Valproic Acid

BRAND NAMES:

Depakene – Depakena is available in soft gelatin capsules of 250 mg Valproic acid and in the form of an oral solution of 250 mg valproic acid.

 Epival – Epival contains sodium valproate 200 mg used in treating conditions such as epilepsy and bipolar disorders. 

MECHANISM OF ACTION:

Valproic acid is a medication with diverse mechanisms of action.

Enhancement of GABA Synthesis: It improves GABA synthesis by enhancing the expression and activity of glumatic acid decarboxylase, an enzyme that converts glutamate, the brain's principal excitatory neurotransmitter, into GABA. The procedure also adds to higher GABA levels and activity.GABA is synthesized from alpha-ketoglutarate using the tricarboxylic acid cycle and metabolized to succinate semialdehyde. This intermediate is subsequently converted to succinate by GABA transaminase and succinate semialdehyde dehydrogenase. The study found valproic acid inhibits GABA transaminase and succinate semialdehyde dehydrogenase, increasing GABA levels by decreasing breakdown.

Inhibition of voltage-gated sodium channels: Valproic acid prevents sodium ions from entering neurons, causing lower excitability and firing rate. This prevents the development and propagation of aberrant electrical impulses that cause seizures. 

PHARMACOKINETICS:

Absorption: Valproic acid's bioavailability ranges between 81% and 89%, depending on the medication formulation. Immediate-release tablets attain their maximal plasma concentration in 1 to 4 hours but delayed or extended-release tablets take 4 to 17 hours. Food enhances valproic acid absorption, particularly when we consume high-fat meals. Depending on this, bioavailability can increase by up to 35% and the time required to achieve peak concentration by up to 4 hours.

Distribution: The valproic acid binding rate is approximately 90%. The valproic acid distribution volume is low ranging from 0.1 to 0.4 L/Kg.

Metabolism: It is mostly metabolised in the liver by many routes, including glucuronidation, oxidation, and beta-oxidation, as well as conjugation with carnitine or glycine.

Excretion: The drug is mostly excreted through the kidneys, involving the excretion of its metabolites through urine. 30 % to 50% of the administered dose is excreted through urine.

PHARMACODYNAMICS: 

Valproic acid acts on Gamma amino butyrate levels in the brain, blocks voltage-gated ion channels, and also acts as an HDAC inhibitor.

DOSAGE AND ADMINISTRATION:

Valproic acid is available in the form of tablets, capsules, and sprinkles and is also administrated through the intravenous route

The tablets are available in the form of delayed-release formulations with strengths of 25 mg, 250 mg, and 500 mg and extended-release tablets with strengths of 250 mg and 500 mg. The injectable is available in the strengths of 100 mg/ml.

• For adult use in seizures, the starting dosage for the treatment is 5 mg/kg/d. The maximum dosage is 60 mg/kg/d and the doses should not exceed more than 250 mg daily.
• For the treatment of mania, the initial dose starts from 250 to 500 mg which can be taken thrice a day.
• For migraines, the recommended initial dose is 250 to 500 mg taken twice daily. The extended-release of tablets can be initiated with 500 mg once daily.

CONTRAINDICATIONS:

Valproic acid is contraindicated in patients with hypersensitivity, Mitochondrial disorders, and hepatic impairment.

DRUG INTERACTIONS:

Valproic acid interacts with some drugs and causes some severe side effects. So it is important to discuss with the doctor before taking valproic acid. Below are some medications which interact with valproic acid.

• Antidepressants – Amitriptyline, nortriptyline, phenelzine
• Seizures – Ethosuximide, lamotrigine, rufinamide, topiramate
• Antibiotics – Impipenem, orlistat, mefloquine
• Drowsiness medicines – Marijuana
• Antihistamines – Cetirizine, Diphenhydramine
• Anxiety medicines – Alprazolam, zolpidem
• Muscle relaxants – Carisoprodol, cyclobenzaprine

FOOD INTERACTIONS:

Avoid alcohol consumption it may increase dizziness and drowsiness.

ADVERSE EFFECTS:

• Nausea
• Irregular periods
• Tremors
• Blurred vision
• Diarrhea
• Indigestion
• Liver failure
• Pancreatitis
• Respiratory infection
• Hemorrhage
• Anemia
• Drowsiness
• Arthrosis
• Walking or coordination
• Dyspnea
• Myalgia
• Arthralgia

TOXICITY:

Overdose of medication leads to cause toxic effects.

• Multiorgan failure
• Hyperammonemia
• Central nervous system depression
• Metabolic acidosis
• Hypoglycemia
• Hypernatremia
• Pancreatitis.