Valproic acid

Valproic acid
File:Valproic acid.svg
File:Valproic acid 3d structure.png
Systematic (IUPAC) name
2-propylpentanoic acid
Clinical data
Trade names Convulex, Depakote, Epilim, Stavzor, Vilapro
AHFS/ monograph
MedlinePlus a682412
Licence data US FDA:link
  • AU: D
  • US: X (Contraindicated)
Oral, intravenous
Pharmacokinetic data
Bioavailability Rapid absorption
Protein binding 80-90%[1]
Metabolism Hepaticglucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Half-life 9–16 hours[1]
Excretion Urine (30-50%)[1]
99-66-1 7pxY
PubChem CID 3121
DrugBank DB00313 7pxY
ChemSpider 3009 7pxY
UNII 614OI1Z5WI 7pxY
KEGG D00399 7pxY
ChEBI CHEBI:39867 7pxY
NIAID ChemDB 057177
Synonyms 2-Propylvaleric acid
Chemical data
Formula C8H16O2
144.211 g/mol
 14pxY (what is this?)  (verify)

Valproic acid (VPA, valproate), an acidic chemical compound, has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder and prevention of migraine headaches. VPA is a liquid at room temperature, but it can be reacted with a base such as sodium hydroxide to form the salt sodium valproate, which is a solid.

The acid, salt, or a mixture of the two (valproate semisodium) are marketed under a number of different brand names, including: Convulex, Depakote, Epilim, Valparin, Valpro, Vilapro and Stavzor. It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[2]

Medical uses

Its primary use in medicine is in the treatment of epilepsy, bipolar mania and to protect against the development of migraines.[3] Valproate products are also used to treat manic or mixed episodes associated with bipolar disorder.[4] Off-label uses include impulse control disorders, suggested by recent evidence of efficacy in controlling this adverse effect of Parkinson's disease medical therapy.[5] Recently, it has been trialled in the treatment of HIV and cancer, owing to its histone deacetylase-inhibiting effects.[6] 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.[3][7] It has also been successfully given intravenously to treat status epilepticus.[8][9][10]

Adverse effects

The most common adverse effects of valproic acid are digestive complaints like diarrhea, nausea, vomiting and indigestion; vision problems like seeing double or lazy eye; hormonal disturbances (increased testosterone production in females and menstrual irregularities), hair loss, memory problems, weight gain, infections, low platelet count (which can make one bleed more easily), dizziness, drowsiness, tremor and headache.[3][11] Less common, yet serious side effects include liver damage, brittle bones (becomes far more common with long-term use), polycystic ovaries, movement disorders (which may be irreversible like tardive dyskinesia), psychiatric/neurologic disturbances like hallucinations, anxiety and confusion; pancreatic inflammation, low body temperature and potentially life-threatening blood abnormalities.[3]

Other possible side effects

There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[12][13][14][15] Valproic acid can also cause mydriasis, a protracted dilation of the pupils.[16]


Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida and, more rarely, with several other defects, possibly including a "valproate syndrome".[17] Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle shaped forehead due to earlier than normal fusion of the metopic suture, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.[18]

Women who intend to become pregnant should switch to a different medication if possible.[19] Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have even worse consequences.) They should take high-dose folic acid and be offered antenatal screening (alpha-fetoprotein and second-trimester ultrasound scans), although screening and scans do not find all birth defects.[20]

Valproate can cause neural tube defects. Folic acid supplements may reduce the risk of birth defects, however. A recent study showed children of mothers taking valproate during pregnancy are at risk for significantly lower IQs.[21][22][23] Maternal valproate use during pregnancy has been associated with a significantly higher risk of autism in the offspring.[24] Exposure of the human embryo to valproic acid is associated with risk of autism, and it is possible to duplicate features characteristic of autism by exposing rat embryos to valproic acid at the time of neural tube closure.[25] Valproate exposure on embryonic day 11.5 led to significant local recurrent connectivity in the juvenile rat neocortex, consistent with the underconnectivity theory of autism.[26] A 2009 study found that the 3 year old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.[27][28][29]


Contraindications include:[30]

  • Pregnancy
  • Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related.
  • Known hypersensitivity to valproate or any of the excipients used in the preparation
  • Urea cycle disorders
  • Hepatic porphyria
  • Hepatotoxicity[30]
  • Mitochondrial disease[30]
  • Pancreatitis[30]


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.[30] It may also potentiate the CNS depressant effects of alcohol.[30] It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including carbamazepine, lamotrigine, phenytoin and phenobarbitone) and itself.[30] It may also interact with:[30]

  • Anticoagulants, due to its ability to prolong the bleeding time.
  • Psychotropic agents; potential pharmacokinetic interactions.
  • Benzodiazepines; may potentiate CNS depression and there are possible pharmacokinetic interactions.
  • Ethosuximide; potential for ethosuximide toxicity.
  • Primidone; may reduce pyrimidone's clearance leading to toxicity.
  • Zidovudine; may raise its (zidovudine's) serum concentration and lead to toxicity.
  • Aspirin; may displace valproate from plasma proteins, leading to increased plasma concentrations. Also interferes with valproate's metabolism.
  • Felbamate; may increase plasma concentrations of valproate.
  • Mefloquine; potential for increased valproate metabolism combined with the direct epileptogenic effects of mefloquine.
  • Cimetidine; inhibits valproate's metabolism in the liver, hence leading to increased plasma concentrations of valproate.
  • Erythromycin; inhibits valproate's metabolism in the liver, hence leading to increased plasma concentrations of valproate.
  • Carbapenem antibiotics; reduces valproate levels, potentially leading to seizures.

Overdose and toxicity

Excessive amounts of valproic acid can result in 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.[31] 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 (pKa of 4.9).[32]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[33][34] Supplemental L-carnitine is indicated in patients having an acute overdose[35][36] and also prophylactically[35] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[37] than L-carnitine.

Mechanism of action

Although the mechanism of action of valproate is not fully understood,[30] it has recently been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[38] In addition, its anticonvulsant effect has been attributed to the blockade of voltage-dependent sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).[30] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[30] In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, 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.[30] It also possesses histone deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.[39][40]


Valproic acid was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian.[41] Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a "metabolically inert" solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats.[42] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[43] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[44]

Society and culture

Approval status

Indications 23x15px
FDA-labelled indication?[1]
TGA-labelled indication?[3]
MHRA-labelled indication?[11]
Literature support
Epilepsy Yes Yes Yes Limited (depends on the seizure type; it can help with certain kinds of seizures: drug-resistant epilepsy, partial and absence seizures, can be used against glioblastoma and other tumors both to improve survival and treat seizures, and against tonic-clonic seizures and status epilepticus).[45][46][47][48]
Bipolar mania Yes Yes Yes Limited.[49]
Bipolar depression No No No Moderate.[50]
Bipolar maintenance No No No Limited.[51]
Migraine prophylaxis Yes No No Limited.
Acute migraine management No No No Only negative results.[52]
Schizophrenia No No No Weak and mostly negative evidence.[53]
Agitation in dementia No No No Weak and mostly negative evidence.[54]
Fragile X syndrome Yes (orphan) No No Limited.[55]
Familial adenomatous polyposis Yes (orphan) No No Limited.
Chronic pain & fibromyalgia No No No Limited.[56]
Alcohol hallucinosis No No No One randomised double-blind placebo-controlled trial.[57]
Intractable hiccups No No No Limited, five case reports support its efficacy, however.[58]
Non-epileptic myoclonus No No No Limited, three case reports support its efficacy, however.[59]
Cluster headaches No No No Limited, two case reports support its efficacy.[60]
West syndrome No No No A prospective clinical trial supported its efficacy in treating infantile spasms.[61]
HIV infection eradication No No No Double-blind placebo-controlled trials have been negative.[62][63][64]
Myelodysplastic syndrome No No No Several clinical trials have confirmed its efficacy as a monotherapy,[65] as an adjunct to tretinoin[65] and as an adjunct to hydralazine.[66]
Acute myeloid leukaemia No No No Two clinical trials have confirmed its efficacy in this indication as both a monotherapy and as an adjunct to tretinoin.[67][68][69]
Cervical cancer No No No One clinical trial supports its use here.[70]
Malignant melanoma No No No One phase II study has seemed to discount its efficacy.[71]
Breast cancer No No No A phase II study has supported its efficacy.[72]
Impulse control disorder No No No Limited.[5][73]


Branded products include:


Valproic acid, 2-propylvaleric acid, is synthesized by the alkylation of ethyl cyanoacetate with two equivalents of propyl bromide, to give dipropylcyanoacetic ester. Hydrolysis and decarboxylation of the carboethoxy group gives 2-propylpentanenitrile, which is hydrolyzed into valproic acid.[74][75][76][77]


See also


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Further reading

External links