General Description
Clear colorless liquid.
Reactivity Profile
VALPROIC ACID(99-66-1) is a carboxylic acid. Carboxylic acids donate hydrogen ions if a base is present to accept them. They react in this way with all bases, both organic (for example, the amines) and inorganic. Their reactions with bases, called "neutralizations", are accompanied by the evolution of substantial amounts of heat. Neutralization between an acid and a base produces water plus a salt. Carboxylic acids with six or fewer carbon atoms are freely or moderately soluble in water; those with more than six carbons are slightly soluble in water. Soluble carboxylic acid dissociate to an extent in water to yield hydrogen ions. The pH of solutions of carboxylic acids is therefore less than 7.0. Many insoluble carboxylic acids react rapidly with aqueous solutions containing a chemical base and dissolve as the neutralization generates a soluble salt. Carboxylic acids in aqueous solution and liquid or molten carboxylic acids can react with active metals to form gaseous hydrogen and a metal salt. Such reactions occur in principle for solid carboxylic acids as well, but are slow if the solid acid remains dry. Even "insoluble" carboxylic acids may absorb enough water from the air and dissolve sufficiently in VALPROIC ACID(99-66-1) to corrode or dissolve iron, steel, and aluminum parts and containers. Carboxylic acids, like other acids, react with cyanide salts to generate gaseous hydrogen cyanide. The reaction is slower for dry, solid carboxylic acids. Insoluble carboxylic acids react with solutions of cyanides to cause the release of gaseous hydrogen cyanide. Flammable and/or toxic gases and heat are generated by the reaction of carboxylic acids with diazo compounds, dithiocarbamates, isocyanates, mercaptans, nitrides, and sulfides. Carboxylic acids, especially in aqueous solution, also react with sulfites, nitrites, thiosulfates (to give H2S and SO3), dithionites (SO2), to generate flammable and/or toxic gases and heat. Their reaction with carbonates and bicarbonates generates a harmless gas (carbon dioxide) but still heat. Like other organic compounds, carboxylic acids can be oxidized by strong oxidizing agents and reduced by strong reducing agents. These reactions generate heat. A wide variety of products is possible. Like other acids, carboxylic acids may initiate polymerization reactions; like other acids, they often catalyze (increase the rate of) chemical reactions. This chemical is incompatible with bases, oxidizing agents and reducing agents. VALPROIC ACID(99-66-1) is corrosive. .
Air & Water Reactions
Insoluble in water.
Fire Hazard
This chemical is combustible.
Chemical Properties
Colorless Liquid
Originator
Depakote,Abbott
Uses
Antiepileptic; Anticonvulsant that also acts as a mood stabilizer for those with bipolar disorder.
Uses
Antiepileptic; increases levels of -aminobutyric acid(GABA) in the brain. Anticonvulsant that also has efficacy as a mood stabilizer in bipolar disorder
Uses
For treatment and management of seizure disorders, mania, and prophylactic treatment of migraine headache. In epileptics, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, and the seizures asso
Definition
ChEBI: A branched-chain saturated fatty acid that comprises of a propyl substituent on a pentanoic acid stem.
Manufacturing Process
Dipropyl acetic acid or valproic acid may be prepared the next way.
Propylbromide is mixed with cyanacetic acid in the presence of sodium
ethylate, made from absolute ethanol and sodium. By that prepared α,α-
dipropylcyanacetic acid ethyl ester is saponified with equimolecular amounts
of NaOH to give dipropylacetonitril. The desired dipropylacetic acid is produced
by saponification of dipropylacetonitryl with aquatic NaOH. It is colorless
liquid. BP 219°-220°C.
Sodium salt of this acid may be prepared by adding of equivalent of NaOH.
Brand name
Depakene (Abbott);Valproine;Vederon.
Therapeutic Function
Anticonvulsant
Biological Functions
Although it is marketed as both valproic acid
(Depakene) and as sodium valproate (Depakote), it is
the valproate ion that is absorbed from the gastrointestinal
tract and is the active form.
As with several other AEDs, it is difficult to ascribe
a single mechanism of action to valproic acid.This compound
has broad anticonvulsant activity, both in experimental
studies and in the therapeutic management of
human epilepsy.Valproic acid has been shown to block
voltage-dependent sodium channels at therapeutically
relevant concentrations. In several experimental studies,
valproate caused an increase in brain GABA; the
mechanism was unclear.There is evidence that valproate may also inhibit T-calcium channels and that this may
be important in its mechanism of action in patients with
absence epilepsy.
Biochem/physiol Actions
Anticonvulsant that also has efficacy as a mood stabilizer in bipolar disorder
Mechanism of action
Although its mechanism of action is not clearly established, valproate appears to increase the inhibitory effect of GABA,
possibly by activation of glutamic acid decarboxylase or inhibition of GABA-transaminase). The high drug
concentrations required, however, cast doubt on the clinical relevance of this effect. Furthermore, valproate recently has been
shown to decrease the uptake of GABA into cultured astrocytes; this action may contribute to the AED efficacy. Valproate
is known to produce a blockade of high-frequency repetitive firing by slowing the rate of Na+
recovery from inactivation, a
mechanism consistent with the actions of phenytoin and CBZ. Valproate blocks the low-threshold T-type Ca2+ channel.
Consequently, the overall therapeutic utility of valproate is likely caused by multiple effects.
Valproate is indicated for initial or adjunct treatment of absence seizures or as an adjunct when absence seizures occur in
combination with either tonic-clonic seizures, myoclonic seizures, or both. For patients with unambiguous idiopathic generalized
epilepsy, valproate often is the drug of choice, because it controls absence, myoclonic, and generalized tonic-clonic seizures
well. It also is approved by U.S. FDA for use in complex partial seizures, occurring with or without other seizure types in
adults or children 10 years of age or older. In new patients with typical absence seizures, ethosuximide is preferred to
valproate because of the latter drug's risk of producing hepatotoxicity. In a comparative trial, sodium valproate and
ethosuximide were equally effective when either drug was given alone or in combination with other AEDs in children with typical
absence seizures. In atypical absence seizures (Lennox-Gastaut syndrome), sodium valproate is more effective, whereas in
myoclonic seizures, it is less effective than clonazepam. Valproate is approved by the U.S. FDA for use in bipolar disorder and
against migraine headaches.
Pharmacokinetics
Valproate undergoes rapid and complete absorption, which is only slightly slowed by food. It is 90% protein bound, and its
clearance is dose-dependent because of an increase in the free fraction of the drug at higher doses. It is metabolized almost
entirely by the liver, with 30 to 50% of an orally administered dose being eliminated in the urine as its acyl glucuronide
conjugate, 40% from mitochondrial β-oxidation, approximately 15 to 20% by ω-oxidation, and less than 3% is excreted
unchanged in urine. Its major active metabolite is (E)-2-ene valproate (trans 2-ene valproate). Its 4-ene metabolite has been
proposed to be a reactive metabolite responsible for the hepatotoxicity of valproate. Other metabolites found
in the urine include 3-oxo- and 4-hydroxyvalproate. The elimination half-life for valproate ranged from 9 to 16 hours following
oral dosing regimens of 250 to 1,000 mg. Patients who are not taking enzyme-inducing AEDs (carbamazepine, phenytoin, and
phenobarbital) will clear valproate more rapidly; therefore, monitoring of AED plasma concentrations should be intensified
whenever concurrent AEDs are introduced or withdrawn.
Clinical Use
Valproic acid is well absorbed from the gastrointestinal
tract and is highly bound (~90%) to plasma protein,
and most of the compound is therefore retained
within the vascular compartment.Valproate rapidly enters
the brain from the circulation; the subsequent decline
in brain concentration parallels that in plasma, indicating
equilibration between brain and capillary
blood. A large number of metabolites have been identified,
but it is not known whether they play a role in the
anticonvulsant effect of the parent drug. Valproic acid
inhibits the metabolism of several drugs, including phenobarbital,
primidone, carbamazepine, and phenytoin,
leading to an increased blood level of these compounds.
At high doses, valproic acid can inhibit its own metabolism.
It can also displace phenytoin from binding sites
on plasma proteins, with a resultant increase in unbound
phenytoin and increased phenytoin toxicity. In
this instance, the dosage of phenytoin should be adjusted
as required. These examples reinforce the need
to determine serum anticonvulsant levels in epileptic
patients when polytherapy is employed.
Valproic acid has become a major AED against several
seizure types. It is highly effective against absence
seizures and myoclonic seizures. In addition, valproic
acid can be used either alone or in combination with
other drugs for the treatment of generalized tonic–
clonic epilepsy and for partial seizures with complex
symptoms.
Side effects
The most serious adverse effect associated with valproic
acid is fatal hepatic failure. Fatal hepatotoxicity is
most likely to occur in children under age 2 years, especially
in those with severe seizures who are given multiple
anticonvulsant drug therapy. The hepatotoxicity is
not dose related and is considered an idiosyncratic reaction;
it can occur in individuals in other age groups,
and therefore, valproic acid should not be administered
to patients with hepatic disease or significant hepatic
dysfunction or to those who are hypersensitive to it.
Valproic acid administration has been linked to an increased
incidence of neural tube defects in the fetus of
mothers who received valproate during the first
trimester of pregnancy. Patients taking valproate may
develop clotting abnormalities.
Valproic acid causes hair loss in about 5% of patients,
but this effect is reversible. Transient gastrointestinal
effects are common, and some mild behavioral
effects have been reported. Metabolic effects, including
hyperglycemia, hyperglycinuria, and hyperammonemia,
have been reported. An increase in body weight also
has been noted. Valproic acid is not a CNS depressant,
but its administration may lead to increased depression
if it is used in combination with phenobarbital, primidone,
benzodiazepines, or other CNS depressant agents.
Synthesis
Valproic acid, 2-propylvaleric acid (9.4.3), is synthesized by the alkylation of cyanoacetic
ester with two moles of propylbromide, to give dipropylcyanoacetic ester (9.4.1).
Hydrolysis and decarboxylation of the carbethyoxy group gives dipropylacetonitrile
(9.4.2), which is hydrolyzed into valproic acid (9.4.3) [12¨C15].
Solubility in organics
soluble in most organic solvents, including methanol, chloroform, and ether, solubility in water: 1.27 mg/mL.
References
[1] phiel c j, zhang f, huang e y, et al. histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. journal of biological chemistry, 2001, 276(39): 36734-36741.
[2] chateauvieux s, morceau f, dicato m, et al. molecular and therapeutic potential and toxicity of valproic acid. biomed research international, 2010, 2010.
