Valproate

Valproate
INN: valproic acid
Clinical data
Trade namesDepakote, Epilim, Convulex, others
Other namesVPA; valproic acid; sodium valproate (sodium); valproate semisodium (semisodium); 2-propylvaleric acid
AHFS/Drugs.comMonograph
MedlinePlusa682412
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityRapid absorption
Protein binding80–90%[6]
MetabolismLiver—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Elimination half-life9–16 hours[6]
ExcretionUrine (30–50%)[6]
Identifiers
  • 2-propylpentanoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard100.002.525 Edit this at Wikidata
Chemical and physical data
FormulaC8H16O2
Molar mass144.214 g·mol−1
3D model (JSmol)
  • O=C(O)C(CCC)CCC
  • InChI=1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10) checkY
  • Key:NIJJYAXOARWZEE-UHFFFAOYSA-N checkY
  (verify)

Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches.[7] They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures.[7] They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.[7]

Common side effects of valproate include nausea, vomiting, somnolence, and dry mouth.[7] Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended.[7] Other serious risks include pancreatitis and an increased suicide risk.[7] Valproate is known to cause serious abnormalities or birth defects in the unborn child if taken during pregnancy,[7][8] 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.[7][9][4] Reproductive warnings have also been issued for men using the drug.[10] The United States Food and Drug Administration has indicated a black box warning given the frequency and severity of the side effects and teratogenicity.[4] Additionally, there is also a black box warning due to risk of hepatotoxicity and pancreatitis.[11] 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.[12]

Valproate's precise mechanism of action is unclear.[7][13] Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, inhibiting histone deacetylases, and increasing LEF1.[14][15][16] Valproic acid is a branched short-chain fatty acid (SCFA), a derivative of valeric acid.[14]

Valproate was originally synthesized in 1881 and came into medical use in 1962.[17] It is on the World Health Organization's List of Essential Medicines[18][19] and is available as a generic medication.[7] In 2022, it was the 174th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[20][21]

  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 3 August 2023.
  3. ^ "Product monograph brand safety updates". Health Canada. 7 July 2016. Retrieved 13 July 2024.
  4. ^ a b c Cite error: The named reference Depakote FDA label was invoked but never defined (see the help page).
  5. ^ Cite error: The named reference Depakote ER FDA label was invoked but never defined (see the help page).
  6. ^ a b c "Depakene, Stavzor (valproic acid) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 21 February 2014. Retrieved 13 February 2014.
  7. ^ a b c d e f g h i j "Valproic Acid". The American Society of Health-System Pharmacists. 24 November 2020. Archived from the original on 31 July 2017.
  8. ^ "Valproate banned without the pregnancy prevention programme". GOV.UK. Archived from the original on 24 April 2018. Retrieved 26 April 2018.
  9. ^ "Drug Safety Update - Valproate medicines (Epilim, Depakote): contraindicated in women and girls of childbearing potential unless conditions of Pregnancy Prevention Programme are met". GOV.UK - Medicines and Healthcare products Regulatory Agency. 24 April 2018. Archived from the original on 7 January 2023. Retrieved 17 April 2022.
  10. ^ "Men on sodium valproate told to use contraception". BBC News. BBC. Retrieved 5 September 2024.
  11. ^ "FDA Information on Valporate" (PDF).
  12. ^ Davis N (17 April 2022). "Sodium valproate: what are dangers of epilepsy drug for unborn babies?". The Observer. Archived from the original on 28 July 2022. Retrieved 17 April 2022.
  13. ^ Owens MJ, Nemeroff CB (2003). "Pharmacology of valproate". Psychopharmacology Bulletin. 37 (Suppl 2): 17–24. PMID 14624230.
  14. ^ a b Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, et al. (April 2013). "Valproic acid pathway: pharmacokinetics and pharmacodynamics". Pharmacogenetics and Genomics. 23 (4): 236–241. doi:10.1097/FPC.0b013e32835ea0b2. PMC 3696515. PMID 23407051.
  15. ^ "Valproic acid". DrugBank. University of Alberta. 29 July 2017. Archived from the original on 31 July 2017. Retrieved 30 July 2017.
  16. ^ Santos R, Linker SB, Stern S, Mendes AP, Shokhirev MN, Erikson G, et al. (June 2021). "Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients". Molecular Psychiatry. 26 (6): 2440–2456. doi:10.1038/s41380-020-00981-3. PMC 9129103. PMID 33398088.
  17. ^ Scott DF (1993). The history of epileptic therapy : an account of how medication was developed (1st ed.). Carnforth u.a.: Parthenon Publ. Group. p. 131. ISBN 978-1-85070-391-4. Archived from the original on 14 January 2023. Retrieved 17 September 2017.
  18. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  19. ^ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  20. ^ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  21. ^ "Valproate Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.