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Tuesday, March 10, 2015

Valproic Acid Dosage - Valproic Acid Side Effects

What is valproic acid?

Valproic acid or sodium valproate is a non-naturally occurring branched fatty acid. Valproic acid and its salt (valproate) - are used in medicine as an anti-epileptic drug. The plea came in 1968 on the market under the brand name Depakote. Because of this drug's patent has expired in the meantime, there are also generic medicines with the same active ingredient on the market.


The first synthesis of valproic acid took place in 1882, when the Beverly Burton synthesized as an analogue of valeric acid, which occurs naturally in valerian. For decades, it was only in the laboratory and acid 'metabolically inert' solvent is used for water-insoluble organic compounds. In the examination of the anticonvulsant activity of several, dissolved in valproic acid, khellininederivaten discovered the French researcher Pierre Eymard in 1962 by chance that not the solutes, but the solvent was responsible for the pharmacological effect of valproic acid. In 1967 it was approved in France as an anti-epileptic drug. Meanwhile, valproic acid has become the most commonly prescribed antiepileptic drug worldwide.

Valproic acid mechanism of action

Valproic acid works in different ways in the human organism. An important mechanism of action involves increased neurotransmission of GABA.

  • Of valproate is believed that the activity of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) increases in the human brains, degrades by inhibiting GABA transaminase GABA and the activation of the synthesis of GABA. As a result, it can be an alternative for lithium salts as a mood stabilizer.

Nevertheless, have been proposed in the last few years, several other mechanisms of action for valproic acid:

  • For its antiepileptic effect is, inter alia, the blockade of excitatory ion channels (voltage-dependent sodium channels and calcium channels) responsible.
  • Valproic acid is an inhibitor of the enzyme histone deacetylase 1 (HDAC1), so it belongs to the group of histone deacetylase inhibitors. HDI have a long history of use in psychiatry and neurology as mood stabilizers and anticonvulsants. More recently they are being studied as possible treatments for cancer and inflammatory diseases.
  • Valproic acid acts epigenetic, i.e., it engages via acetylations in the epigenetic system. As a result, the activity of individual cells and genes is affected.

Valproic acid is well absorbed by the body and can be administered orally and intravenously. The half-time is between 12 and 16 hours. Coadministration of other AEDs, such as phenytoin or carbamazepine, the half-life can go down to about four to nine hours.


Valproic acid is used:

  • It is a drug of first choice in the treatment of partial epilepsy, idiopathic generalized epilepsy, myoklonie├źn and absences. empirical observation: after setting of the patient by the physician leads valproic acid in about in about six out of ten patients to be prolonged seizure free.
  • For the treatment of manic episodes in bipolar disorder
  • Since valproic acid is a mood and impulse stabilizing effect, it could also be of use in refractory depression as well as for the avoidance of aggressive impulses.
  • Additional treatment in schizophrenic psychoses, especially schizoaffective disorders.
  • To avoid relapse on withdrawal from alcohol and drug use.
  • Migraine prophylaxis (ie unregistered use)
  • In the preventive treatment of cluster headache (this is also non-registered use).
  • In PhelanMcDermid Syndrome

valproic acid level

Valproic acid dosage

Valproic acid is available in different dosage forms. The addition chrono indicates controlled release means the active ingredient is released more slowly and regularly released from the tablet. In an ordinary tablet, the concentration of the substance in the blood, the highest 1 to 6 hours after ingestion, by chrono tablets is that only after 6 to 10 hours. The enteric and acid additions have been made to enteric coated tablets, which are tablets having a coating which dissolves only in the intestine. As a result, the active substance is protected from the acidic gastric contents.


If enzyme inhibitor valproic acid slows the breakdown of certain substances, so that a dose adjustment may be necessary. Such is the case with the anticonvulsant primidone, phenobarbital and its metabolite lamotrigine. Conversely, phenobarbital, phenytoin, primidone, carbamazepine, and their enzyme-inducing effect by accelerating the operation and excretion of valproic acid. Valproic acid may also reduce the albumin binding of phenytoin. In combination with aspirin or anticoagulants, there is an increased risk of bleeding. Alcohol consumption increased during the treatment has a potentially hepatotoxic effects and is therefore not recommended (in bijlsuiter).

Valproic acid inhibits the mitochondrial beta-oxidation of fatty acids (both long-chain and medium-chain).

Furthermore, valproic acid can react with carnitine acyltransferases. This reaction can lead to a carnitine and potentially give rise to phenomena resembling Reye's Syndrome by blocking the production of ketolichamen, which serve as an alternative energy source for the brains, especially in a condition of hypoglycaemia. The use of other anticonvulsants, such as carbamazepine, phenobarbital and phenytoin may be associated with reduced carnitine. The measurement of the carnitine levels, as well as to monitor for signs of carnitine deficiency may be in place patients at risk. Especially in combination with other anticonvulsants, ketogenic diet or reduced energy intake by disease. There is evidence that therapy with L-carnitine can counteract the negative effects of valproic acid overdose.

Valproic acid side effects

Beneficial in the treatment is that valproic acid does not sedating and often appeals to unrecognized idiopathic generalized epilepsy.

Besides some harmless and temporary side effects can lead to treatment with valproic acid to unacceptable side effects, which make it necessary to discontinue treatment:

The most common side effects are drowsiness, tremors, feeding problems (low or excessive appetite), diarrhea, excessive salivation and temporary hair loss.

Occasionally occur hearing loss, headaches, loss of muscle tone / hypotonia, unsteady gait, excessive activity, stupor, edema and confusion.

Rarely develops a chronic disease of the brains with disorders of cognitive performance (encephalopathy). This latter phenomenon is particularly observed in long-term therapy and is often associated with seizures and severe systemic changes in the EEG.

In women, use of valproic acid can lead to polycystic ovary syndrome. Especially at the beginning of the treatment may cause abdominal pain, nausea, vomiting and fatigue may occur.

Often there is a change in the blood picture, for example, a reduction of blood platelets (thrombocytopenia), and enzyme inhibition. Valproic acid may also have an effect on the clot, which may lead to an increased bleeding tendency. In rare cases, there is a renal failure in the form of Fanconi syndrome, liver damage (sometimes fatal), or pancreas (also with a number of fatal / especially in the presence of a metabolic disease and in combination therapy with other medicines).

Valproic acid pregnancy

In women in the child the use of valproic acid during pregnancy are more common malformations, including spina bifida. Also, cognitive disorders and autism are more common in this group. Valproic acid may cause symptoms in animals that closely resemble autism.

In addition to the malformations are also evidence of a dose-dependent cognitive reduction in offspring by use of valproic acid during pregnancy. Children whose mother is treated with valproic acid during pregnancy appear to have lower verbal intelligence quotient than the offspring that are not prenatally exposed to this drug come. Primary school age, problems occur especially in the verbal skills and memory.

However, it must be assumed that a seizure during pregnancy are dangerous for both mother and child. How to behave during a planned or existing pregnancy and whether the medication should be changed can best be determined at a medical consultation. While taking valproic acid during pregnancy may possibly be carried out a specialized prenatal monitoring to identify potential neural tube defects and other symptoms of malformation.

Animal studies are indications that Panax ginseng and spirulina may reduce the teratogenic effects of valproic acid.

In infants valproic acid can be applied only in exceptional cases, for example when other antiepileptic really can not be used.

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