Valproate

Breast Feeding; Lactation; Milk, Human; Anticonvulsants; Antimanic Agents; GABA Agents

Breast Feeding; Lactation; Milk, Human; Anticonvulsants; Antimanic Agents; GABA Agents

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).

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.

Prospective studies suggest that 5% to 10% of persons develop ALT elevations during long term valproate therapy, but these abnormalities are usually asymptomatic and can resolve even with continuation of drug. Unlike phenytoin and carbamazepine, valproate does not induce elevations in serum GGT levels. More importantly and not uncommonly, valproate can cause several forms of clinically apparent hepatotoxicity. Indeed, more than 100 fatal cases of acute or chronic liver injury due to valproate have been reported in the literature. Three clinically distinguishable forms of hepatotoxicity (besides simple aminotransferase elevations) can occur with valproate.

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).

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.

◉ Summary of Use during Lactation

◉ Summary of Use during Lactation

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).

Drugs used to prevent SEIZURES or reduce their severity.

Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Substances used for their pharmacological actions on GABAergic systems. GABAergic agents include agonists, antagonists, degradation or uptake inhibitors, depleters, precursors, and modulators of receptor function.

Agents that are used to treat bipolar disorders or mania associated with other affective disorders.

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).