indication

For treatment and management of seizure disorders, mania, and prophylactic treatment of migraine headache.

pharmacology

Valproic Acid is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder. It is also used to treat migraine headaches and schizophrenia. In epileptics, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, and the seizures associated with Lennox-Gastaut syndrome. Valproic Acid is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain. Valproic Acid dissociates to the valproate ion in the gastrointestinal tract. Valproic acid has also been shown to be an inhibitor of an enzyme called histone deacetylase 1 (HDAC1). HDAC1 is needed for HIV to remain in infected cells. A study published in August 2005 revealed that patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a 75% reduction in latent HIV infection.

mechanism of action

Valproic Acid binds to and inhibits GABA transaminase. The drug's anticonvulsant activity may be related to increased brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS, by inhibiting enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. Valproic Acid may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels. It is also a histone deacetylase inhibitor.

toxicity

Oral, mouse: LD₅₀ = 1098 mg/kg; Oral, rat: LD₅₀ = 670 mg/kg. Symptoms of overdose may include coma, extreme drowsiness, and heart problems.

biotransformation

Valproic Acid is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial ß-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.

absorption

Rapid absorption from gastrointestinal tract.

half life

9-16 hours

route of elimination

Valproate is metabolized almost entirely by the liver. Less than 3% of an administered dose is excreted unchanged in urine. Mitochondrial ß-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose.

drug interactions

Acetylsalicylic acid: Acetylsalicylic acid increases the effect of valproic acid.

Carbamazepine: Decreases the effect of valproic acid

Clarithromycin: The macrolide antibiotic, Erythromycin, may increase the serum concentratin of Valproic acid. Consider alternate therapy or monitor for changes in Valproic acid therapeutic and adverse effects if Clarithromycin is initiated, discontinued or dose changed.

Erythromycin: The macrolide antibiotic, Erythromycin, may increase the serum concentratin of Valproic acid. Consider alternate therapy or monitor for changes in Valproic acid therapeutic and adverse effects if Erythromycin is initiated, discontinued or dose changed.

Felbamate: Felbamate, a CYP2C19 inhibitor, may decrease the metabolism of Valproic acid, a CYP2C19 substrate. Consider alternate therapy or monitor for changes in Valproic acid therapeutic and adverse effects if Felbamate is initiated, discontinued or dose changed.

Lamotrigine: Valproic acid may increase the adverse effects of Lamotrigine by increasing Lamotrigine serum concentration. The Lamotrigine dose should be reduced by 50% during concomitant therapy. Monitor for changes in Lamotrigine therapeutic and adverse effects if Valproic acid is initiated, discontinued or dose changed.

Lorazepam: Valproic acid may increase the serum concentration of Lorazepam by reducing Lorazepam metabolism. The Lorazepam dose should be reduced by 50% during concomitant therapy. Monitor for increased Lorazepam effects and toxicity.

Nimodipine: Valproic acid increases the effect of nimodipine

Rifampin: Rifampin may reduce the serum concentration of Valproic acid by increasing Valproic acid metabolism. Valproic acid dose adjustments may be required during concomitant therapy. Monitor Valproic acid serum concentrations, efficacy and toxicity if Rifampin is initiated, discontinued or dose changed.

Telithromycin: The macrolide antibiotic, Erythromycin, may increase the serum concentratin of Valproic acid. Consider alternate therapy or monitor for changes in Valproic acid therapeutic and adverse effects if Telithromycin is initiated, discontinued or dose changed.

Tipranavir: Tipranavir decreases the concentration of Valproic acid. Monitor Valproid acid efficacy.