Carbamazepine

Mechanism

Chemical and Commercial Profile

Common trade names: Tegretol, Carbatrol, Carbamazepine Normon.
Group: Iminostilbenic antiepileptic (dibenzazepine derivative).

Mechanism of Action

It exerts its membrane stabilizing action by selectively and voltage-dependent blocking of open and inactive sodium channels. This depresses the propagation of synchronous nociceptive and epileptogenic impulses. In addition, it presents a secondary modulation on adenosine receptors.

Pharmacokinetics

Pharmacokinetics

• Absorption: Slow but almost complete orally, with a C_max that is reached after 4-8 hours. Extended release formulations avoid toxicity peaks.
• Distribution: Moderate lipophilia; binding to plasma proteins of 75%. The volume of distribution is 0.8-1.4 L/kg. It easily crosses the blood-brain barrier and the placenta.
• Metabolism: Hepatic oxidative catalyzed mainly by the isoenzyme CYP3A4. It generates the clinically relevant active metabolite carbamazepine-10,11-epoxide (which presents intrinsic anticonvulsant activity and toxicity equivalent to the parent compound).
• Excretion: Renal (70%) mainly in the form of inactive hydrolyzed epoxide-diol metabolites.
• Half-life (t_1/2):

  The Clinical Process of Self-induction

  Carbamazepine is a potent inducer of its own metabolism by induction of the transcriptional operon of the CYP3A4 isoenzyme. After an initial dose, the half-life is 36 hours; However, after 2-4 weeks of continuous daily use, enzyme induction is complete and the half-life decreases drastically to 12-16 hours. This phenomenon requires progressive dosing and reassessment of plasma levels after titration.

Indicators and dose

Indications

• Focal seizures (motor and hypomotor).
• Bilateral tonic-clonic seizures.
• Treatment of choice for idiopathic and secondary Trigeminal Neuralgia.
• Second-line treatment of manic phases of bipolar disorder in patients refractory to lithium.

Dosage and Settings

• Start of Schedule (Titrated): 100-200 mg once or twice a day.
• Increments: Increase 100-200 mg weekly progressively.
• Usual therapeutic range: 400-1200 mg/day divided into two or three doses.
• Target plasma range: 4-12 mcg/mL trough concentration.
• Renal Failure: No special dose adjustments are required, but strict control of serum electrolytes is recommended due to the increased risk of hyponatremia.
• Liver Failure: Decrease by 25-50% in moderate liver failure (Child-Pugh B); contraindicated in severe stages (Child-Pugh C) due to the possibility of accumulation of the active metabolite 10,11-epoxide.

Security

Contraindications

• Pre-existing atrioventricular block.
• History of bone marrow depression (marrow aplasia, severe leukopenia).
• Concurrent or recent use (less than 14 days) of monoamine oxidase inhibitors (MAOIs).
• Typical or atypical absence seizures and myoclonic seizures (risk of symptomatic exacerbation).

Adverse Effects (ADR)

Genetic Alert · HLA-B*1502 allele

Patients of Asian origin (particularly Han Chinese, Thai and Filipino) who carry the human leukocyte antigen allele HLA-B*1502 are at extremely high risk of developing life-threatening dermatological reactions, such as Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). It is mandatory to perform genetic screening prior to starting treatment in this population. For Caucasian patients, the HLA-A*3101 allele has been associated with generalized hypersensitivity induced by this drug.

• Neurological: Diplopia (transient double vision after ingestion), dizziness, marked motor ataxia, headache and daytime sedation.
• Endocrine / Electrolytic: Severe dilutional hyponatremia and SIADH (induced by sensitization of the renal collecting ducts to antidiuretic hormone). It occurs in up to 10% of patients and causes mental confusion and muscle cramps.
• Hematological: Transient benign leukopenia (very common, does not usually require suspension), severe idiopathic aplastic anemia (exceptional but lethal, rate of ~2 per million patients exposed per year).

Clinical Interactions

• Potent CYP inducer: Markedly reduces the concentration of contraceptives, clobazam, valproate, lamotrigine and voriconazole.
• Drugs that inhibit CYP3A4: Grapefruit juice, erythromycin, clarithromycin, diltiazem, fluoxetine and ketoconazole increase carbamazepine levels exponentially, inducing acute toxicity characterized by nystagmus, ataxia, extreme drowsiness and arrhythmias.

Pregnancy and Breastfeeding

FDA Category: D. It is associated with an increase in the rate of first trimester structural fetal malformations, mainly neural tube defects (spina bifida) in 1% of exposed pregnancies, orofacial cleft and cardiovascular anomalies. It is mandatory to associate folic acid supplementation at a dose of 5 mg/day before conception. Breastfeeding: Compatible with caution. It passes into breast milk, reaching a milk/plasma ratio of 0.4. Monitor neonatal cholestasis or jaundice.