Sodium valproate

Generic Name: Sodium Valproate
Synonyms: Valproic acid, Valproate semisodium, Divalproex sodium
Drug Class: Antiepileptic (AED), mood stabilizer
Formulations:
– Oral tablets (immediate- and extended-release)
– Oral solution or syrup
– Intravenous injection (for status epilepticus)
Route of Administration: Oral, Intravenous
Therapeutic Range (Total Plasma Concentration): 50–100 µg/mL
ATC Code: N03AG01

Sodium valproate is a widely used antiepileptic medication with multiple central nervous system applications, including seizure management, mood stabilization in bipolar disorder, and prevention of migraines.

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2. Mechanism of Action

Sodium valproate acts via multiple pathways in the central nervous system:

• Inhibits GABA transaminase, increasing the brain’s GABA levels and enhancing inhibitory neurotransmission

• Inhibits voltage-gated sodium channels, stabilizing neuronal membranes and reducing high-frequency neuronal firing

• Blocks T-type calcium channels, particularly useful in absence seizures

• Reduces excitatory glutamatergic transmission

• Inhibits histone deacetylases (HDAC), possibly contributing to mood-stabilizing and epigenetic effects

This multimodal activity accounts for its broad-spectrum antiepileptic efficacy and mood-regulating properties.

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3. Pharmacokinetics

Absorption:

• Rapidly absorbed after oral administration

• Bioavailability >90%

• Peak plasma concentration reached within 1–4 hours (immediate-release) or 6–12 hours (extended-release)

Distribution:

• Highly protein-bound (~90%)

• Displacement occurs with hypoalbuminemia or co-administered protein-binding drugs

• Crosses blood-brain barrier and placenta

Metabolism:

• Primarily hepatic metabolism via glucuronidation and β-oxidation

• Multiple active and inactive metabolites

• Involves cytochrome P450 enzymes

Elimination:

• Excreted mainly in urine as metabolites

• Half-life ranges: 9–16 hours (adults), shorter in children

• Prolonged in liver dysfunction

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4. Therapeutic Indications

Epilepsy:

• Generalized seizures (tonic-clonic, absence, myoclonic)

• Focal seizures (with or without secondary generalization)

• Lennox-Gastaut syndrome

• Status epilepticus (IV form)

Bipolar Disorder:

• Acute manic episodes

• Maintenance therapy for mood stabilization

• Effective in rapid-cycling bipolar disorder and mixed features

Migraine Prophylaxis:

• Used off-label in adults for preventing migraines

• Not effective for acute treatment

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5. Dosage and Administration

Adults (Oral):

• Initial: 600–1000 mg/day in 2–3 divided doses

• Titrated every 3–5 days

• Typical maintenance: 1000–2000 mg/day

• Maximum: 2500–3000 mg/day (based on body weight and tolerability)

Pediatrics (≥2 years):

• Dosing based on weight: 20–30 mg/kg/day initially

• Titrated to 30–60 mg/kg/day if needed

• Younger children may require higher doses due to faster metabolism

Elderly:

• Lower initial doses (e.g., 250 mg/day)

• Careful monitoring due to altered protein binding and metabolism

IV Use (Status Epilepticus):

• Loading dose: 20–30 mg/kg IV over 15–60 minutes

• Maintenance: 15–30 mg/kg/day in divided infusions

• Maximum duration of IV use: 14 days

Hepatic Impairment:

• Contraindicated in significant liver dysfunction

• Use extreme caution in mild impairment

Tapering:

• Reduce dose gradually over weeks to avoid seizure recurrence or withdrawal symptoms

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6. Contraindications

• Hypersensitivity to valproate or formulation components

• Known liver disease or hepatic dysfunction

• Urea cycle disorders

• POLG gene mutations (e.g., Alpers-Huttenlocher syndrome)

• History of drug-induced pancreatitis

• Pregnancy (unless no alternatives exist and stringent precautions taken)

• Children <2 years with metabolic disorders

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7. Warnings and Precautions

Hepatotoxicity:

• Life-threatening liver failure can occur, particularly in the first 6 months

• Higher risk in children <2 years, especially on polytherapy or with metabolic disorders

• Monitor liver function tests before treatment and frequently during therapy

Pancreatitis:

• Acute and potentially fatal; can occur early or late in therapy

• Requires discontinuation if diagnosed

Suicidality:

• Increased risk of suicidal thoughts and behavior

• Monitor closely for depression or mood changes

Hyperammonemia and Encephalopathy:

• May occur with or without liver dysfunction

• More likely in combination with topiramate

Teratogenicity:

• High risk of neural tube defects (spina bifida), craniofacial abnormalities, and reduced cognitive function

• Avoid in women of childbearing age unless essential

• Requires risk management, contraception, and folic acid supplementation

Weight Gain and Metabolic Syndrome:

• Regular monitoring of weight, lipids, and glycemic parameters is advised

Bone Health:

• Long-term use may reduce bone mineral density

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8. Adverse Effects

Very Common (>10%):

• Gastrointestinal disturbances (nausea, vomiting, abdominal pain)

• Tremor

• Weight gain

• Drowsiness or sedation

• Elevated liver enzymes

• Hair loss (reversible)

Common (1–10%):

• Ataxia

• Diplopia

• Behavioral changes

• Headache

• Menstrual irregularities or amenorrhea

• Increased appetite

• Thrombocytopenia

• Rash

Uncommon to Rare (<1%):

• Hepatitis

• Pancreatitis

• Aplastic anemia or agranulocytosis

• Stevens-Johnson syndrome

• Encephalopathy

• Hearing loss

• Peripheral edema

• Fanconi syndrome

• Renal tubular dysfunction

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9. Drug Interactions

Pharmacodynamic Interactions:

• CNS depressants (e.g., benzodiazepines, alcohol): additive sedation

• Antipsychotics: increased risk of EPS or sedation

• Aspirin: may increase valproate levels and free fraction

Pharmacokinetic Interactions:

• Enzyme inducers (e.g., carbamazepine, phenytoin, phenobarbital): reduce valproate levels

• Enzyme inhibitors (e.g., fluoxetine, erythromycin): may increase valproate levels

• Lamotrigine: valproate inhibits lamotrigine metabolism, increasing toxicity risk

• Topiramate: increases risk of hyperammonemia and encephalopathy

• Oral contraceptives: no significant interaction with ethinylestradiol

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10. Use in Special Populations

Pregnancy:

• Highly teratogenic; contraindicated unless no alternatives

• Causes neural tube defects and neurodevelopmental delay

• Requires effective contraception and risk acknowledgment

Lactation:

• Excreted in breast milk

• Monitor infants for sedation or hepatotoxicity

Pediatrics:

• Higher risk of hepatotoxicity and pancreatitis

• Use only when essential with frequent monitoring

Elderly:

• Lower doses may be needed due to reduced clearance

• Monitor for sedation, confusion, and falls

Renal Impairment:

• Usually no dose adjustment; monitor for accumulation of metabolites

Hepatic Impairment:

• Contraindicated in moderate to severe dysfunction