Mechanism of Action of Carbamazepine

Introduction

Carbamazepine is a classic antiepileptic drug (AED) and mood stabilizer. It is mainly used to treat partial and generalized tonic-clonic seizures, trigeminal neuralgia, and bipolar disorder. Its primary action involves blocking voltage-gated sodium channels, which stabilizes neuronal membranes and prevents repetitive firing.

It is frequently tested in pharmacology sections of USMLE, NCLEX, GPAT, and NEET-PG.

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Stepwise Mechanism of Action of Carbamazepine

1. Blockade of voltage-gated Na⁺ channels
   Carbamazepine binds to the inactivated state of voltage-gated sodium channels, prolonging their inactivation and preventing repetitive neuronal firing.
2. Reduction of high-frequency firing
   By inhibiting rapid firing of action potentials, carbamazepine reduces neuronal hyperexcitability, which is crucial in epilepsy control.
3. Inhibition of presynaptic neurotransmitter release
   It may reduce the presynaptic release of glutamate, contributing to its anticonvulsant and mood-stabilizing effects.
4. Secondary GABA enhancement (minor)
   Although not a primary action, it may enhance GABA-mediated inhibition indirectly in some regions.

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Pharmacokinetic Parameters of Carbamazepine

Parameter	Value
Bioavailability	70–80%
Half-life	25–65 hrs initially; 12–17 hrs (autoinduction)
Metabolism	Hepatic via CYP3A4
Autoinduction	Yes – induces its own metabolism
Excretion	Renal (after hepatic metabolism)
Therapeutic range	4–12 μg/mL

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Clinical Uses of Carbamazepine

• Partial seizures (focal onset)
• Generalized tonic-clonic seizures
• Trigeminal neuralgia (first-line)
• Bipolar disorder (alternative to lithium)
• Glossopharyngeal neuralgia
• Diabetic neuropathy (off-label)

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Adverse Effects of Carbamazepine

• Diplopia and ataxia
• Sedation
• SIADH – leads to hyponatremia
• Aplastic anemia and agranulocytosis
• Hepatotoxicity
• Stevens-Johnson Syndrome (SJS), especially in HLA-B*1502 positive individuals (Asians)
• Teratogenicity – causes neural tube defects
• Autoinduction – reduced drug levels over time

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Comparative Analysis: Carbamazepine vs Oxcarbazepine

Feature	Carbamazepine	Oxcarbazepine
Sodium channel block	Yes	Yes
Autoinduction	Present	Minimal
Hyponatremia risk	High	Higher than carbamazepine
Hepatotoxicity	Yes	Lower risk
Active metabolites	Carbamazepine-10,11-epoxide	Less active

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Practice MCQs

Q1. Carbamazepine acts by blocking:
a. Calcium channels
b. GABA-A receptors
c. Sodium channels ✅
d. Potassium channels

Q2. What is the genetic risk factor for SJS with carbamazepine?
a. HLA-A0201
b. HLA-B1502 ✅
c. HLA-DR4
d. HLA-B*0702

Q3. Which adverse effect requires CBC monitoring?
a. Ataxia
b. Hyponatremia
c. Agranulocytosis ✅
d. Hepatitis

Q4. Which condition is treated first-line with carbamazepine?
a. Bipolar depression
b. Trigeminal neuralgia ✅
c. Status epilepticus
d. Absence seizures

Q5. What happens to carbamazepine levels over time due to autoinduction?
a. Increase
b. Remain stable
c. Decrease ✅
d. Unpredictable

Q6. Carbamazepine is contraindicated in which seizure type?
a. Tonic-clonic
b. Myoclonic
c. Absence ✅
d. Focal

Q7. What is the mechanism of hyponatremia with carbamazepine?
a. Nephrogenic DI
b. Inhibition of aldosterone
c. SIADH ✅
d. Hyperkalemia

Q8. Carbamazepine is metabolized primarily by:
a. CYP2C19
b. CYP3A4 ✅
c. CYP1A2
d. UGT

Q9. Therapeutic plasma level of carbamazepine is:
a. 2–6 μg/mL
b. 4–12 μg/mL ✅
c. 12–18 μg/mL
d. 18–25 μg/mL

Q10. Which adverse effect is associated with Asian ancestry?
a. Agranulocytosis
b. Hepatotoxicity
c. Stevens-Johnson Syndrome ✅
d. Ataxia

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FAQs

Q1: Is carbamazepine used for absence seizures?
No. It can worsen absence seizures and should be avoided.

Q2: Why monitor sodium levels during therapy?
Carbamazepine can cause SIADH, leading to hyponatremia.

Q3: Can it be used in bipolar disorder?
Yes, as an alternative mood stabilizer when lithium is not tolerated.

Q4: What test should be done before starting in Asian populations?
HLA-B*1502 testing to avoid SJS/TEN.

Q5: Is it safe in pregnancy?
No. It’s teratogenic, associated with neural tube defects.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Sparsh Gupta – Review of Pharmacology
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK470284/