Valproic acid/Sodium valproate

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This is a combination of Valproic acid and Sodium valproate in a 1:1 molar relationship.

The mechanism of action of Valproic Acid is not fully understood. it may be involved in multiple mechanisms of action, probably accounting for its broad efficacy:

  • GABA is an inhibitory neurotransmitter in the CNS that is catabolized by GABA transaminase; Valproic acid is believed to increase the activity of the neurotransmitter gamma-amino butyric acid (GABA); It inhibits the metabolism of GABA by acting as a GABA transaminase inhibitor in the human brain. An increase in GABA in the brain is linked to mood stabilisation, and this helps to control the manic episodes (extremely high mood) associated with bipolar disorder.
  • Valproic acid may also augment the the activity of glutamic acid decarboxylase (GAD), a GABA-synthesizing enzyme that catalyzes the decarboxylation of glutamate to GABA and CO2.
  • Valproic acid blocks high-frequency, repetitive neuronal firing by blocking voltage-dependent sodium channels (anticonvulsant mechanism)
  • Valproic acid blocks T-type calcium channels (anticonvulsant mechanism)


  • Epilepsy: Primary generalised epilepsy (petit mal absences, various forms of myoclonic epilepsy and tonic-clonic grand mal seizures). Partial (focal) epilepsy either alone or as adjuvant therapy.
  • Mania: Acute treatment of manic or mixed episodes associated with bipolar disorder
  • Migraine: Prophylaxis of migraine headaches

[edit] DOSAGE

  • Mania: Initial dose is 25 mg/kg/day, increasing as rapidly as possible to achieve therapeutic response or desired plasma level. The maximum recommended dosage is 60 mg/kg/day.
  • Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response (usually 20-30 mg/Kg/day); if response is not satisfactory, check valproate plasma level; The maximum recommended dosage is 60 mg/kg/day.
  • Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or limiting side effects. The maximum recommended dosage is 60 mg/kg/day.
  • Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed

Therapeutic Serum Levels: 50-100 mcg/mL


  • Hepatic disease or significant hepatic dysfunction
  • Known hypersensitivity to the drug
  • Urea cycle disorders: Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency.
  • Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG)
  • Suspected POLG-related disorder in children under two years of age
  • Pregnancy


  • Hepatotoxicity, including fatalities, usually during first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter.
  • Valproic acid can produce birth defects, particularly neural tube defects, other major malformations, and decreased IQ. Only use to treat pregnant women with epilepsy if other medications are unacceptable; Should not be administered to a woman of childbearing potential unless essential
  • Pancreatitis: cases of life threatening pancreas disorder have been reported in both children and adults. Some cases have occurred shortly after first use as well as after several years of use. Abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that require immediate medical evaluation.
  • Suicidal behavior or ideation: Antiepileptic drugs, including Valproic acid, increase the risk of suicidal thoughts or behavior


  • Decreased effects of valproic acid:
    • Several antiepileptic drugs often used in conjunction with valproate (eg phenytoin, carbamazepine, phenobarbital) have the ability to increase the intrinsic clearance of valproate, presumably by enzymatic induction of metabolism.
  • Dosage adjustment of amitriptyline/nortriptyline, warfarin, and zidovudine may be necessary if used concomitantly with Valproic acid (Valproic acid may raise plasma concentrations of these drugs).
  • Topiramate: Concomitant administration of valproate and topiramate has been associated with encephalopathy and/or hyperammonemia
  • Alcohol: Valproic acid may potentiate the CNS depressant activity of alcohol. Alcohol intake is not recommended during treatment with valproate.
  • Aspirin: Concomitant administration of sodium valproate and aspirin may result in displacement of valproate from protein binding sites, resulting in a rise in free levels.


  • Pregnancy: Valproic acid can cause congenital malformations including neural tube defects, other major malformations, and decreased IQ, which may occur very early in pregnancy. valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition
  • Nursing Mothers: Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman


Most common adverse reactions are: Nausea, somnolence, dizziness, vomiting, asthenia, abdominal pain, dyspepsia, rash, diarrhea, increased appetite, tremor, weight gain, back pain, alopecia, headache, fever, anorexia, constipation, diplopia, amblyopia/blurred, ataxia, nystagmus, emotional lability, thinking abnormal, amnesia, flu syndrome, infection, bronchitis, rhinitis, ecchymosis, peripheral edema, insomnia, nervousness, depression, pharyngitis, dyspnea, tinnitus.

Serious adverse reactions: rare fatal hepatitis, decrease or dysfunction in platelets (thrombocytopenia) with increased coagulation time, anemia, Acute pancreatitis including fatalities.


Pharmacology of Antiepileptic Drugs