Valproic acid

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Valproic acid (Brand names: Depakin, Depakine, Depakene, Encorate, among others), is an anticonvulsant and mood-stabilizing drug, primarily used in the treatment of epilepsy, bipolar disorder and prevention of migraine headaches.

Contents

[edit] BRAND NAMES

[edit] STRUCTURE

Valproic acid.jpg

[edit] MECHANISM OF ACTION

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:

  • Valproic acid increases GABA levels: 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)

[edit] INDICATIONS

  • Valproic acid is a broad spectrum anticonvulsant used for:
    • Absence seizures
    • Tonic-clonic (grand mal)
    • Partial seizures
    • Juvenile myoclonic epilepsy
    • Lennox-Gastaut syndrome
  • Acute treatment of manic or mixed episodes associated with bipolar disorder. It is also used as adjunctive treatment in depressive episodes.
  • Prophylaxis of migraine headaches

[edit] DOSAGE

Bipolar Mania: Valproic acid is generally initiated at doses of 20 mg/kg/day given in divided doses for inpatients and 250 mg three times daily for outpatients. Not to exceed 60 mg/kg/day.

Migraine: 250 mg PO q12hr; adjust dose based on clinical response, not to exceed 1000 mg/day.

[edit] CONTRAINDICATIONS

  • Hepatic disease or significant hepatic dysfunction
  • Known hypersensitivity to the drug
  • Valproic acid is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder.
  • 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.

[edit] WARNINGS AND PRECAUTIONS

  • 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

[edit] INTERACTIONS

  • 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.

[edit] PREGNANCY AND LACTATION

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

Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman

[edit] SIDE EFFECTS

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

[edit] RELATED LINKS

Pharmacology of Antiepileptic Drugs

[edit] BIBLIOGRAPHY

[edit] REFERENCES