Drug Interaction Express Report

Publication date: 2006-06-30

Metabolic Drug-Drug Interactions Associated with Antiepileptic Agents

Introduction

Epilepsy is a chronic disease that may require long-term antiepileptic drug therapy. The efficacy of single-agent antiepileptic drug therapy for the treatment of epilepsy is well established. ¹ For those patients with epilepsy who do not respond to single-agent therapy, treatment with multiple antiepileptic drugs is necessary. A recent survey indicated that 28% of patients with epilepsy were prescribed polytherapy. ² Because antiepileptic drugs are well known for their drug interactions, between each other as well as with other pharmacologic agents, clinicians must vigilantly monitor concomitant administration of antiepileptic drugs for possible clinical consequences of such drug interactions. Indeed, approximately 6% of patients experiencing anti-epileptic drug intoxication do so because of a drug interaction. ³

Polytherapy is frequently necessary for the treatment of comorbidities in patients with epilepsy. Antiepileptic drugs are known to interact with cardiovascular agents including anticoagulants, beta-blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, calcium channel blockers, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (“statins”). Moreover, antiepileptic drugs are commonly prescribed to treat a variety of non-epileptic conditions including migraine headache, chronic neuropathic pain, mood disorders, and schizophrenia. In 2003, 45% of anti-epileptic drugs prescribed by neurologists were for conditions other than epilepsy, ⁴ while 96% of antiepileptic drugs prescribed by psychiatrists were for nonepileptic use; predominantly bipolar disorder and schizophrenia. ⁴< p>Whether an antiepileptic drug is utilized as a single-agent or in combination with another antiepileptic drug to treat epilepsy, or to treat nonepileptic conditions, a thorough understanding by the clinician of antiepileptic drug interactions is critical in maximizing long-term patient outcomes. For example, clinicians must be cognizant that discontinuing an antiepileptic agent may have an equally serious impact on the efficacy or toxicity of remaining drug therapy as does adding an antiepileptic drug to existing drug therapy.

This Drug Interaction Express Report^TM reviews the impact of anti-epileptic drugs on the pharmacokinetics of concomitantly administered pharmacologic agents, including other antiepileptic drugs. This report focuses on identifying and predicting clinically relevant drug-drug interactions associated with antiepileptic agents.

Understanding the Mechanisms of Metabolic Drug Interactions

The cytochrome P450(CYP) enzyme system consists of a family of hemoproteins that catalyze the oxidative metabolism of a variety of exogenous chemicals, including drugs, and endogenous compounds such as corticosteroids, fatty acids, and prostaglandins. ⁵ The CYP enzyme system contains 2 large subgroups: steroidogenic and xenobiotic enzymes. The steroidogenic enzymes are not involved in drug metabolism. The xenobiotic enzymes include 4 major enzyme families: CYP1, CYP2, CYP3, and CYP4. Although the xenobiotic enzymes perform several physiologic functions, their primary role is drug metabolism. Subfamilies of enzymes are designated according to the similarity of amino acid sequences of the encoded CYP isoenzymes (eg, CYP3A) and further classified by gene type (eg, CYP2C9) (Table 1). Thus, the enzymes that play a major role in the metabolism of most drugs include the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 isoenzymes located primarily in the liver. Alterations in enzyme activity can change substrate drug (defined as a drug dependent on cytochrome P450 for metabolism) concentrations leading to toxicity, or alternatively, decreased efficacy. Many drug interactions are a result of induction or inhibition of CYP enzymes. Understanding the mechanisms by which enzyme activity is altered has made dramatic advancement in the past 2 decades