Molecular and therapeutic potential and toxicity of valproic acid. The first part of this article presents the hypotheses of the mechanism of action of the antiepileptic drug, valproic acid vpa. In the case of the gabaergic hypothesis, two major types of mechanism of action have been proposed, one at the presynaptic level, the other at the postsynaptic level. Valproic acid in association with hyponatremia and siadh introduction valproic acid is an antiepileptic drug which has been approved for the treatment of the primary form of generalized epilepsy and for. The combined use of valproic acid and a carbapenem is likely to occur in patients with central nervous system infections resulting from head trauma or surgical procedures. Because there are many more sodium ions on the outside, and the inside of the neuron is negative relative to the outside, sodium ions rush into the neuron. Although the precise mechanism of action for valproic acid is unknown, its antiepileptic effect is thought to result from its ability to increase concentrations of the neuroinhibitor. Depakene valproic acid is available as orangecolored soft gelatin capsules of 250 mg valproic acid, bearing the trademark depakene for product identification, in bottles of 100 capsules and as a red oral solution containing the equivalent of 250 mg valproic acid per 5 ml as the sodium salt in bottles of 16 ounces.
Valproic acid side effects, dosage, interactions drugs. Valproic acid was the first antiepilepsy medication approved by the food and drug. Burton as an analogue of valeric acid, found naturally in valerian. This accounts for its broad clinical activity and use in several. Valproic acid dissociates to the valproate ion in the gastrointestinal tract. Antiepileptic properties have been attributed to inhibition of gamma amino butyrate gaba transaminobutyrate and of ion channels. Dec 08, 2017 valproic acid vpa is a broadspectrum, carboxylic acid derived anticonvulsant that has been used in the treatment of first line therapy of mania,epilepsy, bipolar disease, schizophrenia, and migraine headache. Mechanisms of action and biochemical toxicology of valproic. Valproic acid dissociates to form valproate ions in the body, which has numerous effects on the neuronal tissue in the brain. Get emergency medical help if you have signs of an allergic reaction hives, difficult breathing, swelling in your face or throat or a severe skin reaction fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling. Valproic acid vpa is a wellknown drug used for the treatment of epilepsy and bipolar disease. It has a marked effect on generalized spikewave discharges.
Enzymeinducing drugs reduce serum valproic acid levels. Multiple therapeutic effects of valproic acid in spinal. Molecular and therapeutic potential and toxicity of. Nov 09, 2018 valproic acid affects chemicals in the body that may be involved in causing seizures. Pancreatitis, hepatotoxicity and teratogenicity are the most significant. Valproic acid clinical trials, side effects aidsinfo.
The drug is now used to treat around onethird of patients newly diagnosed with epilepsy, although its mechanism of action remains unclear. It is rapidly absorbed from the gastrointestinal gi tract. Oral dosage forms valproic acid capsules usp usual adult and adolescent dose anticonvulsant monotherapy. Depakene valproic acid dose, indications, adverse effects. Valproic acid ndipropylacetic acid or valproate vpa is a unique drug, as it is a. Antiepileptic properties have been attributed to inhibition of gamma amino butyrate gaba.
Mechanism of action of valproic acid valproic acid prolongs the inactivated state of voltage sensitive neuronal sodium ion channel either by increasing the efflux or by decreasing the influx of sodium ion across the cell membrane and inhibits the high frequency neuronal discharge. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. Valproic acid and its derivatives, hereafter given the generic term valproate, are weak blockers of sodium ion channels that produce a weak inhibitor of enzymes that deactivate gamma. Pharmacology of valproate request pdf researchgate. Vpa is widely used in pediatric epilepsy because of its multiple mechanisms of action and acceptable safety profile 3. The risk of developing liver damage is greater in children who are younger than 2 years of age and are also taking more than one medication to prevent seizures, have certain inherited diseases that may prevent the body from changing food to energy normally. Parenteral dosage forms valproate sodium injection usual adult and adolescent dose anticonvulsant initial exposure to valproate. Aug 23, 2018 valproic acid dissociates to form valproate ions in the body, which has numerous effects on the neuronal tissue in the brain. Dionne, in pharmacology and therapeutics for dentistry seventh edition, 2017. Valproic acid may cause serious or lifethreatening damage to the liver that is most likely to occur within the first 6 months of therapy. Mechanisms of action of antiepileptic drugs open access journals. It was extended to the anticonvulsants, valproic acid, carbamazepine and lamotrigine, yet the first two have little efficacy against depression and lamotrigine shows little efficacy against mania sobo, s. The antiepileptic action of valproic acid also results from its ability to strengthen the inhibitory action.
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. The exact mechanisms that contribute to the efficacy of valproate in treating bipolar disorder remain unclear. Felbamate other drugs may increase valproic acid levels. In this study, we investigated the mechanisms of action of vpa in the treatment of type iii like sma mice. Valproic acid and derivatives dpx therapeutics brands depakote, depakote er, depakene, depacon, episenta, epilim, epival, divalproex, dicorate, disorate, divaa, divalpro, soval dx, trend xr, valna, stavzor generic. Attenuation of phospholipid signaling provides a novel. Pdf valproic acid is a commonly used antiepileptic drug aed for prescription to control convulsion. Since its first marketing as an antiepileptic drug aed 35 years ago in france, valproate has become established worldwide as one of the most widely used aeds in the treatment of both.
Aug 23, 2018 valproic acid is an antiepileptic drug that is commonly used in conjunction with other pharmaceutical therapies, which has the potential to lead to interactions between the drugs. Valproic acid is excreted into breast milk at concentrations corresponding to 1% to 10% of serum concentrations. Valproic acid is a synthetic derivative of propylpentanoic acid with antiepileptic properties and potential antineoplastic and antiangiogenesis activities. Depakene valproic acid is available as orangecolored soft gelatin capsules of 250 mg valproic acid, bearing the trademark depakene for product identification, in bottles of 100 capsules and as a red oral. Many of the newer antiepileptic drugs aeds have clinical advantages over older, socalled firstgeneration aeds in that they are more predictable in their. Oral, initially, 5 to 15 mg per kg of body weight a day, the dosage being increased at oneweek intervals by 5 to 10 mg per kg of body weight a day as needed and tolerated. Pdf interaction of valproic acid and the antidepressant. Coupled modeling of pbpk and toxic mechanisms of action of valproic acid in liver joachim bucher i, juan diaz, klaus mauchi, lothar terfloth i insilico biotechnology ag, stuttgart, germany 1. Valproic acid plasma concentration decreases in a doseindependent manner following administration of meropenem. Haroutiunian s, ratz y, rabinovich b, adam m, hoffman a. It is used to treat partial and generalized seizures and acute. The mechanisms by which valproate exerts its therapeutic effects have not been established.
Valproic acid vpa is a monocarboxylic acid with unclear mechanism of action and this is widely prescribed for epilepsy, bipolar disorder, migraine, alzheimers. 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. While valproic acid vpa is a potential treatment for sma, its therapeutic mechanisms are still controversial. 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. Get emergency medical help if you have signs of an allergic reaction hives, difficult breathing, swelling in your face or throat or a severe skin reaction fever, sore. Valproic acid, a drug with multiple molecular targets. Unknown but there are multiple mechanisms of action activates glutamic acid decarboxylase to increase gammaaminobutyric acid gaba. The predominant mechanism of action of vpa described in the literature is its action on ion channels, like the other traditionally used anticonvulsive agents phenytoin and carbamazepine.
Vpa was recently classified among the histone deacetylase inhibitors, acting directly at the level of gene transcription by inhibiting histone. Analysis of the valproic acid meropenem interaction in hospitalized patients. The drug is now used to treat around onethird of patients newly. Mechanisms of action of antiepileptic drugs the therapeutic armamentarium for the treatment of seizures has broadened significantly over the past decade 1. Valproic acid modulates neuronal hyperexcitability, especially by blocking the ttype calcium channel. Read the medication guide and, if available, the patient information leaflet provided by your pharmacist before you start taking valproic acid and each time you get a. Sma and wildtype mice were treated with vpa from 6 to 12 months and 10 to 12 months of age, respectively. Mechanism of action of valproic acid valproic acid prolongs the inactivated state of voltage sensitive neuronal sodium ion channel either by increasing the efflux or by decreasing the influx of sodium ion. In epilepsy, valproic acid appears to act by increasing the concentration of gammaaminobutyric acid gaba in the brain.
All of the formulations of valproic acid have bioavailabilities near 100 percent f 1, reflecting the absence of a firstpass effect in the liver. Action potentials are caused by an exchange of ions across the neuron membrane. Yes, except for er formulation class antiepileptic drug aed commonly prescribed for fda approved in bold. Pharmacology, mechanisms of action and clinical implications pharmacology research, safety testing and regulation. Depakene valproic acid is indicated for use as sole and adjunctive therapy in. Valproic acid ndipropylacetic acid or valproate vpa is a unique drug, as it is. Valproic acid vpa, or 2propyl pentanoic acid, was accidentally found to be an effective antiepileptic treatment in the 1960s.
Valproic acid, a drug with multiple molecular targets related. Novel applications of the anticonvulsant drug valproic acid in cancer. Valproic acid and carbapenem antibiotics interaction. Coupled modeling of pbpk and toxic mechanisms of action of. In epilepsy, valproic acid appears to act by increasing.
Depakene and depakote er is a drug that has been approved by the u. Valproic acid promotes the formation and inhibits the endogenous degrada tion of gaba, although the clinical impact of this mechanism of action is illdefined. Valproic acid is an antiepileptic drug that is commonly used in conjunction with other pharmaceutical therapies, which has the potential to lead to interactions between the drugs. Food and drug administration to treat certain symptoms of bipolar disorder a type of mental illness, to treat some types of seizures, and to prevent migraine headaches. One proposed mechanism of action for va is enhancement of central gabaergic tone by inhibition of gaba transaminase. It is used to treat partial and generalized seizures and acute mania, and as prophylaxis for bipolar disorder and migraine headaches. Definitive conclusions about the basis for the acute anti convulsant action of valproate must await experimental demonstration of. Valproic acid vpa, a branched shortchain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. The mechanisms by which valproate exerts its therapeutic effects have not been. Early reports linked its biochemical mechanism of action to alterations ingammaaminobutyric acid gabaergic function. Depakene valproic acid is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of. Its mechanism of action involves an increase in cerebral levels of. Valproic acid, a drug with multiple molecular targets related to its potential neuroprotective action 109.
Mechanism of action of valproic acid and its derivatives. In the case of the gabaergic hypothesis, two major types of mechanism of action. Valproate has been in clinical use for nearly 40 years for the treatment of avariety of neuropsychiatric illnesses, including bipolar disorder and epilepsy. Valproic acid in association with hyponatremia and siadh. Mechanism of action overview sodium channel blockers. No single mechanism of action of vpa which is presented, can account for its. Vpa is a branchedchain carboxylic acid introduced as an antiepileptic drug in 1978 in the united states. Valproic acid, valproate and divalproex in the maintenance. Valproic acid is used to treat various types of seizure disorders. Coupled modeling of pbpk and toxic mechanisms of action.
Mechanisms of action and biochemical toxicology of. Valproic acid va is used worldwide as an antiepileptic drug and a mood stabilizer. Depakene valproic acid capsules and oral solution, usp. Analysis of therapeutic drug monitoring data under naturalistic conditions. Food and drug administration to treat certain symptoms of bipolar disorder a type of mental illness. Algorithm for treating epilepsy patients with valproate. Valproic acid vpa has been used in clinical practice since 60s, with a relatively favourable safety and efficacy profile.
Depakene valproic acid is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Interaction of valproic acid and the antidepressant drugs doxepin and venlafaxine. Valproate vpa, and its valproic acid, sodium valproate, and valproate semisodium forms, are medications primarily used to treat epilepsy and bipolar disorder and to prevent migraine headaches. Valproic acid is often used as an addon medication for patients who continue to have complex partial seizures while taking other seizure medicines. Vpa is widely used in pediatric epilepsy because of its. Valproic acid vpa, valproate, an acidic chemical compound, has found clinical use as an anticonvulsant and moodstabilizing drug, primarily in the treatment of epilepsy, bipolar disorder and prevention of. Pancreatitis, hepatotoxicity and teratogenicity are the most significant adverse drug reactions. Valproic acid va is a commonly used anticonvulsant. Valproic acid inhibits the metabolism of a number of drugs, most notably.
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