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Valproate

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===Valproate Mode of Action===
The exact mode of action of valproate on molecular level is unknown, as there are many different substances that participate simultaneously in the regulation of neuronal activity. <ref name=”[15]”> Sodium valproate (Epilim, Epival, Episenta). (2018, June 5) , at [https://www.netdoctor.co.uk/medicines/brain-nervous-system/a6665/epilim-sodium-valproate/ “https://www.netdoctor.co.uk/medicines/brain-nervous-system/a6665/epilim-sodium-valproate/”].</ref> VPA is connected to cortical inhibition in order to contribute to ‘neural synchrony’ and is known to provide protection from neural degradation and damage[. <ref name=”[16]”> Williams, R. S. B., Cheng, L., Mudge, A. W., & Harwood, A. J. (2002). A common mechanism of action for three mood-stabilizing drugs , at [https://www.nature.com/articles/417292a “https://www.nature.com/articles/417292a”].</ref>
VPA inhibits histone deacetylase, which causes hyperacetylation of histones. The drug is furthermore connected to inositol depletion by preventing the gene prolyl oligopeptidase to be expressed through indirect inhibition of myo-inositoal-1-phophate-synthetase. <ref name=”[16]”> Williams, R. S. B., Cheng, L., Mudge, A. W., & Harwood, A. J. (2002). A common mechanism of action for three mood-stabilizing drugs , at [https://www.nature.com/articles/417292a “https://www.nature.com/articles/417292a”].</ref> In terms of epilepsy, it is believed that VPA is affecting the activity of GABA. By increasing the activity of GABA, the epileptic attacks are prevented. This is established through inhibition of succinic semialdehyde dehydrogenase which then increases the amount of succinic semialdehyde and subsequently increases GABA neurotransmission. <ref name=”[37]”> Flyyn, S., & Babi, M. A. (2017). Pathophysiology of Epilepsy , at [https://www.sciencedirect.com/topics/medicine-and-dentistry/pathophysiology-of-epilepsy “https://www.sciencedirect.com/topics/medicine-and-dentistry/pathophysiology-of-epilepsy”].</ref>
Only 3% of the drug is eliminated through urine, about 30-50% is eliminated through hepatic metabolism, as well as about 40% being excreted through mitochondrial-beta oxidation. <ref name=”[18]”> Gugler, R., & Unruh, G. E. von. (2012, December 13). Clinical Pharmacokinetics of Valproic Acid , at [https://link.springer.com/article/10.2165/00003088-198005010-00002 “https://link.springer.com/article/10.2165/00003088-198005010-00002”].</ref>
===Efficacy and influence on hepatic function===
Different side effects of VPA, such as vomiting, nausea, dyspepsia, were found to be reduced by using the enteric-coated VPA. VPA impacts the hepatic drug metabolism by inhibiting it and displacing other strongly bound drugs from proteins, which implies that dosage changes need to be considered when using it in combination with other drugs. <ref name=”[20]”> Valproic Acid (2018, October 1) , at [https://labtestsonline.org/tests/valproic-acid“https://labtestsonline.org/tests/valproic-acid”].</ref>However, even though the serious damage is a very uncommon case, the increase in liver enzymes (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) is likely to occur in 20% of patients taking VPA. These usually fall back to normal levels in later stages of therapy <ref name=”[15]”> Sodium valproate (Epilim, Epival, Episenta). (2018, June 5) , at [https://www.netdoctor.co.uk/medicines/brain-nervous-system/a6665/epilim-sodium-valproate/ “https://www.netdoctor.co.uk/medicines/brain-nervous-system/a6665/epilim-sodium-valproate/”].</ref> When daily dose of 250 mg of VPA is applied, it needs to be divided accordingly. Optimal dose and effects are achieved with upper limit of 60 mg/kg/day. If the desired effects are not achieved (in other words, the seizures are not gone or the side effects are too strong), testing for blood levels of VPA needs to be executed in order to determine whether they fall within the optimal range of total VPA 50-100 µg/mL. Otherwise, the dose is altered in agreement with the doctor according to the individual state of the patient, his/her other conditions or other medication that they take. The toxicity level of valproate in blood, although not very conclusive, is taken as 150 µg/mL[19].<ref name=”[19]”> valproic Acid Dosage Guide with Precautions. (2019, March 28), at [https://www.drugs.com/dosage/valproic-acid.html “https://www.drugs.com/dosage/valproic-acid.html”].</ref>.  VPA impacts the hepatic drug metabolism by inhibiting it and displacing other strongly bound drugs from proteins, which implies that dosage changes need to be considered when using it in combination with other drugs. <ref name=”[20]”> Valproic Acid (2018, October 1) , at [https://labtestsonline.org/tests/valproic-acid“https://labtestsonline.org/tests/valproic-acid”].</ref>  
==Number of patients==
Epilepsy affects around 50 million people worldwide. This includes people having less than one seizure per year. The prevalence of active epilepsy (i.e. patients who have frequent seizures or use medication) is between 0.4% and 1%. On a global scale, an estimated five million people are diagnosed with epilepsy each year.
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