Valproic Acid (Depakote)(R),S

Valproate (valproic acid; divalproex sodium, a compound containing sodium valproate and valproic acid) controls absence, myoclonic, and tonic-clonic seizures in generalized, idiopathic, and symptomatic epilepsy. It is most useful in typical absence seizures. Valproate is as effective as ethosuximide in patients with absence seizures alone and is variably effective in atypical absence seizures. Although some clinicians prefer valproate for absence seizures, the American Academy of Pediatrics (Committee on Drugs, 1982) recommended that it be reserved for use when therapeutic failure or intolerance to ethosuximide occurs, because valproate causes rare but potentially fatal hepatotoxicity. Many neurologists consider valproate the drug of choice for patients with both absence and other generalized seizure types, including tonic-clonic convulsions. Its efficacy is about the same as in patients with the latter type alone.

Valproate is an alternative drug in the treatment of complex partial seizures but may be considered for initial therapy in patients with partial and secondarily generalized seizures.

Valproate is the drug of choice in myoclonic epilepsy, with or without generalized tonic-clonic seizures, including juvenile myoclonic epilepsy of Janz, that begins in adolescence or early adulthood. Photosensitive myoclonus is usually easily controlled. Valproate also is effective in the treatment of benign myoclonic epilepsy, postanoxic myoclonus, and, with clonazepam, in severe progressive myoclonic epilepsy that is characterized by tonic-clonic seizures as well. It also may be preferred in certain stimulus-sensitive (reflex, startle) epilepsies.

Although valproate may be effective for infantile spasms, it is relatively contraindicated in children whose spasms are due to hyperglycinemia or other underlying metabolic (mitochondrial) abnormalities. In general, atonic and akinetic seizures in patients with Lennox-Gastaut syndrome are difficult to control, but valproate is the drug of choice for treatment of mixed seizure types. Since this drug has been useful in some patients who are refractory to all other antiepileptic drugs, it may warrant a trial in nearly all nonresponsive patients regardless of seizure type.

Hepatotoxicity may be fatal, but is idiosyncratic and not preventable by routinely monitoring liver enzymes. Hepatotoxicity occurs in very young children, most often those on multiple anticonvulsants.1 Valproate-induced cytopenias may be dose-related and warrant monitoring of complete blood counts during therapy.2 Encephalopathy with hyperammonemia without liver function test abnormalities may occur.3 Pregnant women in first month are at risk for neural tube defects.

Valproate is absorbed rapidly and completely following oral administration; peak plasma concentrations usually occur within two hours after ingestion of liquid preparations and three to four hours after ingestion of the delayed-release tablet preparation, divalproex sodium, which contains sodium valproate and valproic acid. Food delays absorption but does not affect bioavailability.

The plasma protein binding of valproate is saturable within the usual therapeutic range (approximately 90% at 75 μg/mL). Usual effective plasma concentrations range from 50−120 μg/mL.4 With a daily dose of more than 500 mg, plasma concentrations may not increase proportionately because clearance increases with an increase in the free fraction. Daily fluctuations (up to two times higher) in free fraction and clearance also occur as a result of displacement by free fatty acids or circadian influences; thus, when plasma concentrations are being monitored, samples should be taken at a uniform time. Many neurologists recommend measuring trough concentrations.

Valproate is eliminated almost exclusively by hepatic metabolism. The metabolic fate is complex. A variety of conjugation and oxidative processes are involved, including entry into pathways (eg, beta oxidation) normally reserved for endogenous fatty acids. As the dose is increased, mitochondrial beta oxidation becomes saturated and increased glucuronidation occurs.

Metabolites may contribute to both antiepileptic and hepatotoxic effects. The antiepileptic activity of valproate (including the time course) is poorly correlated with steady-state valproate plasma concentrations. One unsaturated metabolite, 2-n-propyl-4-pentenoic acid (4-ene-VPA), has been proposed as a key hepatotoxic metabolite. The formation of this metabolite is increased by concomitant use of phenytoin, phenobarbital, carbamazepine, and other drugs that induce cytochrome P450. Due to inhibition of the same enzyme system, valproic acid may cause elevated levels of clomipramine with resultant seizures when the two agents are co-administered.5

The half-life of valproate in adults is 12 to 16 hours. In epileptic patients receiving polytherapy, the half-life is approximately nine hours, although five hours has also been reported. The half-lives in school-age children and young adolescents are well within the range of values in adults. Elimination half-lives are longer in neonates and generally shorter during middle and late infancy. Although hepatic clearance is reduced, the half-life in geriatric patients is approximately 15 hours. This has been attributed to the larger free fraction observed in this age group, especially in those with hypoalbuminemia.

1. Dreifuss FE, Santilli N, Langer DH, Sweeney KP, Moline KA, Menander KB. Valproic acid hepatic fatalities: A retrospective review. Neurology. 1987 Mar; 37(3):379-385. PubMed 3102998
2. Watts RG, Emanuel PD, Zuckerman KS, Howard TH. Valproic acid-induced cytopenias: Evidence for a dose-related suppression of hematopoiesis. J Pediatr. 1990 Sep; 117(3):495-499. PubMed 2118175
3. Zaret BS, Bockner RR, Marini AM, Waglw W, Passarelli C. Sodium valproate-induced hyperammonemia without clinical hepatic dysfunction. Neurology. 1982 Feb; 32(2):206-208. PubMed 6798491
4. Warner A, Annesley TA, eds. Guidelines for Therapeutic Drug Monitoring Services. Washington, DC: National Academy of Clinical Biochemistry;1999.
5. DeToledo JC, Haddad H, Ramsay RE. Status epilepticus associated with the combination of valproic acid and clomipramine. Ther Drug Monit. 1997 Feb; 19(1):71-73. PubMed 9029750

American Medical Association, Division of Drugs and Toxicology. Drug Evaluations Subscription. Chicago, Ill: AMA; Fall, 1992.
Bourgeois BF. Pharmacokinetic properties of current antiepileptic drugs. What improvements are needed? Neurology. 2000; 55(Suppl 3):S11-S16. PubMed 11147563