Valproic acid …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 09.14.2021
Released 12.17.1998
Expires For CME 09.14.2024

Valproic acid

Author: K K Jain MD†

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Valproic acid

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Introduction

Historical note and terminology

Valproic acid was synthesized in 1882 (07) and was used as an organic solvent. Antiepileptic properties of valproic acid, which is structurally unrelated to other antiepileptic drugs, were discovered by chance in 1963 (25). Around this same time, carbamazepine was introduced into clinical practice as an antiepileptic drug. The first clinical trials with valproic acid were reported in 1964 (08). It was marketed in France in 1967 and released in the United States in 1978. By the late 1970s, valproic acid was marketed worldwide and had attained the status of a major antiepileptic drug. It is now approved for the prophylaxis of migraine also.

Pharmacology

Valproic acid (di-N-propylacetic acid, 2-propylpentanoic acid, 2-propylvaleric acid) is a branched-chain fatty acid sold as the acid itself or as one of its salts, but the common substance in plasma is valproate ion, and there are only minor pharmacokinetic differences between various preparations. Divalproex sodium is a stable coordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. The next generation of valproic acid should possess the following characteristics: broad-spectrum antiepileptic activity, better potency than current generation of valproic acid, lack of teratogenicity and hepatotoxicity, and a favorable pharmacokinetic profile compared with conventional valproic acid, including a low potential for drug interactions.

Pharmacodynamics. Initially, it was believed that valproic acid acts through the GABA system because it inhibits the major GABA-degrading enzyme GABA-transaminase. However, concentrations of valproic acid that are therapeutically effective do not inhibit GABA-transaminase. There is evidence that the antiepileptic effect of valproic acid may be mediated via multiple mechanisms, which include the inhibition of excitatory amino acids (glutamate, aspartate, etc.) and the reduction of the excitability of neuronal membranes through its influence on sodium and potassium channels. Valproic acid has been demonstrated to reduce the number and frequency of spike-wave discharges seen on EEG in patients with absence seizures.

Pharmacokinetics. Valproic acid is rapidly absorbed within one to two hours following oral intake, but this absorption is prolonged in cases of slow-release formulations. Plasma half-life is about 10 hours in adults and is four times this value in neonates. Concomitant treatment with other enzyme-inducing antiepileptic drugs reduces the half-life of valproic acid, but valproic acid does not have enzyme-inducing potential by itself. Within the therapeutic range, valproic acid is highly protein-bound, with 10% as a free fraction. Valproic acid is extensively metabolized in the liver. The therapeutic range of valproic acid is 50 to 100 µg/mL, but no correlation has been proven of plasma concentrations of the drug with seizure control, even though the dose and its plasma concentrations are highly correlated. Dosage of valproic acid is guided by the clinical response, and therapeutic drug monitoring is done only in special situations.

A population-based pharmacokinetic-pharmacodynamic model has been developed to determine the optimal concentration of valproic acid according to the clinical characteristics of each patient (26). This model showed that age, seizure locus, the sodium channel neuronal type I alpha subunit rs3812718 polymorphism and coadministration of carbamazepine, clonazepam, phenytoin, or topiramate are associated with an over 50% reduction in the seizure frequency. This model may be useful for determining the optimal therapeutic concentration of valproic acid for each patient according to the principles of personalized medicine.

Pharmacogenetics. A patients CYP2C9 status may account for predisposition to adverse reactions. Knowledge of pediatric patients' CYP2C9 status enables adjustment of valproic acid dosing by predicting the patients ability to metabolize the drug and, thus, avoid dose-related adverse effects (06). UGT2B7 G211T and C161T polymorphisms can alter the pharmacokinetics in epilepsy patients treated with valproic acid, requiring adjustment of its dose to ensure therapeutic effect (36). A meta-analysis of the influence of UGT1A6 genetic polymorphisms on valproic acid pharmacokinetics has shown that concentration-to-dose ratio are significantly lower for UGT1A6 homozygous variants 541A>G and 552A>C than for the wild type (17).

Indications

Valproic acid is indicated as monotherapy or adjunct therapy in simple and complex absence seizures and as adjunct therapy in patients with multiple seizure types, including absence seizures.

Extended-release valproic acid is indicated for prophylaxis of migraine headaches in adults. There is no evidence that it is useful in the acute treatment of migraine headaches.

Divalproex sodium extended-release tablets are approved for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features.

Off-label uses

	(1) Treatment of social anxiety disorder.
	(2) Valproic acid enhances the antineoplastic effect of mesenchymal stem cell-mediated herpes simplex virus--thymidine kinase gene therapy in intracranial glioma (33).
	(3) Patients with panic disorder and mood instability who have not responded to conventional therapy.
	(4) Valproic acid, a histone deacetylase inhibitor, may sensitize high-grade gliomas to radiochemotherapy (02). Retrospective review of patient records has shown that use of valproic acid during radiotherapy for glioblastoma was associated with improved overall survival (01). However, a combined analysis of survival with use of valproic acid at the start of chemoradiotherapy with temozolomide in the pooled patient cohort of four randomized clinical trials in newly diagnosed glioblastoma did not show any association with improved outcomes (12). These results do not justify the use of valproic acid for reasons other than seizure control in patients with newly diagnosed glioblastoma outside clinical trials.
	(5) Treatment-resistant Tourette disorder (38).
	(6) Sydenham chorea.
	(7) Treatment of idiopathic restless legs syndrome.
	(8) Treatment of latent HIV infection.
	(9) Intravenous valproic acid has not been proven effective for acute migraine treatment, and controlled trials are suggested.
	(10) Rapid intravenous administration of valproic acid for status epilepticus can be considered as first-line therapy in patients with medical conditions contraindicating the use of traditional first-line antiepileptic drugs (20).
	(11) Treatment of a subgroup of Huntington disease patients suffering from myoclonic hyperkinesia.
	(12) Spinal muscular atrophy (10).
	(13) Valproic acid inhibits amyloid beta production, neuritic plaque formation, and behavioral deficits in Alzheimer disease mouse models, suggesting potential application for prevention and treatment of the disease in humans. Valproic acid has a potential neuroprotective effect in Alzheimer disease, as it can induce neurogenesis of neural stem cells via multiple signaling pathways (39).
	(14) Phase 1 study showed that valproic acid was well tolerated in pediatric patients with refractory solid or CNS tumors (34).
	(15) Retinitis pigmentosa (09). However, a retrospective long-term follow-up of patients with pigmentary retinal dystrophies has shown decline in visual fields and visual acuity as adverse effects of valproic acid (03).
	(16) Electroconvulsive therapy-induced migraine (Rovers and Roks (2012).
	(17) Sleep bruxism (22).
	(18) Valproic acid has been reported to have a beneficial effect on the visual functions in retinitis pigmentosa patients, and long-term studies to evaluate dose modifications, genetic analysis, and change in visual fields may be worthwhile (18).
	(19) Glaucoma (23).
	(20) In a population-based cohort study, valproic acid improved overall survival in high-grade gliomas under chemotherapy with temozolomide (19).
	(21) Epigenetic modulation through the alteration of cellular acetylation by valproic acid administration is a novel treatment for traumatic brain injury and improves clinical outcomes through multiple mechanisms (04).
	(22) Valproic acid is effective in the management of delirium in intensive care unit patients (28).

Special considerations

Pregnancy. Valproic acid is excreted in breast milk, and caution should be exercised when valproic acid is administered to a nursing woman. Maternal exposure to valproic acid during the first trimester of pregnancy significantly increased the risk of major malformations (15). Tests for the detection of neural tube defects and other congenital malformations should be carried out as a part of routine prenatal care. In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at three years of age (24). Valproic acid exposure in rats leads to autistic-like behavior in their offspring, including social and communication deficits, but this animal model of autism, although valid, has limitations in translation to a clinical setting (30).

In 2014, the European Medicine Agency (EMA) recommended that valproate not be used to treat epilepsy or bipolar disorder or for prevention of migraine in girls and women who are pregnant or who can become pregnant unless other treatments are ineffective or not tolerated. The European Medicine Agencys data show that children exposed to valproate in the womb are at an approximately 11% risk for malformations at birth such as neural tube defects and cleft palate compared with a 2% to 3% risk among children in the general population. EMA further recommends that women for whom valproate is the only option should use effective contraception.

Pediatrics. Children under the age of 2 years and those with congenital metabolic disorders or mental retardation are more susceptible to hepatotoxicity. Valproic acid was well tolerated in clinical trials of pediatric patients.

Geriatric. Pharmacokinetics of valproic acid in the elderly do not differ significantly from those in younger adults. However, there may be reduced drug clearance due to lower plasma protein binding and drug metabolizing capacity in the elderly that requires a slightly lower dose than in younger adults. Dose adjustments are based on clinical response rather than on total plasma drug concentrations.

Anesthesia. There are no special precautions for anesthesia in patients on valproic acid therapy.

Adverse effects

The most frequently reported adverse reactions are gastrointestinal disturbances (nausea, vomiting), transient hair loss, and neurologic disorders (tremor, somnolence, dizziness, headache). Endocrine and metabolic dysfunctions such as hyperandrogenism, menstrual disorders, polycystic ovary syndrome, hyperinsulinism, changes in sex hormones, abnormalities in pubertal development, and impaired skeletal growth have been reported as adverse effects of long-term valproic acid therapy. The most important adverse effect is hepatic failure, which is more likely to occur in infants under the age of two years. Patients on long-term (over two years) treatment with valproic acid should be monitored carefully as 25.3% of them develop isolated hyperammonemia (31).

Adverse effects on the nervous system. Valproic acid-induced dementia is well known. Several other adverse effects on the nervous system have been reported, but it is difficult to sort them out when valproic acid is used in conjunction with other antiepileptic drugs. Rare cases of altered consciousness with cerebral atrophy have been reported but improvement usually occurs with reversal of cerebral atrophy after discontinuation of valproic acid. Hyperammonemic encephalopathy is a rare but serious adverse reaction to valproic acid and monitoring of serum ammonia levels are recommended (37). However, several cases of valproic acid-induced encephalopathy have been reported with increased seizure frequency and with or without hyperammonemia. A patient who developed encephalopathy during valproic acid therapy without hyperammonemia or hepatic impairment recovered following discontinuation of the drug (29). Valproic acid can occasionally aggravate absence seizure in patients with absence epilepsy.

Valproic acid has histone deacetylaserelated and neurotoxic effects, but other mechanisms are also being studied. Valproic acid can induce neuronal cell death through a calpain-dependent apoptotic pathway (05).

Pancreatitis. Pancreatitis is recognized as an adverse event in patients receiving various valproic acid preparations. The serum lipase level is more sensitive than the serum amylase level and should be obtained when pancreatitis is suspected. Rechallenge with valproic acid is dangerous and should be avoided. Based on the review of published literature on this topic, the FDA has recommended the following black box warning:

Pancreatitis: Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

For details, see the Physicians Desk Reference.

Metabolic side effects of valproic acid therapy. These include an increase in glucose-stimulated pancreatic insulin secretion, which might be followed by an increase in body weight and obesity. Long-term valproic acid use can increase bone resorption in adult epileptic patients and lead to a decreased bone mineral density. Controlled clinical trials are required to determine whether treatment with bisphosphonates or calcitonin might be of benefit in preventing osteoclastic bone resorption and consequent hypercalcemia in valproic acid-treated patients. Weight gain has also been reported as a sequel of valproic acid therapy (35).

Treatment of toxic effects. Carnitine supplementation may be useful for treating valproic acid-induced toxicity by limiting cytosolic omega-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation (21).

References

01: Barker CA, Bishop AJ, Chang M, Beal K, Chan TA. Valproic acid use during radiation therapy for glioblastoma associated with improved survival. Int J Radiat Oncol Biol Phys 2013;86(3):504-9. PMID 23523186
02: Berendsen S, Broekman M, Seute T, et al. Valproic acid for the treatment of malignant gliomas: review of the preclinical rationale and published clinical results. Expert Opin Investig Drugs 2012;21(9):1391-415. PMID 22668241
03: Bhalla S, Joshi D, Bhullar S, Kasuga D, Park Y, Kay CN. Long-term follow-up for efficacy and safety of treatment of retinitis pigmentosa with valproic acid. Br J Ophthalmol 2013;97(7):895-9. PMID 23603755
04: Bhatti UF, Williams AM, Georgoff PE, Alam HB. The 'omics' of epigenetic modulation by valproic acid treatment in traumatic brain injury-what we know and what the future holds. Proteomics Clin Appl 2019;13(6):e1900068.** PMID 31441601
05: Bollino D, Balan I, Aurelian L. Valproic acid induces neuronal cell death through a novel calpain-dependent necroptosis pathway. J Neurochem 2015;133(2):174-86. PMID 25581256
06: Bűdi T, Tóth K, Nagy A, et al. Clinical significance of CYP2C9-status guided valproic acid therapy in children. Epilepsia 2015;56(6):849-55. PMID 25967074
07: Burton BS. On the propyl derivatives and decomposition products of ethylacetoacetate. Am Chem J 1882;3:385-95.
08: Carraz G, Farr R, Chateau R, et al. First clinical trials of the antiepileptic activity of n-dipropylacetic acid. Ann Med Psychol (Paris) 1964;122:577-84. PMID 14230742
09: Clemson CM, Tzekov R, Krebs M, et al. Therapeutic potential of valproic acid for retinitis pigmentosa. Br J Ophthalmol 2011;95(1):89-93. PMID 20647559
10: Darbar IA, Plaggert PG, Resende MB, Zanoteli E, Reed UC. Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid. BMC Neurol 2011;11:36. PMID 21435220
11: Gesche J, Khanevski M, Solberg C, Beier CP. Resistance to valproic acid as predictor of treatment resistance in genetic generalized epilepsies. Epilepsia 2017;58(4):e64-9.** PMID 28230254
12: Happold C, Gorlia T, Chinot O, et al. Does valproic acid or levetiracetam improve survival in glioblastoma? A pooled analysis of prospective clinical trials in newly diagnosed glioblastoma. J Clin Oncol 2016;34(7):731-9. PMID 26786929
13: Hommers L, Scharl M, Hefner G, et al. Comedication of valproic acid Is associated with increased metabolism of clozapine. J Clin Psychopharmacol 2018;38(3):188-92. PMID 29620699
14: Huang CR, Lin CH, Hsiao SC, et al. Drug interaction between valproic acid and carbapenems in patients with epileptic seizures. Kaohsiung J Med Sci 2017;33(3):130-6. PMID 28254115
15: Jentink J, Loane MA, Dolk H, et al; EUROCAT Antiepileptic Study Working Group. Valproic acid monotherapy in pregnancy and major congenital malformations. N Engl J Med 2010;362(23):2185-93. PMID 20558369
16: Kim DW, Kim W, Lee CH, Chun YI. Thrombocytopenia during intravenous valproic acid therapy in the neurological intensive care unit. J Clin Pharm Ther 2020;45(5):1014-20.** PMID 32040242
17: Kim SC, Kim MG. A meta-analysis of the influence of UGT1A6 genetic polymorphisms on valproic acid pharmacokinetics. Int J Clin Pharmacol Ther 2019;57(3):144-51.** PMID 30686291
18: Kumar A, Midha N, Gogia V, Gupta S, Sehra S, Chohan A. Efficacy of oral valproic acid in patients with retinitis pigmentosa. J Ocul Pharmacol Ther 2014;30(7):580-6. PMID 24955739
19: Kuo YJ, Yang YH, Lee IY, et al. Effect of valproic acid on overall survival in patients with high-grade gliomas undergoing temozolomide: a nationwide population-based cohort study in Taiwan. Medicine (Baltimore) 2020;99(28):e21147.** PMID 32664146
20: Lapenta L, Morano A, Casciato S, et al. Clinical experience with intravenous valproate as first-line treatment of status epilepticus and seizure clusters in selected populations. Int J Neurosci 2014;124(1):30-6. PMID 23777558
21: Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila) 2009;47(2):101-11. PMID 19280426
22: Lin XL, Tang SY. Sodium valproate may be a treatment for sleep bruxism. J Child Adolesc Psychopharmacol 2013;23(9):636-7. PMID 24168714
23: Mahalingam K, Chaurasia AK, Gowtham L, et al. Therapeutic potential of valproic acid in advanced glaucoma: a pilot study. Indian J Ophthalmol 2018;66(8):1104-8. PMID 30038151
24: Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med 2009;360(16):1597-605. PMID 19369666
25: Meunier H, Carraz G, Meunier Y, et al. Pharmacology of 2-propylvaleric acid. Therapie 1963;18:435-83.
26: Nakashima H, Oniki K, Nishimura M, et al. Determination of the optimal concentration of valproic acid in patients with epilepsy: a population pharmacokinetic-pharmacodynamic analysis. PLoS One 2015;10(10):e0141266.** PMID 26484865
27: Park MK, Lim KS, Kim TE, et al. Reduced valproic acid serum concentrations due to drug interactions with carbapenem antibiotics: overview of 6 cases. Ther Drug Monit 2012;34(5):599-603. PMID 22929406
28: Quinn NJ, Hohlfelder B, Wanek MR, Duggal A, Torbic H. Prescribing practices of valproic acid for agitation and delirium in the intensive care unit. Ann Pharmacother 2021;55(3):311-7.** PMID 32748626
29: Raspall-Chaure M, Lainez E, Toledo M, Salas-Puig J, Macaya-Ruiz A, Roig-Quilis M. Reversible encephalopathy caused by valproic acid in an adolescent with idiopathic generalised epilepsy. Rev Neurol 2012;55(11):663-8. PMID 23172093
30: Roullet FI, Lai JK, Foster JA. In utero exposure to valproic acid and autism--a current review of clinical and animal studies. Neurotoxicol Teratol 2013;36:47-56. PMID 23395807
31: Rousseau MC, Montana M, Villano P, et al. Valproic acid-induced encephalopathy in very long course treated patients. Brain Inj 2009;23(12):981-4. PMID 19831495
32: Rovers JM, Roks G. Electroconvulsive therapy-induced migraine successfully treated with valproic acid. J ECT 2012;28(1):64-5. PMID 22343586
33: Ryu CH, Park KY, Kim SM, et al. Valproic acid enhances anti-tumor effect of mesenchymal stem cell mediated HSV-TK gene therapy in intracranial glioma. Biochem Biophys Res Commun 2012;421(3):585-90. PMID 22525671
34: Su JM, Li XN, Thompson P, et al. Phase 1 study of valproic acid in pediatric patients with refractory solid or CNS tumors: a children's oncology group report. Clin Cancer Res 2011;17(3):589-97. PMID 21115653
35: Verrotti A, D'Egidio C, Mohn A, Coppola G, Chiarelli F. Weight gain following treatment with valproic acid: pathogenetic mechanisms and clinical implications. Obes Rev 2011;12(5):e32-43. PMID 20880119
36: Wang P, Lin XQ, Cai WK, et al. Effect of UGT2B7 genotypes on plasma concentration of valproic acid: a meta-analysis. Eur J Clin Pharmacol 2018;74(4):433-42. PMID 29243113
37: Yamada H, Shishido T, Mukai T, Araki M, Naka H, Tokinobu H. Valproic acid-induced hyperammonemic encephalopathy in a patient receiving valproic acid monotherapy. Rinsho Shinkeigaku 2019;59(5):258-63. PMID 31061301
38: Ye L, Lippmann S. Tourette disorder treated with valproic acid. Clin Neuropharmacol 2014;37(1):36-7. PMID 24434532
39: Zhang XZ, Li XJ, Zhang HY. Valproic acid as a promising agent to combat Alzheimer's disease. Brain Res Bull 2010;81(1):3-6. PMID 19748552

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Valproic acid

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Valproic acid …

Valproic acid

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

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Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Headache associated with intracranial neoplasms

Alcohol withdrawal seizures

Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Sleep and epilepsy

Valproic acid

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Anti-LGI1 encephalitis

Self-limited (familial) neonatal epilepsy

Headache associated with intracranial neoplasms

Alcohol withdrawal seizures

Acupuncture

Epileptic lesions due to malformation of cortical development

Epileptic spasms

Sleep and epilepsy

This is an article preview.
Start a Free Account
to access the full version.