It is a broad spectrum anticonvulsant
Mechanism of Action
Valproate appears to act by multiple mechanisms:
(a) A Phenytoin like frequency dependent prolongation of Na+ channel inactivation
(b) Attenuation of Ca2+ mediated ‘T’ current
(c) Augmentation of release of inhibitory transmitter GABA by inhibiting its degradation as well as increasing its synthesis.
Oral absorption of Valproic acid is good. Peak plasma levels are achieved in 1-4 hrs. It is 90% bound to plasma proteins; 95% metabolized in liver by oxidation and glucuronide conjugation – excreted in urine. Plasma t½ is 15 hours; but anticonvulsant effects are longer lasting
Indications
Valproic acid is highly effective in absence seizures and is an alternative / adjuvant drug for generalized and partial seizures
To prevent recurrent febrile seizures in children, also used in some cases of Myoclonic and Atonic seizures
Dosage
Adults : 200mg 3 times a day, gradually increased at weekly intervals upto a maximum of 600mg 3 times a day according to response.
Children : 10-15mg/kg/day in three divided doses, increase according to response at weekly interval by 5mg/kg/day upto 30-40mg/kg/day
Contraindications
Known hypersensitivity
Special Precautions
Caution in patients in hepatic and renal diseases
Monitor liver function test
Adverse Drug Reactions
Anorexia, nausea, vomiting, drowsiness, ataxia are dose related effects Alopecia, hyperammonemia, sedation, vertigo, tremor, nystagmus and confusion can occur with prolonged use Hypersensitivity reactions like rashes and thrombocytopenia
Asymptomatic increase in serum transaminases, rarely hepatitis and pancreatitis It is teratogenic
Status in
1. Pregnancy: Contraindicated
2. Lactation : Use with caution
3. Old age : May be given in reduced dose
4. Children : May be given in dose as advised
Interactions
Phenytoin: Increases its level by inhibiting metabolism and displacing it from protein binding
Phenobarbital, primidone: Inhibits their metabolism Clonazepam: Simultaneous administration may precipitate absence syndrome Carbamazepine: Induce each other’s metabolism
Presentation
Wallbrurate Blister of 10 Tablets
Valproic acid (by its official name 2-propylvaleric acid) was first synthesized in 1882 by Burton as an analogue of valeric acid, found naturally in valerian. A clear liquid fatty acid 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 anti-seizure activity. He found that it prevented pentylenetetrazol-induced convulsions in rodents. Since then it has also been used for migraine and bipolar disorder.
The risk of birth defects with valproate is two to five times higher than other frequently-used anti-epileptic drugs (absolute rates of birth defects 6-11%). Children born to mothers using valproate have significantly lower I.Q. scores (9 points). However, some epilepsy can only be controlled by valproate, and seizures in pregnancy, which can have grave consequences for mother and child. Doctors recommend that women who intend to become pregnant should be switched to a different drug using combined therapy if possible, which takes several months. Women who are already pregnant and taking a high dose of valproate should try to lower their dose.
All antiepilepic medications have been shown to be associated with higher risks of fetal abnormalities (mostly for spina bifida) since at least 1983 with the risks being related to the strength of medication used and use of more than one drug[
Valproate has also been recognised as sometimes causing a specific facial changes ("facial phenotype") termed "fetal valproate syndrome". Sodium valproate has been associated with the rare condition paroxysmal tonic upgaze of childhood, also known as Ouvrier-Billson syndrome, from childhood or fetal exposure (this condition resolved after discontinuing valproate therapy
While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.
A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.The normal incidence for autism in the general population is estimated at less than one percent. It has been suggested that Valproate may best be avoided in women with localisation epilepsy, where there are more effective and less risky alternatives such as carbamazepine. A 2008 study also suggested a correlation between higher rates of autism in children whose mothers were treated for seizure disorders during pregnancy using sodium valproate (less than 1% for children who didn't receive the drug in vitro vs. 6.3% for children who did). However, only 632 children were followed in this study, prompting criticism that this study was too small to rely on to say whether there was a definitive correlation between the use of sodium valproate in pregnant mothers and higher autism rates in their children, or whether other anti-seizure medications used during pregnancy don't cause this effect.
One multi-centre trial in the UK and US looked at cognitive function in 309 children born to mothers with epilepsy and found that sodium valproate-use was associated with an IQ level eight points lower in children born to mothers taking sodium valproate than mothers taking other anti-epileptic drugs. The authors of the study attempted to correct for confounding factors, but this is an observational study, and therefore cannot prove a causal link. It should be noted, however, that to prove a causal link requires a randomised-controlled trial, which is not possible to perform. is therefore unlikely that any stronger evidence will become available.
A class action is currently underway in the United Kingdom regarding the claim that the drug used in pregnancy caused a range of problems in children, including autism, learning and social difficulties, ADHD, spinal stenosis, facial abnormalities, vision defects, dyslexia, dyspraxia, delayed speech and motor development
Summary of Interactions with Vitamins, Herbs, and Foods
In some cases, an herb or supplement may appear in more than one category, which may seem contradictory. For clarification, read the full article for details about the summarized interactions.
Beneficial May Be Beneficial: Depletion or interference—The medication may deplete or interfere with the absorption or function of the nutrient. Taking these nutrients may help replenish them.
Biotin*
Calcium*
Copper*
Folic acid*
L-Carnitine*
Vitamin A*
Vitamin B12*
Vitamin B6*
Vitamin D*
Vitamin K*
Beneficial May Be Beneficial: Side effect reduction/prevention—Taking these supplements may help reduce the likelihood and/or severity of a potential side effect caused by the medication.
Folic acid*
L-Carnitine*
Vitamin B12*
Vitamin D*
Vitamin K*
Beneficial May Be Beneficial: Supportive interaction—Taking these supplements may support or otherwise help your medication work better.
Folic acid*
Avoid Avoid: Adverse interaction—Avoid these supplements when taking this medication because taking them together may cause undesirable or dangerous results.
Folic acid*
Check Check: Other—Before taking any of these supplements or eating any of these foods with your medication, read this article in full for details.
Antioxidants (Selenium, Vitamin E)
Zinc
Reduced drug absorption/bioavailability
None known
An asterisk (*) next to an item in the summary indicates that the interaction is supported only by weak, fragmentary, and/or contradictory scientific evidence.
Interactions with Dietary Supplements
Antioxidants
On the basis of the biochemical actions of valproic acid, it has been suggested that people taking valproic acid should make sure they have adequate intakes of vitamin E and selenium.1 The importance of supplementation with either nutrient has not yet been tested, however.
Biotin
Several controlled studies have shown that long-term anticonvulsant treatment decreases blood levels of biotin.2 3 4 5 In children, a deficiency of biotin can lead to withdrawn behavior and a delay in mental development. Adults with low biotin levels might experience a loss of appetite, feelings of discomfort or uneasiness, mental depression, or hallucinations. To avoid side effects, individuals taking anticonvulsants should supplement with biotin either alone or as part of a multivitamin.
Calcium
Individuals on long-term multiple anticonvulsant therapy may develop below-normal blood levels of calcium, which may be related to drug-induced vitamin D deficiency.6 Two infants born to women taking high doses of phenytoin and phenobarbital while pregnant developed jitteriness and tetany (a syndrome characterized by muscle twitches), cramps, and spasms that can be caused by calcium deficiency during the first two weeks of life.7 Controlled research is needed to determine whether pregnant women who are taking anticonvulsant medications should supplement with additional amounts of calcium and vitamin D.
Carnitine
Valproic acid causes depletion of carnitine in children,8 and blood carnitine levels are often low in people taking valproic acid for long periods of time. While there have been several case reports of valproic acid-related carnitine deficiency causing abdominal pain in children, there is controversy about the need for carnitine supplements in children taking valproic acid.9 10 11
Complete disappearance of severe valproic acid-induced abdominal pain was achieved in one child with intractable epilepsy immediately following the introduction of 300 mg per day of L-carnitine.12 Carnitine supplementation (50 mg per 2.2 pounds of body weight) has protected children from valproic acid-induced increases in blood ammonia levels in some research,13 though other published work has questioned whether the depletion of carnitine and the increase in blood ammonia levels (both caused by valproic acid) are actually related to each other.14 This last report found that the depletion of carnitine was significantly more severe when epileptics were taking valproic acid together with other anti-seizure medications. A double-blind, crossover study found that carnitine supplementation (100 mg per 2.2 pounds of body weight) was no more effective than placebo in improving the sense of well-being in children treated with valproic acid.15 To date, the question of whether carnitine supplementation is beneficial for people taking valproic acid remains unresolved.16 However, a panel of pediatric neurologists and experts on L-carnitine supplementation strongly recommended oral L-carnitine supplementation for all infants and children taking valproic acid, as well as for adults with carnitine deficiency syndromes, people with valproic acid-induced liver and kidney toxicity, people on kidney dialysis, and premature infants on total parenteral nutrition (intravenous feeding). The panel recommended an amount of 100 mg per 2.2 pounds of body weight per day, up to a maximum of 2 grams per day
Copper and Zinc
In various studies of children treated with valproic acid for epilepsy compared with control groups, serum zinc levels remained normal18 19 or decreased,20 serum copper levels remained normal21 22 or decreased,23 and red blood cell zinc levels were decreased.24 The importance of these changes and how frequently they occur remain unclear.
Folic acid
Several studies have shown that multiple anticonvulsant therapy reduces blood levels of folic acid and dramatically increases homocysteine levels.25 26 27 Homocysteine, a potential marker for folic acid deficiency, is a compound used experimentally to induce seizures and is associated with atherosclerosis.
One preliminary study showed that pregnant women who use anticonvulsant drugs without folic acid supplementation have an increased risk of having a child with birth defects, such as heart defects, cleft lip and palate, neural tube defects, and skeletal abnormalities. However, supplementation with folic acid greatly reduces the risk.28 Consequently, some healthcare practitioners recommend that women taking multiple anticonvulsant drugs supplement with 5 mg of folic acid daily, for three months prior to conception and during the first trimester, to prevent folic acid deficiency-induced birth defects.29 Other practitioners suggest that 1 mg or less of folic acid each day is sufficient to prevent deficiency during pregnancy.30
One well-controlled study showed that adding folic acid to multiple anticonvulsant therapy resulted in reduced seizure frequency.31 In addition, three infants with seizures who were unresponsive to medication experienced immediate relief following supplementation with the active form of folic acid.32
Despite the apparent beneficial effects, some studies have indicated that as little as 0.8 mg of folic acid taken daily can increase the frequency and/or severity of seizures.33 34 35 36 However, a recent controlled study showed that both healthy and epileptic women taking less than 1 mg of folic acid per day had no increased risk for seizures.37 Until more is known about the risks and benefits of folic acid, individuals taking multiple anticonvulsant drugs should consult with their healthcare practitioner before supplementing with folic acid. In addition, pregnant women or women who might become pregnant while taking anticonvulsant drugs should discuss folic acid supplementation with their practitioner.
Vitamin A
Anticonvulsant drugs can occasionally cause birth defects when taken by pregnant women, and their toxicity might be related to low blood levels of vitamin A. One controlled study showed that taking multiple anticonvulsant drugs results in dramatic changes in the way the body utilizes vitamin A.38 Further controlled research is needed to determine whether supplemental vitamin A might prevent birth defects in children born to women on multiple anticonvulsant therapy. Other research suggests that ingestion of large amounts of vitamin A may promote the development of birth defects, although the studies are conflicting.
Vitamin B6
Preliminary research has linked anticonvulsant therapy with possible depletion of vitamin B6 in children.39 One preliminary study found that a combination of 10–50 mg per 2.2 pounds of body weight of vitamin B6 plus valproic acid was more effective than valproic acid or vitamin B6 alone at treating children with recurrent seizures.40 On the other hand, supplementation with large amounts of vitamin B6 (80–200 mg per day) has been reported to reduce blood levels of some anticonvulsant drugs, which could theoretically trigger seizures. People taking anticonvulsant drugs should discuss with their doctor whether supplementing with vitamin B6 is advisable.
Vitamin B12
Anemia is an uncommon side effect experienced by people taking anticonvulsant drugs. Though the cause may be folic acid deficiency in many cases, a deficiency of vitamin B12 may also be a factor in some cases. Deficiencies of folic acid and vitamin B12 can lead to nerve and mental problems. One study revealed that individuals on long-term anticonvulsant therapy had dramatically lower levels of vitamin B12 in their cerebrospinal fluid (the fluid that bathes the brain) when compared with people who were not taking seizure medications. Improvement in mental status and nerve function was observed in a majority of symptomatic individuals after taking 30 mcg of vitamin B12 daily for a few days.41 Another study found that long-term anticonvulsant therapy had no effect on blood levels of vitamin B12.42 Despite these contradictory findings, people taking anticonvulsant drugs for several months or years might prevent nerve and mental problems by supplementing with vitamin B12.
Vitamin D
Though research results vary, long-term use of anticonvulsant drugs appears to interfere with vitamin D activity, which might lead to softening of bones (osteomalacia). One study showed that blood levels of vitamin D in males taking anticonvulsants were lower than those found in men who were not taking seizure medication.43 In a controlled study, bone strength improved in children taking anticonvulsant drugs who were supplemented with the activated form of vitamin D and 500 mg per day of calcium for nine months.44 Some research suggests that differences in exposure to sunlight—which normally increases blood levels of vitamin D—might explain why some studies have failed to find a beneficial effect of vitamin D supplementation. In one controlled study, blood vitamin D levels in children taking anticonvulsants were dramatically lower in winter months than in summer months.45 Another study of 450 people in Florida taking anticonvulsants found that few had drug-induced bone disease.46 Consequently, people taking anticonvulsant drugs who do not receive adequate sunlight should supplement with 400 IU of vitamin D each day to help prevent osteomalacia.
Vitamin E
Two studies showed that individuals taking phenytoin and phenobarbital had lower blood vitamin E levels than those who received no treatment for seizures.47 48 It is not known whether this same interaction occurs with valproic acid. Though the consequences of lower blood levels of vitamin E are unknown, people taking multiple anticonvulsant drugs should probably supplement with 100 to 200 IU of vitamin E daily to prevent a deficiency.
Vitamin K
Some studies have shown that babies born to women taking anticonvulsant drugs have low blood levels of vitamin K, which might cause bleeding in the infant.49 Though some researchers recommend vitamin K supplementation prior to delivery,50 51 not all agree that supplementation for women taking anticonvulsant drugs is necessary.52 Until more information is available, pregnant women or women who might become pregnant while taking anticonvulsant drugs should discuss vitamin K supplementation with their healthcare practitioner.
Interactions with Foods and Other Compounds
Food
Valproic acid, valproate, and divalproex may be taken with food to avoid/reduce stomach upset.53 Capsules, tablets, and sprinkles containing these drugs should not be chewed, to avoid mouth and throat irritation.54
Alcohol
Valproic acid, valproate, and divalproex may all cause drowsiness and dizziness.55 Alcohol may intensify these actions and increase the risk of accidental injury. People taking valproic acid, valproate, or divalproex should avoid alcohol.
Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide.
Valproate (2-propylpentanoic acid) is an anticonvulsant drug used in the treatment of bipolar disorder, although it is only licensed in the UK for the treatment of epilepsy. Valproate is available clinically in a number of forms: these include sodium valproate alone, valproic acid alone, and sodium valproate in combination with valproic acid. In the UK, sodium valproate and valproic acid are available in enteric coated formulations, but this is not the case in the USA. A modified release formulation of a combination of sodium valproate and valproic acid in a 2.3:1 ratio is also available in the UK.
Now, does it make any difference? I'm not aware of any literature comparing the two mixtures (1:1 versus 2:1). There could be such a literature (send me some if you find it). From what I know so far, always open to learning more, it shouldn't make any difference in the effectiveness of the medications, because all of these forms end up yielding the valproate ion which is the active form of the medication. The difference is said to be, as I understand it, that the combinations are better in terms of side effects than the Sodium Valproate version (in the U.S., that's Depakene). The latter causes much more stomach irritation and thus nausea.
So if your friend is not having stomach problems with the current one, and there's no other reason to look at switching, I don't think there would be any improvement to be had from switching. Again, I could be wrong, let me know if you learn otherwise.
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