Singapore Drugs Database

Indication

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

Mechanism of Action

Valproic Acid dissociates to the valproate ion in the gastrointestinal tract and then 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. 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.

Pharmacokinetics

Absorption

Rapid absorption from gastrointestinal tract. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. Food has a greater influence on the rate of absorption of the Depakote tablet (increases Tmax from 4 to 8 hours) than on the absorption of Depakote sprinkle capsules (increase Tmax from 3.3 to 4.8 hours). Furthermore, studies suggest that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control.

Distribution

* 11 L/1.73 m2 [total valproate] * 92 L/1.73 m2 [free valproate]

Metabolism

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.

Elimination

Clearance

* 0.56 L/hr/1.73 m2 [plasma clearance, total valproate] * 4.6 L/hr/1.73 m2 [plasma clearance, free valproate] * 4.8 ± 0.17 L/hr/1.73 m2 [males, unbound clearance] * 4.7 ± 0.07 L/hr/1.73 m2 [females, unbound clearance]

Toxicity

Oral, mouse: LD₅₀ = 1098 mg/kg; Oral, rat: LD₅₀ = 670 mg/kg. Symptoms of overdose may include coma, extreme drowsiness, and heart problems. The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults.

Active Ingredient/Synonyms

2-n-propyl-n-valeric acid | 2-propyl-pentanoic acid | 2-Propylpentanoic Acid | 2-Propylvaleric Acid | 4-heptanecarboxylic acid | acide valproïque | ácido valproico | acidum valproicum | di-n-propylacetic acid | Di-n-propylessigsäure | Dipropylacetic acid | DPA | n-DPA | Valproate | Valproinsäure | VPA | Valproic Acid |