What is the role of valproate (VPA) in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Valporate (VPA) is one of the most commonly used AEDs around the world. It is the drug of choice for primary generalized epilepsies and is also approved for the treatment of partial seizures. It was discovered by accident; first synthesized in 1882, its antiepileptic properties were recognized when it was used as a solvent for the experimental screening of new AEDs. It was licensed in Europe in the early 1960s, where its use became extensive. It has been used in different forms (eg, divalproex sodium, magnesium or calcium salt, and valpromide), which do not differ significantly.

The mechanism of action is uncertain. VPA enhances GABA function, but this effect is observed only at high concentrations. It may increase the synthesis of GABA by stimulating GAD. It also produces selective modulation of voltage-gated sodium currents during sustained, rapid, repetitive neuronal firing. [63, 64, 65]

VPA is a simple molecule, similar to endogenous fatty acids. It is slightly soluble in water and highly soluble in organic solvents. The sodium salt is highly water soluble, whereas the calcium and magnesium salts are insoluble. VPA is absorbed rapidly and nearly completely, with a bioavailability close to 100%.

The peak plasma level after oral administration is reached in 13 minutes to 2 hours. The acid form takes a longer time to reach peak plasma concentration (3-4 h), and divalproex sodium reaches peak plasma concentration slightly faster. The enteric-coated divalproex sodium reaches peak concentration in approximately 3-8 hours. The sprinkle form peaks in 4 hours.

VPA is 85-95% bound to plasma proteins. Protein binding decreases at higher levels (ie, >100 mg/mL), in renal and hepatic diseases, and during pregnancy. Some other drugs (eg, aspirin, phenylbutazone) displace VPA, but other AEDs do not. Total serum VPA levels affect protein binding so that at serum concentrations lower than 75 µg/mL, the unbound fraction ranges from 7% to 9%. At serum concentrations of 100 µg /mL, the free fraction increases to 15%. The volume of distribution is 0.1-0.4 L/kg.

VPA reaches the brain by an active transport process that is saturable. It is metabolized in the liver (96%) mainly by beta-oxidation and then glucuronidation. Less than 4% is excreted unchanged in urine. Some metabolites may be responsible for adverse effects, particularly the 4-ene metabolite, which may cause hepatic toxicity. The plasma half-life is 16 hours. When VPA is used with enzyme-inducing AEDs, the half-life is reduced to 9 hours.

An intravenous (IV) form of VPA (Depacon; Abbott Pharmaceuticals) is available. It is well tolerated, with only 2% of patients discontinuing treatment because of adverse effects, and has no significant effect on the cardiovascular system. Bioavailability is similar to that of the oral preparation. The Tmax after IV VPA is at the end of 1-hour infusion, and thus the drug should be administered every 6 hours.

VPA is a potent inhibitor of both oxidation and glucuronidation. It increases plasma levels of free fractions of phenytoin (PHT), phenobarbital (PHB), carbamazepine (CBZ) epoxide, and lamotrigine (LTG). It reduces the total PHT level. The levels of VPA are decreased by enzyme-inducing drugs and are increased by felbamate and clobazam.

VPA is a potent AED, effective against a wide range of seizure types. It is the drug of choice in idiopathic generalized epilepsy. Open and comparative studies have shown excellent control rates in patients with newly diagnosed typical absence seizure. It is the drug of choice for juvenile myoclonic epilepsy and can be used in other types of myoclonus. In addition, it is a first-line drug in photosensitive epilepsy and Lennox-Gastaut syndrome. It is a second choice in the treatment of infantile spasms. In focal epilepsy, VPA has been shown to be as effective as other first-line agents.

The usual starting dose is 250 mg/d, with a maintenance dose of 500-1500 mg/d. In the author’s opinion, 3 times–daily dosing is better tolerated, but twice-daily dosage is usual. Rapid titration usually is well tolerated. In children, the usual dose is 20 mg/kg/d and the maintenance dose is 40 mg/kg. Serum level has poor correlation with clinical effect and has significant daily fluctuations. IV VPA should be administered as a 60-minute infusion with a rate not exceeding 20 mg/min.

VPA is available as 125 mg, 250 mg, and 500 mg delayed-release tablets; 125 mg and 250 mg sprinkle capsules; 500 mg extended-release tablets; 250 mg/5 mL syrup; and parenteral preparation for IV injection.

Meador et al found that in utero exposure to VPA, as compared with other antiepileptic agents, is associated with a lower IQ in children. [66] The study took place over 5 years in 25 epilepsy centers in the United States and the United Kingdom. The design was a prospective, observational, cohort study of pregnant women with epilepsy who took a single agent (CBZ, LTG, PHT, or PHB).

The cohort study assessed the neurodevelopmental outcomes of children who were exposed in utero to several antiepileptic drugs. A planned interim analysis conducted when the children were 3 years of age found an increased risk of impaired cognitive function compared with other commonly used antiepileptic drugs; this association was dose-dependent. The investigators concluded that VPA should not be used as a first-line agent in women of childbearing potential. [66]

This interim analysis was updated in 2013 with data from children completing 6 years of follow-up. The final results of the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study showed that children exposed to valproate products while their mothers were pregnant had decreased IQs at age 6 compared to children exposed to other antiepileptic drugs. [67]

The prescribing information was changed to reflect this risk including a Black Box Warning stating not to use valproate derivatives in women of childbearing age unless the drug is essential to the management of seizures, or for manic episodes associated with bipolar disorder (FDA fetal risk category D). It should not be used for migraine headache prophylaxis during pregnancy (FDA fetal risk category X).

Even though VPA has been used for many years, large controlled and blinded studies to determine the frequency of adverse effects have not been conducted. On the basis of clinical experience, dose-related adverse effects include nausea, vomiting (mainly during initiation of therapy and improved by administration of enteric-coated preparations), tremor, sedation, confusion or irritability, and weight gain.

Metabolic effects from interference in mitochondrial metabolism include hypocarnitinemia, hyperglycinemia, and hyperammonemia. Severe sedation or even coma may result from hyperammonemia, typically with normal liver function tests. Patients with an underlying urea cycle enzyme defect may become encephalopathic from acute hyperammonemia, which may be fatal occasionally.

Hair loss or curling of hair may occur, which in the author’s patients has improved when the patients used baby shampoo and a multivitamin supplement. VPA has adverse endocrine effects, including insulin resistance and change in sex hormone levels causing anovulatory cycles, amenorrhea, and polycystic ovary syndrome. Bone marrow suppression with neutropenia and allergic rashes are rare. Acute pancreatitis is rare but potentially fatal and usually reverses after withdrawal of VPA.

The most serious idiosyncratic adverse effect is hepatotoxicity. This is observed mainly in patients younger than 2 years and with polytherapy.

Because of its adverse-effect profile, VPA is being replaced by newer AEDs. The new extended-release preparation may decrease dose-related adverse effects and may be better tolerated. It may be useful in patients with concomitant migraine headache. Hepatic failure from VPA is extremely rare in adulthood. VPA should be used with caution in women of reproductive age.

The inhibition of kindling in experimental models suggests a potential use as a prophylactic agent for seizures; however, no clinical studies support this hypothesis. IV VPA is useful in patients when oral administration is not possible and when rapid IV loading is necessary. It is also helpful in patients with poorly controlled repetitive seizures that require a rapid IV load. Unlike PHT or PHB, IV VPA is not associated with hemodynamic changes.

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