Carbamazepine
1. Drug Name
Generic Name: Carbamazepine
Brand Names: Tegretol, Carbatrol, Equetro
2. Drug Classification
Class: Anticonvulsant
Subclass: Iminostilbene derivative
3. Mechanism of Action
Carbamazepine stabilizes hyperexcited neural membranes by inhibiting voltage-gated sodium channels.
It limits the repetitive firing of action potentials, thereby reducing seizure propagation and controlling abnormal neural activity.
Additionally, it has GABA receptor effects that may contribute to its anticonvulsant action and antidepressant-like properties, which are beneficial in mood disorders.
4. Pharmacokinetics
Absorption:
Bioavailability: Approximately 70–80% after oral administration.
Tmax: Peaks within 4–8 hours (extended-release forms may have a delayed Tmax).
Distribution:
Volume of Distribution (Vd): Roughly 0.8–1.2 L/kg.
Protein Binding: Approximately 75–80% bound to plasma proteins.
Metabolism:
Primary Site: Extensively metabolized in the liver, primarily via CYP3A4 to an active metabolite, carbamazepine-10,11-epoxide.
Autoinduction: Induces its own metabolism, requiring dose adjustments over time.
Excretion:
Half-life (t½): Initially 25–65 hours, but reduces to 12–17 hours with chronic use due to autoinduction.
Routes: Primarily excreted in the urine (70%) and some in the feces.
Special Considerations:
Renal/Hepatic Impairment: Dose adjustment required due to altered metabolism or excretion.
Elderly and Children: May have altered pharmacokinetics, requiring individualized dosing.
5. Indications
Primary Indications:
Epilepsy: Effective for partial seizures, generalized tonic-clonic seizures.
Trigeminal Neuralgia: First-line treatment for idiopathic trigeminal neuralgia.
Off-label Uses:
Bipolar Disorder: Particularly for acute manic and mixed episodes.
Neuropathic Pain: Management of certain neuropathic pain syndromes.
Special Populations:
Commonly used in adults with epilepsy; less favorable for use in children due to adverse effect profile.
6. Dosage and Administration
Adult Dosing:
Epilepsy: Start with 200 mg twice daily, increase gradually by 200 mg/day to reach typical maintenance doses of 800–1200 mg/day.
Trigeminal Neuralgia: Start with 100 mg twice daily, titrate to effective doses (commonly 400–800 mg/day).
Pediatric Dosing:
Epilepsy: Initial dose of 5 mg/kg/day, divided into 2–4 doses; maintenance dose ranges from 10–20 mg/kg/day.
Dose Adjustments:
Renal or Hepatic Impairment: Lower doses recommended, and plasma levels should be monitored.
Autoinduction Consideration: Doses may need to be increased after 2–4 weeks due to autoinduction of metabolism.
7. Contraindications
Absolute Contraindications:
Hypersensitivity to carbamazepine or tricyclic antidepressants.
Bone Marrow Depression: Avoid in patients with known bone marrow suppression.
Relative Contraindications:
Liver Disease: Use with caution due to impaired metabolism.
Porphyria: May exacerbate porphyria.
8. Warnings and Precautions
Black Box Warnings:
Aplastic Anemia and Agranulocytosis: Increased risk of potentially fatal blood dyscrasias; baseline and periodic complete blood counts (CBC) are essential.
Serious Skin Reactions: Increased risk of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), especially in patients of Asian descent with HLA-B*1502 allele.
Other Warnings:
Hyponatremia and SIADH: Risk of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Liver Toxicity: Monitor liver enzymes, especially with preexisting liver disease.
Pregnancy: Category D; may cause teratogenic effects, such as neural tube defects.
9. Adverse Effects
Common Adverse Effects:
Dizziness, drowsiness, nausea, vomiting, ataxia, and blurred vision.
Hyponatremia: Particularly common in elderly patients.
Less Common but Clinically Significant:
Hematologic Effects: Leukopenia, thrombocytopenia, aplastic anemia.
Dermatologic Reactions: Rash, SJS, and TEN.
Rare/Serious:
Hepatotoxicity: Elevated liver enzymes and rarely, severe liver injury.
Pancreatitis: Rare cases reported with long-term use.
10. Drug Interactions
Inducer of CYP450: Strong inducer of CYP3A4, leading to reduced efficacy of drugs metabolized by this enzyme, including oral contraceptives, antipsychotics, and antivirals.
Other Antiepileptics: Interacts with phenytoin, valproic acid, and others, leading to altered plasma levels.
Food and Alcohol: Grapefruit juice may increase carbamazepine levels; alcohol can increase sedation and CNS depression.
Other: May interfere with certain lab tests (e.g., thyroid function tests).
11. Clinical Pharmacology
Pharmacodynamics: Carbamazepine stabilizes neuronal membranes and limits repetitive firing, primarily through its action on sodium channels.
Therapeutic Range: Optimal plasma levels for seizure control typically range from 4–12 μg/mL.
12. Special Populations
Pregnancy: Category D due to teratogenic risk (e.g., spina bifida); benefits should outweigh risks.
Lactation: Excreted in breast milk; use with caution if breastfeeding.
Geriatrics: May require lower doses due to increased sensitivity to adverse effects, especially hyponatremia.
Renal/Hepatic Impairment: Dose reduction and close monitoring are recommended in liver and kidney impairment.
13. Therapeutic Uses
First-Line: Effective for partial and generalized tonic-clonic seizures.
Second-Line: Sometimes used for neuropathic pain syndromes and bipolar disorder as an alternative to lithium or valproic acid.
14. Monitoring and Follow-Up
Blood Levels: Monitor carbamazepine levels periodically to maintain therapeutic range.
Hematologic Monitoring: Regular CBCs due to risk of blood dyscrasias.
Liver Function Tests: Baseline and periodic liver function monitoring.
Electrolytes: Monitor serum sodium for hyponatremia, especially in elderly patients.
15. Overdose Management
Symptoms of Overdose: Nystagmus, ataxia, drowsiness, tremors, seizures, and in severe cases, respiratory depression or coma.
Treatment:
Supportive care including airway management and gastric lavage if ingestion is recent.
Activated charcoal may be effective in early overdose.
Hemodialysis may be considered in life-threatening cases, although effectiveness is variable.
16. Patient Counseling Information
Key Points:
Take carbamazepine consistently as prescribed, either with or without food.
Report any signs of unusual bleeding, rash, or bruising immediately.
Avoid grapefruit juice, as it can alter carbamazepine levels.
Signs to Watch For:
Skin rash or allergic reactions which may indicate SJS or TEN.
Unusual fatigue or bleeding, which could signal blood dyscrasias.
Dizziness or visual disturbances, especially at therapy initiation or dose adjustment.