Carbonic anhydrase inhibitor anticonvulsants

1. Introduction

• Carbonic anhydrase inhibitor anticonvulsants are antiepileptic drugs (AEDs) that exert part of their therapeutic effect through inhibition of the carbonic anhydrase (CA) enzyme in the central nervous system.

• CA inhibition leads to changes in brain pH and ion gradients that can stabilize neuronal membranes and reduce hyperexcitability.

• Many CAI anticonvulsants have additional mechanisms beyond CA inhibition, contributing to their broader antiepileptic efficacy.

• Main agents in this group:

  • Acetazolamide (primarily CA inhibition).

  • Topiramate (multiple mechanisms, including CA inhibition).

  • Zonisamide (multiple mechanisms, including CA inhibition).

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2. Mechanism of Action

• Primary CA inhibition effect in CNS:

  • Carbonic anhydrase catalyzes conversion of CO₂ + H₂O ↔ H₂CO₃ ↔ H⁺ + HCO₃⁻.

  • Inhibition reduces HCO₃⁻ formation, causing mild metabolic acidosis in brain tissue.

  • This alters neuronal ionic balance and decreases excitability of hyperactive neurons.

• Additional mechanisms (agent-specific):

  • Topiramate:

    • Blocks voltage-dependent sodium channels.

    • Enhances GABA-A receptor activity.

    • Antagonizes AMPA/kainate glutamate receptors.

  • Zonisamide:

    • Blocks voltage-gated sodium and T-type calcium channels.

    • Weak dopaminergic and serotonergic modulation.

  • Acetazolamide:

    • Pure CA inhibition; does not significantly affect sodium or calcium channels.

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3. Pharmacological Agents

Acetazolamide

• Oral or IV administration.

• Short-term adjunct in seizure control (especially catamenial epilepsy, absence seizures).

• Rapid tolerance often develops → limits chronic use.

Topiramate

• Oral administration (immediate and extended-release).

• Broad-spectrum AED for partial-onset and generalized seizures.

• Also used in migraine prophylaxis and weight management.

Zonisamide

• Oral administration (capsules).

• Broad-spectrum AED for partial-onset seizures; sometimes used off-label for other seizure types.

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4. Clinical Indications

Epilepsy

• Partial-onset seizures.

• Primary generalized tonic–clonic seizures.

• Absence seizures (acetazolamide, occasionally zonisamide).

• Myoclonic seizures (topiramate, zonisamide).

• Lennox–Gastaut syndrome (topiramate).

• Catamenial epilepsy (acetazolamide as adjunct).

Other Neurological Uses

• Migraine prophylaxis (topiramate).

• Idiopathic intracranial hypertension (acetazolamide; not primarily anticonvulsant use).

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5. Pharmacokinetics (General Trends)

• Absorption: Good oral bioavailability.

• Distribution: Crosses blood–brain barrier; binds variably to plasma proteins.

• Metabolism:

  • Acetazolamide largely excreted unchanged in urine.

  • Topiramate partially metabolized in liver; ~70% excreted unchanged.

  • Zonisamide extensively metabolized in liver (CYP3A4).

• Elimination half-life:

  • Acetazolamide: 6–9 h.

  • Topiramate: ~21 h.

  • Zonisamide: 50–70 h (allows once-daily dosing).

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6. Contraindications

• Hypersensitivity to sulfonamides (all three agents are sulfonamide derivatives).

• Severe hepatic or renal impairment.

• Metabolic acidosis (existing, untreated).

• Hyperchloremic acidosis.

• For topiramate in migraine prophylaxis: pregnancy (risk of fetal malformations).

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7. Adverse Effects

Common to CA inhibition

• Paresthesia.

• Fatigue.

• Mild metabolic acidosis.

• Nephrolithiasis (alkalinized urine promotes calcium phosphate stone formation).

• Electrolyte disturbances: hypokalemia, hyponatremia.

Agent-specific

• Topiramate: cognitive slowing, word-finding difficulty, weight loss, taste alteration, risk of acute myopia and secondary angle-closure glaucoma.

• Zonisamide: somnolence, dizziness, anorexia, rash (rare severe reactions like SJS/TEN).

• Acetazolamide: drowsiness, GI upset, rapid tolerance when used in epilepsy.

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8. Drug Interactions

• Additive CNS depression with alcohol, sedatives, and other AEDs.

• May alter serum concentrations of other AEDs (topiramate can decrease effectiveness of oral contraceptives; zonisamide affected by CYP3A4 inducers like phenytoin, carbamazepine).

• Increased risk of hypokalemia when combined with potassium-wasting diuretics.

• Salicylates can potentiate acetazolamide toxicity.

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9. Monitoring

• Serum electrolytes and bicarbonate (especially with chronic use).

• Renal function tests.

• Signs of cognitive effects (with topiramate).

• Skin monitoring for rash (zonisamide).

• Seizure frequency and severity logs for efficacy assessment.

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10. Advantages and Limitations

Advantages

• Broad-spectrum activity for multiple seizure types (topiramate, zonisamide).

• Additional benefits in migraine prevention and intracranial pressure control.

• Long half-life for zonisamide → once-daily dosing convenience.

Limitations

• Risk of metabolic acidosis and kidney stones limits use in some patients.

• Sulfonamide allergy risk.

• Cognitive and psychiatric side effects (especially with topiramate).

• Acetazolamide limited by rapid tolerance in epilepsy.