Dibenzazepine anticonvulsants are a subclass of tricyclic compounds derived structurally from imipramine and related tricyclic antidepressants, yet pharmacologically tailored for antiepileptic action. This class includes agents such as carbamazepine, oxcarbazepine, and eslicarbazepine acetate. These drugs are widely used in the management of various seizure disorders and neurologic conditions such as trigeminal neuralgia and bipolar disorder. They function primarily by modulating voltage-gated sodium channels, stabilizing hyperexcited neuronal membranes, and reducing synaptic transmission.
1. Chemical and Structural Characteristics
Dibenzazepines are tricyclic compounds consisting of:
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Two benzene rings fused to a seven-membered azepine ring
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Structural relation to tricyclic antidepressants, but differing in pharmacological profile
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Lipophilic, enabling blood-brain barrier penetration
Primary members:
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Carbamazepine
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Oxcarbazepine
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Eslicarbazepine acetate
2. Mechanism of Action
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Voltage-gated sodium channel blockade: These drugs stabilize inactivated sodium channels, thereby inhibiting repetitive neuronal firing.
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Inhibition of glutamate release: Secondary effect leading to decreased excitatory neurotransmission.
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Reduction of synaptic transmission: Inhibits rapid discharge associated with seizure activity.
Eslicarbazepine acetate and oxcarbazepine are keto-analogues of carbamazepine and are considered to offer improved tolerability profiles.
3. Approved Therapeutic Indications
| Condition | Drug(s) Involved |
|---|---|
| Focal (partial-onset) seizures | Carbamazepine, Oxcarbazepine, Eslicarbazepine |
| Generalized tonic-clonic seizures | Carbamazepine |
| Trigeminal neuralgia | Carbamazepine (first-line) |
| Bipolar disorder (manic episodes) | Carbamazepine (alternative to lithium/valproate) |
| Neuropathic pain | Off-label: Carbamazepine, Oxcarbazepine |
| Postherpetic neuralgia | Off-label: Carbamazepine |
| Alcohol withdrawal (limited use) | Carbamazepine (off-label) |
4. Drug Profiles
Carbamazepine
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Brand names: Tegretol, Carbatrol, Epitol
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Formulations: Tablets, chewable tablets, oral suspension, extended-release tablets
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Dosage: Initial 100–200 mg BID; titrated to 800–1,200 mg/day
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Half-life: 12–17 hours (autoinduction causes variation)
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Metabolism: Hepatic (CYP3A4), active metabolite carbamazepine-10,11-epoxide
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Therapeutic range: 4–12 mcg/mL (monitor levels)
Oxcarbazepine
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Brand names: Trileptal, Oxtellar XR
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Formulations: Tablets, oral suspension, extended-release tablets
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Dosage: 600–1,200 mg/day in divided doses
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Active metabolite: 10-monohydroxy derivative (MHD)
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No autoinduction; fewer drug interactions
Eslicarbazepine Acetate
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Brand names: Aptiom
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Formulation: Oral tablets (once daily dosing)
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Dosage: 400–1,200 mg once daily
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Less risk of hepatic enzyme induction; used as adjunctive or monotherapy for focal seizures
5. Adverse Effects
| Common Effects | Serious Effects |
|---|---|
| Dizziness, drowsiness | Aplastic anemia, agranulocytosis (carbamazepine) |
| Ataxia, diplopia | Stevens-Johnson syndrome (SJS)/TEN |
| Nausea, vomiting | Hepatotoxicity |
| Hyponatremia (esp. with oxcarbazepine/eslicarbazepine) | SIADH |
| Rash (dose-dependent or immunologic) | Suicidality risk (class effect of AEDs) |
| Cognitive slowing | Pancreatitis (rare) |
6. Contraindications
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Hypersensitivity to dibenzazepine derivatives or tricyclic compounds
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Bone marrow depression (esp. for carbamazepine)
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Use of MAO inhibitors within 14 days
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Positive HLA-B*1502 allele in patients of Asian descent due to high SJS risk
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Porphyria (carbamazepine is porphyrogenic)
7. Drug Interactions
Carbamazepine is a strong CYP3A4 inducer and induces other CYPs and UGT enzymes, leading to multiple interactions:
| Drug Class or Agent | Interaction Mechanism |
|---|---|
| Oral contraceptives | ↓ Effectiveness (↑ metabolism of estrogens) |
| Warfarin | ↓ Anticoagulant effect |
| Phenytoin, phenobarbital | Mutual induction, altered levels |
| Macrolide antibiotics (erythromycin) | ↑ Carbamazepine levels (CYP3A4 inhibition) |
| Grapefruit juice | ↑ Carbamazepine levels |
| Lithium | ↑ Neurotoxicity when used with carbamazepine |
| SSRIs (e.g., fluoxetine) | Potential ↑ toxicity, serotonin syndrome |
8. Therapeutic Drug Monitoring
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Carbamazepine: Routine monitoring required (target: 4–12 mcg/mL)
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Monitor CBC, LFTs, serum sodium, and renal function
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HLA-B*1502 screening in at-risk populations
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Periodic thyroid function tests recommended in long-term users
9. Use in Special Populations
Pediatrics:
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Approved for focal seizures (oxcarbazepine, eslicarbazepine)
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Monitor growth and development
Pregnancy:
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Category D (Carbamazepine): Teratogenic, associated with neural tube defects
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Folic acid supplementation is essential
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Consider alternatives or close monitoring
Elderly:
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Increased risk of hyponatremia and sedation
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Start at low dose; titrate slowly
Renal Impairment:
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Dosage adjustments needed for oxcarbazepine and eslicarbazepine
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Monitor sodium levels due to risk of SIADH
10. Comparative Notes
| Feature | Carbamazepine | Oxcarbazepine | Eslicarbazepine Acetate |
|---|---|---|---|
| Autoinduction | Yes | No | No |
| CYP Enzyme Induction | High | Moderate | Mild |
| Active Metabolite | Carbamazepine epoxide | MHD | S-licarbazepine (MHD) |
| Hyponatremia Risk | Moderate | High | Moderate |
| Frequency of Dosing | BID to TID | BID | QD |
| SJS/TEN Risk | Highest (HLA-B*1502) | Moderate | Low |
11. Clinical Guidelines and Use
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ILAE (International League Against Epilepsy): Carbamazepine and its analogues are first-line agents for focal seizures
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NICE (UK): Oxcarbazepine recommended as monotherapy in newly diagnosed partial seizures
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AAN (American Academy of Neurology): Endorses use for trigeminal neuralgia and bipolar disorder (carbamazepine)
12. Overdose and Toxicity
Carbamazepine overdose is serious and presents with:
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Nystagmus, ataxia, tremor
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Cardiac conduction delays (AV block)
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Coma, respiratory depression
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Treatment: Activated charcoal, supportive care, ECG monitoring
13. Summary Recommendations
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Preferred in focal epilepsy syndromes
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Avoid carbamazepine in Asian populations unless HLA screening done
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Monitor sodium regularly during treatment with oxcarbazepine or eslicarbazepine
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Evaluate for potential drug interactions, especially with CYP-metabolized drugs
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Consider patient comorbidities (e.g., liver disease, psychiatric conditions)
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