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{{drugbox |
{{drugbox | Watchedfields = changed
| IUPAC_name = 2-propylpentanoic acid
| verifiedrevid = 477003327
| image = Valproic-acid-2D-skeletal.png
| IUPAC_name = 2-Propylpentanoic acid
| width=180
| image = Valproic_acid.svg
| width = 180px
| image2 = Valproic_acid_3d_structure.png
 
<!--Clinical data-->
| Drugs.com = {{drugs.com|monograph|valproic_acid}}
| MedlinePlus = a682412
| licence_US = Valproic+acid
| pregnancy_category = X—[[teratogenic]]
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = [[Oral administration|Oral]], [[intravenous therapy|intravenous]]
 
<!--Pharmacokinetic data-->
| bioavailability = Rapid absorption
| protein_bound = Concentration-dependent, from 90% at 40&nbsp;µg/mL to 81.5% at 130&nbsp;µg/mL
| metabolism = [[Liver|Hepatic]]—[[glucuronidation|glucuronide conjugation]] 30–50%, mitochondrial β-oxidation over 40%
| elimination_half-life = 9–16 h
| excretion = Less than 3% excreted unchanged in urine.
 
<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 99-66-1
| CAS_number = 99-66-1
| ATC_prefix = N03
| ATC_prefix = N03
| ATC_suffix = AG01
| ATC_suffix = AG01
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 39867
| PubChem = 3121
| PubChem = 3121
| DrugBank = APRD00256
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00313
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3009
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 614OI1Z5WI
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00399
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 109
| NIAID_ChemDB = 057177
| synonyms = 2-Propylvaleric acid
 
<!--Chemical data-->
| C=8 | H=16 | O=2
| C=8 | H=16 | O=2
| smiles = CCCC(CCC)C(=O)O
| molecular_weight = 144.211 g/mol
| molecular_weight = 144.211 g/mol
| bioavailability = Rapid absorption
| smiles = O=C(O)C(CCC)CCC
| protein_bound = Concentration-dependent, from 90% at 40&nbsp;µg/mL to 81.5% at 130&nbsp;µg/mL
| InChI = 1/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)
| metabolism = [[Liver|Hepatic]]—[[glucuronidation|glucuronide conjugation]] 30–50%, mitochondrial β-oxidation over 40%
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| elimination_half-life = 9–16 hours
| StdInChI = 1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)
| excretion = Less than 3% excreted unchanged in urine.
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| pregnancy_category = D—[[teratogenic]]
| StdInChIKey = NIJJYAXOARWZEE-UHFFFAOYSA-N
| legal_status =
| routes_of_administration = Oral, [[intravenous therapy|intravenous]]
}}
}}
__NOTOC__
{{CMG}}
==Overview==
==Overview==
'''Valproic acid''' ('''VPA''') is a [[chemical compound]] that has found clinical use as an [[anticonvulsant]] and [[mood stabilizer|mood-stabilizing]] [[medication|drug]], primarily in the treatment of [[epilepsy]] and [[bipolar disorder]]. It is also used to treat [[migraine headache|migraine]] [[headache]]s and [[schizophrenia]].


Related drugs include the sodium salts [[sodium valproate]], used as an anticonvulsant, and a combined formulation, [[valproate semisodium]], used as a mood stabilizer and additionally in U.S. also as an anticonvulsant.
'''Valproic acid''' ('''VPA, Valproate'''), an [[acid]]ic [[chemical compound]], has found clinical use as an [[anticonvulsant]] and [[mood stabilizer|mood-stabilizing]] [[medication|drug]], primarily in the treatment of [[epilepsy]], [[bipolar disorder]], and, less commonly, [[major depressive disorder|major depression]]. It is also used to treat [[migraine headache|migraine]] [[headache]]s. 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 the various brand names Depakote, Depakote ER, Depakene, Depakine, Depakine Crono (extended release in Spain), Depacon, Dépakine, Valparin, and Stavzor.


==Pharmacology==
Approved uses of the various formulations vary by country; e.g., valproate semisodium is used as a mood stabilizer and also in the US as an anticonvulsant.
Valproate is believed to affect the function of the [[neurotransmitter]] [[GABA]] (as a [[transaminase|GABA transaminase]] inhibitor) in the human brain, making it an alternative to [[Lithium pharmacology|lithium salt]]s in treatment of bipolar disorder. However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years.<ref>{{cite journal | author = Rosenberg G | title = The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? | journal = [[Cellular and Molecular Life Sciences]] |[Epub ahead of print]| year =2007 | id = PMID 17514356}}</ref>


Valproic acid is an [[Enzyme inhibitor|inhibitor]] of the [[enzyme]] [[histone deacetylase 1]] (HDAC1).  
VPA is a [[histone deacetylase inhibitor]] and is under investigation for treatment of HIV and  various cancers.<ref>{{cite pmid|22318143}}</ref>


==Uses==
==Uses==
In epileptics, valproic acid is used to control [[absence seizure]]s, [[tonic-clonic seizure]]s ([[grand mal]]), [[complex partial seizure]]s, [[juvenile myoclonic epilepsy]] and the [[seizure]]s associated with [[Lennox-Gastaut syndrome]]. It is also used in treatment of [[myoclonus]]. In some countries, [[parenteral]] (administered [[intravenous]]ly) preparations of valproate are used also as second-line treatment of [[status epilepticus]], alternatively to [[phenytoin]].


HDAC1 is needed for [[HIV]] to remain in infected cells. A study published in August 2005 revealed that patients treated with valproic acid in addition to [[highly active antiretroviral therapy]] (HAART) showed a median 75% reduction in latent HIV infection.<ref>{{cite journal | author = Lehrman G, Hogue I, Palmer S, Jennings C, Spina C, Wiegand A, Landay A, Coombs R, Richman D, Mellors J, Coffin J, Bosch R, Margolis D | title = Depletion of latent HIV-1 infection in vivo: a proof-of-concept study | journal = [[The Lancet|Lancet]] | volume = 366 | issue = 9485 | pages = 549–55 | year = | id = PMID 16099290}}</ref><!--Further developments?-->
As an anticonvulsant, valproic acid is used to control [[absence seizure]]s, [[tonic-clonic seizure]]s ([[grand mal]]), [[complex partial seizure]]s, [[juvenile myoclonic epilepsy]], and the [[seizure]]s associated with [[Lennox-Gastaut syndrome]]. It is also used in treatment of [[myoclonus]]. In some countries, [[parenteral]] preparations of valproate are used also as second-line treatment of [[status epilepticus]], as an alternative to [[phenytoin]].  Valproate is one of the most common drugs used to treat [[post-traumatic epilepsy]].<ref name=PosnerLorenzo>Posner E, Lorenzo N (October 11, 2006). "[http://www.emedicine.com/NEURO/topic318.htm Posttraumatic epilepsy]".  Emedicine.com.  Retrieved on 2008-07-30.</ref> It is more recently being used to treat neuropathic pain, as a second-line agent, particularly lancinating pain from [[A delta fiber]]s.


According to the U.S. National Institutes of Health and others, valproic acid appears to have wide implications in the treatment of various [[cancer]]s,<ref>{{cite journal | author = Isenberg JS, Jia Y, Field L, Ridnour LA, Sparatore A, Del Soldato P, Sowers AL, Yeh GC, Moody TW, Wink DA, Ramchandran R, Roberts DD | title = Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid. | journal = [[Br J Pharmacol.|British Journal of Pharmacology]] | volume = Mar 12 | issue = | pages = | year = 2007 | id = PMID 17273758}}</ref> including [[multiple myeloma]] (bone marrow cancer),<ref>{{cite journal | author = Schwartz C, Palissot V, Aouali N, Wack S, Brons NH, Leners B, Bosseler M, Berchem G | title = Valproic acid induces non-apoptotic cell death mechanisms in multiple myeloma cell lines. | journal = [[Int J Oncol.|International Journal of Oncology]] | volume = Mar | issue = 30 | pages = 573-82 | year = 2007 | id = PMID 17273758}}</ref> [[glioma]] (an aggressive type of [[brain tumor]]),<ref>{{cite journal | author = A.M. Admirant, J. A. Hendricks, P.C. De Witt Hamer, S. Leenstra, W.P. Vandertop, C.J.F. van Noorden, and J.P. Medema | title = Valproic Acid is toxic to malignant glioma cells and increases sensitivity to irradiation and chemotherapy | journal = [[Abstracts for the Seventh Congress of the European Association for Neuro-Oncology (EANO)]] | volume = Sept 14-17 | issue = | pages = 334 | year = 2006 | id = }}</ref> and melanoma.<ref>{{cite journal | author = Valentini A, Gravina P, Federici G, Bernardini S. | title = Valproic Acid Induces Apoptosis, p(16INK4A) Upregulation and Sensitization to Chemotherapy in Human Melanoma Cells | journal = [[Cancer Biol Ther. | Cancer Biology & Therapy]] | volume = Feb 5 | issue = 6 | pages =  | year = 2007 | id = PMID 17218782}}</ref> Valproic acid is cytotoxic to many different cancer types through its action as a histone-deacetylase inhibitor.
In the United States, valproic acid is approved by the [[Food and Drug Administration]] only for the treatment of [[manic episodes]] associated with [[bipolar disorder]], adjunctive therapy in multiple seizure types (including epilepsy), and prophylaxis of migraine headaches.<ref>{{cite news
 
   | last =
Another potential indication may be [[leukemia]] in juvenile patients. Studies conducted by several European centres are ongoing. Although it is too early to make a definitive statement, preliminary results are encouraging.
 
According to [[Medical News Today]], valproic acid can be used for the treatment of [[manic episodes]] associated with [[bipolar disorder]], adjunctive therapy in multiple seizure types (including epilepsy), and prophylaxis of migraine headaches<ref> {{cite news  
   | last =  
   | first =
   | first =
   | coauthors =
   | coauthors =
   | title = FDA Issues Approvable Letter For Stavzor™ Delayed Release Valproic Acid Capsules
   | title = FDA Issues Approvable Letter For Stavzor Delayed Release Valproic Acid Capsules
   | publisher = 2007 MediLexicon International Ltd
   | publisher = 2007 MediLexicon International Ltd
   | date = 2007-10-25
   | date = 2007-10-25
   | url = http://www.medicalnewstoday.com/articles/86674.php
   | url = http://www.medicalnewstoday.com/articles/86674.php
   | accessdate = 2007-10-29 }} </ref>.
   | accessdate = 2007-10-29 }}</ref><ref name = "Off-label">{{cite web | url = http://www.justice.gov/opa/pr/2012/May/12-civ-585.html | title = Abbott Labs to Pay $1.5 Billion to Resolve Criminal & Civil Investigations of Off-label Promotion of Depakote | publisher = Justice News, U.S. Department of Justice | accessdate = 2012-09-04}}</ref>
 
Valproic acid is also used [[off-label]] for controlling [[human behavior|behavioral]] [[post-traumatic Amnesia#Symptoms|disturbances]] in [[dementia]] patients.<ref name = "Off-label" />
 
Some randomized controlled studies have repeatedly indicated that sodium valproate and valproic acid, in [[borderline personality disorder]] and [[antisocial personality disorder]], may have some slight to moderate mood-stabilizing advantage over no drug treatment or placebo. This is because it is believed to help reduce impulsive aggressive behavioral episodes and improving interpersonal sensitivity. These improvements would likely be somewhat better when used along with the standard psychotherapeutic regimen for these disorders- which often incorporates, among other elements, individual intensive one-on-one [[cognitive behavioral therapy]], perhaps in a secure setting. However, these two personality disorders are widely known to still normally be lifelong and quite treatment-resistant, with a significant recidivism rate.<ref>http://apt.rcpsych.org/content/10/5/389.full.pdf</ref>
 
===Investigational===
 
====HIV====
 
The enzyme [[HDAC1|histone deacetylase 1]] (HDAC1) is needed for [[HIV]] to remain [[Virus latency|latent]], or dormant, in infected cells. When the virus is latent, it cannot be destroyed by anti-HIV drugs. A study published in August 2005 found that three of four patients treated with valproic acid in addition to [[highly active antiretroviral therapy]] (HAART) showed a mean 75% reduction in latent HIV infection.<ref>{{cite pmid|16099290}}</ref> The idea was that valproic acid, by inhibiting HDAC1, forced HIV out of latency (reactivation) and into its replicative cycle. The highly active antiretroviral drugs could then stop the virus, whilst the immune system could destroy the infected cell. Flushing out all latent virus in this manner would potentially cure HIV patients. Subsequent trials, however, found no long-term benefits of valproic acid in HIV infection.<ref>{{cite pmid|18525257}}</ref>
 
====Other diseases====
 
Three distinct formulations of valproic acid have been investigated in clinical trials for the treatment of [[colorectal polyps]] in [[familial adenomatous polyposis]] patients; treatment of hyperproliferative skin diseases (e.g., [[basal cell carcinoma]]); and treatment of inflammatory skin diseases (e.g., [[acne]]) by [[TopoTarget]].  The current names for these therapeutics are Savicol, Baceca and Avugane, respectively.<ref name=2007TopoTargetAnnual>{{cite web|title= Annual Report 2007 |url= http://www.topotarget.com/multimedia/Topotarget_rapport_web_2007_UK_final.pdf |format= PDF|accessdate= 2008-11-23 |publisher= TopoTarget |date= 14 March 2008
}}</ref>
 
====Stem cells====
 
Valproic acid's function as an [[histone deacetylase inhibitor|HDAC inhibitor]] has also led to its use in [[induced pluripotent stem cell|direct reprogramming in generation of induced pluripotent stem (iPS) cells]], where it has been shown that addition of VPA allows for reprogramming of human fibroblasts to iPS cells without addition of genetic factors ''[[Klf4]]'' and ''[[c-myc]]''.<ref>Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, Muhlestein W, Melton DA (2008). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnology, 26, 1269 - 1275.</ref>  This function has also been investigated as an [[epigenetic therapy]] for treatment of [[lupus]].<ref>http://news.e-healthsource.com/index.php?p=news1&id=529147</ref>
 
====Learning====
 
In a single small study, adult men who took valproate learned to identify pitch better than those taking placebo.  It is believed that the drug affects the "plasticity" of the human brain, though the mechanisms of how are not fully understood.<ref>{{cite pmid|24348349}}</ref>


==History==
==History==
Valproic acid (by its official name ''2-propylvaleric acid'') was first synthesized in 1882 by Burton as an analogue of valeric acid, found naturally in [[Valerian (herb)|Valerian]].<ref>Burton BS (1882). On the propyl derivatives and decomposition products of ethylacetoacetate. ''Am Chem J.'' 3:385-395.</ref> A clear liquid fatty acid 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 valproic acid's antiseizure activity while using it as a vehicle for a number of other compounds that were being screened for anti-seizure activity. He found that it prevented [[pentylenetetrazol]]-induced convulsions in rodents.<ref>Meunier H, Carraz G, Meunier Y, Eymard P, Aimard M. (1963). Propriétés pharmacodynamiques de l’acide n-dipropylacetique. ''Therapie'' 18:435-438.</ref> Since then it has also been used for migraine and bipolar disorder.<ref>Henry T.R. (2003). The History of Valproate in Clinical Neuroscience. ''Psychopharmacology bulletin'' 37 (Suppl 2):5-16</ref>


For more details see T.R. Henry, "The History of Valproate in Clinical Neuroscience." [http://www.medworksmedia.com/psychopharmbulletin/pdf/19/1-PB_VOL%2037%20SUPPL%202.pdf ''Psychopharmacology bulletin'' (2003) 37 (Suppl 2):5-16]
Valproic acid was first synthesized in 1882 by B.S. Burton as an [[analog (chemistry)|analogue]] of [[valeric acid]], found naturally in [[Valerian (herb)|valerian]].<ref>{{cite journal | author = Burton B.S. | year = 1882 | title = On the propyl derivatives and decomposition products of ethylacetoacetate | url = | journal = Am Chem J. | volume = 3 | issue = | pages = 385–395 }}</ref> It has two propyl groups, hence the name "val.pro~ic".  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]].<ref>{{cite pmid|13935231}}</ref> It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.<ref>{{cite pmid|12269862}}</ref> Valproic acid has also been used for migraine prophylaxis and bipolar disorder.<ref>{{cite pmid|14624229}}</ref>
 
==Mechanism of Action==
 
Valproate is believed to affect the function of the [[neurotransmitter]] [[GABA]] in the human brain, making it an alternative to [[Lithium pharmacology|lithium salt]]s in treatment of bipolar disorder. Its mechanism of action includes enhanced neurotransmission of GABA (by inhibiting [[GABA transaminase]], which breaks down GABA). However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years.<ref>{{cite pmid|17514356}}</ref>
 
Valproic acid also blocks [[voltage-gated sodium channel]]s and [[T-type calcium channels]]. These mechanisms make valproic acid a broad-spectrum anticonvulsant drug.
 
Valproic acid is an [[Enzyme inhibitor|inhibitor]] of the [[enzyme]] [[histone deacetylase 1]] (HDAC1), hence it is a [[histone deacetylase inhibitor]].
 
==Dosing==
 
Dosing depends on which disease is being treated and whether valproic acid is being treated for maintenance or acute application. For maintenance of bipolar disorder type 1 the dose range can be tested through blood serum testing or by mg per kilogram of weight: minimum of 250&nbsp;mg a day of Depakote up to 3000&nbsp;mg a day. For acute treatment of bipolar type 1 the minimum dose would be 1000&nbsp;mg a day.
 
===Combination therapy===
 
Valproic acid<ref name=pmid18322101>{{cite pmid|18322101}}</ref><ref name=pmid18640245>{{cite pmid|18640245}}</ref> or valproate<ref name=pmid21796107>{{cite pmid|21796107}}</ref><ref name=pmid20092882>{{cite pmid|20092882}}</ref> are synergistic with [[Lithium (medication)|lithium]], with [[combination therapy]] proving more efficacious than monotherapy with valproic acid or valproate alone. This is true at least for glutamate excitotoxicity,<ref name=pmid18322101/> amyotrophic lateral sclerosis,<ref name=pmid18640245/> Huntington's disease,<ref name=pmid21796107/> and bipolar disorder.<ref name=pmid20092882/><ref>{{cite pmid|8067959}}</ref>
 
==Safety==
 
===Contraindications===
 
====Safety in pregnancy====
 
Valproate causes birth defects; exposure during [[pregnancy]] is associated with about three times as many major anomalies as usual, mainly [[spina bifida]] and, more rarely, with several other defects, possibly including a "valproate syndrome".<ref>{{cite pmid|19490988}}</ref> Characteristics of this valproate syndrome include facial features that tend to evolve with age, including [[trigonocephaly]], tall forehead with bifrontal narrowing, [[epicanthic fold]]s, medial deficiency of eyebrows, flat nasal bridge, broad [[nasal root]], [[anteverted nares]], shallow [[philtrum]], long upper lip and thin [[vermillion border]]s, thick lower lip and small downturned mouth.<ref>{{cite pmid|17090909}}</ref>
 
Women who intend to become pregnant should switch to a different drug if possible.<ref>http://www.lawyersandsettlements.com/lawsuit/valproate-not-to-be-used-migraine-during-pregnancy.html#.UZPulit35cI</ref> 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 vaproate 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 scan]]s), although screening and scans do not find all birth defects.<ref name="BNF">[[British National Formulary]] (March 2003) '''45'''</ref>
 
Valproate is a [[antifolate|folate antagonist]],<ref>{{cite pmid|22246336}}</ref> which can cause [[neural tube defects]]. Thus, folic acid supplements may alleviate the teratogenic problems. A recent study showed children of mothers taking valproate during pregnancy are at risk for significantly lower [[IQ]]s.<ref>{{cite web | url = http://www.medscape.com/viewarticle/549073 | title = NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids | last = Cassels | first = Caroline | date = December 8, 2006 | publisher = Medscape | accessdate = 2007-05-23}}</ref><ref>{{cite pmid|16894099}}</ref>
 
=====Risk of autism=====
Maternal valproate use during pregnancy has been associated with a significantly higher risk of autism in the offspring.<ref>{{cite pmid|23613074}}</ref> Exposure of the human [[embryo]] to valproic acid is associated with risk of [[autism spectrum|autism]], and it is possible to duplicate features characteristic of autism by exposing [[animal testing on rodents|rat embryos]] to valproic acid at the time of neural tube closure.<ref>{{cite pmid|15749245}}</ref> 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.<ref>{{cite pmid|17638926}}</ref>
 
=====Risk of low IQ=====
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.<ref>[http://www.nytimes.com/2009/04/16/health/research/16child.html I.Q. Harmed by Epilepsy Drug in Utero] By RONI CARYN RABIN, ''New York Times'', April 15, 2009</ref><ref>{{cite pmid|19369666}}</ref><ref>[http://www.drugs.com/fda/valproate-products-safety-communication-risk-impaired-cognitive-development-children-exposed-utero-12994.html Valproate Products: Drug Safety Communication - Risk of Impaired Cognitive Development in Children Exposed In Utero (During Pregnancy)]. FDA. June 2011</ref>
 
===Adverse effects===
 
Adverse effects are dosage-related.
 
The foremost and most severe concern for anyone taking valproic acid is its potential for sudden and severe, possibly fatal, fulminating impairments in liver and impairments of hematopoietic or pancreatic function, especially in those just starting the medication. This particular warning is the first one listed on any drug adverse effect listing when one receives the drug at the pharmacy.
 
In rare reports, individuals having used valproic acid for a long time (chronic users) have suffered [[renal]] impairment, usually as a result of having been injured or ill or on a drug regimen already and, so, having been overwhelmed.
 
Valproate is also cautioned against in many patients because it can cause weight gain.<ref>{{cite web|url=http://www.rxabbott.com/pdf/dep3.pdf|title=Highlights of Prescribing Information}}</ref>


==Contraindications==
Absolute '''contraindications''' are pre-existing severe hepatic (liver) or renal (kidney) damage and certain cases of metastatic [[cancer]], severe [[hepatitis]] or [[pancreatitis]], end-stage [[AIDS]] [[HIV]] infection, marked [[bone marrow]] depression, urea cycle disorders, and [[coagulation]] hematological disorders that have caused impairment. Some patients with symptomatic but manageable AIDS, cancer, and hepatic or renal disease are kept on the medication (usually at a reduced dose with more frequent blood tests) to avoid having to manipulate the drug regimen for as long as possible.
Valproate is relatively contraindicated in pregnancy due to its [[teratogenesis|teratogenicity]]; women who become pregnant while taking valproate should be counselled as to its risks, take high dose [[folic acid]] and be offered [[antenatal screening]] ([[alpha-fetoprotein]] and second [[trimester]] [[ultrasound scan]]s).<ref name="BNF">[[British National Formulary]] (March 2003) '''45'''</ref> It is a known folate antagonist, which can cause [[neural tube defects]].  Thus, folic acid supplements may alleviate the teratogenic problems. A recent study showed that children of mothers taking valproate during pregnancy are at risk for significantly lower IQs.<ref>{{cite web | url = http://www.medscape.com/viewarticle/549073 | title = NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids | last = Cassels | first = Caroline | date = [[December 8]] [[2006]] | publisher = Medscape | accessdate = 2007-05-23}}</ref><ref>{{cite journal |author=Meador KJ, Baker GA, Finnell RH, ''et al'' |title=In utero antiepileptic drug exposure: fetal death and malformations |journal=Neurology |volume=67 |issue=3 |pages=407-12 |year=2006 |pmid=16894099 |doi=10.1212/01.wnl.0000227919.81208.b2}}</ref> Exposure of the human [[embryo]] to valproic acid is also 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.<ref name=Arndt>{{cite journal|journal=Int J Dev Neurosci|date=2005|volume=23|issue=2–3|pages=189–99|title=The teratology of autism|author=Arndt TL, Stodgell CJ, Rodier PM|doi=10.1016/j.ijdevneu.2004.11.001|pmid=15749245}}</ref> One study found that 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.<ref>{{cite journal|journal=Cereb Cortex|date=2007|title=Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid|author=Rinaldi T, Silberberg G, Markram H|doi=10.1093/cercor/bhm117|pmid=17638926}}</ref>


Valproate is contraindicated in overweight patients because it causes weight gain.
Common [[adverse drug reaction|side effects]] are [[dyspepsia]] or weight gain. Less common are [[fatigue (medical)|fatigue]], [[peripheral edema]], acne, feelings of feeling cold or chills, blurred vision, burning of the eyes, [[dizziness]], drowsiness, [[hair loss]], headaches, [[nausea]], [[sedation]], and [[tremor]]s. Valproic acid also causes [[hyperammonemia]], an increase of ammonia levels in the blood, which can lead to vomiting and sluggishness, and ultimately to mental changes and brain damage.<ref>{{cite pmid|17823470}}</ref> Valproate levels within the normal range are capable of causing hyperammonemia and ensuing [[encephalopathy]]. Lactulose has been used on a temporary basis to alleviate the hyperammonemia caused by valproic acid.<ref>{{cite pmid|22305367}}</ref> <small>L</small>-Carnitine is used for hyperammonemia caused by valproic acid toxicity. There have been reports of the development of brain encephalopathy without hyperammonemia or elevated valproate levels.<ref>{{cite pmid|16787750}}</ref>


Preexisting hepatic (liver) and/or renal (kidney) damage or [[cancer]], [[hepatitis]], [[pancreatitis]], end-stage [[AIDS]] [[HIV]] infection, [[bone marrow]] depression, urea cycle disorders, and [[coagulation]] hematological disorders are [[absolute contraindications]].
In rare circumstances, valproic acid can cause blood [[dyscrasia]], impaired [[liver]] function, [[jaundice]], [[thrombocytopenia]], and prolonged [[coagulation]] (clotting) times due to a lack of blood cells. In about 5% of pregnant users, valproic acid will cross the [[placenta]] and cause [[congenital defect|congenital anomalies]] that resemble fetal alcohol syndrome, with a possibility of cognitive impairment.  Due to these side effects, most doctors will try to continue the medication, but will ask for blood tests, initially as often as once a week and then once every two months (those taking it for a long period may go six months before being retested; if a pregnant woman and her doctor decide to keep using the drug and to keep the pregnancy, then frequent blood testing, and possibly a higher frequency of diagnostic ultrasounds to identify fetal problems, is a must). Temporary liver enzyme increase has been reported in 20% of cases during the first few months of taking the drug. Inflammation of the liver ([[hepatitis]]), the first symptom of which is [[jaundice]], is found in rare cases.


==Side effects==
Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome.<ref>{{cite pmid|17262798}}</ref><ref>{{cite pmid|15795916}}</ref>
Common [[adverse drug reaction|side effects]] are  [[dyspepsia]] and/or weight gain. Less common are [[fatigue (medical)|fatigue]], [[peripheral edema]], [[dizziness]], drowsiness, [[hair loss]], headaches, [[nausea]], [[sedation]] and [[tremor]]s. Valproic acid also causes [[hyperammonemia]], which can lead to brain damage.<ref>http://www.jabfm.org/cgi/content/abstract/20/5/499</ref> Valproate levels within the normal range are capable of causing hyperammonemia and ensuing encephalopathy. Actually, there have been reports of brain encephalopathy developing without hyperammonemia or elevated valproate levels.<ref>http://www.thieme-connect.com/ejournals/abstract/neuropediatrics/doi/10.1055/s-2006-973995</ref>


Rarely, valproic acid can cause [[dyscrasia|blood dyscrasia]], impaired [[liver]] function, [[jaundice]], [[thrombocytopenia]], and prolonged [[coagulation]] times. In about 5% of pregnant users, valproic acid will cross the [[placenta]] and cause [[congenital defect|congenital anomalies]].  Due to these side effects, most doctors will ask for blood tests, initially as often as once a week and then once every 2 months. Temporary liver enzyme increase has been reported in 20% of cases during the first few months of taking the drug. Inflammation of the liver ([[hepatitis]]), the first symptom of which is [[jaundice]], is found in rare cases.  
Valproate use in women with epilepsy<ref>{{cite pmid|21820873}}</ref><ref name=pmid19012099>{{cite pmid|19012099}}</ref> or bipolar disorder<ref name=pmid19012099/> is associated with an increased prevalence of [[polycystic ovary syndrome]].


Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome.<ref>{{cite journal | author = Williams DC Jr, Massey GV, Russell EC, Riley RS, Ben-Ezra J. | title = Translocation positive acute myeloid leukemia associated with valproic acid therapy | journal = [[Pediatric Blood and Cancer]] | volume = Mar 29 | issue = | pages = | year = 2007 | id = PMID 17262798}}</ref><ref>{{cite journal | author = Coyle TE, Bair AK, Stein C, Vajpayee N, Mehdi S, Wright J. | title = Acute leukemia associated with valproic acid treatment: a novel mechanism for leukemogenesis? | journal = [[Pediatric Blood and Cancer]] | volume = Apr | issue = 78 | pages = 256-60 | year = 2005 | id = PMID 15795916}}</ref>
Cognitive dysfunction, [[Parkinson's_disease#Signs_and_symptoms|Parkinsonian symptoms]],<ref>{{cite pmid|15971646}}</ref> and even reversible pseudoatrophic brain changes have been reported<ref>{{cite pmid|3117347}}</ref> in long-term treatment with valproic acid.


There have also been reports of cognitive dysfunction, [[Parkinson's disease]]<ref name="pmid15971646">{{cite journal |author=Ricard C, Martin K, Tournier M, Bégaud B, Verdoux H |title=[A case of Parkinsonian syndrome, cognitive impairment and hyperammonemia induced by divalproate sodium prescribed for bipolar disorder] |language=French |journal=L'Encéphale |volume=31 |issue=1 Pt 1 |pages=98–101 |year=2005 |pmid=15971646 |doi=}}</ref>, and even pseudoatrophic brain changes<ref name="pmid3117347">{{cite journal |author=McLachlan RS |title=Pseudoatrophy of the brain with valproic acid monotherapy |journal=The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques |volume=14 |issue=3 |pages=294–6 |year=1987 |pmid=3117347 |doi=}}</ref> in long-term treatment with valproic acid.
According to the information provided with a prescription of this drug, some individuals have become depressed or had a suicidal ideation while on the drug; those taking it should be monitored for this side effect.


==Interactions==
===Overdose and toxicity===
Valproic acid may interact with [[carbamazepine]], as valproates inhibit [[epoxide hydrolase|microsomal epoxide hydrolase]] (mEH), the [[enzyme]] responsible for the breakdown of carbamazepine-10,11 epoxide (the main active metabolite of carbamazepine) into inactive metabolites.<ref>{{cite book |last=Gonzalez |first=Frank J. |coauthors=Robert H. Tukey |editor=Laurence Brunton, John Lazo, Keith Parker (eds.) |title=[[Goodman & Gilman's The Pharmacological Basis of Therapeutics]] |edition=11<sup>th</sup> ed. |year=2006 |publisher=[[McGraw-Hill]] |location=New York |isbn=978-0071422802|pages=p. 79 |chapter=Drug Metabolism }}</ref> By inhibiting mEH, valproic acid causes a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.
Excessive amounts of valproic acid can result in tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. Overdosage in children is usually of an accidental nature, whereas with adults it is more likely to be an intentional act. In general, serum or plasma valproic acid concentrations are in a range of 20–100&nbsp;mg/l during controlled therapy, but may reach 150–1500&nbsp;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.<ref>{{cite pmid|12475192}}</ref>
 
In severe intoxication, [[hemoperfusion]] or [[hemofiltration]] can be an effective means of hastening elimination of the drug from the body.<ref>{{cite pmid|19656009}}</ref><ref>R. Baselt, ''Disposition of Toxic Drugs and Chemicals in Man'', 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1622-1626.</ref> Supplemental [[Carnitine|<small>L</small>-carnitine]] is indicated in patients having an acute overdose<ref>{{cite pmid|22180549}}</ref><ref name=pmid16277730>{{cite pmid|16277730}}</ref> and also [[Preventive medicine|prophylactically]]<ref name=pmid16277730/> in high risk patients. [[Acetylcarnitine|Acetyl-<small>L</small>-carnitine]] lowers [[hyperammonemia]] less markedly<ref>{{cite pmid|8347126}}</ref> than [[Carnitine|<small>L</small>-carnitine]]. <!-- It is important for people to know the comparison between L-carnitine and Acetyl-L-carnitine for VPA induced hyperammonemia. -->
 
===Interactions===
 
Valproic acid may interact with [[carbamazepine]], as valproates inhibit [[epoxide hydrolase|microsomal epoxide hydrolase]] (mEH), the [[enzyme]] responsible for the breakdown of carbamazepine-10,11 epoxide (the main active metabolite of carbamazepine) into inactive metabolites.<ref>{{cite book |last=Gonzalez |first=Frank J. |coauthors=Robert H. Tukey |editor=Laurence Brunton, John Lazo, Keith Parker (eds.) |title=[[Goodman & Gilman's The Pharmacological Basis of Therapeutics]] |edition=11th |year=2006 |publisher=[[McGraw-Hill]] |location=New York |isbn=978-0-07-142280-2|pages=79 |chapter=Drug Metabolism }}</ref> By inhibiting mEH, valproic acid causes a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.


Valproic acid also decreases the [[clearance (medicine)|clearance]] of [[amitriptyline]] and [[nortriptyline]].<ref name="RxList">{{cite web | url = http://www.rxlist.com/cgi/generic/depakene_ad.htm | title = Depakene side effects (Valproic Acid) and drug interactions | year = 2007 | accessdate = 2007-06-07 | publisher = RxList.com}}</ref>
Valproic acid also decreases the [[clearance (medicine)|clearance]] of [[amitriptyline]] and [[nortriptyline]].<ref name="RxList">{{cite web | url = http://www.rxlist.com/cgi/generic/depakene_ad.htm | title = Depakene side effects (Valproic Acid) and drug interactions | year = 2007 | accessdate = 2007-06-07 | publisher = RxList.com}}</ref>
Aspirin may decrease the clearance of valproic acid, leading to higher-than-intended serum levels of the anticonvulsant.  Also, combining valproic acid with the benzodiazepine clonazepam can lead to profound sedation and increases the risk of absence seizures in patients susceptible to them.<ref name="RxList" />
Valproic acid and sodium valproate reduce the apparent clearance of [[lamotrigine]] (Lamictal).  In most patients, the lamotrigine dosage for coadministration with valproate must be reduced to half the monotherapy dosage.
Valproic acid is contraindicated in pregnancy, as it decreases the intestinal reabsorption of folate (folic acid), which leads to neural tube defects.  Because of a decrease in folate, megaloblastic anemia may also result.  Phenytoin also decreases folate absorption, which may lead to the same adverse effects as valproic acid.


==Formulations==
==Formulations==
<!-- Please do not add sodium valproate-based products to this list. That drug has its own article -->
<!-- Please do not add sodium valproate-based products to this list. That drug has its own article -->
Branded products include:<br />
Branded products include:
'''Depakene''' ([[Abbott Laboratories]] in U.S. & Canada)<br />
{{colbegin|2}}
'''Convulex''' ([[Pfizer]] in the UK and Byk Madaus in South Africa)<br />
* '''Absenor''' ([[Orion Corporation]] Finland)
'''Stavzor''' ([[Noven Pharmaceuticals |Noven Pharmaceuticals Inc.]])<br />
* '''Convulex''' ([[Pfizer]] in the UK and Byk Madaus in South Africa)
* '''Depakene''' ([[Abbott Laboratories]] in U.S. & Canada)
* '''Depakine''' ([[Sanofi Aventis]] France)
* '''Depakine''' ([[Sanofi Synthelabo]] Romania)
* '''Deprakine''' ([[Sanofi Aventis]] Finland)
* '''Encorate''' ([[Sun Pharmaceuticals]] India)
* '''Epival''' ([[Abbott Laboratories]] U.S. & Canada)
* '''Epilim''' ([[Sanofi Synthelabo]] Australia)
* '''Stavzor''' ([[Noven Pharmaceuticals|Noven Pharmaceuticals Inc.]])
* '''Valcote''' ([[Abbott Laboratories]] Argentina)
{{colend}}
 
==Chemistry==
 
Valproic acid, 2-propylvaleric acid, is synthesized by the [[alkylation]] of [[Cyanoacetic_acid|ethyl cyanoacetate]] with two moles of [[n-Propyl bromide|propyl bromide]], to give [[dipropylcyanoacetic ester]]. [[Hydrolysis]] and [[decarboxylation]] of the [[carboethoxy group]] gives 2-propylpentanenitrile, which is hydrolyzed into valproic acid.<ref>M. Chignac, C. Grain, {{US Patent|4155929}} (1979)</ref><ref>H.E.J.-M. Meunier, {{Cite patent|GB|980279}} (1963)</ref><ref>H.E.J.-M. Meunier, {{US Patent|3325361}} (1967)</ref><ref>M. Chignac, C. Grain, Ch. Pigerol, {{Cite patent|GB|1522450}} (1977)</ref>
 
[[File:Valproic acid synthesis.svg|800px]]
 
==See also==
 
* [[Sodium valproate]]
* [[Valproate semisodium]]
 
==References==
 
'''Notes'''
{{Reflist|2}}
 
== Further reading ==
 
<!--Only freely available review articles are being added here. The PDF link, if any, can be added directly to the respective template. Items are sorted by recency. -->
* {{cite pmid|20798865}}
* {{cite pmid|20021450}}


==External links==
==External links==
*[http://www.psychotropics.dk/usr_view_molecule.asp?ID=2372&backurl=Alphaindex%2Fview%5Falpha%2Easp%3FStartchar%3DD&backurlname=Alphabetical+index&historyline=&Catalogtype=A The Lundbeck Institute Guide to Psychotropics - Valproic acid]
 
* http://www.psycheducation.org/depression/meds/moodstabilizers.htm
* [http://www.psycheducation.org/depression/meds/valproate.htm PsychEducation: Valproate/divalproex (divalproex)]
* http://www.psycheducation.org/depression/meds/valproate.htm
* [http://ctdbase.org/detail.go?type=chem&acc=D014635 The Comparative Toxicogenomics Database:Valproic Acid]
* [http://ctd.mdibl.org/voc.go?voc=chem&termUI=Valproic+Acid The Comparative Toxicogenomics Database:Valproic Acid]
* [http://www.chemicalland21.com/lifescience/phar/VALPROIC%20ACID.htm Chemical Land21: Valproic Acid]
* [http://www.chemicalland21.com/lifescience/phar/VALPROIC%20ACID.htm Chemical Land21: Valproic Acid]
* [http://www.rxlist.com/cgi/generic2/depakene.htm RXList.com: Depakene (Valproic Acid)] (U.S.)
* [http://www.rxlist.com/cgi/generic2/depakene.htm RXList.com: Depakene (Valproic Acid)] (U.S.)
Line 93: Line 231:


{{Anticonvulsants}}
{{Anticonvulsants}}
==References==
{{Reflist|2}}


[[Category:Anticonvulsants]]
[[Category:Anticonvulsants]]
[[Category:Mood stabilizers]]
[[Category:Carboxylic acids]]
[[Category:Teratogens]]
[[Category:Teratogens]]
[[Category:Carboxylic acids]]
[[de:Valproinsäure]]
[[fr:Acide valproïque]]
[[it:Acido valproico]]
[[no:Valproat]]
[[pl:Kwas walproinowy]]
[[pt:Valproato]]
[[ru:Вальпроевая кислота]]
[[sv:Valproinsyra]]
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Revision as of 19:22, 6 February 2014

Valproic acid
File:Valproic acid.svg
Clinical data
Synonyms2-Propylvaleric acid
AHFS/Drugs.comMonograph
MedlinePlusa682412
[[Regulation of therapeutic goods |Template:Engvar data]]
Pregnancy
category
Routes of
administration		Oral, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityRapid absorption
Protein bindingConcentration-dependent, from 90% at 40 µg/mL to 81.5% at 130 µg/mL
MetabolismHepatic—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Elimination half-life9–16 h
ExcretionLess than 3% excreted unchanged in urine.
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC8H16O2
Molar mass144.211 g/mol
3D model (JSmol)
  (verify)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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, less commonly, major depression. It is also used to treat 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 the various brand names Depakote, Depakote ER, Depakene, Depakine, Depakine Crono (extended release in Spain), Depacon, Dépakine, Valparin, and Stavzor.

Approved uses of the various formulations vary by country; e.g., valproate semisodium is used as a mood stabilizer and also in the US as an anticonvulsant.

VPA is a histone deacetylase inhibitor and is under investigation for treatment of HIV and various cancers.[1]

Uses

As an anticonvulsant, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, juvenile myoclonic epilepsy, and the seizures associated with Lennox-Gastaut syndrome. It is also used in treatment of myoclonus. In some countries, parenteral preparations of valproate are used also as second-line treatment of status epilepticus, as an alternative to phenytoin. Valproate is one of the most common drugs used to treat post-traumatic epilepsy.[2] It is more recently being used to treat neuropathic pain, as a second-line agent, particularly lancinating pain from A delta fibers.

In the United States, valproic acid is approved by the Food and Drug Administration only for the treatment of manic episodes associated with bipolar disorder, adjunctive therapy in multiple seizure types (including epilepsy), and prophylaxis of migraine headaches.[3][4]

Valproic acid is also used off-label for controlling behavioral disturbances in dementia patients.[4]

Some randomized controlled studies have repeatedly indicated that sodium valproate and valproic acid, in borderline personality disorder and antisocial personality disorder, may have some slight to moderate mood-stabilizing advantage over no drug treatment or placebo. This is because it is believed to help reduce impulsive aggressive behavioral episodes and improving interpersonal sensitivity. These improvements would likely be somewhat better when used along with the standard psychotherapeutic regimen for these disorders- which often incorporates, among other elements, individual intensive one-on-one cognitive behavioral therapy, perhaps in a secure setting. However, these two personality disorders are widely known to still normally be lifelong and quite treatment-resistant, with a significant recidivism rate.[5]

Investigational

HIV

The enzyme histone deacetylase 1 (HDAC1) is needed for HIV to remain latent, or dormant, in infected cells. When the virus is latent, it cannot be destroyed by anti-HIV drugs. A study published in August 2005 found that three of four patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a mean 75% reduction in latent HIV infection.[6] The idea was that valproic acid, by inhibiting HDAC1, forced HIV out of latency (reactivation) and into its replicative cycle. The highly active antiretroviral drugs could then stop the virus, whilst the immune system could destroy the infected cell. Flushing out all latent virus in this manner would potentially cure HIV patients. Subsequent trials, however, found no long-term benefits of valproic acid in HIV infection.[7]

Other diseases

Three distinct formulations of valproic acid have been investigated in clinical trials for the treatment of colorectal polyps in familial adenomatous polyposis patients; treatment of hyperproliferative skin diseases (e.g., basal cell carcinoma); and treatment of inflammatory skin diseases (e.g., acne) by TopoTarget. The current names for these therapeutics are Savicol, Baceca and Avugane, respectively.[8]

Stem cells

Valproic acid's function as an HDAC inhibitor has also led to its use in direct reprogramming in generation of induced pluripotent stem (iPS) cells, where it has been shown that addition of VPA allows for reprogramming of human fibroblasts to iPS cells without addition of genetic factors Klf4 and c-myc.[9] This function has also been investigated as an epigenetic therapy for treatment of lupus.[10]

Learning

In a single small study, adult men who took valproate learned to identify pitch better than those taking placebo. It is believed that the drug affects the "plasticity" of the human brain, though the mechanisms of how are not fully understood.[11]

History

Valproic acid was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian.[12] It has two propyl groups, hence the name "val.pro~ic". 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.[13] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[14] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[15]

Mechanism of Action

Valproate is believed to affect the function of the neurotransmitter GABA in the human brain, making it an alternative to lithium salts in treatment of bipolar disorder. Its mechanism of action includes enhanced neurotransmission of GABA (by inhibiting GABA transaminase, which breaks down GABA). However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years.[16]

Valproic acid also blocks voltage-gated sodium channels and T-type calcium channels. These mechanisms make valproic acid a broad-spectrum anticonvulsant drug.

Valproic acid is an inhibitor of the enzyme histone deacetylase 1 (HDAC1), hence it is a histone deacetylase inhibitor.

Dosing

Dosing depends on which disease is being treated and whether valproic acid is being treated for maintenance or acute application. For maintenance of bipolar disorder type 1 the dose range can be tested through blood serum testing or by mg per kilogram of weight: minimum of 250 mg a day of Depakote up to 3000 mg a day. For acute treatment of bipolar type 1 the minimum dose would be 1000 mg a day.

Combination therapy

Valproic acid[17][18] or valproate[19][20] are synergistic with lithium, with combination therapy proving more efficacious than monotherapy with valproic acid or valproate alone. This is true at least for glutamate excitotoxicity,[17] amyotrophic lateral sclerosis,[18] Huntington's disease,[19] and bipolar disorder.[20][21]

Safety

Contraindications

Safety in pregnancy

Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major anomalies as usual, mainly spina bifida and, more rarely, with several other defects, possibly including a "valproate syndrome".[22] Characteristics of this valproate syndrome include facial features that tend to evolve with age, including trigonocephaly, 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.[23]

Women who intend to become pregnant should switch to a different drug if possible.[24] 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 vaproate 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.[25]

Valproate is a folate antagonist,[26] which can cause neural tube defects. Thus, folic acid supplements may alleviate the teratogenic problems. A recent study showed children of mothers taking valproate during pregnancy are at risk for significantly lower IQs.[27][28]

Risk of autism

Maternal valproate use during pregnancy has been associated with a significantly higher risk of autism in the offspring.[29] 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.[30] 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.[31]

Risk of low IQ

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.[32][33][34]

Adverse effects

Adverse effects are dosage-related.

The foremost and most severe concern for anyone taking valproic acid is its potential for sudden and severe, possibly fatal, fulminating impairments in liver and impairments of hematopoietic or pancreatic function, especially in those just starting the medication. This particular warning is the first one listed on any drug adverse effect listing when one receives the drug at the pharmacy.

In rare reports, individuals having used valproic acid for a long time (chronic users) have suffered renal impairment, usually as a result of having been injured or ill or on a drug regimen already and, so, having been overwhelmed.

Valproate is also cautioned against in many patients because it can cause weight gain.[35]

Absolute contraindications are pre-existing severe hepatic (liver) or renal (kidney) damage and certain cases of metastatic cancer, severe hepatitis or pancreatitis, end-stage AIDS HIV infection, marked bone marrow depression, urea cycle disorders, and coagulation hematological disorders that have caused impairment. Some patients with symptomatic but manageable AIDS, cancer, and hepatic or renal disease are kept on the medication (usually at a reduced dose with more frequent blood tests) to avoid having to manipulate the drug regimen for as long as possible.

Common side effects are dyspepsia or weight gain. Less common are fatigue, peripheral edema, acne, feelings of feeling cold or chills, blurred vision, burning of the eyes, dizziness, drowsiness, hair loss, headaches, nausea, sedation, and tremors. Valproic acid also causes hyperammonemia, an increase of ammonia levels in the blood, which can lead to vomiting and sluggishness, and ultimately to mental changes and brain damage.[36] Valproate levels within the normal range are capable of causing hyperammonemia and ensuing encephalopathy. Lactulose has been used on a temporary basis to alleviate the hyperammonemia caused by valproic acid.[37] L-Carnitine is used for hyperammonemia caused by valproic acid toxicity. There have been reports of the development of brain encephalopathy without hyperammonemia or elevated valproate levels.[38]

In rare circumstances, valproic acid can cause blood dyscrasia, impaired liver function, jaundice, thrombocytopenia, and prolonged coagulation (clotting) times due to a lack of blood cells. In about 5% of pregnant users, valproic acid will cross the placenta and cause congenital anomalies that resemble fetal alcohol syndrome, with a possibility of cognitive impairment. Due to these side effects, most doctors will try to continue the medication, but will ask for blood tests, initially as often as once a week and then once every two months (those taking it for a long period may go six months before being retested; if a pregnant woman and her doctor decide to keep using the drug and to keep the pregnancy, then frequent blood testing, and possibly a higher frequency of diagnostic ultrasounds to identify fetal problems, is a must). Temporary liver enzyme increase has been reported in 20% of cases during the first few months of taking the drug. Inflammation of the liver (hepatitis), the first symptom of which is jaundice, is found in rare cases.

Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome.[39][40]

Valproate use in women with epilepsy[41][42] or bipolar disorder[42] is associated with an increased prevalence of polycystic ovary syndrome.

Cognitive dysfunction, Parkinsonian symptoms,[43] and even reversible pseudoatrophic brain changes have been reported[44] in long-term treatment with valproic acid.

According to the information provided with a prescription of this drug, some individuals have become depressed or had a suicidal ideation while on the drug; those taking it should be monitored for this side effect.

Overdose and toxicity

Excessive amounts of valproic acid can result in tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. Overdosage in children is usually of an accidental nature, whereas with adults it is more likely to be an intentional act. 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.[45]

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body.[46][47] Supplemental L-carnitine is indicated in patients having an acute overdose[48][49] and also prophylactically[49] in high risk patients. Acetyl-L-carnitine lowers hyperammonemia less markedly[50] than L-carnitine.

Interactions

Valproic acid may interact with carbamazepine, as valproates inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide (the main active metabolite of carbamazepine) into inactive metabolites.[51] By inhibiting mEH, valproic acid causes a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.

Valproic acid also decreases the clearance of amitriptyline and nortriptyline.[52]

Aspirin may decrease the clearance of valproic acid, leading to higher-than-intended serum levels of the anticonvulsant. Also, combining valproic acid with the benzodiazepine clonazepam can lead to profound sedation and increases the risk of absence seizures in patients susceptible to them.[52]

Valproic acid and sodium valproate reduce the apparent clearance of lamotrigine (Lamictal). In most patients, the lamotrigine dosage for coadministration with valproate must be reduced to half the monotherapy dosage.

Valproic acid is contraindicated in pregnancy, as it decreases the intestinal reabsorption of folate (folic acid), which leads to neural tube defects. Because of a decrease in folate, megaloblastic anemia may also result. Phenytoin also decreases folate absorption, which may lead to the same adverse effects as valproic acid.

Formulations

Branded products include:

Chemistry

Valproic acid, 2-propylvaleric acid, is synthesized by the alkylation of ethyl cyanoacetate with two moles of propyl bromide, to give dipropylcyanoacetic ester. Hydrolysis and decarboxylation of the carboethoxy group gives 2-propylpentanenitrile, which is hydrolyzed into valproic acid.[53][54][55][56]

File:Valproic acid synthesis.svg

See also

References

Notes

  1. ↑ PMID 22318143 (PMID 22318143)
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  2. ↑ Posner E, Lorenzo N (October 11, 2006). "Posttraumatic epilepsy". Emedicine.com. Retrieved on 2008-07-30.
  3. ↑ "FDA Issues Approvable Letter For Stavzor Delayed Release Valproic Acid Capsules". 2007 MediLexicon International Ltd. 2007-10-25. Retrieved 2007-10-29.
  4. ↑ 4.0 4.1 "Abbott Labs to Pay $1.5 Billion to Resolve Criminal & Civil Investigations of Off-label Promotion of Depakote". Justice News, U.S. Department of Justice. Retrieved 2012-09-04.
  5. ↑ http://apt.rcpsych.org/content/10/5/389.full.pdf
  6. ↑ PMID 16099290 (PMID 16099290)
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  7. ↑ PMID 18525257 (PMID 18525257)
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  8. ↑ "Annual Report 2007" (PDF). TopoTarget. 14 March 2008. Retrieved 2008-11-23.
  9. ↑ Huangfu D, Osafune K, Maehr R, Guo W, Eijkelenboom A, Chen S, Muhlestein W, Melton DA (2008). Induction of pluripotent stem cells from primary human fibroblasts with only Oct4 and Sox2. Nature Biotechnology, 26, 1269 - 1275.
  10. ↑ http://news.e-healthsource.com/index.php?p=news1&id=529147
  11. ↑ PMID 24348349 (PMID 24348349)
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  12. ↑ Burton B.S. (1882). "On the propyl derivatives and decomposition products of ethylacetoacetate". Am Chem J. 3: 385–395.
  13. ↑ PMID 13935231 (PMID 13935231)
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  14. ↑ PMID 12269862 (PMID 12269862)
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  15. ↑ PMID 14624229 (PMID 14624229)
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  16. ↑ PMID 17514356 (PMID 17514356)
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  17. ↑ 17.0 17.1 PMID 18322101 (PMID 18322101)
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  18. ↑ 18.0 18.1 PMID 18640245 (PMID 18640245)
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  19. ↑ 19.0 19.1 PMID 21796107 (PMID 21796107)
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  20. ↑ 20.0 20.1 PMID 20092882 (PMID 20092882)
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  21. ↑ PMID 8067959 (PMID 8067959)
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  22. ↑ PMID 19490988 (PMID 19490988)
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  23. ↑ PMID 17090909 (PMID 17090909)
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  24. ↑ http://www.lawyersandsettlements.com/lawsuit/valproate-not-to-be-used-migraine-during-pregnancy.html#.UZPulit35cI
  25. ↑ British National Formulary (March 2003) 45
  26. ↑ PMID 22246336 (PMID 22246336)
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  27. ↑ Cassels, Caroline (December 8, 2006). "NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids". Medscape. Retrieved 2007-05-23.
  28. ↑ PMID 16894099 (PMID 16894099)
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  29. ↑ PMID 23613074 (PMID 23613074)
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  30. ↑ PMID 15749245 (PMID 15749245)
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  31. ↑ PMID 17638926 (PMID 17638926)
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  32. ↑ I.Q. Harmed by Epilepsy Drug in Utero By RONI CARYN RABIN, New York Times, April 15, 2009
  33. ↑ PMID 19369666 (PMID 19369666)
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  34. ↑ Valproate Products: Drug Safety Communication - Risk of Impaired Cognitive Development in Children Exposed In Utero (During Pregnancy). FDA. June 2011
  35. ↑ "Highlights of Prescribing Information" (PDF).
  36. ↑ PMID 17823470 (PMID 17823470)
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  37. ↑ PMID 22305367 (PMID 22305367)
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  38. ↑ PMID 16787750 (PMID 16787750)
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  39. ↑ PMID 17262798 (PMID 17262798)
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  40. ↑ PMID 15795916 (PMID 15795916)
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  41. ↑ PMID 21820873 (PMID 21820873)
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  42. ↑ 42.0 42.1 PMID 19012099 (PMID 19012099)
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  43. ↑ PMID 15971646 (PMID 15971646)
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  44. ↑ PMID 3117347 (PMID 3117347)
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  45. ↑ PMID 12475192 (PMID 12475192)
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  46. ↑ PMID 19656009 (PMID 19656009)
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  47. ↑ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1622-1626.
  48. ↑ PMID 22180549 (PMID 22180549)
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  49. ↑ 49.0 49.1 PMID 16277730 (PMID 16277730)
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  50. ↑ PMID 8347126 (PMID 8347126)
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  51. ↑ Gonzalez, Frank J. (2006). "Drug Metabolism". In Laurence Brunton, John Lazo, Keith Parker (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. p. 79. ISBN 978-0-07-142280-2. Unknown parameter |coauthors= ignored (help)
  52. ↑ 52.0 52.1 "Depakene side effects (Valproic Acid) and drug interactions". RxList.com. 2007. Retrieved 2007-06-07.
  53. ↑ M. Chignac, C. Grain, Template:US Patent (1979)
  54. ↑ H.E.J.-M. Meunier, GB 980279  (1963)
  55. ↑ H.E.J.-M. Meunier, Template:US Patent (1967)
  56. ↑ M. Chignac, C. Grain, Ch. Pigerol, GB 1522450  (1977)

Further reading

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External links

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