Valproic acid

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Valproic acid
Systematic (IUPAC) name
2-propylpentanoic acid
Identifiers
CAS number 99-66-1
ATC code N03AG01
PubChem 3121
DrugBank APRD00256
Chemical data
Formula C8H16O2 
Mol. mass 144.211 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability Rapid absorption
Protein binding Concentration-dependent, from 90% at 40 µg/mL to 81.5% at 130 µg/mL
Metabolism Hepatic—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%
Half life 9–16 hours
Excretion Less than 3% excreted unchanged in urine.
Therapeutic considerations
Licence data

US
Pregnancy cat.

D—teratogenic
Legal status

POM(UK) ℞-only(US)
Routes Oral, intravenous

Valproic acid (VPA) is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and clinical depression. It is also used to treat migraine headaches 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 the U.S. also as an anticonvulsant.

Contents

[edit] 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.[1] 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 the anticonvulsant properties of valproic acid 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.[2] Since then it has also been used for migraine and bipolar disorder.[3]

For more details see T.R. Henry, "The History of Valproate in Clinical Neuroscience." Psychopharmacology bulletin (2003) 37 (Suppl 2):5-16

[edit] Indications

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 (administered intravenously) preparations of valproate are used also as second-line treatment of status epilepticus, as an alternative to phenytoin.

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[4].

[edit] Investigational

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.[5]

According to the U.S. National Institutes of Health and others, valproic acid appears to have wide implications in the treatment of various cancers,[6] including multiple myeloma (bone marrow cancer),[7] glioma (an aggressive type of brain tumor),[8] and melanoma.[9] Valproic acid is cytotoxic to many different cancer types through its action as a histone-deacetylase inhibitor.

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.[citation needed]

[edit] Contraindications

Valproate is relatively contraindicated in pregnancy due to its 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 scans).[10] 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.[11][12] 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.[13] 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.[14]

Valproate is contraindicated in overweight patients because it might cause weight gain.[citation needed]

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.

[edit] Adverse effects

Common side effects are dyspepsia and/or weight gain. Less common are fatigue, peripheral edema, dizziness, drowsiness, hair loss, headaches, nausea, sedation and tremors. Valproic acid also causes hyperammonemia, which can lead to brain damage.[15] 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.[16]

Rarely, valproic acid can cause 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 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.

Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome.[17][18]

There have also been reports of cognitive dysfunction, Parkinsonism[19], and even (reversible) pseudoatrophic brain changes[20] in long-term treatment with valproic acid.

[edit] Pharmacology

Valproate is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain, making it an alternative to lithium salts in treatment of bipolar disorder. However, several other mechanisms of action in neuropsychiatric disorders have been proposed for valproic acid in recent years.[21]. It also blocks voltage-gated sodium channels.

Valproic acid is an inhibitor of the enzyme histone deacetylase 1 (HDAC1). It is a member of a larger class of histone deacetylase inhibitors that have a broad spectrum of epigenetic activities.

[edit] 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.[22] 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.[23]

[edit] Formulations

Branded products include:
Depakene (Abbott Laboratories in U.S. & Canada)
Convulex (Pfizer in the UK and Byk Madaus in South Africa)
Stavzor (Noven Pharmaceuticals Inc.)
Depakine (Sanofi Aventis.)

[edit] References

  1. ^ Burton BS (1882). On the propyl derivatives and decomposition products of ethylacetoacetate. Am Chem J. 3:385-395.
  2. ^ Meunier H, Carraz G, Meunier Y, Eymard P, Aimard M. (1963). Propriétés pharmacodynamiques de l’acide n-dipropylacetique. Therapie 18:435-438.
  3. ^ Henry T.R. (2003). The History of Valproate in Clinical Neuroscience. Psychopharmacology bulletin 37 (Suppl 2):5-16
  4. ^ "FDA Issues Approvable Letter For Stavzor Delayed Release Valproic Acid Capsules", 2007 MediLexicon International Ltd, 2007-10-25. Retrieved on 2007-10-29. 
  5. ^ 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. "Depletion of latent HIV-1 infection in vivo: a proof-of-concept study". Lancet 366 (9485): 549–55. PMID 16099290. 
  6. ^ 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 (2007). "Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid.". British Journal of Pharmacology Mar 12. PMID 17273758. 
  7. ^ Schwartz C, Palissot V, Aouali N, Wack S, Brons NH, Leners B, Bosseler M, Berchem G (2007). "Valproic acid induces non-apoptotic cell death mechanisms in multiple myeloma cell lines.". International Journal of Oncology Mar (30): 573–82. PMID 17273758. 
  8. ^ 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 (2006). "Valproic Acid is toxic to malignant glioma cells and increases sensitivity to irradiation and chemotherapy". Abstracts for the Seventh Congress of the European Association for Neuro-Oncology (EANO) Sept 14-17: 334. 
  9. ^ Valentini A, Gravina P, Federici G, Bernardini S. (2007). "Valproic Acid Induces Apoptosis, p(16INK4A) Upregulation and Sensitization to Chemotherapy in Human Melanoma Cells". Cancer Biology & Therapy Feb 5 (6). PMID 17218782. 
  10. ^ British National Formulary (March 2003) 45
  11. ^ Cassels, Caroline (December 8, 2006). NEAD: In Utero Exposure To Valproate Linked to Poor Cognitive Outcomes in Kids. Medscape. Retrieved on 2007-05-23.
  12. ^ Meador KJ, Baker GA, Finnell RH, et al (2006). "In utero antiepileptic drug exposure: fetal death and malformations". Neurology 67 (3): 407–12. doi:10.1212/01.wnl.0000227919.81208.b2. PMID 16894099. 
  13. ^ Arndt TL, Stodgell CJ, Rodier PM (2005). "The teratology of autism". Int J Dev Neurosci 23 (2–3): 189–99. doi:10.1016/j.ijdevneu.2004.11.001. PMID 15749245. 
  14. ^ Rinaldi T, Silberberg G, Markram H (2007). "Hyperconnectivity of local neocortical microcircuitry induced by prenatal exposure to valproic acid". Cereb Cortex 18: 763. doi:10.1093/cercor/bhm117. PMID 17638926. 
  15. ^ Valproate-associated Hyperammonemic Encephalopathy - Wadzinski et al. 20 (5): 499 - The Journal of the American Board of Family Medicine
  16. ^ Thieme-connect - Abstract
  17. ^ Williams DC Jr, Massey GV, Russell EC, Riley RS, Ben-Ezra J. (2007). "Translocation positive acute myeloid leukemia associated with valproic acid therapy". Pediatric Blood and Cancer Mar 29. PMID 17262798. 
  18. ^ Coyle TE, Bair AK, Stein C, Vajpayee N, Mehdi S, Wright J. (2005). "Acute leukemia associated with valproic acid treatment: a novel mechanism for leukemogenesis?". Pediatric Blood and Cancer Apr (78): 256–60. PMID 15795916. 
  19. ^ Ricard C, Martin K, Tournier M, Bégaud B, Verdoux H (2005). "[A case of Parkinsonian syndrome, cognitive impairment and hyperammonemia induced by divalproate sodium prescribed for bipolar disorder]" (in French). L'Encéphale 31 (1 Pt 1): 98–101. PMID 15971646. 
  20. ^ McLachlan RS (1987). "Pseudoatrophy of the brain with valproic acid monotherapy". The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 14 (3): 294–6. PMID 3117347. 
  21. ^ Rosenberg G (2007). "The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees?". Cellular and Molecular Life Sciences 64: 2090. doi:10.1007/s00018-007-7079-x. PMID 17514356. 
  22. ^ Gonzalez, Frank J.; Robert H. Tukey (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 978-0071422802. 
  23. ^ Depakene side effects (Valproic Acid) and drug interactions. RxList.com (2007). Retrieved on 2007-06-07.

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