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. 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. 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. 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. Caution is necessary as valproic acid increases the elimination half-life of lamotrigine. Furthermore, valproic acid has become widely recognized for the prophylaxis of migraine headache since approved by the FDA for this indication in 1996. 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. Research on the use of valproic acid in cancer therapy is still in its infancy and provides insight into new areas of its application.
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.
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.
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:
For the treatment of Mania:
For Migraine Prophylaxis:
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.
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:
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.
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