Valproic acid dissociates to form valproate ions in the body, which has numerous effects on the neuronal tissue in the brain. Valproate is a mood stabilizer which is approved for use in acute and maintenance mania. Investigation of the mechanism of its antimigraine action is difficult due to the broad range of its biochemical effe. Early reports linked its biochemical mechanism of action to alterations in gammaaminobutyric acid gabaergic function. Its anticonvulsant effects are rapid in onset, while. Some antiepileptic drugs work by acting on combination of channels or through some unknown mechanism of action. Although the mechanism of action remains to be elucidated, valproate sodium increases concentrations of gammaaminobutyric acid in the brain, probably due to inhibition of the enzymes responsible for the catabolism of gaba. There is no single mechanism of action that can explain valproates broad effects on neuronal tissue. Valproic acid dissociates to the valproate ion in the gastrointestinal tract, so its effects are virtually identical to those of other forms of valproate. The established agents phenytoin and carbamazepine are archetypal sodium channel blockers, a mechanism they share with the. Oct 30, 20 valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. Definitive conclusions about the basis for the acute anti convulsant action of valproate must await experimental demonstration of.
Mechanism of action effect on neuronal transmission firstgeneration aeds secondthirdgeneration aeds aeds under development sodium channel blockade fast inactivation slowed recovery from inactivated state phenytoin carbamazepine valproate topiramate zonisamide. Valproate sodium exists as the valproate ion in the blood. Mechanism of action effect on neuronal transmission firstgeneration aeds secondthirdgeneration aeds aeds under development. Valproate, one of the major antiepileptic drugs used today, has besides its wide use in both generalized and partial epilepsies, several new approved indications including the treatment of bipolar disorders, neuropathic pain, and as a migraine prophylaxis. While each might explain lithiums mechanism of action, neither convincingly accounts for the actions of the other mood stabilizers or, moreover, why some antidepressants enhance switching from bipolar depression to mania.
Asked 8 dec 2011 by perski updated 8 december 2011. The gabaergic effect is believed to contribute to the antimanic properties of sodium valproate. In view of the advances in molecular neurobiology and neuroscience, future studies will undoubtedly furcns drugs 2002. Valproate can cause teratogenic effects including spina bifida a neural tube defect. In this respect, it is important to note that, as for valproate, the precise mechanism of action of many other aeds is unknown. Valproic acid vpa is a branched shortchain fatty acid derived from naturally occurring valeric acid.
Recently, va showed pharma cological characteristics similar to those of other anti cancer agents, acting on cell growth, differentiation and apoptosis. The mechanisms by which valproate exerts its therapeutic effects have not been established. Valproate is known to have a broad mechanism of action including blocking sodium channels, increasing gaba. Significant interactions anticonvulsants these drugs when used together with valproate have the ability to increase the intrinsic clearance of. Molecular and therapeutic potential and toxicity of. Although the mechanism of action of valproate is not fully understood, traditionally, its anticonvulsant effect has been attributed to the blockade of voltagegated sodium channels and increased brain levels of gammaaminobutyric acid gaba. Sodium valproate is an anticonvulsant and antipsychotic. The mode of action may include the blockage of calcium channels and perturbation of membrane potential35. Mar 01, 2019 valproate clinical pharmacology mechanism of action. The established agents phenytoin and carbamazepine are archetypal sodium channel. Oldergeneration aeds are effective but have tolerability and pharmacokinetic disadvantages. Topic words that searched were valproic acid, pharmacokinetics. In one study, 144 such patients were given either valproic acid or a placebo in addition to the phenytoin dilantin or carbamazepine tegretol that they had been taking. Valproate sodium is the sodium salt form of valproic acid with antiepileptic activity.
Aug 23, 2018 valproic acid dissociates to form valproate ions in the body, which has numerous effects on the neuronal tissue in the brain. Vpa was recently classified among the histone deacetylase inhibitors, acting directly at the level of gene transcription by inhibiting histone. Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. Even though valproate is available in different names, strengths, and formulations, all provide the same active medicine.
Valproic acid is a commonly used antiepileptic drug aed for prescription to control convulsion attacks. Valproate or lithium in acute mania and in maintenance studies was more effective than carbamazepine. In recent years, a diverse set of molecular and cellular targets of these drugs has been identified. Valproate sodium is converted into its active form, valproate ion, in blood. Mechanisms of action of antiepileptic drugs 3 receive ethosuximide are more likely than those who receive valproic acid to achieve longterm remission is consistent with the disease.
If diagnosed, sodium valproate should be discontinued. We have recently shown that valproate vpa decreases intracellular concentrations of mositol, like lithium but via a different mechanism, namely by inhibiting myoinositol1phosphate mip synthase. After more than 40 years of clinical use, the mechanisms of action of valproate in epilepsy, bipolar disorder and migraine are still not fully understood. Antiseizure drugs are typically grouped by their principal mode of action, although for many drugs, the precise mechanism of action is not known or multiple actions are suspected. In view of the advances in molecular neurobiology and neuroscience, future. This case describes a preadolescent patient who had valproate induced hypertensive urgency. Valproate is available in tablet immediaterelease or enteric coated, syrup and intravenous formulations. Originally, low incidences of toxicity were reported. Mechanism of action of valproate pharmacodynamics the specific biochemical mechanism of valproate action in stabilizing mood is unknown. In a study comparing intravenous valproate and phenytoin in such patients, the incidence of death was found to be higher in the valproate groups % compared to the phenytoin group 8. Department of pharmacology, university of bristol, medical. Anticoagulants drugs like aspirin may result in displacement of valproate from. Mechanisms of action of antiepileptic drugs graeme j.
Valproate has fda approval for acute maniamixed episode in bipolar disorder. Its anticonvulsant effects are rapid in onset, while antimanic and antidepressant effects are slower in onset which require chronic administration. Aug 29, 2012 although it is often proposed that blockade of voltagedependent sodium currents is an important mechanism of antiepileptic action of valproate, the exact role played by this mechanism of action at therapeutically relevant concentrations in the mammalian brain is not clearly elucidated. The first level is at the neuroreceptor itself, the second its coupling mechanism with cpla 2. This relative dearth of data in the area of valproate neuropharmacology is also evident when discussing the mechanism s of action of other mood stabilizers and anticonvulsants. The mechanisms of action of valproate in neuropsychiatric. Valproate val proe ate divalproex dye val pro ex sodium valproic val proe ik acid note. Hyperammonemic encephalopathy is a rare and serious adverse reaction to valproate. Valproate can cause major congenital malformations, particularly neural tube defects e.
Despite extensive clinical utilization, significant questions concerning their mechanisms of action remain. Valproate should not be administered to a woman of childbearing potential unless the drug is essential. They are expressed throughout the neuronal membrane, on dendrites, soma, axons, and nerve terminals. The gabaergic effect is also believed to contribute towards the antimanic properties of valproate. Chapter 43 n mechanisms of action of antiepileptic. Pdf valproic acid is a commonly used antiepileptic drug aed for prescription to control convulsion. Accordingly, it seems currently not very likely that gabaergic transmission is involved in the psychotropic action of valproate, which may also explain the low sedative effect of valproate in the. Valproate is known to have a broad mechanism of action including blocking sodium channels, increasing gaba, and inhibiting glutamatenmda receptor mediated neuronal excitation. Molecular and therapeutic potential and toxicity of valproic acid. This is especially important when valproate use is considered for a. Valpro sodium valproate pdf 20 tga ebusiness services. Valproate has been in clinical use for nearly 40 years for the treatment of a variety of neuropsychiatric illnesses, including bipolar disorder and epilepsy. Vpa is used primarily in the treatment of epilepsy and seizures, but is also used in. Pharmacokinetics, drug interactions, and tolerability of.
Possible mechanisms of valproate in migraine prophylaxis fm. In a study comparing intravenous valproate and phenytoin in such patients, the incidence of. May 22, 2003 accordingly, it seems currently not very likely that gabaergic transmission is involved in the psychotropic action of valproate, which may also explain the low sedative effect of valproate in the. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. This accounts for its broad clinical activity and use in several.
Valproic acid, a drug with multiple molecular targets related. This action appears to result from a combination of mechanisms including. It is the first line drug for bipolar patients with presence rapid cycling, irritable mania, bipolar disorder with. Its anticonvulsant effect is attributed to the blockage of voltage dependent sodium channels and increased brain levels of gammaaminobutyric acid gaba.
In spite of its wide use for many years, the mechanism of vpa action is still not fully understood. Pharmacokinetics and metabolism in order to assess evidence relating to the mechanism of action of valproate it is necessary to consider the phar macokinetics and metabolism of valproate, and to evaluate the possible pharmacological action of metabolites. Valproate has been shown to be an effective prophylactic treatment in migraine. Summary of antiepileptic drugs proposed mechanisms of action. Antiepileptic properties have been attributed to inhibition of gamma amino butyrate gaba transaminobutyrate and of ion channels. Valproic acid, valproate and divalproex in the maintenance. Valproic acid ndipropylacetic acid or valproate vpa is a unique drug, as it is a. Valproate was upgraded to category x in 20 the risk of use in pregnant women clearly outweighs any possible benefit of the drug. Algorithm for treating epilepsy patients with valproate depakote, valproic acid patient presents with seizures or unacceptable side effects diagnose partial or primary generalized epilepsy simple partial, complex partial, primary or secondarily generalized tonic clonic, absence, juvenile myoclonic, atonic, etc. Your specialist will explain to you why they feel valproate is. Mechanisms of action of existing agents sodium channels.
Depakote er divalproex sodium dose, indications, adverse. Valproate should not be used in patients with acute head trauma for the prophylaxis of posttraumatic seizures. The mechanism of va action was initially related to its effects on amino acid neurotransmitters and modulation of intracellular pathways. Aug 01, 2000 valproic acid sodium valproate, vpa is the most commonly used antiepileptic drug today in the treatment of generalized epilepsy, and it is also effective in partial epilepsy. Possible mechanisms of valproate in migraine prophylaxis. Valproic acid vpa, a branched shortchain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Algorithm for treating epilepsy patients with valproate. Valproate should only be used to treat pregnant women with epilepsy if other medications have failed to control their symptoms or are otherwise unacceptable. Mechanisms of action of antiepileptic drugs open access journals. Although there is documentation of this reaction in previous reports, very little is still known about the. Valproate and gabaergic system effects neuropsychopharmacology. To some degree, the cellular effects of antiseizure drugs are linked with the types of seizures against which they are most effective.
Although it is often proposed that blockade of voltagedependent sodium currents is an important mechanism of antiepileptic action of valproate, the exact role played by this mechanism of. Voltagegated sodium channels are responsible for depolarisation of the nerve cell membrane and conduction of action potentials across the surface of neuronal cells. Significant interactions anticonvulsants these drugs when used together with valproate have the ability to increase the intrinsic clearance of valproate. Dec 08, 2011 the mechanisms by which valproate exerts its therapeutic effects have not been established. In addition, valproate can cause decreased iq scores following. Valproic acid is often used as an addon medication for patients who continue to have complex partial seizures while taking other seizure medicines. Throughout this fact sheet, the medication will be referred to as valproate. The subsequent 70 years saw the introduction of phenytoin, ethosuximide, carbamazepine, sodium valproate and a range of benzodiazepines. Find patient medical information for valproic acid as sodium salt oral on webmd including its uses, side effects and safety, interactions, pictures, warnings and user ratings. Mechanisms of action of antiepileptic drugs epilepsy society. Epilim, depakote, convulex, episenta, epival, kentlim. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gammaaminobutyric acid gaba. Vpa is used primarily in the treatment of epilepsy and seizures, but is also used in migraine, bipolar, mood, anxiety, and psychiatric disorders 1. Valproic acid promotes the formation and inhibits the endogenous degrada tion of gaba, although the clinical impact of this mechanism of action is illdefined.
May 15, 20 valproic acid vpa is a monocarboxylic acid with unclear mechanism of action and this is widely prescribed for epilepsy, bipolar disorder, migraine, alzheimers disease and recently, cancer and hiv polytherapies. Bipolar disorders and valproate longdom publishing sl. Pharmacology of valproate request pdf researchgate. Valproic acid, a drug with multiple molecular targets. Algorithm for treating epilepsy patients with valproate depakote, valproic acid patient presents with seizures or unacceptable side effects diagnose partial or primary generalized epilepsy simple partial. Blockade of voltagegated sodium channels is the most common mechanism of action among currently available aeds. May 18, 2007 after more than 40 years of clinical use, the mechanisms of action of valproate in epilepsy, bipolar disorder and migraine are still not fully understood.
Jan 28, 2020 antiepileptic drugs can be grouped according to their major mechanism of action. Valproic acid sodium valproate, vpa is the most commonly used antiepileptic drug today in the treatment of generalized epilepsy, and it is also effective in partial epilepsy. Its action against absence seizures depends on blocking t type calcium channels in the thalamus. Valproate also known as epilim, depakote, convulex, episenta, epival, kentlim, orlept, sodium valproate, syonell, valpal and belvo. The exact mechanisms that contribute to the efficacy of valproate in treating bipolar disorder remain unclear. Moodstabilizing drugs are the most widely prescribed pharmacological treatments for bipolar disorder, a disease characterized by recurrent episodes of mania and depression. Lifethreatening pancreatitis has been reported in both children and adults receiving valproate.
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