Acetazolamide (N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)-acetamide) is a non-bacteriostatic sulfonamide derivative and a potent carbonic anhydrase inhibitor. Carbonic anhydrases are zinc-containing metalloenzymes that catalyze the reversible reaction of CO₂ and water to carbonic acid and bicarbonate ions. They play an important role in tissue acid-base homeostasis, pH regulation, and water balance.
The main indications in ophthalmology are as follows.
Dosage and administration: oral 250–1,000 mg/day, injection 250–1,000 mg/day intravenously or intramuscularly. For IIH treatment, start at 250–500 mg twice daily and increase up to 2–4 g/day (divided doses)1, 2).
Although this drug is highly effective, it causes various ocular and systemic complications. In an IIH treatment trial, 84% of participants reported at least one adverse event, with a median of 5 adverse events1).
It is used for glaucoma, idiopathic intracranial hypertension (IIH), altitude sickness, epilepsy, and cerebrospinal fluid leaks. The intraocular pressure-lowering effect reaches 30–40% with systemic administration, and in IIH treatment, it reduces cerebrospinal fluid production by up to 50% within 60–90 minutes after administration.
Systemic side effects occur frequently. Symptoms that were significantly more frequent in the IIH treatment trial compared to the placebo group are as follows.
Severe systemic symptoms include metabolic acidosis, respiratory failure, hypokalemia, kidney stones, aplastic anemia, hemolytic anemia, agranulocytosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and shock.
Ophthalmologically important clinical findings are classified into three types.
Transient myopia
Degree of refractive change: Myopic changes of 1 to 8 diopters (D) occur.
Onset: Visual changes appear within 4 hours to 5 days after administration.
Course: Improvement begins within 24 hours after discontinuation, and complete resolution takes several days.
Ciliochoroidal effusion and acute angle-closure glaucoma
Nature of reaction: A dose-independent idiosyncratic reaction.
Mechanism: Ciliary body edema → change in lens curvature → narrowing of the anterior chamber → angle closure, in that order.
Urgency: Presents as an acute angle-closure attack requiring immediate intervention.
Choroidal Detachment
Reported cases: There are reports following acetazolamide administration after laser posterior capsulotomy.
Management: Discontinuation of the drug and close observation are necessary.
Improvement begins within 24 hours after discontinuation, and complete resolution may take several days. Onset occurs within 4 hours to 5 days after administration, and switching to an alternative medication is an option.
Risk factors and contraindications that predispose to complications of acetazolamide are listed below.
Acetazolamide should not be administered in any of the following cases.
| Contraindications | Reason/Remarks |
|---|---|
| History of hypersensitivity to sulfonamide drugs | Risk of severe allergic reaction |
| Advanced liver disease or severe hepatic impairment | May induce hepatic coma due to elevated blood ammonia |
| Anuria / acute renal failure | Accumulation and increased toxicity due to impaired excretion |
| Hyperchloremic acidosis | Worsens acidosis |
| Markedly decreased Na and K in body fluids | Further aggravates electrolyte abnormalities |
| Adrenal insufficiency / Addison’s disease | Severity due to loss of electrolyte regulation |
| Chronic angle-closure glaucoma (long-term use) | Risk of masking disease progression |
Use in the following conditions only after adequate risk-benefit assessment.
Acetazolamide lacks the N4 allylamine side chain and N1 aromatic heterocycle found in sulfonamide antibiotics, so the structural cross-reactivity risk is considered low. However, it has been suggested that general susceptibility to allergic reactions may be a cause, and careful judgment is necessary considering the risk of severe reactions.
For IIH, start acetazolamide 250–500 mg twice daily and titrate up to 2–4 g/day. The IIHTT (2014) showed that adding acetazolamide to a low-sodium weight-loss diet modestly improved visual field function (PMD), papilledema grade, and vision-related quality of life in IIH patients with mild visual loss. This was not an intraocular-pressure outcome. Safety and tolerability at up to 4 g/day have been confirmed1). No consistent effect on headache has been demonstrated2).
A 6-month regimen of acetazolamide plus a low-sodium weight-loss diet improved visual field function (PMD), vision-related quality of life, and papilledema grade in IIH patients with mild visual loss; it did not show mild intraocular-pressure reduction1).
In patients with primary open-angle glaucoma (POAG), oral administration of acetazolamide 500 mg one hour before phacoemulsification (PEA) significantly suppresses intraocular pressure (IOP) elevation 1 to 24 hours after surgery 3).
The comparison of the proportion of patients with postoperative IOP elevation of 100% or more is shown below.
| Treatment group | Proportion with IOP elevation ≥100% |
|---|---|
| Preoperative treatment group | 3.3% |
| Postoperative administration group | 23.3% |
| Non-administration group | 26.6% |
(P = 0.0459, Hayashi 2017)3)
Drug discontinuation is the highest priority. After that, systemic and topical steroids, cycloplegics, and aqueous suppressants may be considered, but there is no clinical research evidence showing their efficacy. During acute attacks, since ciliochoroidal effusion is the root cause, miotics (pilocarpine) are often ineffective.
Changes in salt and fluid balance cause edema in the ciliary body. Ciliary body edema alters the curvature of the lens and makes the anterior chamber shallower. Susceptibility factors are thought to contribute to the onset, but the detailed mechanism remains unclear.
It occurs as an idiosyncratic and dose-independent reaction of the uvea. Ciliary body edema causes shallowing of the anterior chamber and leads to angle closure. Similar mechanisms have been reported with topiramate, anticoagulants, furosemide, and glipizide.
Inhibition of carbonic anhydrase in the ciliary body reduces bicarbonate ion production. This suppresses the secretion of bicarbonate ions, sodium ions, and water from the ciliary body, decreasing aqueous humor production and lowering intraocular pressure by 30–40%.
Calcium phosphate stones form due to action on the proximal tubule and urinary alkalinization. This is a different mechanism from calcium oxalate stones caused by hypercalciuria induced by loop diuretics (e.g., furosemide).
Natriuretic action in the proximal tubule and urinary alkalinization can induce rhabdomyolysis, leading to myoglobinuric renal failure. This risk is particularly high in patients with McArdle disease.
Hyperventilation occurs as respiratory compensation for metabolic acidosis. In patients with concomitant lung disease (COPD, asthma), multifactorial hypercapnic respiratory failure may occur. Hyperventilation has been reported even without lung disease.
It is thought to be caused by an immunological reaction or toxic mechanism, but the incidence is extremely low.
Research is ongoing to evaluate correlations that predispose to adverse events of acetazolamide. Regarding cross-reactivity with sulfonamide antibiotic allergy, it has been suggested that the cause may be susceptibility to allergic reactions in general rather than cross-reactivity itself, and further research is needed.
Studies are underway showing that short-term acetazolamide administration improves obstructive and central sleep apnea. Additionally, promising results have been reported for low-dose acetazolamide therapy to prevent high-dose methotrexate-induced toxicity in long-term treatment of central nervous system lymphoma and acute lymphoblastic leukemia.
A randomized controlled trial (RCT) comparing venous stenting versus shunt surgery for IIH is ongoing in the UK, and evidence regarding superiority compared to acetazolamide is accumulating2).
