Valproate


Valproate are medications primarily used to prevent migraine headaches, to treat epilepsy and as a mood stabilizer in the treatment of bipolar disorder. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.
Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth. Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended. Other serious risks include pancreatitis and an increased suicide risk.
Valproate is known to cause serious abnormalities or birth defects in the unborn child if taken during pregnancy, and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition and the person is also prescribed a contraceptive. Reproductive warnings have also been issued for men using the drug.
Valproate is restricted in the United Kingdom for both women and men under age 55 due to teratogenicity in pregnant women and fertility problems in men. It is also restricted in the European Union. The United States Food and Drug Administration has indicated a black box warning given the frequency and severity of the side effects and teratogenicity. Additionally, there is also a black box warning due to risk of hepatotoxicity and pancreatitis.
Valproate has been in use in Japan for the prophylaxis of migraine since 2011. It is approved as an antimanic and antiseizure in Japan as well. In UK, valproate is approved for bipolar mania and epilepsy, and both valproate and divalproex are approved, although divalproex sodium is known as valproate semisodium.
Valproate's precise mechanism of action is unclear. Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, inhibiting histone deacetylases, and increasing LEF1. Valproic acid is a branched short-chain fatty acid, a derivative of valeric acid.
Valproate was originally synthesized in 1881 and came into medical use in 1962. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2023, it was the 160th most commonly prescribed medication in the United States, with more than 3million prescriptions.

Medical uses

Valproate or valproic acid is used primarily to treat epilepsy and bipolar disorder and to prevent migraine headaches.

Epilepsy

Valproate has a broad spectrum of anticonvulsant activity, although it is primarily used as a first-line treatment for tonic–clonic seizures, absence seizures and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms. It has also been successfully given intravenously to treat status epilepticus.
In the US, valproic acid is also prescribed as an anti-epileptic drug indicated for the treatment of manic episodes associated with bipolar disorder; monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in people with multiple seizure types that include absence seizures.

Mental illness

Valproate products are used to treat manic or mixed episodes of bipolar disorder.
A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:

Other neurological indications

Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the dopamine dysregulation syndrome that arise from the treatment of Parkinson's disease with levodopa.
Valproate is not commonly used to prevent or treat migraine headaches, but it may be prescribed if other medications are not effective.

Other

The medication has been tested in the treatment of AIDS and cancer, owing to its histone-deacetylase-inhibiting effects. It has cardioprotective, kidney protective, antiinflammatory, and antimicrobial effects.

Contraindications

Contraindications include:
Most common adverse effects include:
Serious adverse effects include:
Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.
There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height. Valproic acid can also cause mydriasis, a dilation of the pupils. There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder. Weight gain is also possible.

Pregnancy

Valproate is a teratogen. Teratogens can cause birth defects. Valproate is restricted for all women under age 55 in the United Kingdom and European Union. It has a black box warning for pregnancy in the United States.

Elderly

Valproate may cause increased somnolence in the elderly. In a trial of valproate in elderly patients with dementia, a significantly higher portion of valproate patients had somnolence compared to placebo. In approximately one-half of such patients, there was associated reduced nutritional intake and weight loss.

Overdose and toxicity

Excessive amounts of valproic acid can result in somnolence, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/L during controlled therapy, but may reach 150–1500 mg/L following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography.
In contrast to other antiepileptic drugs, at present there is little favorable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, partly due to valproate's weak acid property.
In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body. Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored. Supplemental L-carnitine is indicated in patients having an acute overdose and also prophylactically in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly than L-carnitine.

Interactions

Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves. It may also potentiate the CNS depressant effects of alcohol. It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics and itself. It may also interact with:
  • Aspirin: may increase valproate concentrations. May also interfere with valproate's metabolism.
  • Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions.
  • Carbapenem antibiotics: reduce valproate levels, potentially leading to seizures.
  • Cimetidine: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.
  • Erythromycin: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations.
  • Ethosuximide: valproate may increase ethosuximide concentrations and lead to toxicity.
  • Felbamate: may increase plasma concentrations of valproate.
  • Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine.
  • Oral contraceptives: may reduce plasma concentrations of valproate.
  • Primidone: may accelerate metabolism of valproate, leading to a decline of serum levels and potential breakthrough seizure.
  • Rifampicin: increases the clearance of valproate, leading to decreased valproate concentrations.
  • Warfarin: valproate may increase free warfarin concentration and prolong bleeding time.
  • Zidovudine: valproate may increase zidovudine serum concentration and lead to toxicity.

    Pharmacology

Pharmacodynamics

Although the mechanism of action of valproate is not fully understood, traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of the inhibitory synaptic neurotransmitter gamma-aminobutyric acid. The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate. In animals, sodium valproate raises cerebral and cerebellar levels of GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.
Prevention of neurotransmitter-induced hyperexcitability of nerve cells via Kv7.2 channel and AKAP5 may also contribute to its mechanism. Valproate has been shown to protect against a seizure-induced reduction in phosphatidylinositol -trisphosphate as a potential therapeutic mechanism.
Valproate is a histone deacetylase inhibitor. By inhibition of histone deacetylase, it promotes more transcriptionally active chromatin structures, that is it exerts an epigenetic effect. This has been proven in mice: Valproic acid induced histone hyperacetylation had brain function effects on the next generation of mice through changes in sperm DNA methylation. Intermediate molecules include VEGF, BDNF, and GDNF.