Carbamazepine - BioPharma Notes

Carbamazepine is a tricyclic (iminostilbene) compound with structural resemblance to antidepressant, imipramine and is a popular anti-epileptic drug.
It was discovered in 1953 and came into medical use in 1962. Carbamazepine is included in World Health Organization’s List of Essential Medicines and is available both as brand and generic medicine.

Indications of carbamazepine

In grandmal and focal seizures. Used alone or in combination with other drugs.
Trigeminal neuralgia.
In deafferentation pain in diabetic neuropathy, cancer and multiple sclerosis.
In the treatment of alcohol withdrawal syndrome.
As an alternative to lithium carbonate in management of manic-depressive psychosis.
In diabetes insipidus of pituitary origin.
Used as adjunct in treatment of drug-resistant schizophrenia.

It blocks sodium channels and inhibits the generation of repetitive action potentials in the epileptic focus and hence, prevent the spread of seizures.
Its mechanism of action is like phenytoin. It causes less cognitive impairment than phenytoin.

Absorption takes place slowly and erratically after oral administration. The overall bioavailability is around 90%. Peak plasma concentration occurs 4-8 hours after oral administration. The drug distribution takes place all over the body. Around 75% of drug binds to plasma proteins. It can cross CSF (Cerebrospinal Fluid).
Metabolism takes place in liver and active metabolite formed is 10,11- epoxide. It is active as carbamazepine and its concentration in plasma and brain may reach 50% of carbamazepine. It is further metabolized into inactive compounds. Carbamazepine is also inactivated by hydroxylation and conjugation.
It induces CYP2C, CYP3A4 and UGT (UDP glucuronosyltransferase) and enhances metabolism of drugs degraded by these enzymes. It also induces its own metabolism leading to lower total carbamazepine blood concentration at higher dose. The plasma half-life is 24-36 hours which may decrease to around 12 hours due to high or chronic dosing.
Excretion takes place vi urinary route.

Acute intoxication can cause coma, respiratory depression, stupor and hyperirritability. The common side effects of long-term therapy are nausea, vomiting, dizziness, drowsiness and problems with walking and coordination. Diplopia and blurred vision can make driving dangerous.
The serious side effects include severe skin reaction (skin rashes, hives, swelling or blister), low blood cell count (characterized by red or purple spots on different body parts, intense fatigue, bruising), agranulocytosis, liver problems, suicidal thoughts and low sodium level in blood.
Serious adverse events like Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms. It has a black box warning for severe skin reaction and low blood cell count.
It is a minor teratogen.
Sudden stoppage of drug administration may increase risk of seizures.

Drugs like phenytoin, phenobarbital and valproic acid can increase metabolism of carbamazepine. Its metabolism can be inhibited by drugs like diltiazem, erythromycin, cimetidine, fluoxetine and isoniazid.
It induces various CYP enzymes and induce metabolism of drugs like lamotrigine, lorazepam, divalproex, phenytoin, oral contraceptive, warfarin and clobazam.
Concurrent administration with MAOI (Mono amine Oxidase Inhibitors) can cause serious adverse events so MAOIs are discontinued for minimum of 14 days before carbamazepine administration.

Contraindicated in patients with hypersensitivity to carbamazepine or tri-cyclic antidepressants.
Contraindicated in patients with history of bone marrow depression.
Avoided in pregnancy and lactation.
Used cautiously in patients with history of adverse hematologic reaction to any drug (increased risk of severe hematologic toxicity), glaucoma or increased IOP.
Used cautiously in patients with history of cardiac, hepatic or renal damage.
Should not be used in absence seizures.

It is available as 100, 200 and 400 mg oral tablets and as 400 mg-controlled release (CR) tablets.

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