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Valproic Acid

Valproic acid is a derivative of carboxylic acid.

Mechanism of action
  1. Drug acts by inhibiting enzymes responsible for breakdown of GABA. These are:
  • GABA transaminases
  • Succinic semi aldehyde dehydrogenase

When inhibited, increase in GABA occurs, epilepsy is reduced.

  1. Some effects like phenytoin are produced, sodium channel blockage contributes to antiepileptic effects.
  2. Act by inhibiting calcium channels, mainly T channels are blocked, which are present in thalamus. They are responsible for generation of specific pattern of petit mal epilepsy (absence seizures), thus a decrease in seizures is observed.

Effective both in grand mal and petit mal epilepsy.

Pharmacokinetics
  1. Well absorbed after oral administration
  2. Peak plasma concentration occurs after 1-4 hours, food can interfere with absorption
  3. Plasma protein binding is in range of 90%
  4. Concentration in CSF is equal to that in plasma after oral administration.
  5. About 3% of drug is excreted unchanged in urine, rest is metabolized in liver.
  6. Some metabolites are active.
  7. Has a half life of 15 hours.
Uses
  1. Effective in grand mal and petit mal epilepsy, having a wider range.
  2. Drug of choice in myoclonic seizures
  3. Treatment of grand mal epilepsy
  4. Treatment of petit mal epilepsy
  5. Mixed type of epilepsy
Adverse Effects
1. GIT
  • Anorexia
  • Vomiting
  • nausea
  • Drowsiness
  • Vertigo
  • tremors
2. CNS

3. Allergic reactions (skin rash, urticarial)
4. Weight gain on prolonged administration, due to increase in apetite
5. Increase bleeding time due to thrombocytopenia and inhibition of platelet aggregation.
6. Hair loss on prolonged administration
7. Pancreatitis
Increased ammonia levels in blood

8. Hepatotoxicity/ Valproate’s Idiosyncratic hepatotoxicity

Most important. It is metabolized in liver to active metabolite, idiosyncratic reaction occurs esp. in:

  1. Children under 2 years of age.
  2. Patients taking multiple drugs.

Sometimes may lead to hepatic failure. Occurs after 2-12 weeks of administration. Incidence is more when in combination with other antiepileptics, enzyme inducers due to formation of toxic metabolites.

Remedy

  1. Careful monitoring of liver functions
  2. Oral or I/V L-carnitine once toxicity has occurred
  3. Withdrawal of drug.
10. Spina bifida

If given during pregnancy, has teratogenic effect, spina bifida may occur in fetus.

Interactions of drug

Drug in low doses decreases the metabolism of itself and other epileptics like phenobarbitone, phenytoin and carbamazepine, when combined.

Dose

Start at low dose. Increase gradually, range being 1000-3000 mg.

This drug is much safer than phenytoin sodium.

Start at low dose of 15 mg/kg body weight, increase dose until seizures are controlled or toxic effects appear.

Plasma concentration is monitored and maintained between 30-100 µg/ml.

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