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| {{drugbox | Watchedfields = changed
| | #REDIRECT [[Valproate]] |
| | verifiedrevid = 477003327
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| | IUPAC_name = 2-Propylpentanoic acid
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| | image = Valproic-acid-2D-skeletal.png
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| | width = 180px
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| | image2 = Valproic acid 3d structure.jpg
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| | |
| <!--Clinical data-->
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| | Drugs.com = {{drugs.com|monograph|valproic_acid}}
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| | MedlinePlus = a682412
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| | licence_US = Valproic+acid
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| | pregnancy_category = X—[[teratogenic]]
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| | legal_UK = POM
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| | legal_US = Rx-only
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| | routes_of_administration = [[Oral administration|Oral]], [[intravenous therapy|intravenous]]
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| <!--Pharmacokinetic data-->
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| | bioavailability = Rapid absorption
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| | protein_bound = Concentration-dependent, from 90% at 40 µg/mL to 81.5% at 130 µg/mL
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| | metabolism = [[Liver|Hepatic]]—[[glucuronidation|glucuronide conjugation]] 30–50%, mitochondrial β-oxidation over 40%
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| | elimination_half-life = 9–16 h
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| | excretion = Less than 3% excreted unchanged in urine.
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| | |
| <!--Identifiers-->
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| | CASNo_Ref = {{cascite|correct|CAS}}
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| | CAS_number_Ref = {{cascite|correct|??}}
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| | CAS_number = 99-66-1
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| | ATC_prefix = N03
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| | ATC_suffix = AG01
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| | ChEBI_Ref = {{ebicite|correct|EBI}}
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| | ChEBI = 39867
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| | PubChem = 3121
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| | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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| | DrugBank = DB00313
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| | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
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| | ChemSpiderID = 3009
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| | UNII_Ref = {{fdacite|correct|FDA}}
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| | UNII = 614OI1Z5WI
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| | KEGG_Ref = {{keggcite|correct|kegg}}
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| | KEGG = D00399
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| | ChEMBL_Ref = {{ebicite|correct|EBI}}
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| | ChEMBL = 109
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| | NIAID_ChemDB = 057177
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| | synonyms = 2-Propylvaleric acid
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| | |
| <!--Chemical data-->
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| | C=8 | H=16 | O=2
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| | molecular_weight = 144.211 g/mol
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| | smiles = O=C(O)C(CCC)CCC
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| | InChI = 1/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)
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| | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
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| | StdInChI = 1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10)
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| | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
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| | StdInChIKey = NIJJYAXOARWZEE-UHFFFAOYSA-N
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| }}
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| __NOTOC__
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| {{CMG}}
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| '''''For patient information about Valproic acid, click [[Valproic Acid (patient information)|here]]'''''
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| {{SK}} Divalproex Na; Divalproex Sodium; Sodium Valproate; Valproate Na; Valproate Semisodium; Valproate Sodium; Valproate
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| {{SB}} '''[[Depakene]], [[Depacon]], [[Stavzor]], [[Depakote Sprinkles]], [[Depakote ER]]'''
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| ==Overview==
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| 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.
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| 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]].
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| Valproate is a [[histone deacetylase inhibitor]] and is under investigation for treatment of HIV and various cancers.<ref>{{cite pmid|22318143}}</ref>
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| ==Formulations==
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| ======Capsule, Oral, as '''[[Valproic acid]]'''======
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| Depakene: 250 mg
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| Generic: 250 mg
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| ======Capsule Delayed Release, Oral, as '''[[Valproic acid]]'''======
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| Stavzor: 125 mg, 250 mg, 500 mg [contains fd&c yellow #6 (sunset yellow)]
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| ======Capsule Sprinkle, Oral, as '''[[Divalproex sodium]]'''======
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| Depakote Sprinkles: 125 mg [contains brilliant blue fcf (fd&c blue #1)]
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| Generic: 125 mg
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| ======Solution, Intravenous, as '''[[Valproate sodium]]'''======
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| Depacon: 100 mg/mL (5 mL)
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| Generic: 100 mg/mL (5 mL)
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| ======Solution, Intravenous, as '''[[Valproate sodium]]'''======
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| Generic: 100 mg/mL (5 mL); 500 mg/5 mL (5 mL); 100 mg/mL (5 mL)
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| ======Solution, Oral, as '''[[Valproate sodium]]'''======
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| Generic: 250 mg/5 mL (473 mL)
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| ======Syrup, Oral, as '''[[Valproate sodium]]'''======
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| Depakene: 250 mg/5 mL (480 mL)
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| Generic: 250 mg/5 mL (5 mL, 10 mL, 473 mL)
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| ======Tablet Delayed Release, Oral, as '''[[Divalproex sodium]]'''======
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| Depakote: 125 mg [contains brilliant blue fcf (fd&c blue #1), fd&c red #40]
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| Depakote: 250 mg [contains fd&c yellow #6 (sunset yellow)]
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| Depakote: 500 mg [contains fd&c blue #2 (indigotine)]
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| Generic: 125 mg, 250 mg, 500 mg
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| ======Tablet Extended Release 24 Hour, Oral, as '''[[Divalproex sodium]]'''======
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| Depakote ER: 250 mg, 500 mg
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| Generic: 250 mg, 500 mg
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| ==Uses==
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| 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.
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| 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
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| | last =
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| | first =
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| | coauthors =
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| | title = FDA Issues Approvable Letter For Stavzor Delayed Release Valproic Acid Capsules
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| | publisher = 2007 MediLexicon International Ltd
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| | date = 2007-10-25
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| | url = http://www.medicalnewstoday.com/articles/86674.php
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| | 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>
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| Valproic acid is also used [[off-label]] for controlling [[human behavior|behavioral]] [[post-traumatic Amnesia#Symptoms|disturbances]] in [[dementia]] patients.<ref name = "Off-label" />
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| 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>
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| ===Investigational===
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| ====HIV====
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| 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>
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| ====Other diseases====
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| 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
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| }}</ref>
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| ====Stem cells====
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| 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>
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| ====Learning====
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| 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>
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| ==History==
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| 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>
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| ==Mechanism of Action==
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| 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>
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| Valproic acid also blocks [[voltage-gated sodium channel]]s and [[T-type calcium channels]]. These mechanisms make valproic acid a broad-spectrum anticonvulsant drug.
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| Valproic acid is an [[Enzyme inhibitor|inhibitor]] of the [[enzyme]] [[histone deacetylase 1]] (HDAC1), hence it is a [[histone deacetylase inhibitor]].
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| ==Dosing==
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| 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.
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| ===Combination therapy===
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| 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>
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| ==Safety==
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| ===Contraindications===
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| ====Safety in pregnancy====
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| 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>
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| 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>
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| 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>
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| =====Risk of autism=====
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| 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>
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| =====Risk of low IQ=====
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| 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>
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| ===Adverse effects===
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| Adverse effects are dosage-related.
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| 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.
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| 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.
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| 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>
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| 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.
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| 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>
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| 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.
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| 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>
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| 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]].
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| 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.
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| 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.
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| ===Overdose and toxicity===
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| 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.<ref>{{cite pmid|12475192}}</ref>
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| 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. -->
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| ===Interactions===
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| 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.
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| 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>
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| 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" />
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| 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.
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| 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.
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| ==Chemistry==
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| 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>
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| [[File:800px-Valproic acid synthesis.svg.png|800px]]
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| ==References==
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| {{Reflist|2}}
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| {{Anticonvulsants}}
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| [[Category:Anticonvulsants]]
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| [[Category:Carboxylic acids]]
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| [[Category:Teratogens]]
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