Zonisamide (DB00909): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Zonisamide is a second-generation, broad-spectrum antiepileptic drug (AED) distinguished by its unique 1,2-benzisoxazole chemical structure and its classification as a sulfonamide.[1] Its therapeutic efficacy is attributed to a multi-modal mechanism of action that is not yet fully elucidated but is primarily understood to involve the blockade of voltage-gated sodium channels and low-threshold (T-type) calcium channels. These primary actions are complemented by secondary modulatory effects on major neurotransmitter systems, including the GABAergic, glutamatergic, dopaminergic, and serotonergic pathways.[1]

The primary approved indication for zonisamide in the United States and Europe is as an adjunctive therapy for the treatment of partial-onset seizures in adults and, in some jurisdictions, older pediatric patients.[1] The drug's pharmacokinetic profile is notable for its high oral bioavailability, exceptionally long elimination half-life, and extensive, saturable binding to erythrocytes, which acts as a significant drug reservoir and necessitates a prolonged period to achieve steady-state concentrations.[2]

The clinical use of zonisamide must be carefully balanced against its significant safety considerations, which are mechanistically linked to its fundamental chemical properties. As a sulfonamide, it carries a risk of severe and potentially fatal hypersensitivity reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Furthermore, its weak but clinically relevant activity as a carbonic anhydrase inhibitor predisposes patients to metabolic acidosis and nephrolithiasis, requiring diligent monitoring.[11] This monograph provides an exhaustive review of zonisamide's chemistry, pharmacology, clinical efficacy, and safety profile to guide its optimal use in clinical practice.