Valproate

Valproate
Clinical data
Trade names Convulex, Depakote, Epilim, Stavzor, others
AHFS/Drugs.com Monograph
MedlinePlus a682412
Pregnancy
category
  • AU: D
  • US: X (Contraindicated) - for control of conditions other than severe epilepsy
Routes of
administration		 By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Rapid absorption
Protein binding 80–90%[1]
Metabolism Hepatic—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Biological half-life 9–16 hours[1]
Excretion Urine (30-50%)[1]
Identifiers
Synonyms 2-Propylvaleric acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
ECHA InfoCard 100.002.525
Chemical and physical data
Formula C8H16O2
Molar mass 144.211 g/mol
3D model (JSmol)
  (verify)

Valproate (VPA), and its valproic acid, sodium valproate, and divalproex sodium forms, are medications primarily used to treat epilepsy and bipolar disorder and to prevent migraine headaches.[2] It is useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures.[2] It can be given intravenously or by mouth.[2] Long and short acting formulation of tablets exist.[2]

Common side effects include nausea, vomiting, sleepiness, and a dry mouth.[2] Serious side effects can include liver problems and regular monitoring of liver function tests is therefore recommended.[2] Other serious risks include pancreatitis and an increased suicide risk.[2] It is known to cause serious abnormalities in the baby if taken during pregnancy.[2] Because of this it is not typically recommended in women of childbearing age who have migraines.[2]

It is unclear exactly how valproate works.[2][3] Proposed mechanisms include affecting GABA levels, blocking voltage-gated sodium channels, and inhibiting histone deacetylases.[4][5] Valproic acid is a branched short-chain fatty acid (SCFA) made from valeric acid.[4]

Valproate was first made in 1881 and it came into medical use in 1962.[6] Valproate is included in the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[7] It is available as a generic medication.[2] The wholesale cost in the developing world is between 0.14 and 0.52 USD per day.[8] In the United States, it costs roughly $0.90 USD per day.[2] It is marketed under the brand name Depakote among others.[2]

Terminology

Valproic acid (VPA) is an organic weak acid. The conjugate base is valproate. The sodium salt of the acid is sodium valproate and a coordination complex of the two is known as divalproex sodium.

Medical uses

It is used primarily to treat epilepsy and bipolar disorder. It is also used to prevent migraine headaches.[9]

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.[9][10] It has also been successfully given intravenously to treat status epilepticus.[11][12]

Mental illness

Bipolar disorder

Valproate products are also used to treat manic or mixed episodes of bipolar disorder.[13]

Schizophrenia

A 2016 systematic review compared the efficacy of valproate as an add-on for people with schizophrenia:[14]

Summary
There is limited evidence that the augmentation of antipsychotics with valproate may be effective for overall response and also for specific symptoms, especially in terms of excitement and aggression. Evidence was entirely based on open randomized controlled trials. Valproate was associated with a number of adverse events among which sedation and dizziness appeared significantly more frequently than in the control groups.[14]

Dopamine dysregulation syndrome

Valproic acid may have efficacy in controlling the symptoms of the dopamine dysregulation syndrome that arise from the treatment of Parkinson's disease with dopamine receptor agonists.[15][16][17]

Migraines

Valproate is also used to prevent migraine headaches. Because this medication can be potentially harmful to the fetus, valproate should be considered for women of childbearing potential only after the risks have been discussed.[18]

Other

The medication has been tested in the treatment of AIDS and cancer, owing to its histone deacetylase-inhibiting effects.[19]

Adverse effects

Most common adverse effects include:[18]

Serious adverse effects include:[18]

Valproic acid has a black box warning for hepatotoxicity, pancreatitis, and fetal abnormalities.[18]

Other possible side effects

There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[20][21][22][23] Valproic acid can also cause mydriasis, a dilation of the pupils.[24] 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.[25]

Pregnancy

Valproate causes birth defects;[26] 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.[27][28] More rarely, with several other defects, possibly including a "valproate syndrome".[29] Characteristics of this valproate syndrome 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.[30] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[31]

Children of mothers taking valproate during pregnancy are at risk for lower IQs.[32][33][34] Maternal valproate use during pregnancy has been associated with a significantly higher probability of autism in the offspring.[35] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[36] The normal incidence for autism in the general population is estimated at less than one percent.[37] 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.[38][39][40]

Sodium valproate has been associated with the rare condition paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.[41][42]

Women who intend to become pregnant should switch to a different medication if possible, or decrease their dose of valproate.[43] 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.) Studies have shown that taking folic acid can reduce the risk of congenital neural tube defects.[18]

Elderly

Valproate in elderly people with dementia caused increased sleepiness. More people stopped the medication for this reason. Additional side effects of weight loss and decreased food intake was also associated in one half of people who become sleepy.[18]

Contraindications

Contraindications include:[44]

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.[44] It may also potentiate the CNS depressant effects of alcohol.[44] 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.[44] It may also interact with:[18][44][46]

Overdose and toxicity

Therapeutic range of valproic acid
Form Lower limit Upper limit Unit
Total (including
protein bound)		 50[47] 125[47] µg/mL or mg/l
350[48] 700[48] μmol/L
Free 6[47] 22[47] µg/mL or mg/l
35[48] 70[48] μmol/L

Excessive amounts of valproic acid can result in sleepiness, 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.[49] 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).[50]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[51][52] Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored.[18] Supplemental L-carnitine is indicated in patients having an acute overdose[53][54] and also prophylactically[53] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[55] than L-carnitine.

Pharmacology

Pharmacodynamics

Although the mechanism of action of valproate is not fully understood,[44] traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).[44] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[44] 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.[44]

Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism.[56] Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[57]

It also has 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.[58][59]

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.[60] In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations.[61] These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.[60][61]

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.[62][63] High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.[63]

Chemistry

Valproic acid is a branched short-chain fatty acid and a derivative of valeric acid.[4]

History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.[64] 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.[65] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[66] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[67]

Society and culture

Cost

It is available as a generic medication.[2] The wholesale cost in the developing world is between $0.14 and $0.52 USD per day.[8] In the European Union, end-user costs are less than 0.60 EUR for an average daily dose in Germany.[68] In the United States, it costs about $0.90 USD per day.[2]

Approval status

Indications United States
FDA-labelled indication?[1]		 Australia
TGA-labelled indication?[9]		 United Kingdom
MHRA-labelled indication?[69]		 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).[70][71][72][73]
Bipolar mania Yes Yes Yes Limited.[74]
Bipolar depression No No No Moderate.[75]
Bipolar maintenance No No No Limited.[76]
Migraine prophylaxis Yes Yes (accepted) No Limited.
Acute migraine management No No No Only negative results.[77]
Schizophrenia No No No Weak evidence.[78]
Agitation in dementia No No No Weak and mostly negative evidence.[79]
Fragile X syndrome Yes (orphan) No No Limited.[80]
Familial adenomatous polyposis Yes (orphan) No No Limited.
Chronic pain & fibromyalgia No No No Limited.[81]
Alcohol hallucinosis No No No One randomised double-blind placebo-controlled trial.[82]
Intractable hiccups No No No Limited, five case reports support its efficacy, however.[83]
Non-epileptic myoclonus No No No Limited, three case reports support its efficacy, however.[84]
Cluster headaches No No No Limited, two case reports support its efficacy.[85]
West syndrome No No No A prospective clinical trial supported its efficacy in treating infantile spasms.[86]
HIV infection eradication No No No Double-blind placebo-controlled trials have been negative.[87][88][89]
Myelodysplastic syndrome No No No Several clinical trials have confirmed its efficacy as a monotherapy,[90] as an adjunct to tretinoin[90] and as an adjunct to hydralazine.[91]
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.[92][93][94]
Cervical cancer No No No One clinical trial supports its use here.[95]
Malignant melanoma No No No One phase II study has seemed to discount its efficacy.[96]
Breast cancer No No No A phase II study has supported its efficacy.[97]
Impulse control disorder No No No Limited.[98][99]

Formulations

Sodium valproate
Identifiers
CAS Number
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.002.525
Chemical and physical data
Formula C8H15NaO2
Molar mass 166.20 g·mol−1
3D model (JSmol)
  (verify)

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 of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself.[100]

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.[101]

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
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

Brand names of valproate semisodium

Research

As of 2016 it is also registered for 45 phase II clinical trials (some completed) for various cancers.[102]

References

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  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 "Valproic Acid". The American Society of Health-System Pharmacists. Retrieved Oct 23, 2015.
  3. ↑ Owens MJ, Nemeroff CB (2003). "Pharmacology of valproate". Psychopharmacol Bull. 37 Suppl 2: 17–24. PMID 14624230.
  4. 1 2 3 4 Ghodke-Puranik Y, Thorn CF, Lamba JK, Leeder JS, Song W, Birnbaum AK, Altman RB, Klein TE (April 2013). "Valproic acid pathway: pharmacokinetics and pharmacodynamics". Pharmacogenet. Genomics. 23 (4): 236–241. PMC 3696515 Freely accessible. PMID 23407051. doi:10.1097/FPC.0b013e32835ea0b2.
  5. ↑ "Valproic acid". DrugBank. University of Alberta. 29 July 2017. Retrieved 30 July 2017.
  6. ↑ Scott, D.F. (1993). The history of epileptic therapy : an account of how medication was developed (1. publ. ed.). Carnforth u.a.: Parthenon Publ. Group. p. 131. ISBN 9781850703914.
  7. ↑ "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Retrieved 8 December 2016.
  8. 1 2 "Sodium Valproate". International Drug Price Indicator Guide.
  9. 1 2 3 Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  10. ↑ Löscher W (2002). "Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy". CNS Drugs. 16 (10): 669–694. PMID 12269861. doi:10.2165/00023210-200216100-00003.
  11. ↑ Olsen KB, Taubøll E, Gjerstad L (2007). "Valproate is an effective, well-tolerated drug for treatment of status epilepticus/serial attacks in adults". Acta Neurol. Scand. Suppl. 187: 51–4. PMID 17419829. doi:10.1111/j.1600-0404.2007.00847.x.
  12. ↑ Kwan SY (2010). "The role of intravenous valproate in convulsive status epilepticus in the future" (PDF). Acta Neurol Taiwan. 19 (2): 78–81. PMID 20830628.
  13. ↑ "Valproate Information". Fda.gov. Retrieved 2015-04-24.
  14. 1 2 Wang, Y; Xia, J; Helfer, B (2016). "Valproate for schizophrenia". Cochrane Database of Systematic Reviews. 11: CD004028.pub4. doi:10.1002/14651858.CD004028.pub4.
  15. ↑ Pirritano D, Plastino M, Bosco D, Gallelli L, Siniscalchi A, De Sarro G (2014). "Gambling disorder during dopamine replacement treatment in Parkinson's disease: a comprehensive review". Biomed Res Int. 2014: 728038. PMC 4119624 Freely accessible. PMID 25114917. doi:10.1155/2014/728038.
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  29. ↑ Ornoy A (2009). "Valproic acid in pregnancy: how much are we endangering the embryo and fetus?". Reprod. Toxicol. 28 (1): 1–10. PMID 19490988. doi:10.1016/j.reprotox.2009.02.014.
  30. ↑ Kulkarni ML, Zaheeruddin M, Shenoy N, Vani HN (2006). "Fetal valproate syndrome". Indian J Pediatr. 73 (10): 937–939. PMID 17090909. doi:10.1007/bf02859291.
  31. ↑ Adab N, Kini U, Vinten J, et al. (November 2004). "The longer term outcome of children born to mothers with epilepsy". J. Neurol. Neurosurg. Psychiatr. 75 (11): 1575–83. PMC 1738809 Freely accessible. PMID 15491979. doi:10.1136/jnnp.2003.029132. This argues that the fetal valproate syndrome constitutes a real clinical entity that includes developmental delay and cognitive impairments, but that some children might exhibit some developmental delay without marked dysmorphism.
  32. ↑ Umur AS, Selcuki M, Bursali A, Umur N, Kara B, Vatansever HS, Duransoy YK (2012). "Simultaneous folate intake may prevent adverse effect of valproic acid on neurulating nervous system". Childs Nerv Syst. 28 (5): 729–737. PMID 22246336. doi:10.1007/s00381-011-1673-9.
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  37. ↑ Autism Society of America: About Autism
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  43. ↑ Valproate Not To Be Used for Migraine During Pregnancy, FDA Warns
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  47. 1 2 3 4 Bentley, Suzanne (Dec 11, 2013). "Valproic Acid Level". Medscape. Retrieved 2015-06-05.
  48. 1 2 3 4 "Free Valproic Acid Assay (Reference — 2013.03.006) Notice of Assessment" (PDF). Canadian Agency for Drugs and Technologies in Health (CADTH) with INESSS’s permission. April 2014. Retrieved 2015-06-05.
  49. ↑ Sztajnkrycer MD (2002). "Valproic acid toxicity: overview and management". J. Toxicol. Clin. Toxicol. 40 (6): 789–801. PMID 12475192. doi:10.1081/CLT-120014645.
  50. ↑ Patsalos PN, Berry DJ (2013). "Therapeutic drug monitoring of antiepileptic drugs by use of saliva". Ther Drug Monit. 35 (1): 4–29. PMID 23288091. doi:10.1097/FTD.0b013e31827c11e7.
  51. ↑ Thanacoody RH (2009). "Extracorporeal elimination in acute valproic acid poisoning". Clin Toxicol (Phila). 47 (7): 609–616. PMID 19656009. doi:10.1080/15563650903167772.
  52. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1622-1626.
  53. 1 2 Lheureux PE, Penaloza A, Zahir S, Gris M (2005). "Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence?". Crit Care. 9 (5): 431–440. PMC 1297603 Freely accessible. PMID 16277730. doi:10.1186/cc3742.
  54. ↑ Mock CM, Schwetschenau KH (2012). "Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy". Am J Health Syst Pharm. 69 (1): 35–39. PMID 22180549. doi:10.2146/ajhp110049.
  55. ↑ Matsuoka M, Igisu H (1993). "Comparison of the effects of L-carnitine, D-carnitine and acetyl-L-carnitine on the neurotoxicity of ammonia". Biochem. Pharmacol. 46 (1): 159–164. PMID 8347126. doi:10.1016/0006-2952(93)90360-9.
  56. ↑ Kay, Hee Yeon; Greene, Derek L.; Kang, Seungwoo; Kosenko, Anastasia; Hoshi, Naoto (2015-10-01). "M-current preservation contributes to anticonvulsant effects of valproic acid". The Journal of Clinical Investigation. 125 (10): 3904–3914. ISSN 0021-9738. PMC 4607138 Freely accessible. PMID 26348896. doi:10.1172/JCI79727.
  57. ↑ Chang P, Walker MC, Williams RS (2014). "Seizure-induced reduction in PIP3 levels contributes to seizure-activity and is rescued by valproic acid". Neurobiol. Dis. 62: 296–306. PMC 3898270 Freely accessible. PMID 24148856. doi:10.1016/j.nbd.2013.10.017.
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