Clinically Significant Carbamazepine Drug Interactions: An Overview

Summary: Knowledge of the principles of drug action and distribution contributes to an understanding of the occurrence of drug interactions. The pharmacologic action of most drugs is postulated to occur by the formation of a drug‐receptor complex at the site of action that is capable of altering the physiologic response of the target system. The therapeutic response observed depends on the sum of the numerous factors that can affect the disposition pattern of a drug. In an individual, the response to a given drug dose remains relatively constant, but in a large population, a fixed dose can produce a range of plasma concentrations and therefore varied clinical responses. For most drugs, there is a linear relationship between the total dose and the plasma concentration achieved at steady state. Saturation, or zero‐order, kinetics accounts for nonlinear increases in drug concentration with dosage increase. Drug‐drug interactions with carbamazepine include several types. (1) Autoinduction of carbamazepine metabolism increases the carbamazepine clearance rate, decreases the half‐life, and decreases serum concentrations; the clinician must reevaluate a patient's serum levels at 4 to 6 weeks after initiation of therapy. (2) Carbamazepine induces the metabolism of other antiepileptic drugs, enhancing the clearance of phenytoin, primidone, valproic acid, clonazepam, and ethosuximide. (3) Other drugs added to the epileptic patient's drug regimen may induce the metabolism of carbamazepine, causing increased serum concentrations. (4) Inhibition of carbamazepine metabolism by other drugs can also occur; symptoms of drug intoxication rapidly follow. Interactions occur between carbamazepine and macrolide antibiotics, cimetidine, propoxyphene, and isoniazid. Drug‐drug interactions are preventable. It is the responsibility of every physician to be alert to the potential for their occurrence whenever a change in the epileptic patient's drug regimen is made.