Usage
Valproic acid is an anticonvulsant and mood-stabilizing drug prescribed for various conditions:
- Epilepsy: Management of various seizure types, including absence seizures (petit mal), generalized tonic-clonic seizures (grand mal), and partial seizures. It’s used both as monotherapy and adjunctive therapy.
- Bipolar Disorder: Treatment of acute manic episodes and prevention of recurrent episodes.
- Migraine: Prevention of migraine headaches (prophylaxis).
Pharmacological Classification: Anticonvulsant, Mood Stabilizer
Mechanism of Action: The precise mechanism isn’t fully understood, but it’s believed to involve:
- Increased levels of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the brain.
- Modulation of voltage-gated sodium and calcium channels, affecting neuronal excitability.
- Possible effects on other neurotransmitter systems.
Alternate Names
- Sodium Valproate
- Valproate semisodium
- Divalproex sodium
Brand Names: Depakene, Depakote, Stavzor, Epilim, Dyzantil
How It Works
Pharmacodynamics: Valproic acid enhances GABAergic inhibition, reduces neuronal excitability by affecting ion channels, and potentially influences other neurotransmitter pathways, leading to anticonvulsant and mood-stabilizing effects.
Pharmacokinetics:
- Absorption: Well-absorbed orally.
- Metabolism: Primarily hepatic, via glucuronidation and mitochondrial beta-oxidation. CYP2C9 involvement is minor.
- Elimination: Mostly renal excretion, with some biliary elimination.
Mode of Action (Cellular/Molecular):
- Increases GABA levels by inhibiting GABA transaminase, the enzyme that breaks down GABA.
- Modulates voltage-gated sodium channels, reducing their ability to open and propagate electrical signals in neurons.
- May affect potassium channels and other neurotransmitter systems (e.g., dopamine, serotonin).
Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation:
- Inhibits GABA transaminase.
- Modulates voltage-gated sodium and possibly potassium channels.
Elimination Pathways:
- Primarily renal excretion of metabolites.
- Some biliary elimination.
Dosage
Standard Dosage
Adults:
- Epilepsy: Starting dose 10-15 mg/kg/day, increased weekly by 5-10 mg/kg/day until seizure control or maximum of 60 mg/kg/day. Divided doses if total daily dose exceeds 250 mg.
- Mania: Starting dose 750 mg/day (divided), or 25 mg/kg/day (extended-release). Increase rapidly as tolerated to achieve the lowest effective dose or target plasma concentration. Maximum 60 mg/kg/day.
- Migraine Prophylaxis: Starting dose 250 mg twice daily, increasing as needed up to a maximum of 1000 mg/day.
Children:
- Epilepsy: Starting dose 10-15 mg/kg/day, increased weekly by 5-10 mg/kg/day until seizure control or maximum of 60 mg/kg/day. Divided doses if total daily dose exceeds 250 mg.
- Children <20kg: Starting dose 20 mg/kg/day, divided into two doses
- Children >20kg: Starting dose 400 mg/day, divided into two doses, and increasing the dose gradually to target
- Pediatric Safety: Monitor liver function, especially in children under 2 years old, due to increased risk of hepatotoxicity.
Special Cases:
- Elderly Patients: Start with lower doses and titrate slowly.
- Patients with Renal Impairment: No specific dose adjustments are usually needed.
- Patients with Hepatic Dysfunction: Contraindicated in severe hepatic impairment. Use with caution in mild to moderate impairment with close monitoring.
- Patients with Comorbid Conditions: Consider individual patient factors (e.g., diabetes, cardiovascular disease) when adjusting the dosage.
Clinical Use Cases
Valproic acid’s standard oral or IV formulations are used in various clinical settings, including the ICU, but there are no specific dosage adjustments for procedures like intubation, surgery, or mechanical ventilation. Dosage is adjusted based on the patient’s indication (epilepsy, bipolar disorder) and individual response. For acute seizure management (e.g., status epilepticus), IV valproate sodium can be administered.
Dosage Adjustments:
Dose adjustments might be needed based on:
- Renal or hepatic dysfunction
- Concomitant medications (especially enzyme-inducing drugs)
- Therapeutic drug monitoring (TDM) for optimal serum concentrations
Side Effects
Common Side Effects:
- Nausea, vomiting, diarrhea
- Tremor
- Drowsiness, dizziness
- Hair loss
- Weight changes
Rare but Serious Side Effects:
- Hepatotoxicity (especially in children under 2)
- Pancreatitis
- Thrombocytopenia
- Hyperammonemia
- Encephalopathy
- Suicidal thoughts
Long-Term Effects:
- Polycystic ovary syndrome (PCOS)
- Osteoporosis
Adverse Drug Reactions (ADR):
- Drug-induced liver injury
- Severe thrombocytopenia
- Hyperammonemic encephalopathy
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
Contraindications
- Known or suspected mitochondrial disorders (e.g., Alpers-Huttenlocher syndrome)
- Hepatic disease or significant hepatic dysfunction
- Urea cycle disorders
- Hypersensitivity to valproic acid
Drug Interactions
- Enzyme-inducing antiepileptics: (e.g., carbamazepine, phenytoin, phenobarbital) decrease valproic acid levels.
- Enzyme-inhibiting drugs: (e.g., cimetidine, erythromycin) may increase valproic acid levels.
- Other: Warfarin, aspirin, lamotrigine, felbamate, and many others can interact with valproic acid.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: D/X. Valproic acid is contraindicated during pregnancy due to the high risk of birth defects (e.g., neural tube defects), developmental delays, and neurodevelopmental disorders (e.g., autism).
- Breastfeeding: Valproic acid is excreted in breast milk, but levels are generally low. Breastfeeding can be considered if benefits outweigh risks, and infant monitoring is essential. The Pregnancy Prevention Programme remains highly relevant for breastfeeding mothers.
Drug Profile Summary
- Mechanism of Action: Increases GABA levels, modulates ion channels.
- Side Effects: Nausea, tremor, drowsiness, hepatotoxicity, pancreatitis.
- Contraindications: Mitochondrial disorders, hepatic disease, urea cycle disorders.
- Drug Interactions: Enzyme-inducing drugs, warfarin, lamotrigine.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy, caution in breastfeeding.
- Dosage: Varies by indication and age; individualized titration.
- Monitoring Parameters: Liver function tests, complete blood count, serum valproate levels.
Popular Combinations
Valproic acid may be used in combination with other antiepileptic drugs when monotherapy is insufficient, although close monitoring for drug interactions is crucial.
Precautions
- General Precautions: Monitor liver function, especially in children under 2. Assess for suicidal ideation.
- Specific Populations: Avoid in pregnancy. Caution in breastfeeding and patients with hepatic/renal impairment.
- Lifestyle Considerations: May cause drowsiness, affecting driving and operating machinery.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Valproic Acid?
A: Dosage depends on the indication and patient-specific factors. Standard adult starting doses are 10-15 mg/kg/day for epilepsy, 750 mg/day for mania, and 250 mg twice daily for migraine prophylaxis. Pediatric dosing is also weight-based, starting at 10-15 mg/kg/day for epilepsy. Dosages should be titrated upwards based on individual response and tolerability. For children weighing under 20kg a starting dose of 20 mg/kg/day can be considered, while for children over 20kg the starting dose would be 400 mg/day.
Q2: What are the most serious side effects of Valproic Acid?
A: Hepatotoxicity (especially in children under 2), pancreatitis, blood disorders (e.g., thrombocytopenia, leukopenia), hyperammonemia, encephalopathy, and suicidal thoughts.
Q3: Can Valproic Acid be used during pregnancy?
A: No, valproic acid is contraindicated during pregnancy due to the risk of birth defects and developmental problems.
Q4: How does Valproic Acid interact with other antiepileptic drugs?
A: It can interact with enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin), decreasing its own levels. Conversely, it can increase the levels of some other antiepileptics, such as lamotrigine. Close monitoring and dose adjustments are important when combining valproic acid with other anticonvulsants.
Q5: What are the common side effects patients should be aware of?
A: Nausea, vomiting, tremor, hair loss, weight gain, drowsiness, and dizziness are common side effects. Patients should report any unusual or bothersome effects to their doctor.
Q6: Is Valproic Acid safe for breastfeeding mothers?
A: Valproic acid does pass into breast milk. Though usually present in low amounts, the decision to breastfeed while taking valproic acid should be made in consultation with a doctor, weighing the benefits against the potential risks to the infant. Careful infant monitoring is crucial. The Pregnancy Prevention Programme rules remain applicable.
A: Primarily in the liver, mainly through glucuronidation and beta-oxidation, with minimal CYP450 enzyme involvement.
Q8: Should Valproic Acid dosage be adjusted for patients with kidney problems?
A: Usually, no dosage adjustment is necessary for patients with renal impairment. However, individual patient assessment is always recommended.
Q9: Can Valproic Acid be used for nerve pain?
A: While it is primarily used for epilepsy, bipolar disorder, and migraine prophylaxis, valproic acid is occasionally used off-label for neuropathic pain, though its efficacy for this purpose is not definitively established.
Q10: Can Valproic Acid be stopped abruptly?
A: No, discontinuing valproic acid abruptly can lead to withdrawal symptoms or increased seizure frequency. Dosage should be gradually tapered down under medical supervision.
