Valproic acid (Sodium Valproate)

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

Treatment:

  • Carnitine –ameliorate mitochondrial enzyme deficiency.
  • Intake during pregnancy: 
  • Neural tube defects in offspring 
Other adverse effects:
  • 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.
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