  • Less effective for focal epilepsies compared to carbamazepine and newer AEDs.
  • Serious adverse drug reactions (ADRs) in women of childbearing age and young children.
• Seizure Aggravation:
  • Rare and typically in specific clinical contexts (overdose, encephalopathy, hepatic or metabolic disorders).

Dosage and Titration

• Adults:

  • Initial dose: 200 mg/day in two divided doses for 3 days.
  • Increment: 200 mg/day every 3 days.
  • Maintenance: 1000–1500 mg/day (max 3000 mg/day).

• Children:

  • Initial dose: 10 mg/kg/day.
  • Increment: 10 mg/kg/day every 3 days.
  • Maintenance: 20–30 mg/kg/day in two divided doses.

• Combined Therapy:

  • Dose increase: 30–50% with enzyme-inducing AEDs.
  • Dose reduction: Possible when enzyme-inducing AEDs are withdrawn.

• Dosing Frequency:

  • Twice or three times daily; once daily for slow-release formulations.

• Therapeutic Drug Monitoring (TDM):

  • Often not useful due to poor correlation between dose and plasma levels.
  • Helpful when monitoring interactions with enzyme-inducing drugs.
  • Reference range: 50–100 mg/l (300–700 μmol/l).

Main Adverse Drug Reactions (ADRs)

• Serious ADRs:

  • Acute liver necrosis and pancreatitis, rare but potentially fatal.
  • Increased risk of neural tube defects in offspring of women on valproate.
  • Polycystic ovary syndrome and other endocrine issues in women.

• Central Nervous System (CNS) Effects:

  • Generally does not cause drowsiness or significant cognitive effects.
  • Valproate encephalopathy is rare.
  • Tremor: Can be mild to severe, reversible with dose reduction.

• Systemic Effects:

  • Fatal hepatotoxicity and acute hemorrhagic pancreatitis.
  • Hepatic failure risk: Age-dependent, higher in young children on polypharmacy.
  • Elevated liver enzymes common, but not always indicative of severe hepatotoxicity.

• Pancreatitis:

  • Rare, develops within first 3 months, more prevalent in children and polytherapy.

• Hyperammonaemic Encephalopathy:

  • Reported in patients with urea cycle disorders.
  • Metabolic investigations recommended before starting therapy.

• Hematological Abnormalities:

  • Thrombocytopenia and coagulation issues.
  • Regular platelet counts and coagulation tests recommended.

• Weight Gain:

  • Occurs in 20% of patients, more common in women.

• Other ADRs:

  • Hair loss and texture changes.
  • Gastrointestinal issues (anorexia, constipation, dry mouth).
  • Urogenital issues (urinary incontinence, vaginitis).

Considerations in Women

• Pregnancy:
  • Category D: Teratogenic, causing neural tube defects and other anomalies.
• Breastfeeding:
  • No contraindication; low excretion in breast milk.
• Hormonal Contraception:
  • No interaction.

Mechanisms of Action

• Unknown Main Mechanism:
  • Likely a combination of several mechanisms.
  • Inhibits voltage-sensitive sodium channels.
  • Elevates brain GABA levels.
  • Reduces T-type calcium-channel current (not consistently supported).

Pharmacokinetics

• Absorption:
  • Almost complete, varies with formulation.
  • Rapid absorption with syrup or uncoated tablets (peak in 2 hours).
  • Slower with enteric-coated tablets (3–8 hours).
• Protein Binding:
  • Highly protein-bound (90%).
  • Free drug increases with high plasma levels or low serum albumin.
• Metabolism:
  • Hepatic, with numerous active metabolites.
  • Major pathway: Glucuronidation (40–60%).
  • Oxidation pathways: β-oxidation (30–40%), ω-oxidation (CYP-dependent).
• Elimination:
  • Half-life: 8–12 hours (variable, shorter with enzyme-modifying AEDs).
  • Mainly eliminated in urine.

Drug Interactions

• Sensitivity to Enzymatic Induction:

  • Metabolism affected by enzyme inducers (e.g., phenobarbital, phenytoin).
  • Inhibits metabolism of other drugs.
  • High serum protein affinity.

• Effects on Other AEDs:

  • Increases plasma concentrations of ethosuximide and phenobarbital.
  • Decreases carbamazepine plasma levels.
  • Displaces phenytoin from plasma proteins.

Main Disadvantages

• Serious ADRs:

  • Unsuitable for women due to hormonal changes, weight gain, and teratogenicity.
  • High doses required for focal epilepsies, limited efficacy.
  • More effective and safer alternatives available for focal seizures.

• Litigation Risks:

  • Increasing lawsuits related to fetal valproate syndrome, even with risk warnings.

• Usage in Children:

  • Limited value due to higher doses required and serious ADRs.