2599 Valproic acid Valproic acid (VPA) is considered to be a drug of first choice and one of the most frequently-prescribed antiepileptic drugs worldwide for the therapy of generalized and focal epilepsies, including special epileptic. It is a broad-spectrum antiepileptic drug and is usually well tolerated. Rarely, serious complications may occur in some patients, including hemorrhagic pancreatitis, coagulopathies, bone marrow suppression, VPA-induced hepatotoxicity and encephalopathy, but there is still a lack of knowledge about the incidence and occurrence of these special side effects. VPA has been approved for stabilization of manic episodes in patients with bipolar disorder. It is also used to treat migraine headaches and schizophrenia. As the use of VPA increases, the number of both accidental and intentional exposures increases. This is paralleled by more reports of VPA-induced toxicity. VPA is relatively contraindicated in pregnancy due to its teratogenicity. It is a known folate antagonist, which can cause neural tube defects. Thus, folic acid supplements may alleviate teratogenic problems. Women who become pregnant whilst taking valproate should be counselled as to its risks. VPA is an inhibitor of the enzyme histone deacetylase 1 (HDAC1). HDAC1 is needed for HIV to remain in infected cells. Patients treated with valproic acid in addition to highly active antiretroviral therapy (HAART) showed a median 75% reduction in latent HIV infection. VPA is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor) in the human brain. Valproic Acid dissociates to the valproate ion in the gastrointestinal tract. (A7818, A7819). 99-66-1 3121 C8H16O2 144.115030 White crystals. 120 - 130°C 222°C 1.3 mg/mL Inhalation. Rapid absorption from gastrointestinal tract. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. Food has a greater influence on the rate of absorption of the Depakote tablet (increases Tmax from 4 to 8 hours) than on the absorption of Depakote sprinkle capsules (increase Tmax from 3.3 to 4.8 hours). Furthermore, studies suggest that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control. Valproic Acid binds to and inhibits GABA transaminase. This leads to increased brain concentrations of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the CNS. Acute poisoning by VPA can lead to severe CNS depression including coma, confusion, somnolence, dizziness or hallucinations. Hypotension, respiratory depression and hypo/hyperthermia are also common. VPA is also hepatotoxic, which is likely due to its mitochondrial toxicity. VPA appears to exert its mitochondrial toxicity by impairing mitochondrial functions leading to oxidative stress and cytochrome c expulsion, which leads to apoptosis (A15078). VPA is contraindicated in pregnancy due to its teratogenicity. VPA is a known folate antagonist, which can cause neural tube defects in developing fetuses. Thus, folic acid supplements in pregnant women may alleviate teratogenic problems associated with VPA use. VPA and its metabolites inhibit the biosynthesis of carnitine by decreasing the concentration of alpha-ketoglutarate (through direct inhibition of alpha-ketoglutarate dehydrogenase) and may contribute to carnitine deficiency. It is postulated that carnitine supplementation may increase the beta-oxidation of VPA, thereby limiting cytosolic omega-oxidation and the production of toxic metabolites that are involved in liver toxicity and ammonia accumulation. VPA-induced hepatotoxicity and hyperammonemic encephalopathy may be promoted either by a pre-existing carnitine deficiency or by deficiency induced by VPA per se. VPA has been shown to downregulate levels of superoxide dismutase (SOD), glutathione (GSH), histone deacetylase (HDAC) and folate. It has also been shown to upregulate H2O2 and homocysteine. Elevated levels of H2O2 negatively affect the NADPH reducing system for dihydrofolate reductase (DHFR) and methylene tetrahydrofolate reductase (MTHFR) (A15079). Valproic acid is rapidly absorbed from gastrointestinal tract. Valproic acid is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. These products include 2-n-propylpent-2-enoic acid (delta 2,3 VPE) and several coenzyme A (CoA) derivatives including VPA-CoA, and delta 2,3 VPE-CoA. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine (A308). Half Life: 9-16 hours (following oral administration of 250 mg to 1000 mg). Oral, mouse: LD50 = 1098 mg/kg; Oral, rat: LD50 = 670 mg/kg. In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/l during controlled therapy, but may reach 150–1500 mg/l following acute poisoning. No indication of carcinogenicity to humans (not listed by IARC). For treatment and management of seizure disorders, mania, and prophylactic treatment of migraine headache. In epileptics, valproic acid is used to control absence seizures, tonic-clonic seizures (grand mal), complex partial seizures, and the seizures associated with Lennox-Gastaut syndrome (A308). Valproic acid causes hyperammonemia, which can lead to brain damage. Rarely, it can cause blood dyscrasia, impaired liver function, jaundice, thrombocytopenia, and prolonged coagulation times. In about 5% of pregnant users, valproic acid will cross the placenta and cause congenital anomalies. Valproic acid may also cause acute hematological toxicities, especially in children, including rare reports of myelodysplasia and acute leukemia-like syndrome (L1132). May cause a potentially dangerous rash that may develop into Stevens Johnson syndrome, an extremely rare but potentially fatal skin disease. Acute overdoses of VPA can lead to hypo/hyperthermia, tachycardia, hypotension, respiratory depression, coma, confusion, somnolence, dizziness, headaches and cerebral edema. Extended use of VPA can cause hepatotoxicity. Allopecia, anorexia, renal failure, tremors and miosis are also associated with chronic toxicity. VPA is a known teratogen (due to folate antagonism). The teratogenicity of VPA is mostly found at genetic and somatic levels, causing teratogenesis involving neural tube defects (NTDs), anencephaly, lumbosacral meningomyelocele, and leg dysfunction due to spina bifida aperta. Acute toxicity symptoms include hypo/hyperthermia, tachycardia, hepatic toxicity, hypotension, respiratory depression, coma, confusion, somnolence, dizziness, headaches and cerebral edema. Allopecia, anorexia, liver toxicity, renal failure, tremors and miosis are also associated with chronic toxicity. In case of acute oral exposure, administer charcoal as a slurry. Consider gastric lavage after ingestion of a potentially life-threatening amount of the compound if it can be performed soon after ingestion (generally within 1 hour). Protect the patient’s airway by placement in Trendelenburg position (head down) and on their left side (left lateral decubitus position) or by endotracheal intubation. Control any seizures first. Some experimental and clinical data suggest that early intravenous supplementation with l-carnitine could improve survival in severe VPA-induced hepatotoxicity. Carnitine administration has been shown to speed the decrease of ammonemia in patients with VPA-induced encephalopathy. As it does not appear to be harmful, l-carnitine is commonly recommended in severe VPA poisoning, especially in children (A15080). In case of inhalation, move patient to fresh air, monitor for respiratory distress. If the exposure occurred via eye contact, irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. Remove contaminated clothing and wash exposed area thoroughly with soap and water if the exposure occurred via dermal contact. (T36). 2009-07-05T02:58:24Z 2014-12-24T20:25:42Z http://en.wikipedia.org/wiki/Valproic_Acid C07185 125480176860188550237310609442 39867 Valproic acid DB00313 2PP true CCCC(CCC)C(O)=O C8H16O2 InChI=1S/C8H16O2/c1-3-5-7(6-4-2)8(9)10/h7H,3-6H2,1-2H3,(H,9,10) InChIKey=NIJJYAXOARWZEE-UHFFFAOYSA-N 144.2114 144.115029756 Exogenous Solid 2.75 HMDB01877 CHEMBL109 3009 <p>Daniel Aubert, Francis Blanc, Henri Desmolin, Michel Morre, Lucette Sindely, &#8220;Valproic acid preparations.&#8221; U.S. Patent US5017613, issued January, 1965.</p>