Acetazolamide

Acetazolamide, an heterocyclic sulfonamide, is a carbonic anhydrase-inhibiting drug used predominantly for the treatment of glaucoma.

Authorised indications

UK-SmPC: second-line drug for both tonic–clonic and focal seizures. It is occasionally helpful in atypical absence, atonic and tonic seizures.

FDA-PI: adjunctive treatment of centrencephalic epilepsies (petit mal, unlocalised seizures).

Clinical applications

Acetazolamide has limited use as an adjunctive therapy for a variety of seizures, but mainly absences (Panayiotopoulos, 2001). However, it also controls myoclonic jerks, generalised tonic–clonic seizures (GTCSs) and focal seizures. It is particularly used for intermittent administration in catamenial epilepsy (5 days before the expected onset of menses and continued until termination of bleeding) (Lim et al., 2001); it is not recommended if there is a likelihood of pregnancy.

Dosage and titration

Adults: start treatment with 250 mg and increase to 500–750 mg. Children: 10–20 mg/day. Dosing: two or three times daily. Therapeutic drug monitoring (TDM): not needed. Reference range: 10–14 mg/l (400–700 μmol/l).

Main ADRs

Frequent and/or/or important: flushing, lethargy, anorexia, nausea, vomiting, paraesthesiae and increased diuresis.

Serious: idiosyncratic reactions, as with other sulfonamides (rash, aplastic anaemia, Stevens–Johnson synd rome), renal failure; nephrolithiasis in chronic treatment and metabolic acidosis, as with other carbonic anhydrase inhibitors (see also topiramate).

Mechanism of action

Acetazolamide is a carbonic anhydrase-inhibiting drug that reversibly catalyses the hydration of CO₂ and the dehydration of carbonic acid. It blocks the action of brain carbonic anhydrase, resulting in an elevation of intracellular CO₂, a decrease of intracellular pH and depression of 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 levels of acetazolamide due to competition at the renal tubule for secretion.

Main disadvantages

Unpredictable seizure efficacy, development of tolerance and idiosyncratic reactions that exceptionally may be fatal.

Useful clinical notes

• Risk of withdrawal seizures.
• Combination with carbamasepine or oxcarbazepine increased the risk of hyponatraemia.
• Avoid concurrent use with other carbonic anhydrase inhibitors (i.e. sulthiame, topiramate, zonisamide).
• It shoudl be withdrawn prior to 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):746-9. PMID: 11422329.