Pharmacology Of Valproic Acid

Indication	For treatment and management of seizure disorders, mania, and prophylactic treatment of migraine headache.
Pharmacodynamics	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.
Absorption	Rapid absorption from gastrointestinal tract.
Volume of distribution	11 L/1.73 m2 [total valproate] 92 L/1.73 m2 [free valproate]
Protein binding	Concentration-dependent, from 90% at 40 µg/mL to 81.5% at 130 µg/mL.
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.
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.
Half life	9-16 hours
Clearance	total valproate cl=0.56 L/hr/1.73 m2 free valproate cl=4.6 L/hr/1.73 m2 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.