Valproic acid

Monopgraph

Therapeutic action

• Anticonvulsant and mood stabilizer. Indicated for:
• Treatment of acute manic episodes associated with bipolar disorder.
• Monotherapy or adjunctive therapy for the treatment of simple and complex partial seizures.
• Adjuvant therapy for the treatment of patients with multiple types of seizures including absence seizures.
• Monotherapy or adjunctive therapy for the treatment of complex absence seizures.
• Prophylaxis of migraine headaches.

More information

Valproic acid is contraindicated in patients withurea cycle disorders (UCDs).The administration of valproic acid in patients of this group of genetic diseases has been related  to hyperammonemic encephalopathy, sometimes fatal, specially in the case of ornitine transcarbamilase deficiency. FDA recommends evaluating the possibility of UCDs in patients before administering valproic acid.

These are reasons to suspect of UCDs:  1) Antecedents of nonfiliated encephalopathy or coma, encephalopathy related to a protein load, postpartum or pregnancy-related encephalopathy, unfiliated mental retardation, antecedents of elevated plasmatic ammonia or glutamine. 2) Vomits or cyclic lethargy, extreme irritability episodes, ataxia, low urea nitrogen in blood, o protein deprivation. 3) Family history of UCDs or unfiliated infantile death (specially males). 4) Other signs or symptoms of UCDs.

FDA in the drug label recommends excluding this treatment in patients with an urea cycle disorder, which is highlighted in the following sentence:“Stavzor is contraindicated in patients with known urea cycle disorders.”

Metabolism

Orally administered valproic acid is bound to plasma proteins in a dose-dependent way, leaving a free fraction of 10% at low doses (40 µg/mL) to 18% at high doses (130 µg/mL). About this same proportion can be found in the cerebrospinal fluid. The metabolism of valproic acid takes place almost exclusively in the liver. The main metabolic pathways are the conjugation with glucuronic acid (30%-50%) and mitochondrial β-oxidation (40%), while other oxidative metabolic pathways are responsible for the elimination of 15% to 20% of the dose. Less than 3% is eliminated in urine as unchanged drug.

Other factors to be considered

Valproic acid is contraindicated in patients with an urea cycle disorder.Valproic acid moderately inhibits CYP2C9, as well as several UGTs including 1A4, 1A9, 2B7, 2B15 and also epoxide hydrolase.

Conclusions

Because patients with urea cycle disorders (UCD) can develop severe, life threatening, adverse reactions, the possibility of these disorders should be carefully evaluated and avoid administering valproic acid if the diagnosis is confirmed.If a patient receiving valproic acid develops hyperammonemic encephalopathy, immediately suspend the treatment and evaluate the possibility of urea cycle disorders.

Bibliography

• Turcato M de F et al (2005). Hyperammonemia secondary to the use of valproic acid: case report. Arq Neuropsiquiatr.  63(2A):364-6.
• Schmidt J et al (2005). Patients with ornithine transcarbamylase deficiency. Anaesthesiological and intensive care management. Anaesthesist. 54(12):1201-8.
• Scaglia F et al (2004). Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr. 134(10 Suppl):2775S-2782S; discussion 2796S-2797S.
• Schwarz S et al (1999). Enzyme defects of the urea cycle in differential acute encephalopathy diagnosis in adulthood. Diagnosis and current therapy concepts. Nervenarzt. 70(2):111-8.

Marc Bertran CendrósDegree in BiologyMaster in Genetic Counseling

Last modified: Sep 6, 2017 @ 09:59 am