|Systematic (IUPAC) name|
|Trade names||Depakote, Epilim, Stavzor, Vilapro|
|Licence data||US FDA:|
|Pregnancy cat.||D (AU) X (US)|
|Legal status||Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)|
|Metabolism||Hepatic—glucuronide conjugation 30–50%, mitochondrial β-oxidation over 40%|
|Mol. mass||144.211 g/mol|
|(what is this?)|
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.
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. 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. In mice, valproic acid reversed fatty liver disease and lowered blood glucose.
A study conducted on rats concluded that valproic acid's histone deacetylase-inhibiting effects prevented downregulation of the GluA1 and GluA2 AMPA receptors caused by heavy, chronic methamphetamine use. The authors suggested that this may make valproic acid an effective treatment for methamphetamine addiction, but this use has not been studied clinically.
|Indications for Valproate|
Common (1-10% frequency):
- Abdominal pain
- Increased appetite
- Weight gain
- Asymptomatic hyperammonaemia
- Polycystic ovaries
- Memory impairment
- Menstrual irregularities
- Back pain
- Mood changes
- Abnormal gait
- Tardive dyskinesia
Uncommon (0.1-1% frequency):
- Peripheral oedema
Rare (<0.1% frequency):
- Liver failure
- Pancreatitis (these usually occur in first 6 months and can be fatal)
- Pure red cell aplasia
- Extrapyramidal syndrome (including parkinsonism, may be reversible)
- Hyperammonaemic encephalopathy
- Hypersensitivity reactions including multi-organ hypersensitivity syndrome
- Eosinophilic pleural effusion
- Bone fractures (reduced BMD with long-term use)
Other possible side effects
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.
- 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
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 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
The mechanism of action of valproate is not fully understood. Its anticonvulsant effect is 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.
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.
Branded products include:
- Absenor (Orion Corporation Finland)
- Convulex (Pfizer in the UK and Byk Madaus in South Africa)
- Depakene (Abbott Laboratories in U.S. & Canada)
- Depakine (Sanofi Aventis France)
- Depakine (Sanofi Synthelabo Romania)
- Depalept (Sanofi Aventis Israel)
- Deprakine (Sanofi Aventis Finland)
- Encorate (Sun Pharmaceuticals India)
- Epival (Abbott Laboratories U.S. & Canada)
- Epilim (Sanofi Synthelabo Australia)
- Stavzor (Noven Pharmaceuticals Inc.)
- Valcote (Abbott Laboratories Argentina)
- Valpakine (Sanofi Aventis Brazil)
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.
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