Zonisamide
Zonisamide
Generic Name
Zonisamide
Mechanism
- Voltage‑gated sodium channel blockade: Prolongs inactivation of neuronal membranes, reducing burst firing in epileptic foci.
- Carbonic anhydrase inhibition: Mildly alkalinizes extracellular fluid and contributes to the formation of urinary acid crystals, underlying its propensity for kidney stone formation.
- Metabotropic and GABAergic modulation: Enhances synaptic inhibition via increased GABA turnover and reduces glutamate release, providing additional seizure suppression.
Pharmacokinetics
| Parameter | Details |
| Absorption | ~85 % bioavailability; peak plasma concentration (Tmax) in 1–4 h. Food delays Tmax but does not alter AUC. |
| Distribution | 70 % protein‑binding (primarily albumin). Cumulative brain penetration is moderate, consistent with its antiepileptic activity. |
| Metabolism | Primarily hepatic via glucuronidation (UGT enzymes); minimal CYP450 involvement, limiting extensive drug‑drug interactions. |
| Excretion | Renally cleared (≈70 % unchanged; rest via biliary excretion). Half‑life: 48–56 h (steady‑state). Dose adjustment required for eGFR < 30 mL/min/1.73 m². |
| Key Interactions | • Metabolized by UGT → inhibitors (e.g., valproate) may modestly raise plasma levels. |
| • Low CYP3A4/2C9 interaction; co‑administration with carbamazepine, phenytoin, or lamotrigine is generally safe, but titration may be needed. |
Indications
- Adjunctive treatment of partial‑onset seizures (with or without secondary generalization).
- Adjunctive therapy for refractory generalized tonic‑clonic seizures in adults.
- Pre‑treatment in acute seizure clusters may be considered in specialized settings.
- Note: Not approved for status epilepticus.
Contraindications
- Contraindicated in patients with known hypersensitivity to zonisamide or any study substance.
- Warning: Use with caution in renal impairment (eGFR < 30 mL/min/1.73 m²) due to increased risk of metabolic acidosis and crystal nephropathy.
- Pregnancy: Category D; teratogenic in animal studies (neural tube defects).
- Lactation: Excreted in milk; avoid in nursing mothers.
- Concurrent use: Carriers of urolithiasis or metabolic alkalosis risk increased.
- Severe hepatic impairment is a relative contraindication; monitor LFTs closely.
Dosing
- Adults:
- Initiate 25 mg twice daily (BID).
- Titrate by 50 mg BID every 2–4 weeks based on seizure control and tolerability.
- Typical maintenance: 200–400 mg BID (max 600 mg/day).
- Pediatrics (≥ 12 yrs, > 30 kg): Use weight‑based dosing similar to adults.
- Renal impairment:
- eGFR 30–70 mL/min/1.73 m² → start at 25 mg BID and titrate slowly, max 200 mg BID.
- eGFR < 30 mL/min/1.73 m² → consider dose reduction or non‑renal adjunct.
- Re‑initiation after withdrawal: 1–2 weeks of tapering to avoid seizure rebound.
- Administration: Oral tablet; may be taken with or without food. Avoid crushing or cutting tablets due to altered release.
Adverse Effects
| Class | Common (≤ 10 %) | Serious (≤ 1 %) |
| CNS | Dizziness, ataxia, headache, fatigue, insomnia | Seizure exacerbation, rare psychiatric disturbances |
| GI | Nausea, vomiting, anorexia | Severe mucocutaneous reactions (Stevens‑Johnson/TEN) |
| Metabolic | Metabolic acidosis, increased urinary pH | Kidney stones (urinary crystals), renal dysfunction |
| Renal | Crystal nephropathy | Acute tubular necrosis (rare) |
| Hepatic | Elevated ALT/AST | Hepatotoxicity (rare) |
| Dermatologic | Rash | Severe skin reactions (SJS, TEN) |
| Other | Dry mouth, visual changes (blurry vision) | None reported; monitor for rare intracranial events |
Monitoring
- Baseline: CBC, LFTs, electrolytes (including bicarbonate), urinalysis, serum creatinine/eGFR, pregnancy test if indicated.
- During therapy:
- Every 4–6 weeks: CBC, LFTs, creatinine, electrolytes, bicarbonate.
- Annual: Renal ultrasound for chronic stone formation in high‑risk groups.
- Assess for:
- Signs of metabolic acidosis: abdominal pain, constipation, elevated serum CO₂.
- Urinary pH > 7.5 → risk of stone formation; prophylactic measures (hydration, citrate supplements).
- Skin lesions or mucosal ulcers → immediate drug discontinuation.
- Special: In patients with diabetes, monitor blood glucose due to potential influence on GABA activity.
Clinical Pearls
1. “Stone‑Prevention” Check – Screen for history of nephrolithiasis before starting zonisamide; recommend high fluid intake and citrate supplementation if baseline risk is high.
2. Renal‑Adjustment Shortcut – For eGFR 30–50 mL/min/1.73 m², a 33 % dose reduction can be made (e.g., 133 mg BID instead of 200 mg BID).
3. Serum Bicarbonate as a “Sodium‑Channel Sieve” – A drop in bicarbonate may hint at drug accumulation; adjust dose or consider alternative therapy.
4. Pregnancy Awareness – Provide counseling on teratogenic risks and consider neonatal monitoring for malformations if conception occurs.
5. Elderly Vulnerability – In older patients, start at the lowest effective dose (50 mg BID) and titrate slowly; monitor for falls and cognitive changes.
6. Drug‑Interaction Alert – Co‑treatment with valproate may raise zonisamide levels; monitor serum concentrations if available and watch for increased toxicity.
7. Metformin‑Co‑therapy – Avoid combining with metformin in patients with significant renal impairment due to additive metabolic acidosis risk.
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• *Zonisamide* remains a valuable tool in the antiepileptic arsenal, particularly when partial seizures are refractory. Its dual sodium‑channel and metabolic inhibition profile necessitates careful dose titration, renal safety monitoring, and patient education to mitigate renal lithiasis and metabolic complications.