Valproate Explained

Watchedfields:changed
Verifiedrevid:477003327
Width:250
Width2:250
Inn:valproic acid
Tradename:Depakote, Epilim, Convulex, others
Dailymedid:Valproic acid
Pregnancy Au:D
Routes Of Administration:By mouth, intravenous
Atc Prefix:N03
Atc Suffix:AG01
Legal Au:S4
Legal Br:C1
Legal Br Comment:[1]
Legal Ca:Rx-only
Legal Ca Comment:[2]
Legal Uk:POM
Legal Us:Rx-only
Bioavailability:Rapid absorption
Protein Bound:80–90%[3]
Metabolism:Liver—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Elimination Half-Life:9–16 hours
Excretion:Urine (30–50%)
Cas Number:99-66-1
Pubchem:3121
Iuphar Ligand:7009
Drugbank:DB00313
Chemspiderid:3009
Unii:614OI1Z5WI
Kegg:D00399
Chebi:39867
Chembl:109
Niaid Chemdb:057177
Synonyms:VPA; valproic acid; sodium valproate (sodium); valproate semisodium (semisodium); 2-propylvaleric acid
Iupac Name:2-propylpentanoic acid
C:8
H:16
O:2
Smiles:O=C(O)C(CCC)CCC
Stdinchi:1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)
Stdinchikey:NIJJYAXOARWZEE-UHFFFAOYSA-N

Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches.[4] They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures.[4] They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.[4]

Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth.[4] Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended.[4] Other serious risks include pancreatitis and an increased suicide risk.[4] Valproate is known to cause serious abnormalities in fetuses if taken during pregnancy,[4] [5] and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition and the recipient is also prescribed a contraceptive.[4] [6] 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.[7] As of 2022 the drug was still prescribed in the UK to potentially pregnant women, but use declined by 51% from 2018–19 to 2020–21.[8]

Valproate's precise mechanism of action is unclear.[4] [9] Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, inhibiting histone deacetylases, and increasing LEF1.[10] [11] [12] Valproic acid is a branched short-chain fatty acid (SCFA), a derivative of valeric acid.[10]

Valproate was originally synthesized in 1881 and came into medical use in 1962.[13] It is on the World Health Organization's List of Essential Medicines[14] [15] and is available as a generic medication.[4] In 2021, it was the 155th most commonly prescribed medication in the United States, with more than 3million prescriptions.[16] [17]

Medical uses

It 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.[18] It has also been successfully given intravenously to treat status epilepticus.[19] [20]

In the US, valproic acid is 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.[21]

Mental illness

Valproate products are used to treat manic or mixed episodes of bipolar disorder.[22] [23]

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:[24]

There is limited evidence that adding valproate to antipsychotics may be effective for overall response and also for specific symptoms, especially in terms of excitement and aggression. Valproate was associated with a number of adverse events among which sedation and dizziness appeared more frequently than in the control groups.

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.[25] [26] [27]

Valproate is also used to prevent migraine headaches.

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.[28]

Contraindications

Contraindications include:

Adverse effects

See also: List of adverse effects of valproic acid and List of adverse effects of valproate semisodium. Most common adverse effects include:[31]

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.[32] [33] [34] Valproic acid can also cause mydriasis, a dilation of the pupils.[35] There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome (PCOS) 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.[36] Weight gain is also possible.[37]

Pregnancy

Valproate causes birth defects;[38] exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug.[39] [40] "Fetal Valproate Syndrome" (FVS) has been used to refer to the effects of valproate exposure in utero.[41] However, similar to the discussion about the adverse effect of exposure to alcohol in utero ("fetal alcohol spectrum disorder"), a 2019 study proposed the term "Fetal valproate spectrum disorder" (FVSD) because valproate exposure can lead to a wide range of possible presentations, which can be influenced by various factors (including dosage and timing of exposure). The dysmorphic features associated with VPA exposure can be subtle and age-dependent, making it challenging to designate individuals as having the characteristic dysmorphism or not, especially for those with limited expertise in the area. While the presence of typical facial dysmorphism is suggestive of the condition, it is not required for diagnosis. This change in terminology to FVSD would benefit individuals affected by the neurodevelopmental effects of VPA exposure without significant malformations, since they can experience impairments in their everyday functioning similar to those with classical FVS.[42] Characteristics of valproate syndrome may include facial features that tend to evolve with age, including a triangle-shaped forehead, 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.[43] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[44]

Children of mothers taking valproate during pregnancy are at risk for lower IQs.[45] [46] [47] Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%.[48] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[49] The normal incidence for autism in the general population in 2018 was estimated at 1 in 44 (2.3%).[50] An updated March 2023 report estimates the number increased to 1 in 36 in 2020 (approximately 4% of boys and 1% of girls).[51] 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.[52] [53] [54]

Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.[55] [56]

Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate.[57] 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 worse outcomes for the fetus than exposure to valproate). Studies have shown that taking folic acid supplements can reduce the risk of congenital neural tube defects. The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the European Union and the United States, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.[58]

Paternal exposure

A 2023 retrospective study of Norway Denmark and Sweden found a significantly increased risk of neurodevelopmental disabilities in the children of fathers exposed to valproate up to 3 months prior to conception, compared to offspring paternally exposed to lamotrigine/levetiracetam.[59] This led the EMA to recommend "the need to consider effective contraception, while using valproate and for at least 3 months after treatment discontinuation. Male patients should not donate sperm during treatment and for at least 3 months after treatment discontinuation."

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

Therapeutic range of valproic acid
FormLower limitUpper limitUnit
Total (including
protein bound)		50[60] 125 μg/mL or mg/L
350[61] 700 μmol/L
Free6 22 μg/mL or mg/L
35 70 μmol/L

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.[62] 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).[63]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[64] [65] 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[66] [67] and also prophylactically[66] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[68] 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.[29] It may also potentiate the CNS depressant effects of alcohol.[29] 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.[29] It may also interact with:[29] [69]

Pharmacology

Pharmacodynamics

Although the mechanism of action of valproate is not fully understood,[29] 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 (GABA).[29] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[29] 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.[29] Prevention of neurotransmitter-induced hyperexcitability of nerve cells via Kv7.2 channel and AKAP5 may also contribute to its mechanism.[70] Valproate has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[71]

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.[72] Intermediate molecules include VEGF, BDNF, and GDNF.[73] [74]

Endocrine actions

Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a nonsteroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels.[75] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.[76] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.

Valproic acid has been found to directly stimulate androgen biosynthesis in the gonads via inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased 4-androstenedione levels in men.[77] [78] High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.

Pharmacokinetics

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut. When in the bloodstream, 80–90% of the substance are bound to plasma proteins, mainly albumin. Protein binding is saturable: it decreases with increasing valproate concentration, low albumin concentrations, the patient's age, additional use of other drugs such as aspirin, as well as liver and kidney impairment.[79] [80] Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.

The vast majority of valproate metabolism occurs in the liver. Valproate is known to be metabolized by the cytochrome P450 enzymes CYP2A6, CYP2B6, CYP2C9, and CYP3A5. It is also known to be metabolized by the UDP-glucuronosyltransferase enzymes UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15. Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image):

All in all, over 20 metabolites are known.

In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate. The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose. Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.[81] Only a small amount is excreted via the faeces. Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.

Chemistry

Valproic acid is a branched short-chain fatty acid and the 2-n-propyl derivative of valeric acid.

History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.[82] 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.[83] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[84] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[85]

Society and culture

Valproate is available as a generic medication.[4]

Approval status

Indications
FDA-labelled indication?
TGA-labelled indication?[86]
MHRA-labelled indication?[87] 		Literature support
Epilepsy 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).[88] [89] [90] [91]
Bipolar mania Limited.[92]
Bipolar depression Moderate.[93]
Bipolar maintenance Limited.[94]
Migraine prophylaxis (accepted) Limited.
Acute migraine management Only negative results.[95]
Schizophrenia Weak evidence.[96]
Agitation in dementia Weak evidence. Not recommended for agitation in people with dementia.[97] Increased rate of adverse effects, including a risk of serious adverse effects.
(orphan) Limited.
(orphan) Limited.
Chronic pain & fibromyalgia Limited.[98]
Alcohol hallucinosis One randomised double-blind placebo-controlled trial.[99]
Intractable hiccups Limited, five case reports support its efficacy, however.[100]
Non-epileptic myoclonus Limited, three case reports support its efficacy, however.[101]
Cluster headaches Limited, two case reports support its efficacy.[102]
A prospective clinical trial supported its efficacy in treating infantile spasms.[103]
HIV infection eradication Double-blind placebo-controlled trials have been negative.[104] [105] [106]
Several clinical trials have confirmed its efficacy as a monotherapy,[107] as an adjunct to tretinoin and as an adjunct to hydralazine.[108]
Two clinical trials have confirmed its efficacy in this indication as both a monotherapy and as an adjunct to tretinoin.[109] [110] [111]
One clinical trial supports its use here.[112]
One phase II study has seemed to discount its efficacy.[113]
A phase II study has supported its efficacy.[114]
Limited.[115] [116]

Off-label uses

In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.[117] [118]

Some studies have suggested that valproate may reopen the critical period for learning absolute pitch and possibly other skills such as language.[119] [120]

Formulations

Drug Name:Sodium valproate
Verifiedrevid:464404696
Width:250
Usan:valproate sodium
Dailymedid:Valproate sodium
Cas Number:1069-66-5
Pubchem:16760703
Drugbank:DBSALT001257
Chemspiderid:13428
Unii:5VOM6GYJ0D
Kegg:D00710
Chebi:9925
Chembl:433
Legal Us:Rx-only
Legal Us Comment:[121] [122]
Iupac Name:sodium 2-propylpentanoate
C:8
H:15
Na:1
O:2
Smiles:CCCC(CCC)C(=O)[O-].[Na+]
Stdinchi:1S/C8H16O2.Na/c1-3-5-7(6-4-2)8(9)10;/h7H,3-6H2,1-2H3,(H,9,10);/q;+1/p-1
Stdinchikey:AEQFSUDEHCCHBT-UHFFFAOYSA-M
Drug Name:Valproate semisodium
Imagel:Sodium valproate.svg
Widthl:250
Imager:2-propylpentanoic acid 200.svg
Widthr:250
Usan:divalproex sodium
Tradename:Depakote, others
Dailymedid:Divalproex sodium
Legal Us:Rx-only
Cas Number:76584-70-8
Pubchem:23663956
Drugbank:DBSALT000185
Chemspiderid:48337
Unii:644VL95AO6
Kegg:D00304
Chebi:4667
Chembl:2105613
Synonyms:semisodium valproate
Iupac Name:sodium 2-propylpentanoate;2-propylpentanoic acid
C:16
H:31
Na:1
O:4
Smiles:CCCC(CCC)C(=O)O.CCCC(CCC)C(=O)[O-].[Na+]
Stdinchi:1S/2C8H16O2.Na/c2*1-3-5-7(6-4-2)8(9)10;/h2*7H,3-6H2,1-2H3,(H,9,10);/q;;+1/p-1
Stdinchikey:MSRILKIQRXUYCT-UHFFFAOYSA-M

Valproate exists in two main molecular variants: sodium valproate and valproic acid without sodium (often implied by simply valproate). A mixture between these two is termed semisodium valproate. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more mass of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself.[123]

Terminology

Valproate is a negative ion. The conjugate acid of valproate is valproic acid (VPA). Valproic acid is fully ionized into valproate at the physiologic pH of the human body, and valproate is the active form of the drug. Sodium valproate is the sodium salt of valproic acid. Divalproex sodium is a coordination complex composed of equal parts of valproic acid and sodium valproate.[124]

Brand names of valproic acid

Branded products include:

Brand names of sodium valproate

Portugal
United States
Australia
New Zealand

All the above formulations are Pharmac-subsidised.[128]

UK
=UK only

=

Germany, Switzerland, Norway, Finland, Sweden
South Africa
Malaysia
Romania
Canada
Japan
Europe

In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.

Taiwan
Iran
Israel

Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by Sanofi-Aventis.

India, Russia and CIS countries
Uruguay

Brand names of valproate semisodium

Research

A 2023 systematic review of the literature identified only one study in which valproate was evaluated in the treatment of seizures in infants aged 1 to 36 months. In a randomized control trial, valproate alone was found to show poorer outcomes for infants than valproate plus levetiracetam in terms of reduction of seizures, freedom from seizures, daily living ability, quality of life, and cognitive abilities.[131]

Notes and References

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