Acetazolamide is a heterocyclic sulfonamide and carbonic anhydrase-inhibiting drug primarily used to treat glaucoma. It also has applications in the management of various types of seizures.

Authorized Indications

• UK-SmPC:
  • Second-line drug for tonic-clonic and focal seizures.
  • Occasionally helpful in atypical absence, atonic, and tonic seizures.
• FDA-PI:
  • Adjunctive treatment of centrencephalic epilepsies (petit mal, unlocalized seizures).

Clinical Applications

• Limited use as an adjunctive therapy for various seizures, mainly absences.
• Controls myoclonic jerks, generalized tonic-clonic seizures (GTCS), and focal seizures.
• Used for intermittent administration in catamenial epilepsy (5 days before expected menses onset until termination of bleeding).
• Not recommended if there is a likelihood of pregnancy.

Dosage and Titration

• Adults:
  • Start with 250 mg.
  • Increase to 500–750 mg.
• Children:
  • 10–20 mg/day.
• Dosing:
  • Two or three times daily.
  • Therapeutic drug monitoring (TDM) is not needed.
  • Reference range: 10–14 mg/l (400–700 μmol/l).

Main Adverse Drug Reactions (ADRs)

• Frequent/Important:
  • Flushing, lethargy, anorexia, nausea, vomiting, paraesthesiae, increased diuresis.
• Serious:
  • Idiosyncratic reactions: rash, aplastic anemia, Stevens-Johnson syndrome.
  • Renal failure, nephrolithiasis with chronic treatment.
  • Metabolic acidosis, as with other carbonic anhydrase inhibitors.

Mechanism of Action

• Inhibits carbonic anhydrase, which catalyzes the hydration of CO2 and dehydration of carbonic acid.
• Blocks brain carbonic anhydrase, increasing intracellular CO2, decreasing intracellular pH, and depressing neuronal activity.

Pharmacokinetics

• Oral Bioavailability: >90%
• Protein Binding: 90–95%
• Metabolism: Does not undergo metabolic alteration.
• Excretion: Renal.
• Elimination Half-life: 12–14 hours.

Drug Interactions

• Not Significant:
  • Reduces carbamazepine levels.
  • Salicylates increase acetazolamide levels due to competition at the renal tubule for secretion.

Main Disadvantages

• Unpredictable seizure efficacy.
• Development of tolerance.
• Idiosyncratic reactions that may be fatal.

Useful Clinical Notes

• Risk of withdrawal seizures.
• Combination with carbamazepine or oxcarbazepine increases the risk of hyponatremia.
• Avoid concurrent use with other carbonic anhydrase inhibitors (e.g., sulthiame, topiramate, zonisamide).
• Withdraw before starting a ketogenic diet.
• Concurrent use with aspirin can lead to high plasma concentrations of acetazolamide and toxicity.

References

• Panayiotopoulos CP (2001). Treatment of typical absence seizures and related epileptic syndromes. Paediatr Drugs, 3(5), 379-403. PMID: 11393330.
• Lim LL, Foldvary N, Mascha E, Lee J (2001). Acetazolamide in women with catamenial epilepsy. Epilepsia, 42(6), 746-749. PMID: 11422329.