Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

and

bipolar disorder Bipolar disorder (BD), previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that each last from days to weeks, and in ...

and prevent

migraine headache Migraine (, ) is a complex neurological disorder characterized by episodes of moderate-to-severe headache, most often unilateral and generally associated with nausea, and light and sound sensitivity. Other characterizing symptoms may includ ...

s. They are useful for the prevention of seizures in those with

absence seizure Absence seizures are one of several kinds of generalized seizures. Absence seizures are characterized by a brief loss and return of consciousness, generally not followed by a period of lethargy (i.e. without a notable postictal state). Absence ...

partial seizure Focal seizures are Seizure, seizures that originate within brain networks limited to one Cerebral hemisphere, hemisphere of the brain. In most cases, each seizure type has a consistent site of onset and characteristic patterns of spread, although ...

s, and generalized seizures. They can be given

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

ly or by mouth, and the tablet forms exist in both long- and short-acting formulations. Common side effects of valproate include nausea, vomiting,

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

, and dry mouth. Serious side effects can include

liver failure Liver failure is the inability of the liver to perform its normal synthetic and metabolic functions as part of normal physiology. Two forms are recognised, acute and chronic (cirrhosis). Recently, a third form of liver failure known as acute- ...

, and regular monitoring of

liver function test Liver function tests (LFTs or LFs), also referred to as a hepatic panel or liver panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial ...

s is therefore recommended. Other serious risks include

pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormone A hormone (from the Ancient Greek, Greek participle , "se ...

and an increased

suicide Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...

risk. Valproate is known to cause serious abnormalities or birth defects in the unborn child if taken during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

, and is contra-indicated for women of childbearing age unless the drug is essential to their medical condition and the person is also prescribed a

contraceptive Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth control only be ...

. Reproductive warnings have also been issued for men using the drug. The

United States Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

has indicated a

black box warning In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears near the beginning of the package insert for certain prescription drugs, so called because the U.S. Food and Drug Administratio ...

given the frequency and severity of the side effects and teratogenicity. Additionally, there is also a black box warning due to risk of

hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...

and pancreatitis. As of 2022 the drug was still prescribed in the UK to potentially pregnant women, but use declined by 51% from 2018–19 to 2020–21. Valproate has been in use in Japan for the prophylaxis of migraine since 2011. It is approved as an antimanic and antiseizure in Japan as well. In UK, valproate is approved for bipolar mania and epilepsy, and both valproate and divalproex are approved, although divalproex sodium is known as valproate semisodium. Valproate's precise mechanism of action is unclear. Proposed mechanisms include affecting

GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

levels, blocking

voltage-gated sodium channel Voltage-gated sodium channels (VGSCs), also known as voltage-dependent sodium channels (VDSCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeability t ...

s, inhibiting

histone deacetylase Histone deacetylases (, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important becaus ...

s, and increasing LEF1. Valproic acid is a branched

short-chain fatty acid Short-chain fatty acids (SCFAs) are fatty acids of two to six carbon atoms. The SCFAs' lower limit is interpreted differently, either with one, two, three or four carbon atoms. Derived from intestine, intestinal microbe, microbial fermentation of ...

(SCFA), a

derivative In mathematics, the derivative is a fundamental tool that quantifies the sensitivity to change of a function's output with respect to its input. The derivative of a function of a single variable at a chosen input value, when it exists, is t ...

valeric acid Valeric acid or pentanoic acid is a straight-chain alkyl carboxylic acid with the chemical formula . Like other low-molecular-weight carboxylic acids, it has an unpleasant odor. It is found in the perennial flowering plant '' Valeriana offici ...

. Valproate was originally synthesized in 1881 and came into medical use in 1962. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

. In 2022, it was the 174th most commonly prescribed medication in the United States, with more than 2million prescriptions.

Medical uses

Valproate or valproic acid is used primarily to treat

and

and to prevent

Epilepsy

Valproate has a broad spectrum of

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

activity, although it is primarily used as a first-line treatment for tonic–clonic seizures,

absence seizures Absence seizures are one of several kinds of generalized seizures. Absence seizures are characterized by a brief loss and return of consciousness, generally not followed by a period of lethargy (i.e. without a notable postictal state). Absence ...

and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms. It has also been successfully given

intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

to treat

status epilepticus Status epilepticus (SE), or status seizure, is a medical condition with abnormally prolonged seizures. It can have long-term consequences, manifesting as a single seizure lasting more than a defined time (time point 1), or 2 or more seizures over ...

. In the US, valproic acid is also prescribed as an anti-epileptic drug

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for the treatment of manic episodes associated with bipolar disorder; monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in people with multiple seizure types that include absence seizures.

Mental illness

Valproate products are used to treat manic or mixed episodes of

. A 2016

systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...

compared the efficacy of valproate as an add-on for people with

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

Other neurological indications

Based upon five case reports, valproic acid may have efficacy in controlling the symptoms of the dopamine dysregulation syndrome that arise from the treatment of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

with

levodopa Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. ...

. Valproate is not commonly used to prevent or treat migraine headaches, but it may be prescribed if other medications are not effective.

Other

The medication has been tested in the treatment of

AIDS The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...

and

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

, owing to its histone-deacetylase-inhibiting effects. It has cardioprotective, kidney protective, antiinflammatory, and antimicrobial effects.

Contraindications

Contraindications include: * Pre-existing acute or chronic liver dysfunction or family history of severe liver inflammation (hepatitis), particularly medicine related. *

Pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

11% risk of birth defects and 30-40% risk of neuro-developmental disabilities which can be permanent * Known

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) is an abnormal physiological condition in which there is an undesirable and adverse immune response to an antigen. It is an abnormality in the immune system that causes Imm ...

to valproate or any of the ingredients used in the preparation *

Urea cycle disorders The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic. The urea cycle converts highl ...

* Hepatic

porphyria Porphyria ( or ) is a group of disorders in which substances called porphyrins build up in the body, adversely affecting the skin or nervous system. The types that affect the nervous system are also known as Porphyria#Acute porphyrias, acute p ...

* Hepatotoxicity *

Mitochondrial disease Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy o ...

Pancreatitis Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormone A hormone (from the Ancient Greek, Greek participle , "se ...

Porphyria Porphyria ( or ) is a group of disorders in which substances called porphyrins build up in the body, adversely affecting the skin or nervous system. The types that affect the nervous system are also known as Porphyria#Acute porphyrias, acute p ...

Adverse effects

Most common adverse effects include: * Nausea (22%) *

Drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

(19%) * Dizziness (12%) * Vomiting (12%) *

Weakness Weakness is a symptom of many different medical conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, ...

(10%) Serious adverse effects include: * Bleeding * Low blood platelets *

Encephalopathy Encephalopathy (; ) means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome ...

* Suicidal behavior and thoughts * Low body temperature Valproic acid has a

for

, and fetal abnormalities. There is evidence that valproic acid may cause premature growth plate

ossification Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in t ...

in children and adolescents, resulting in decreased height. Valproic acid can also cause

mydriasis Mydriasis is the Pupillary dilation, dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, Physical trauma, trauma, or the use of c ...

, a dilation of the pupils. There is evidence that shows valproic acid may increase the chance of

polycystic ovary syndrome Polycystic ovary syndrome, or polycystic ovarian syndrome, (PCOS) is the most common endocrine disorder in women of reproductive age. The name is a misnomer, as not all women with this condition develop cysts on their ovaries. The name origin ...

(PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder. Weight gain is also possible.

Pregnancy

Elderly

Valproate may cause increased

in the elderly. In a trial of valproate in elderly patients with

dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...

, a significantly higher portion of valproate patients had somnolence compared to placebo. In approximately one-half of such patients, there was associated reduced nutritional intake and weight loss.

Overdose and toxicity

Excessive amounts of valproic acid can result in

tremor A tremor is an involuntary, somewhat rhythmic muscle contraction and relaxation involving neural oscillations, oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the h ...

stupor Stupor is the lack of critical mental function and a level of consciousness, in which an affected person is almost entirely unresponsive and responds only to intense stimuli such as pain. The word derives from the Latin '' stupor'' ("numbness, in ...

respiratory depression Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...

coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...

metabolic acidosis Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidn ...

, and death. 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. In contrast to other

antiepileptic drugs Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatment ...

, at present there is little favorable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, partly due to valproate's weak acid property (p''K''a of 4.9). In severe intoxication,

hemoperfusion Hemoperfusion or hæmoperfusion (see spelling differences) is a method of filtering the blood extracorporeally (that is, outside the body) to remove a toxin. As with other extracorporeal methods, such as hemodialysis (HD), hemofiltration (HF), an ...

or hemofiltration can be an effective means of hastening elimination of the drug from the body. Supportive therapy should be given to all patients experiencing an overdose and urine output should be monitored. Supplemental L-carnitine is indicated in patients having an acute overdose and also prophylactically in high risk patients. Acetyl-L-carnitine lowers

hyperammonemia Hyperammonemia, or high ammonia levels, is a metabolic disturbance characterised by an excess of ammonia in the blood. Severe hyperammonemia is a dangerous condition that may lead to brain injury and death. It may be primary or secondary. Ammoni ...

less markedly than L-carnitine.

Interactions

Valproate inhibits

CYP2C9 Cytochrome P450 family 2 subfamily C member 9 (abbreviated CYP2C9) is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, t ...

, glucuronyl transferase, and epoxide hydrolase and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves. It may also potentiate the CNS depressant effects of alcohol. It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including

carbamazepine Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as ...

lamotrigine Lamotrigine ( ), sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastau ...

phenytoin Phenytoin (PHT), sold under the brand name Dilantin among others, is an anticonvulsant, anti-seizure medication. It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence se ...

and phenobarbitone) and itself. It may also interact with: *

Aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...

: may increase valproate concentrations. May also interfere with valproate's metabolism. *

Benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s: may cause CNS depression and there are possible pharmacokinetic interactions. *

Carbapenem Carbapenems are a class of very effective antibiotic agents most commonly used for treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Si ...

antibiotics: reduce valproate levels, potentially leading to seizures. *

Cimetidine Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. With the development of proton pump ...

: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations. *

Erythromycin Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used ...

: inhibits valproate's metabolism in the liver, leading to increased valproate concentrations. * Ethosuximide: valproate may increase ethosuximide concentrations and lead to toxicity. * Felbamate: may increase plasma concentrations of valproate. *

Mefloquine Mefloquine, sold under the brand name Lariam among others, is a medication used to prevent or treat malaria. When used for prevention it is typically started before potential exposure and continued for several weeks after potential exposure. It ...

: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine. * Oral contraceptives: may reduce plasma concentrations of valproate. *

Primidone Primidone, sold under various brand names (including Mysoline), is a barbiturate medication that is used to treat partial seizure, partial and generalized seizures and essential tremors. It is taken Oral administration, by mouth. Its common ...

: may accelerate metabolism of valproate, leading to a decline of serum levels and potential breakthrough seizure. *

Rifampicin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires' disease. It is almost always used tog ...

: increases the clearance of valproate, leading to decreased valproate concentrations. *

Warfarin Warfarin, sold under the brand name Coumadin among others. It is used as an anticoagulant, anticoagulant medication. It is commonly used to prevent deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who ha ...

: valproate may increase free warfarin concentration and prolong bleeding time. *

Zidovudine Zidovudine (ZDV), also known as azidothymidine (AZT), was the first antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mothe ...

: valproate may increase zidovudine serum concentration and lead to toxicity.

Pharmacology

Pharmacodynamics

Although the mechanism of action of valproate is not fully understood, traditionally, its anticonvulsant effect has been attributed to the blockade of

s and increased brain levels of the inhibitory synaptic neurotransmitter

gamma-aminobutyric acid GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

(GABA). The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate. In animals, sodium valproate raises cerebral and cerebellar levels of GABA, possibly by inhibiting GABA degradative enzymes, such as

GABA transaminase In enzymology, 4-aminobutyrate transaminase (), also called GABA transaminase or 4-aminobutyrate aminotransferase, or GABA-T, is an enzyme that catalysis, catalyzes the chemical reaction: :4-aminobutanoate + 2-oxoglutarate \rightleftharpoons suc ...

, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells. Prevention of neurotransmitter-induced hyperexcitability of nerve cells via Kv7.2 channel and AKAP5 may also contribute to its mechanism. Valproate has been shown to protect against a seizure-induced reduction in

phosphatidylinositol (3,4,5)-trisphosphate Phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)''P''3), abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases' (PI 3-kinases) phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2). It is a phospholipid ...

(PIP3) as a potential therapeutic mechanism. Valproate is a

histone deacetylase inhibitor Histone deacetylase inhibitors (HDAC inhibitors, HDACi, HDIs) are chemical compounds that enzyme inhibitor, inhibit histone deacetylases. Since acetylation of histones, deacetylation of histones produces transcriptionally silenced heterochromatin ...

. By inhibition of

, it promotes more transcriptionally active chromatin structures, that is it exerts an epigenetic effect. This has been proven in mice: Valproic acid induced histone hyperacetylation had brain function effects on the next generation of mice through changes in sperm DNA methylation. Intermediate molecules include

VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

BDNF Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...

, and

GDNF Glial cell line-derived neurotrophic factor (GDNF) is a protein that, in humans, is encoded by the ''GDNF'' gene. GDNF is a small protein that potently promotes the survival of many types of neurons. It signals through GFRα receptors, particul ...

Endocrine actions

Valproic acid has been found to be an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

and

progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resi ...

s, and hence as a

nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents. List of nonsteroidal steroid receptor mo ...

antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking t ...

and antiprogestogen, at concentrations much lower than therapeutic serum levels. In addition, the drug has been identified as a potent

aromatase inhibitor Aromatase inhibitors (AIs) are a class of drugs used in the treatment of breast cancer in postmenopausal women and in men, and gynecomastia in men. They may also be used off-label to reduce estrogen conversion when supplementing testosterone exo ...

, and suppresses

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

concentrations. These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment. Valproic acid has been found to directly stimulate androgen biosynthesis in the

gonad A gonad, sex gland, or reproductive gland is a Heterocrine gland, mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gon ...

s via inhibition of histone deacetylases and has been associated with

hyperandrogenism Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea, hair loss on the scalp, increased body or facial hair, and infre ...

in women and increased

4-androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroe ...

levels in men. High rates of

and

menstrual disorder A menstrual disorder is characterized as any abnormal condition with regards to a woman's menstrual cycle. There are many different types of menstrual disorders that vary with signs and symptoms, including pain during menstruation, heavy bleeding, ...

s have also been observed in women treated with valproic acid.

Pharmacokinetics

Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut. When in the bloodstream, 80–90% of the substance are bound to

plasma protein Plasma proteins, sometimes referred to as blood proteins, are proteins present in blood plasma. They perform many different functions, including transport of hormones, vitamins and minerals in activity and functioning of the immune system. Other b ...

s, mainly

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

. Protein binding is saturable: it decreases with increasing valproate concentration, low albumin concentrations, the patient's age, additional use of other drugs such as

aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...

, as well as liver and kidney impairment.Valproate . Accessed 6 August 2021. Concentrations in the

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...

and in breast milk are 1 to 10% of blood plasma concentrations. The vast majority of valproate

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

occurs in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

. Valproate is known to be metabolized by the

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzymes

CYP2A6 Cytochrome P450 2A6 (abbreviated CYP2A6) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. CYP2A6 is the primary enzyme responsible for the oxidation of nicotine an ...

CYP2B6 Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances. Func ...

, and

CYP3A5 Cytochrome P450 3A5 is a protein that in humans is encoded by the ''CYP3A5'' gene. Tissue distribution ''CYP3A5'' encodes a member of the cytochrome P450 superfamily of enzymes. Like most of the cytochrome P450, the CYP3A5 is expressed in the ...

. It is also known to be metabolized by the

UDP-glucuronosyltransferase Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UDPGT or UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecu ...

enzymes UGT1A3, UGT1A4,

UGT1A6 UDP-glucuronosyltransferase 1-6 is an enzyme that in humans is encoded by the ''UGT1A6'' gene. Function UDP-glucuronosyltransferase 1-6 is a UDP-glucuronosyltransferase, an enzyme of the glucuronidation pathway that transforms small lipophil ...

, UGT1A8, UGT1A9,

UGT1A10 UDP-glucuronosyltransferase 1-10 is an enzyme that in humans is encoded by the ''UGT1A10'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in D ...

UGT2B7 UGT2B7 (UDP-Glucuronosyltransferase-2B7) is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain. In humans, UDP-Glucuronosyltran ...

, and UGT2B15. Some of the known metabolites of valproate by these enzymes and uncharacterized enzymes include (see image): * via

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gly ...

(30–50%): valproic acid β-O-

glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucu ...

* via

beta oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl-CoA enter ...

(>40%): 2''E''-ene-valproic acid, 2''Z''-ene-valproic acid, 3-hydroxyvalproic acid, 3-oxovalproic acid * via omega oxidation: 5-hydroxyvalproic acid, 2-propyl-glutaric acid * some others: 3''E''-ene-valproic acid, 3''Z''-ene-valproic acid, 4-ene-valproic acid, 4-hydroxyvalproic acid All in all, over 20 metabolites are known. In adult patients taking valproate alone, 30–50% of an administered dose is excreted in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

as the glucuronide conjugate. The other major pathway in the metabolism of valproate is

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

l beta oxidation, which typically accounts for over 40% of an administered dose. Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine. Only a small amount is excreted via the faeces.

Elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

is 16±3 hours and can decrease to 4–9 hours when combined with

enzyme inducer An enzyme inducer is a type of drug that increases the metabolic activity of an enzyme either by binding to the enzyme and activating it, or by increasing the expression of the gene coding for the enzyme. One of the examples of enzyme inducers can ...

Chemistry

Valproic acid is a branched

and the 2-''n''- propyl derivative of

History

Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of

, found naturally in valerian. Valproic acid is a

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...

, 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 Laboratory rats or lab rats are strain (biology), strains of the rat subspecies ''Rattus norvegicus domestica'' (Domestic Norwegian rat) which are bred and kept for scientific research. While Animal testing on rodents, less commonly used for re ...

. It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide. Valproic acid has also been used for migraine

prophylaxis Preventive healthcare, or prophylaxis, is the application of healthcare measures to prevent diseases.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental health a ...

and bipolar disorder.

Society and culture

Valproate is available as a

Approval status

Off-label uses

In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents. Some studies have suggested that valproate may reopen the

critical period In developmental psychology and developmental biology, a critical period is a maturational stage in the lifespan of an organism during which the nervous system is especially sensitive to certain environmental stimuli. If, for some reason, the org ...

for learning

absolute pitch Absolute pitch (AP), often called perfect pitch, is the ability to identify or re-create a given musical note without the benefit of a reference tone. AP may be demonstrated using linguistic labelling ("naming" a note), associating mental image ...

and possibly other skills such as language.

Formulations

Valproate exists in two main molecular variants: ''sodium valproate'' and ''valproic acid without sodium'' (often implied by simply ''valproate''). A mixture between these two is termed ''semisodium valproate''. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more mass of ''sodium valproate'' is needed than ''valproic acid without sodium'' to compensate for the sodium itself. In USA, Europe and many countrie the three variantes of valproate are sold: valproic acid, sodium valproate and valproate semisodium also known as divalproex sodium, the latter is believed to have fewer gastrointestinal side-effects. Divalproex sodium tablets are a formulation comprising valproate sodium and valproic acid in a 1:1 molar relationship. Magnesium valproate is also available in

China China, officially the People's Republic of China (PRC), is a country in East Asia. With population of China, a population exceeding 1.4 billion, it is the list of countries by population (United Nations), second-most populous country after ...

Terminology

Valproate is a negative ion. The

conjugate acid A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid gives a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as it loses a hydrogen ion in the rever ...

of valproate is valproic acid (VPA). Valproic acid is fully ionized into valproate at the physiologic pH of the human body, and valproate is the active form of the drug. Sodium valproate is the sodium

salt In common usage, salt is a mineral composed primarily of sodium chloride (NaCl). When used in food, especially in granulated form, it is more formally called table salt. In the form of a natural crystalline mineral, salt is also known as r ...

of valproic acid. Divalproex sodium is a

coordination complex A coordination complex is a chemical compound consisting of a central atom or ion, which is usually metallic and is called the ''coordination centre'', and a surrounding array of chemical bond, bound molecules or ions, that are in turn known as ' ...

composed of equal parts of valproic acid and sodium valproate.

Brand names of valproic acid

Branded products include: * Absenor ( Orion Corporation Finland) * Convulex ( G.L. Pharma GmbH Austria) * Depakene (

Abbott Laboratories Abbott Laboratories is an American multinational medical devices and health care company with headquarters in Abbott Park, Illinois, in the United States. The company was founded by Chicago physician Wallace Calvin Abbott in 1888 to formulate k ...

in US and Canada) * Depakin ( Sanofi S.R.L. Italy) * Depakine (

Sanofi Aventis Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Synthélabo merg ...

France) * Depakine ( Sanofi Synthelabo Romania) * Depalept (

Israel) * Deprakine (

Finland) * Encorate ( Sun Pharmaceuticals India) * Epilim ( Sanofi Synthelabo Australia and South Africa) * Stavzor ( Noven Pharmaceuticals Inc.) * Valcote (

Argentina) * Valpakine (

Brazil) * Orfiril (Desitin Arzneimittel GmbH Norway)

Brand names of sodium valproate

=Portugal

= * Tablets Diplexil-R by

Bial Kempegowda International Airport is an international airport serving Bengaluru, the capital of the Indian state of Karnataka. Spread over , it is located about north of the city near the suburb of Devanahalli. It is owned and operated by ...

=United States

= * Intravenous injection Depacon by Abbott Laboratories. * Syrup Depakene by Abbott Laboratories. (Note: Depakene ''capsules'' are valproic acid). * Depakote tablets are a mixture of sodium valproate and valproic acid. * Tablets Eliaxim by Bial.

=Australia

= * Epilim Crushable Tablets Sanofi * Epilim Sugar Free Liquid Sanofi * Epilim Syrup Sanofi * Epilim Tablets Sanofi * Sodium Valproate Sandoz Tablets Sanofi * Valpro Tablets Alphapharm * Valproate Winthrop Tablets Sanofi * Valprease tablets Sigma

=New Zealand

= * Epilim by Sanofi-Aventis All the above formulations are

Pharmac The Pharmaceutical Management Agency (Māori: ''Te Pātaka Whaioranga''), better known as Pharmac, is a New Zealand Crown entity that decides, on behalf of Te Whatu Ora – Health New Zealand, which medicines and pharmaceutical products are sub ...

-subsidised.

=UK

= * Depakote Tablets (as in USA) * Tablets Orlept by Wockhardt and Epilim by Sanofi * Oral solution Orlept Sugar Free by Wockhardt and Epilim by Sanofi * Syrup Epilim by Sanofi-Aventis * Intravenous injection Epilim Intravenous by Sanofi * Extended release tablets Epilim Chrono by Sanofi is a combination of sodium valproate and valproic acid in a 2.3:1 ratio. * Enteric-coated tablets Epilim EC200 by Sanofi is a 200 mg sodium valproate enteric-coated tablet.

UK only

* Capsules Episenta prolonged release by Beacon * Sachets Episenta prolonged release by Beacon * Intravenous solution for injection Episenta solution for injection by Beacon

=Germany, Switzerland, Norway, Finland, Sweden

= * Tablets Orfiril by Desitin Pharmaceuticals * Intravenous injection Orfiril IV by Desitin Pharmaceuticals

=South Africa

= * Syrup Convulex by Byk Madaus * Tablets Epilim by Sanofi-synthelabo

=Malaysia

= * Tablets Epilim (''200 ENTERIC COATED'') by Sanofi-Aventis * Controlled release tablets Epilim Chrono (''500 CONTROLLED RELEASE'') by Sanofi-Aventis

=Romania

= * Companies are SANOFI-AVENTIS FRANCE, GEROT PHARMAZEUTIKA GMBH and DESITIN ARZNEIMITTEL GMBH * Types are Syrup, Extended release mini tablets, Gastric resistant coated tablets, Gastric resistant soft capsules, Extended release capsules, Extended release tablets and Extended release coated tablets

=Canada

= * Intravenous injection Epival or Epiject by

. * Syrup Depakene by

its generic formulations includ
Apo-Valproic
an
ratio-Valproic

=Japan

= * Tablets Depakene by Kyowa Hakko Kirin * Extended release tablets Depakene-R by Kyowa Hakko Kogyo and Selenica-R by Kowa * Syrup Depakene by Kyowa Hakko Kogyo

=Europe

= In much of Europe, Dépakine and Depakine Chrono (tablets) are equivalent to Epilim and Epilim Chrono above.

=Taiwan

= * Tablets (white round tablet) Depakine ( zh, c=帝拔癲, p=di-ba-dian) by Sanofi Winthrop Industrie (France)

=Iran

= * Tablets Epival 200 (enteric coated tablet) and Epival 500 (extended release tablet) by Iran Najo * Slow release tablets Depakine Chrono by Sanofi Winthrop Industrie (France)

=Israel

= Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by

Sanofi-Aventis Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Synthélabo merg ...

= India, Russia and CIS countries

= * Valparin Chrono by Sanofi India * Valprol CR by Intas Pharmaceutical (India) * Encorate Chrono by Sun Pharmaceutical (India) * Serven Chrono by Leeven APL Biotech (India)

=Uruguay

= * Tablets DI DPA by Megalabs

Brand names of valproate semisodium

* Brazil Depakote by

and Torval CR by Torrent do Brasil * Canada Epival by Abbott Laboratories * Mexico Epival and Epival ER (extended release) by Abbott Laboratories * United Kingdom Depakote (for psychiatric conditions) and Epilim (for epilepsy) by

and generics * United States Depakote and Depakote ER (extended release) by Abbott Laboratories and generics * India Valance and Valance OD by Abbott Healthcare Pvt Ltd, Divalid ER by Linux laboratories Pvt Ltd, Valex ER by Sigmund Promedica, Dicorate by Sun Pharma * Germany Ergenyl Chrono by Sanofi-Aventis and generics * Chile Valcote and Valcote ER by Abbott Laboratories * France and other European countries Depakote * Peru Divalprax by AC Farma Laboratories * China Diprate OD

Research

A 2023 systematic review of the literature identified only one study in which valproate was evaluated in the treatment of seizures in infants aged 1 to 36 months. In a randomized control trial, valproate alone was found to show poorer outcomes for infants than valproate plus levetiracetam in terms of reduction of seizures, freedom from seizures, daily living ability, quality of life, and cognitive abilities.

References

{{Authority control Anticonvulsants Antiprogestogens Aromatase inhibitors Drugs developed by AbbVie Carboxylic acids CYP3A4 inhibitors Endocrine disruptors GABA analogues GABA transaminase inhibitors Hepatotoxins Histone deacetylase inhibitors Mood stabilizers Nonsteroidal antiandrogens Teratogens World Health Organization essential medicines Wikipedia medicine articles ready to translate Drugs_with_unknown_mechanisms_of_action