Zonisamide

Mechanism

Chemical and Commercial Profile

Common trade names: Zonegran, Zonisamide Normon.
Group: Third generation antiepileptic, sulfonamide derivative of benzisoxazole.

Mechanism of Action

Zonisamide acts through redundant and synergistic cellular mechanisms:

1. Selective blockade of voltage-gated sodium channels (Na_v): Significantly prolongs the inactive state of the neuronal channel, limiting repetitive high-frequency discharge.
2. Selective blockade of low-threshold T-type calcium channels: Like ethosuximide, it depresses synchronous thalamocortical oscillations, providing effectiveness in absence seizures.
3. Weak inhibition of carbonic anhydrase: Secondarily modulates cortical cellular pH.
4. Indirect potentiation of GABAergic tone and facilitation of central dopaminergic transmission.

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid and almost complete orally; bioavailability is 100%. It is not delayed by fat intake. The plasma peak is reached after 2-5 hours.
• Distribution: It selectively binds to blood erythrocytes due to its affinity for intraerythrocytic carbonic anhydrase. Its binding to plasma proteins is moderate (40%). The volume of distribution is 1.1-1.7 L/kg.
• Metabolism: Hepatic oxidative catalyzed mainly by the isoenzyme CYP3A4 through demethylation and active hydroxylation, generating the main inactive metabolite SM-9618.
• Excretion: Renal (60%) mainly in the form of conjugated metabolite and 30% as unchanged drug.
• Half-life (t_1/2): Very long: 50-70 hours in plasma; up to 120 hours in erythrocytes. It allows flexible dosing and reduces the immediate clinical impact of missed doses.

Indicators and dose

Indications

• Monotherapy in focal seizures with or without secondary generalization in adults with newly diagnosed epilepsy.
• Adjuvant therapy in focal crises in adults, adolescents and children over 6 years of age.

Dosage and Settings

• Initial Monotherapy (Adults): Start with 100 mg once a day; increase to 200 mg/day in the third week. Optimal therapeutic range: 300-500 mg/day in one or two doses.
• Adjuvant Therapy (Adults): Start with 25 mg twice daily; progressively increase each week from 50 mg to 50 mg. Common range: 300-400 mg/day.
• Renal Failure: In patients with creatinine clearance Cl_Cr < 50 ml/min, the theoretical dose should be reduced and the titration spaced 50% from the standard dose. Contraindicated in terminal stages of anuria due to systemic erythrocyte accumulation.
• Liver Failure: Not recommended in severe Child-Pugh B or C liver disease. In mild liver failure, limit the dose to a maximum of 200 mg/day and closely monitor transaminases.

Security

Contraindications

• Known hypersensitivity to **sulfonamide** derivatives (risk of secondary anaphylactic shock).
• Do not use for migraine prophylaxis in women of childbearing age without effective contraception.

Adverse Effects (ADR)

Oligohidrosis and Pediatric Hyperthermia

A very characteristic adverse effect of zonisamide, shared with topiramate due to the enzymatic inhibition of glandular carbonic anhydrase, is the development of oligohidrosis (marked decrease in sweating) associated with **central hyperthermia** that is difficult to control thermally, most frequently affecting the pediatric population during the summer. It requires adequate body hydration and avoiding direct exposure to the sun.

• Neurological / Psychiatric: Psychomotor agitation, behavioral irritability, emotional lability, confusion, difficulty concentrating, bradypsychia, postural motor ataxia.
• Metabolic: Hyperchloremic metabolic acidosis, nephrolithiasis due to calcium phosphate crystals (in 2% of patients due to elevated urinary pH and decreased excretion of citrates), marked weight loss (anorexia).
• Dermatological: Early onset rashes (1-2%). Rare cases of erythema multiforme or Stevens-Johnson Syndrome in patients susceptible to sulfas.

Clinical Interactions

• CYP3A4 inducers: Phenytoin, carbamazepine and phenobarbital accelerate the metabolic clearance of zonisamide, reducing its half-life to 25-30 hours, requiring progressive upward dose adjustments.
• CYP3A4 inhibitors: Ketoconazole or grapefruit juice increase serum levels of zonisamide, requiring close monitoring of cognitive tolerance of the compound.

Pregnancy and Breastfeeding

FDA Category: D. Demonstrated high teratogenic potential; It is associated with a substantial increase in fetal septal heart defects, microcephaly, and delayed postnatal development. Avoid in pregnant women. Breastfeeding: Relatively contraindicated due to the marked passage into breast milk (milk/plasma ratio ~0.7) and its long systemic half-life. Monitor sedation.