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Valproic Acid


Valproic Acid

Article Author:
Masum Rahman
Article Editor:
Hoang Nguyen
Updated:
7/5/2020 6:07:34 PM
For CME on this topic:
Valproic Acid CME
PubMed Link:
Valproic Acid

Indications

Valproic acid is a branched, and short-chain fatty acid is a derivative of naturally occurring valeric acid. Valproic acid's primary use is as an anti-seizure medication, as well as in migraine, bipolar, mood, and anxiety disorders. Recent work has also demonstrated its efficacy as adjuvant therapy in HIV, cancer, and neurodegenerative diseases as its histone deacetylase (HDAC) inhibition property. Valproic acid is a widely used therapy for pediatric epilepsy for its multiple targets and acceptable safety profile. The highly variable dose requirements and interactions with a wide range of drugs warrants regular patient follow up and therapeutic drug monitoring. However, the clinical and adverse drug effects correlate poorly with the serum concentrations of the drug. 

Divalproex sodium is the stable, coordinated compound of sodium valproate and valproic acid. Due to its characteristic broad spectrum anticonvulsive activity and divalproex sodium is used in the treatment of a wide range of seizure disorders such as myoclonic epilepsy syndromes, absence epilepsy, generalized convulsions, partial seizures, and status epilepticus.[1][2] Divalproex sodium is also efficient in the management of acute depressive episodes of bipolar mood disorder as well as in severe manic or mixed episodes.[3] Its use has significantly increased over the past decades as a mood stabilizer as well as replacing lithium. However, a retrospective cohort study of patients with bipolar found that patients treated with lithium had a lower risk of suicide attempt and suicide death than when treated with divalproex sodium.[4] Nevertheless, the 2002 APA Guidelines recommendation for treatment of severe manic or mixed episodes is the initiation of lithium or divalproex sodium plus an atypical antipsychotic as first-line therapy.

Patients who experience less severe events can have treatment with divalproex, lithium, or an atypical antipsychotic as monotherapy. Lamotrigine is a modern antiepileptic agent that has received approval for the prevention of depressive episodes in bipolar disorder. The pharmacological guidelines for the treatment of bipolar disorder remain complex and recommend augmentation with lamotrigine for patients who respond partially to combined therapy with lithium and divalproex.[5][6] Caution is necessary as valproic acid increases the elimination half-life of lamotrigine.[7] Furthermore, valproic acid has become widely recognized for the prophylaxis of migraine headache since approved by the FDA for this indication in 1996.[8] In the pediatric population, valproic acid has shown promising efficacy in the treatment of bipolar mood disorder and conduct disorder as well as target symptoms of irritability, aggression, and impulsivity.[7] Research on the use of valproic acid in cancer therapy is still in its infancy and provides insight into new areas of its application.[9] 

Mechanism of Action

Valproic acid exhibits its pharmacologic effects in a couple of ways, such as by acting on GABA (γ aminobutyric acid) levels in the CNS, blocking voltage-gated ion channels, and also by inhibiting histone deacetylase. Impaired GABAergic inhibitory activity is established pathophysiology of seizure initiation and propagation, given that controlling this pathway a potential target for antiepileptic drugs. GABA is synthesized from α-ketoglutarate through the tricarboxylic acid(TCA) cycle and metabolized into succinate semialdehyde and then to succinate by GABA transaminase and succinate semialdehyde dehydrogenase respectively. Previous studies have shown that valproic acid inhibits GABA transaminase and succinate semialdehyde dehydrogenase, therefore increase the GABA concentration by reducing its degradation (Figure-1).

Valproic acid may also exert antiepileptic effects by reducing the high-frequency firing of neurons by voltage-gated sodium, potassium, and calcium channel blockade. Valproic acid modulates the biochemical phenomenon of aura and affects nociception by modulating GABA and/or glutamate-mediated neurotransmission. In neuropathic pain, it has been demonstrated that valproic acid blocks neurogenic inflammation by GABA-A receptor-mediated inhibition. Recently, valproic acid showed to be an inhibitor of histone deacetylase (HDAC), particularly HDAC1, as well as other HDAC. Histone deacetylase inhibition potentially upregulates the expression of genes that regulates apoptosis and antitumor action.[10]

Additionally, valproic acid affects the signaling systems like the Wnt/Beta-Catenin and ERK pathways, that similarly interfere with inositol and arachidonate metabolism. Valproate use plays a role in the expression of multiple genes that are involved in cell survival, transcription regulation, ion homeostasis, signal transduction, and cytoskeletal modifications. Both immediate biochemical effect and genomic influences as a long-term effect can explain the underlying effect of valproic acid in the treatment of all three indications listed above.[11][12][10][13]

Administration

Valproic acid is administered orally in tablet form and sprinkles or capsule. The tablet is available in a delayed-release form 125 mg, 250 mg, and 500 mg or an extended-release form 250 mg and 500 mg. Capsules are available in 125 mg strength.

For the treatment of epilepsy:

  • Valproic acid can be used as monotherapy or as adjunctive therapy in complex partial seizures. The dosage is usually started at 10 to 15 mg/kg/day, not to exceed 60 mg/kg/day. If daily doses exceed 250 mg, it is given in divided doses.

For the treatment of Mania:

  • The initial dose for treatment of mania is 250 mg 3 times a day.
  • For the ER form, the initial dose is 25 mg/kg once a day, with a rapid increase up to 60 mg/kg/day in an attempt to achieve the desired clinical effect.

For Migraine Prophylaxis:

  • Valproic acid's initial dose indicated in migraine prophylaxis is 250 mg twice a day for one week.
  • The ER form can be started at 500 mg once daily for one week. The dose can be increased up to 1000 mg/day if needed.

Therapeutic Range:

  • Epilepsy: 50 to 100 mcg/ml total valproate
  • Mania: 50 to 125 mcg/ml total valproate
  • It takes about 14 days for valproic acid to reach maximum concentration.

Dose Modifications:

  • Renal impairment: no adjustment needed
  • Hepatic impairment: administer with caution and in lower doses. Valproic acid is contraindicated in cases of severe hepatic impairment.

Adverse Effects

Serious reactions:Valproic acid has multiple serious adverse reactions such as hepatotoxicity, hallucinations, suicidality, psychosis, toxic epidermal necrolysis, Steven Johnson Syndrome, anaphylaxis, hyponatremia, SIADH, pancreatitis, thrombocytopenia, pancytopenia, hyperammonemia, myelosuppression, hypothermia, aplastic anemia, bleeding, erythema multiforme, polycystic ovarian syndrome, cerebral pseudo atrophy, encephalopathy, and coma. Abrupt discontinuation of the drug can cause withdrawal seizures.

Common reaction:More common reactions that have been reported in patients using valproic acid are headache, abdominal pain, somnolence, dizziness, thrombocytopenia, asthenia, nausea & vomiting, diarrhea, dizziness, tremor, weight changes, alopecia, constipation, emotional lability, insomnia, petechiae & ecchymosis, depression, rash, nervousness, appetite changes, ALT & AST elevation, tinnitus, blurred vision, nystagmus, photosensitivity, myalgia, and dyspnea.

Contraindications

Valproic acid is contraindicated in patients with hepatic disorders, significant hepatic impairment, hypersensitivity to components of the drug and class of drug, urea cycle disorders, mitochondrial disorders, or suspected disorders in patients <2-year-old, and pregnancy (for migraine headache prophylaxis use of valproic acid).

Also, valproic acid use requires caution in patients under two years old, pediatric, elderly, renal impairment, organic brain disorders, head injury, mental retardation with seizure disorders, congenital metabolic disorders, hereditary mitochondrial disorders, multiple anticonvulsant treatments, myelosuppression, decreased GI transit time, hepatic disease, an active or a history of depression, and bleeding risk.

Black Box Warning:

Valproic acid has several Black Box Warning:

  • Serious or fatal hepatic failure has been reported during the first six months of treatment. Patients <2-year-old is more in danger of hepatic toxicity. There is an increased risk of fatality in anticonvulsant polytherapy. In older patients, hepatotoxicity may present with symptoms of weakness, lethargy, anorexia, facial edema, vomiting, and loss of seizure control; monitoring symptoms and LFTs at baseline and then frequently is recommended, particularly during the first 6months of treatment.
  • The use of valproic acid in patients with mitochondrial disease (POLG-related Mitochondrial disorders) has been demonstrated to increase the risk of hepatotoxicity and death. Valproic acid should only be used in patients over two years old with suspected Mitochondrial disorders who have failed to respond to other anticonvulsant treatments, with frequent monitoring of LFT and POLG mutation screening.
  • It can cause life-threatening pancreatitis. Cases of hemorrhagic-pancreatitis with rapid progression to death have been reported in all ages regardless of treatment duration. If patients have symptoms of pancreatitis such as nausea, vomiting, abdominal pain, or anorexia, advise them to discontinue the medication and start alternative treatment based on clinical indication.[14][15] 
  • It can cause severe congenital malformations such as neural tube defects and lower IQ scores after in-utero exposure. Additionally, in-utero exposure to valproic acid correlates with an increased risk of autism spectrum disorders in children.[16][17] The use of valproic acid in pregnant women for migraine headaches is contraindicated unless there is no other alternative anticonvulsant therapy. According to APA guidelines, additional screening is recommended for women with bipolar disorder who choose to continue taking valproic acid during pregnancy.[18]

Monitoring

  • LFTs should be monitored at baseline and then frequently, especially during the first six months of treatment or in the presence of hereditary mitochondrial disease.
  • CBC with differential, coagulation test, and ammonia should be monitored at baseline, periodically, before planned surgery, and during pregnancy.
  • Screen for symptoms of depression, behavior changes, and suicidality.
  • Serum Drug level (therapeutic level for epilepsy: 50 to 100 mcg/ml; and for mania 50 to 125 mcg/ml) and toxic levels: >175 mcg/ml (before morning dose). As valproate is protein-bound, it is important to test the free levels in the presence of hypoalbuminemia. The concentration of the total may be inaccurate.

Enhancing Healthcare Team Outcomes

Valproic acid is a widely used medication having efficacy in treating multiple neuropsychiatric disorders. A wide range of indications involves multiple medical specialties to administer therapy with valproic acid appropriately. Thus, knowledge of its contraindications, dose adjustments, and potential adverse effects is necessary for health care workers to ensure patient safety and the best outcome.



(Click Image to Enlarge)
Figure-1: Mechanism of action of valproic acid. Figure demonstrates the metabolic pathway of GABA synthesis and metabolism by alfa-ketogluterate dehydrogenase, GABA transaminase and Succinate dehydrogenase. Valproic acid inhibits the two downstream catabolic enzyme of GABA metabolism, thus increase the GABA level in CNS.
Figure-1: Mechanism of action of valproic acid. Figure demonstrates the metabolic pathway of GABA synthesis and metabolism by alfa-ketogluterate dehydrogenase, GABA transaminase and Succinate dehydrogenase. Valproic acid inhibits the two downstream catabolic enzyme of GABA metabolism, thus increase the GABA level in CNS.
Contributed by Masum Rahman

References

[1] Willmore LJ, Divalproex and epilepsy. Psychopharmacology bulletin. 2003     [PubMed PMID: 15021860]
[2] Olsen KB,Taubøll E,Gjerstad L, Valproate is an effective, well-tolerated drug for treatment of status epilepticus/serial attacks in adults. Acta neurologica Scandinavica. Supplementum. 2007     [PubMed PMID: 17419829]
[3] Bond DJ,Lam RW,Yatham LN, Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis. Journal of affective disorders. 2010 Aug     [PubMed PMID: 20044142]
[4] Goodwin FK,Fireman B,Simon GE,Hunkeler EM,Lee J,Revicki D, Suicide risk in bipolar disorder during treatment with lithium and divalproex. JAMA. 2003 Sep 17     [PubMed PMID: 13129986]
[5] Calabrese JR,Vieta E,Shelton MD, Latest maintenance data on lamotrigine in bipolar disorder. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2003 Aug     [PubMed PMID: 12957721]
[6] López-Muñoz F,Shen WW,D'Ocon P,Romero A,Álamo C, A History of the Pharmacological Treatment of Bipolar Disorder. International journal of molecular sciences. 2018 Jul 23     [PubMed PMID: 30041458]
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[8] Freitag FG, Divalproex sodium extended-release for the prophylaxis of migraine headache. Expert opinion on pharmacotherapy. 2003 Sep     [PubMed PMID: 12943487]
[9] Činčárová L,Zdráhal Z,Fajkus J, New perspectives of valproic acid in clinical practice. Expert opinion on investigational drugs. 2013 Dec     [PubMed PMID: 24160174]
[10] Ghodke-Puranik Y,Thorn CF,Lamba JK,Leeder JS,Song W,Birnbaum AK,Altman RB,Klein TE, Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenetics and genomics. 2013 Apr     [PubMed PMID: 23407051]
[11] Owens MJ,Nemeroff CB, Pharmacology of valproate. Psychopharmacology bulletin. 2003     [PubMed PMID: 14624230]
[12] Löscher W, Basic pharmacology of valproate: a review after 35 years of clinical use for the treatment of epilepsy. CNS drugs. 2002     [PubMed PMID: 12269861]
[13] Rosenberg G, The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? Cellular and molecular life sciences : CMLS. 2007 Aug     [PubMed PMID: 17514356]
[14] Cofini M,Quadrozzi F,Favoriti P,Favoriti M,Cofini G, Valproic acid-induced acute pancreatitis in pediatric age: case series and review of literature. Il Giornale di chirurgia. 2015 Jul-Aug     [PubMed PMID: 26712070]
[15] Jones MR,Hall OM,Kaye AM,Kaye AD, Drug-induced acute pancreatitis: a review. The Ochsner journal. 2015 Spring     [PubMed PMID: 25829880]
[16] Chomiak T,Turner N,Hu B, What We Have Learned about Autism Spectrum Disorder from Valproic Acid. Pathology research international. 2013     [PubMed PMID: 24381784]
[17] Nicolini C,Fahnestock M, The valproic acid-induced rodent model of autism. Experimental neurology. 2018 Jan     [PubMed PMID: 28472621]
[18] Gotlib D,Ramaswamy R,Kurlander JE,DeRiggi A,Riba M, Valproic Acid in Women and Girls of Childbearing Age. Current psychiatry reports. 2017 Sep     [PubMed PMID: 28726062]