Valproic Acid & Sodium Valproate

VALPROIC ACID & SODIUM VALPROATE

Sodium valproate, also used as the free acid, valproic acid, was found to have antiseizure properties when used as a solvent in the search for other drugs effective against seizures. It was marketed in France in 1969 but was not licensed in the USA until 1978. Valproic acid is fully ionized at body pH, and for that reason the active form of the drug may be assumed to be the valproate ion regardless of whether valproic acid or a salt of the acid is administered.

Chemistry

Valproic acid is one of a series of fatty carboxylic acids that have antiseizure activity; this activity appears to be greatest for carbon chain lengths of five to eight atoms. The amides and esters of valproic acid are also active antiseizure agents.

Mechanism of Action

The time course of valproate’s anticonvulsant activity appears to be poorly correlated with blood or tissue levels of the parent drug, an observation giving rise to considerable speculation regarding both the active species and the mechanism of action of valproic acid. Valproate is active against both pentylenetetrazol and maxi-mal electroshock seizures. Like phenytoin and carbamazepine, valproate blocks sustained high-frequency repetitive firing of neu-rons in culture at therapeutically relevant concentrations. Its action against partial seizures may be a consequence of this effect on Na⁺ currents. Blockade of NMDA receptor-mediated excita-tion may also be important. Much attention has been paid to the effects of valproate on GABA. Several studies have shown increased levels of GABA in the brain after administration of val-proate, although the mechanism for this increase remains unclear. An effect of valproate to facilitate glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, has been described. An inhibitory effect on the GABA transporter GAT-1 may contribute. At very high concentrations, valproate inhibits GABA transaminase in the brain, thus blocking degradation of GABA. However, at the relatively low doses of valproate needed to abolish pentylenetetrazol seizures, brain GABA levels may remain unchanged. Valproate produces a reduction in the aspartate con-tent of rodent brain, but the relevance of this effect to its anticon-vulsant action is not known.

Valproic acid is a potent inhibitor of histone deacetylase and through this mechanism changes the transcription of many genes. A similar effect, but to a lesser degree, is shown by some other antiseizure drugs (topiramate, carbamazepine, and a metabolite of levetiracetam).

Clinical Uses

Valproate is very effective against absence seizures and is often preferred to ethosuximide when the patient has concomitant generalized tonic-clonic attacks. Valproate is unique in its ability to control certain types of myoclonic seizures; in some cases the effect is very dramatic. The drug is effective in tonic-clonic seizures, especially those that are primarily generalized. A few patients with atonic attacks may also respond, and some evidence suggests that the drug is effective in partial seizures. Its use in epilepsy is at least as broad as that of any other drug. Intravenous formulations are occasionally used to treat status epilepticus.Other uses of valproate include management of bipolar disorder and migraine prophylaxis.

Pharmacokinetics

Valproate is well absorbed after an oral dose, with bioavailability greater than 80%. Peak blood levels are observed within 2 hours. Food may delay absorption, and decreased toxicity may result if the drug is given after meals.

Valproic acid is 90% bound to plasma proteins, although the fraction bound is somewhat reduced at blood levels greater than 150 mcg/mL. Since valproate is both highly ionized and highly protein-bound, its distribution is essentially confined to extracellular water,     with a volume of distribution of approximately 0.15 L/kg. At higher doses, there is an increased free fraction of valproate, resulting in lower total drug levels than expected. It may be clinically useful, therefore, to measure both total and free drug levels. Clearance for valproate is low and dose dependent; its half-life varies from 9 to 18 hours. Approximately 20% of the drug is excreted as a direct conjugate of valproate.

The sodium salt of valproate is marketed in Europe as a tablet and is quite hygroscopic. In Central and South America, the mag-nesium salt is available, which is considerably less hygroscopic. The free acid of valproate was first marketed in the USA in a cap-sule containing corn oil; the sodium salt is also available in syrup, primarily for pediatric use. An enteric-coated tablet of divalproex sodium is also marketed in the USA. This improved product, a 1:1 coordination compound of valproic acid and sodium valproate, is as bioavailable as the capsule but is absorbed much more slowly and is preferred by many patients. Peak concentrations following administration of the enteric-coated tablets are seen in 3–4 hours. Various extended-release preparations are available; not all are bioequivalent and may require dosage adjustment.

Therapeutic Levels & Dosage

Dosages of 25–30 mg/kg/d may be adequate in some patients, but others may require 60 mg/kg/d or even more. Therapeutic levels of valproate range from 50 to 100 mcg/mL.

Drug Interactions

Valproate displaces phenytoin from plasma proteins. In addition to binding interactions, valproate inhibits the metabolism of several drugs, including phenobarbital, phenytoin, and carbamazepine, leading to higher steady-state concentrations of these agents. The inhibition of phenobarbital metabolism, for example, may cause levels of the barbiturate to rise steeply, causing stupor or coma. Valproate can dramatically decrease the clearance of lamotrigine.

Toxicity

The most common dose-related adverse effects of valproate are nausea, vomiting, and other gastrointestinal complaints such as abdominal pain and heartburn. The drug should be started gradu-ally to avoid these symptoms. Sedation is uncommon with val-proate alone but may be striking when valproate is added to phenobarbital. A fine tremor is frequently seen at higher levels. Other reversible adverse effects, seen in a small number of patients, include weight gain, increased appetite, and hair loss.The idiosyncratic toxicity of valproate is largely limited to hepatotoxicity, but this may be severe; there seems little doubt that the hepatotoxicity of valproate has been responsible for more than 50 fatalities in the USA alone. The risk is greatest for patients under 2 years of age and for those taking multiple medications. Initial aspartate aminotransferase values may not be elevated in susceptible patients, although these levels do eventually become abnormal. Most fatalities have occurred within 4 months after initiation of therapy. Some clinicians recommend treatment with oral or intravenous L-carnitine as soon as severe hepatotoxicity is suspected. Careful monitoring of liver function is recommended when starting the drug; the hepatotoxicity is reversible in some cases if the drug is withdrawn. The other observed idiosyncratic response with valproate is thrombocytopenia, although documented cases of abnormal bleeding are lacking. It should be noted that valproate is an effective and popular antiseizure drug and that only a very small number of patients have had severe toxic effects from its use.

Several epidemiologic studies of valproate have confirmed a substantial increase in the incidence of spina bifida in the off-spring of women who took valproate during pregnancy. In addi-tion, an increased incidence of cardiovascular, orofacial, and digital abnormalities has been reported. These observations must be strongly considered in the choice of drugs during pregnancy.