Valproic acid

Valproic acid (VPA, valproate), an acidic chemical compound, has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder and prevention of migraine headaches. VPA is a liquid at room temperature, but it can be reacted with a base such as sodium hydroxide to form the salt sodium valproate, which is a solid.

The acid, salt, or a mixture of the two (valproate semisodium) are marketed under a number of different brand names, including: Depakote, Epilim, Valparin, Valpro, Vilapro and Stavzor. It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.

Medical uses
Its primary use in medicine is in the treatment of epilepsy, bipolar mania and migraine prophylaxis. It is also used off-label for bipolar maintenance. Other off-label uses include impulse control disorders, suggested by recent evidence of efficacy in controlling this adverse effect of Parkinson's Disease medical therapy. Recently, it has been trialled in the treatment of HIV and cancer, owing to its histone deacetylase-inhibiting effects. Valproate has a broad spectrum of anticonvulsant activity, although it is primarily used as a first-line treatment for tonic-clonic seizures, absence seizures and myoclonic seizures and as a second-line treatment for partial seizures and infantile spasms. It has also been successfully given intravenously to treat status epilepticus.

Adverse effects
The most common adverse effects of valproic acid are digestive complaints like diarrhoea, nausea, vomiting and indigestion; vision problems like seeing double or lazy eye; hormonal disturbances (increased testosterone production in females and menstrual irregularities), hair loss, memory problems, weight gain, infections, low platelet count (which can make one bleed more easily), dizziness, drowsiness, tremor and headache. Less common, yet serious side effects include liver damage, brittle bones (becomes far more common with long-term use), polycystic ovaries, movement disorders (which may be irreversible like tardive dyskinesia), psychiatric/neurologic disturbances like hallucinations, anxiety and confusion; swollen pancreas, low body temperature and potentially life-threatening blood abnormalities.

By frequency
Sources: Very common (>10% frequency):


 * Nausea
 * Vomiting
 * Diarrhea
 * Headache
 * Low platelet count (dose-related)
 * Tremor (dose-related)
 * Hair loss (usually temporary)
 * Drowsiness
 * Dizziness
 * Hyperandrogenism in females
 * Seeing double
 * Indigestion
 * Lazy eye
 * Infection
 * Tinnitus


 * Elevated aminotransferase concentrations (dose-related; indicative of liver injury)

Common (1-10% frequency):


 * Paraesthesia
 * Abdominal pain
 * Tremor
 * Increased appetite
 * Weight gain
 * Ataxia
 * Polycystic ovaries
 * Memory impairment
 * Menstrual irregularities
 * Rash
 * Back pain
 * Mood changes
 * Anxiety
 * Confusion
 * Abnormal gait
 * Hallucinations
 * Catatonia
 * Dysarthria
 * Tardive dyskinesia
 * Vertigo


 * High blood levels of ammonia without symptoms

Uncommon (0.1-1% frequency):
 * Peripheral oedema
 * SIADH

Rare (<0.1% frequency):


 * Liver failure
 * Pancreatitis (these two usually occur in first 6 months and can be fatal)
 * Leucopenia (low white blood cell count)
 * Neutropenia (low neutrophil count)
 * Pure red cell aplasia
 * Agranulocytosis
 * Extrapyramidal syndrome (including parkinsonism, may be reversible)
 * Brain problems due to high ammonia levels
 * Hypothermia
 * Hypersensitivity reactions including multi-organ hypersensitivity syndrome
 * Eosinophilic pleural effusion
 * Bone fractures (reduced BMD with long-term use)

Other possible side effects
There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in short stature. Depakote can also cause Mydriasis, a protracted dilation of the pupils

Pregnancy
Valproate causes birth defects; exposure during pregnancy is associated with about three times as many major anomalies as usual, mainly spina bifida and, more rarely, with several other defects, possibly including a "valproate syndrome". Characteristics of this valproate syndrome include facial features that tend to evolve with age, including trigonocephaly, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.

Women who intend to become pregnant should switch to a different drug if possible. Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although vaproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have even worse consequences.) They should take high-dose folic acid and be offered antenatal screening (alpha-fetoprotein and second-trimester ultrasound scans), although screening and scans do not find all birth defects.

Valproate can cause neural tube defects. Folic acid supplements may reduce the risk of birth defects, however. A recent study showed children of mothers taking valproate during pregnancy are at risk for significantly lower IQs. Maternal valproate use during pregnancy has been associated with a significantly higher risk of autism in the offspring. Exposure of the human embryo to valproic acid is associated with risk of autism, and it is possible to duplicate features characteristic of autism by exposing rat embryos to valproic acid at the time of neural tube closure. Valproate exposure on embryonic day 11.5 led to significant local recurrent connectivity in the juvenile rat neocortex, consistent with the underconnectivity theory of autism. A 2009 study found that the 3 year old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.

Contraindications
Contraindications include:
 * Pregnancy
 * Pre-existing acute or chronic hepatic dysfunction or family history of severe hepatitis, particularly medicine related.
 * Known hypersensitivity to valproate or any of the excipients used in the preparation
 * Urea cycle disorders
 * Hepatic porphyria


 * Hepatotoxicity
 * Mitochondrial disease
 * Pancreatitis

Interactions
Valproate inhibits CYP2C9, 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, lamotrigine, phenytoin and phenobarbitone) and itself. It may also interact with:


 * Anticoagulants, due to its ability to prolong the bleeding time.
 * Psychotropic agents; potential pharmacokinetic interactions.
 * Benzodiazepines; may potentiate CNS depression and there are possible pharmacokinetic interactions.
 * Ethosuximide; potential for ethosuximide toxicity.
 * Primidone; may reduce pyrimidone's clearance leading to toxicity.
 * Zidovudine; may raise its (zidovudine's) serum concentration and lead to toxicity.
 * Aspirin; may displace valproate from plasma proteins, leading to increased plasma concentrations. Also interferes with valproate's metabolism.
 * Felbalmate; may increase plasma concentrations of valproate.
 * Mefloquine; potential for increased valproate metabolism combined with the direct epileptogenic effects of mefloquine.
 * Cimetidine; inhibits valproate's metabolism in the liver, hence leading to reduced plasma concentrations of valproate.
 * Erythromycin; inhibits valproate's metabolism in the liver, hence leading to increased plasma concentrations of valproate.
 * Carbapenem antibiotics; reduces valproate levels, potentially leading to seizures.

Overdose and toxicity
Excessive amounts of valproic acid can result in tremor, stupor, respiratory depression, coma, metabolic acidosis, and death. Overdosage in children is usually of an accidental nature, whereas with adults it is more likely to be an intentional act. 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, at present there is little evidence favorable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, at least in part due to valproate's weak acid property (pKa of 4.9).

In severe intoxication, hemoperfusion or hemofiltration can be an effective means of hastening elimination of the drug from the body. Supplemental L -carnitine is indicated in patients having an acute overdose and also prophylactically in high risk patients. Acetyl- L -carnitine lowers hyperammonemia less markedly than L -carnitine.

Mechanism of action
Although the mechanism of action of valproate is not fully understood, it has recently been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism. In addition, its anticonvulsant effect has been attributed to the blockade of voltage-dependent sodium channels and increased brain levels of gamma-aminobutyric acid (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 the inhibitory synaptic transmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells. It also possesses histone deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.

History
Valproic acid was first synthesized in 1882 by B.S. Burton as an analogue of valeric acid, found naturally in valerian. Valproic acid is a carboxylic acid, 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. 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 and bipolar disorder.

Formulations
Branded products include:


 * Absenor (Orion Corporation Finland)
 * Convulex (Pfizer in the UK and Byk Madaus in South Africa)
 * Depakene (Abbott Laboratories in US and Canada)
 * Depakine (Sanofi Aventis France)
 * Depakine (Sanofi Synthelabo Romania)
 * Depalept (Sanofi Aventis Israel)
 * Deprakine (Sanofi Aventis Finland)
 * Encorate (Sun Pharmaceuticals India)
 * Epival (Abbott Laboratories US and Canada)
 * Epilim (Sanofi Synthelabo Australia)
 * Stavzor (Noven Pharmaceuticals Inc.)
 * Valcote (Abbott Laboratories Argentina)
 * Valpakine (Sanofi Aventis Brazil)

Chemistry
Valproic acid, 2-propylvaleric acid, is synthesized by the alkylation of ethyl cyanoacetate with two equivalents of propyl bromide, to give dipropylcyanoacetic ester. Hydrolysis and decarboxylation of the carboethoxy group gives 2-propylpentanenitrile, which is hydrolyzed into valproic acid.