Zonisamide: chemistry, mechanism of action, and pharmacokinetics

Abstract

Zonisamide is a synthetic 1,2-benzisoxazole-3-methanesulfonamide with anticonvulsant properties. The sulfamoyl group on zonisamide was expected to suppress seizures in a manner similar to another sulfonamide analogue, acetazolamide, through inhibition of carbonic anhydrase. However, this does not appear to be the primary mechanism of action since zonisamide requires much higher doses than acetazolamide to achieve equivalent titration in vivo. Studies with cultured neurons indicate that zonisamide blocks repetitive firing of voltage-sensitive sodium channels and reduces voltage-sensitive T-type calcium currents without affecting L-type calcium currents. Its dual mechanism of action may explain its efficacy in patients resistant to other antiepileptic drugs (AEDs). Zonisamide has a pharmacokinetic profile favorable for clinical use. It is rapidly and completely absorbed and has a long half-life (63-69h in healthy volunteers) which allows twice-daily, or even once-daily, dosing. Zonisamide is not highly bound to plasma proteins. Consequently, it does not affect protein binding of other highly protein-bound AEDs. Furthermore, zonisamide does not induce its own metabolism and does not induce liver enzymes. However, since zonisamide is metabolized by cytochrome P450, liver enzyme-inducing AEDs will increase zonisamide clearance, and dosage adjustments may be necessary when it is used in combination with certain AEDs.

Molecular Targets for Antiepileptic Drug Development

“…Two more recently introduced AEDs, zonisamide and topiramate, also inhibit carbonic anhydrase, which may contribute to their side effects, including kidney stones and perhaps also oligohydrosis and hyperthermia. 392,393 The action of topiramate on carbonic anhydrase has been assumed not to contribute to its clinical efficacy, because cross-tolerance to the anticonvulsant activity of topiramate does not occur with acetazolamide in mice. 394 However, a recent study finds closely comparable potency for acetazolamide and the two AEDs against cytosolic carbonic anydrase isozyme II and mitochondrial carbonic anhydrase isozyme V. 395 Carbonic anhydrase is a zinc-containing enzyme that is inhibited by interaction of sulfonamide or sulfamate compounds with the Zn(II) ion and specific residues of the protein.…”

Zonisamide (Zonegran) in the Treatment of Epilepsy in Adults and Children (A Review and Clinical Case)

“…Однако это, по-видимому, не основной механизм действия зонисамида, так как по сравнению с ацета-золамидом требуется применение значительно более высоких доз зонисамида для достижения эффекта ингибирования карбоангидразы in vivo. Зонисамид является достаточно слабым ингибитором карбоанги-дразы, и антиэпилептический эффект этого механиз-ма действия зонисамида не доказан [9,56]. Исследо-вания в культурах нейронов показали, что зонисамид…”

New Add-on Therapy for Partial-onset Epilepsy

“…10,19 Although generally well-tolerated, the most commonly reported adverse reactions with zonisamide were somnolence, fatigue, headache, weight gain, dizziness, anorexia, ataxia, tremor, confusion, speech abnormalities, mental slowing, and irritability. Zonisamide has been associated with renal calculi in 1.5% of patients, and its carbonic anhydrase-inhibiting effects may produce oligohidrosis in some children.…”

“…It binds the alpha-2 delta subunit of Ca channels in the cerebral cortex, hippocampus, and spinal cord, reducing the influx of Ca at nerve terminals, in turn reducing excitatory neurotransmitters release. 3,6,19,16,23,24 Gabapentin, unlike many other newer AEDs, has a relatively poor bioavailability of less than 60%, which is altered primarily by variable absorption via an L-amino acid transporter. At doses greater than 1,200mg, bioavailability further drops off to ~35%.…”

“…In patients with compromised renal function, dosing must be adjusted according to creatinine clearance. 3,6,16,19 Owing to its lack of drug interactions, lack of plasma protein-binding, and renal excretion, gabapentin is particularly useful in patients with hepatic or renal disease, or in patients on complex drug regimens. 3,10,[23][24][25] It is typically well tolerated, with common adverse effects being somnolence, ataxia, and dizziness.…”