Valproic acid (Sodium Valproate)

VALPROIC ACID (SODIUM VALPROATE)

• Broad spectrum anti-convulsant

Chemical Structure:

• Branched aliphatic carboxylic acid.

Mechanism of action:

• Frequency-dependent prolongation of Na+ channel inactivation (Phenytoin-like).
• Attentuation of Ca2+ mediated transient current (Ethosuximide-like action).
• Augmented release of inhibitory neurotransmitter GABA either by, 
• Inhibiting degradation (Blocking GABA-transaminase)
• Increasing synthesis.
• Increased GABA levels in blood.

Pharmacokinetics: 

• Oral absorption 
• 90% protein bound
• Metabolism in liver.
• Oxidative & glucuronide conjugation
• Urinary excretion
• Plasma t 1/2 – 10 to 15 hours.
• Yet long-lasting anti-convulsant effects

Indications: 

• Highly effective and DOC: 
• Absence seizure
• Myoclonic and atonic seizures

Alternative/adjuvant drug of choice: 

• Generalised Tonic-Clonic Seizure
• Simple & Complex Partial Seizure
• Mania & Bipolar disease – Lithium alternative

Interactions: 

With Phenytoin:

• Increase plasma levels of phenobarbitone
• Displacing Phenytoin from protein-binding site, 
• Inhibiting its metabolism
• Resulting in “Phenytoin Toxicity”

Effects of concurrent usage:

• Mutual induction of metabolism
• Carbamazepine
• Concurrent administration
• Clonazepam contra-indicated 
• Risk of absence seizures
• Fetal Abnormalities

Adverse effects:

Hepatotoxicity:

• Fulminant hepatitis.
• Rare yet serious effect.
• Asymptomatic rise in serum transaminase.
• Only in children (Mostly below 3 years).

Risk increased in:

• Known hepatic condition
• Intake of hepatotoxic drug & interaction with another anti-convulsant drug.
• Mitochondrial enzyme deficiency
• Metabolite “4-pantenoic acid” – causes hepatotoxicity

• Thrombocytopenia 
• Rashes 
• Alopecia 
• Curling of hair
• Increased blood ammonia 

Dose-related toxicity: Ataxia, drowsiness, vomiting & anorexia

Exam Question

VALPROIC ACID (SODIUM VALPROATE)

Mechanism of action:

• Augmented release of inhibitory neurotransmitter GABA,
• Increased GABA levels in blood.

Highly effective and DOC: 

• Absence seizure
• Myoclonic and atonic seizures

Interactions:

Effects of concurrent usage:

• Mutual induction of metabolism – with Carbamazepine
• Administration with clonazepam contra-indicated

Adverse effects:

• Hepatotoxicity (Fulminant hepatitis):
• Asymptomatic rise in serum transaminase.
• Metabolite “4-pentanoic acid” – causes hepatotoxicity

Treatment:

• Carnitine – ameliorate mitochondrial enzyme deficiency

Intake during pregnancy: 

• Neural tube defects in offspring.