Valproic Acid: Effects, Uses & Risks

Valproic acid is a non-naturally occurring carboxylic acid. It was first synthesized in 1881 and is used as an antiepileptic. It should not be used in pregnant or breastfeeding women.

What is valproic acid?

Valproic acid is a non-naturally occurring carboxylic acid. Carboxylic acids are organic compounds that have one or more carboxy groups (-COOH). Valproic acid and its salts (called valproates) are used medicinally as antiepileptic drugs (anticonvulsants). The chemical formula of valproic acid is C8H16O2, and its molar mass is 144.21 g-mol-1. Valproic acid was first synthesized in 1881. Initially, it was used as a solvent for water-insoluble substances. Valproic acid is synthesized from the starting materials ethyl cyanoacetate and two equivalents of 1-bromopropane. With the addition of sodium ethanolate, these soaps react via an anion of the enol form of the carbonyl compound to give the α,α-dipropylcyanoacetic ester. In a basic environment, ester cleavage and decarboxylation then take place. These processes give rise to dipropylacetonitrile, which can be converted to valproic acid by a reaction with water (hydrolysis). Malonic ester synthesis is an alternative to the synthesis of valproic acid described above.

Pharmacologic action

Valproates, the salts of valproic acid, which are converted to valproic acid in the stomach, are used primarily for the treatment of epilepsy. Application can be oral or intravenous. The absorption of valproic acid is very rapid, and there is also a plasma protein binding of over 90%. Valproic acid is metabolized hepatically; less than 3% of the drug is excreted unchanged in the urine. The plasma half-life of valproic acid is 14 hours. However, it should be noted that it may decrease in combination with other epileptic drugs. The effect of valproic acid is due to its ability to close ion channels in the central nervous system. By closing the ion channels, ions can no longer enter the cells and trigger action potentials. Both sodium and calcium ion channels are affected by this action of valproic acid. These two ion channels are responsible for the increased occurrence of action potentials in epilepsy. Furthermore, valproic acid enhances the action of the neurotransmitter GABA by inhibiting the breakdown of GABA while stimulating the synthesis of GABA. The neurotransmitter GABA leads to an increased influx of chloride ions into the cell, resulting in decreased excitability of the cell. In addition, valproic acid interferes with the epigenetic system, including through acetylation, which can alter cells and the activity of individual genes. Valproic acid inhibits the enzyme histone deacetylase, thereby loosening the density of DNA packaging. Via the degree of acetylation of histones, valproic acid modulates gene activity. This mechanism causes malformations in embryos, which is why valproic acid should not be used in pregnant women. In addition, however, it makes valproic acid a potential agent in cancer therapy, as the regulation of gene expression is an essential aspect of tumorigenesis. By modulating gene activity, valproic acid is able to either allow normal gene activity by reversing gene blockages or to induce cell death. This effect of valproic acid is currently under further investigation.

Medical application and use

Valproic acid is used as an antiepileptic agent. It is indicated for generalized forms of epilepsy, awakening grand mal epilepsy and juvenile myoclonic epilepsy, bipolar disorder, psychoses of the schizophrenic type, addictive disorders, refractory depression, migraine prophylaxis, and cluster headache prophylaxis. For the last two indications, valproic acid does not have approval, although it is effective. In young children, valproic acid may be used only when other antiepileptic drugs cannot be used. For longer-term phase prophylaxis in bipolar disorder, there is insufficient evidence of benefit, so there is no approval for this indication.

Risks and Side Effects

Valproic acid should not be used in pregnant women because it causes malformations of the embryo.In addition, there is evidence that the use of valproic acid during pregnancy leads to cognitive impairment in children. In particular, problems with verbal skills and memory are common. In addition, the children have a high incidence of disorders from the autism spectrum up to and including actual autism. Valproic acid should also not be used during breastfeeding. Various side effects may occur during therapy with valproic acid. These often include itching and rashes, headache, dizziness, unsteadiness of movement and visual disturbances, loss of appetite or an increase in appetite, weight loss or increase, drowsiness, tremor, nystagmus (uncontrolled, rhythmic movement of an organ; usually of the eyes), transient hair loss, severe and sometimes fatal liver damage, hearing loss, sensory dysfunction and sensitivity, Parkinsonian movement disorders, and blood count changes and blood clotting disorders. Frequently, blood ammonium concentrations are elevated. Occasionally, behavioral disturbances, bleeding, gastrointestinal disorders, pleural effusion, indigestion, increased salivation, increased blood insulin concentration, edema, delusions, menstrual disorders, transient brain damage, coma, blood vessel inflammation, and skin rashes occur. Rarely, tinnitus, myelodysplastic syndrome, hypothyroidism, chronic encephalopathy with brain dysfunction, severe skin reactions, lupus erythematosus, impaired bone marrow function, kidney dysfunction (Fanconi syndrome) occur, hyperacidity (metabolic acidosis), enuresis, disturbances in the metabolism of red blood pigment (porphyria), infertility in men, increased testosterone in the blood (in women) and cystic change of the ovaries, and inflammation of the oral mucosa. Fever, swelling of the face, mouth, and throat, lymphocytosis, biotin deficiency in children, hallucinations, swelling of the gums, and decreased body temperature are also possible.