Acetazolamide: Carbonic Anhydrase Inhibitor for Glaucoma and Altitude Sickness
Acetazolamide is a sulfonamide-derived carbonic anhydrase (CA) inhibitor that has been used clinically since the 1950s. It is one of the earliest drugs developed on a rational mechanistic basis and remains in use today for a remarkably diverse range of indications including glaucoma, high-altitude illness, epilepsy, and correction of metabolic alkalosis.
Carbonic anhydrase is ubiquitous in the body, present in the eye, kidneys, brain, red blood cells, and lungs. Inhibiting this enzyme produces effects in all these tissues simultaneously, which accounts for both the therapeutic versatility and the side effect profile of acetazolamide.
Mechanism of Action
Carbonic anhydrase catalyses the reversible hydration of carbon dioxide to bicarbonate and a proton: CO2 + H2O → HCO3- + H+. In the kidney, CA inhibition reduces bicarbonate reabsorption in the proximal tubule, leading to increased urinary excretion of bicarbonate, sodium, potassium, and water. This diuresis is self-limiting as metabolic acidosis develops. In the eye, CA inhibition reduces aqueous humour production by the ciliary body, lowering intraocular pressure. In the brain, the mechanism for anticonvulsant activity involves CA inhibition in glial cells and neurons, raising the seizure threshold. For altitude sickness prevention, acetazolamide stimulates increased ventilation by inducing metabolic acidosis, which offsets the respiratory alkalosis of high altitude and improves acclimatisation.
Indications
Acetazolamide is approved for open-angle glaucoma and secondary glaucomas as a systemic agent when topical treatments are insufficient. It is the most widely used pharmacological prophylaxis for acute mountain sickness (AMS) and high-altitude cerebral oedema (HACE). In epilepsy, it has historically been used for absence seizures, particularly in women with catamenial epilepsy (seizures worsening around menstruation). Acetazolamide corrects metabolic alkalosis in conditions such as post-hypercapnic alkalosis and can be used for idiopathic intracranial hypertension and periodic paralysis.
Dosage and Administration
For glaucoma: 250 mg two to four times daily orally, or 500 mg sustained-release capsule twice daily. For altitude sickness prevention: 125 to 250 mg twice daily starting one to two days before ascent, continuing for at least 48 hours at altitude. For treatment of established AMS: 250 mg twice to three times daily. For epilepsy: 250 to 1000 mg daily in divided doses. Slow-release formulations improve tolerability. Dose reduction is required in renal impairment; acetazolamide is contraindicated in severe renal failure and sulfa allergy.
Side Effects
Paraesthesia (tingling in the fingers, toes, and face) is a characteristic and near-universal side effect at standard doses, caused by CA inhibition in peripheral neurons; it is harmless but can be bothersome. Metabolic acidosis is an expected pharmacological consequence. Polyuria is expected in the first days of treatment. Nephrolithiasis (kidney stones) occurs in up to four percent of long-term users due to reduced citrate excretion and alkaline urine. Hypokalaemia can develop, particularly with prolonged use. Taste disturbance, specifically altered perception of carbonated drinks, is a reported effect. Stevens-Johnson syndrome and aplastic anaemia are rare but potentially fatal reactions associated with sulfonamide class effects.
Interactions
Acetazolamide alkalinises the urine, which increases renal excretion of acidic drugs (aspirin, phenobarbital) and reduces excretion of basic drugs (quinidine, mexiletine). The metabolic acidosis induced by acetazolamide can increase the effects of other agents causing acidosis. Concurrent use with other diuretics increases the risk of hypokalaemia and dehydration. Salicylates can accumulate to toxic levels when combined with acetazolamide, particularly in elderly patients. Metformin renal clearance may be affected by changes in urinary pH.
Special Notes
Acetazolamide is contraindicated in sulfonamide allergy (cross-reactivity risk), hyponatraemia, hypokalaemia, severe hepatic impairment, renal insufficiency (creatinine clearance below 10 mL/min), hyperchloraemic acidosis, and adrenal failure. Long-term use requires periodic monitoring of serum electrolytes, bicarbonate, and renal function. Acetazolamide is not recommended during the first trimester of pregnancy. The drug can impair driving ability due to fatigue and paraesthesia. For altitude sickness, it is an aid to acclimatisation but does not permit ascent at a faster rate than the body can adapt.
Related Topics
Frequently Asked Questions
Why does acetazolamide cause tingling sensations?
The paraesthesia is caused by carbonic anhydrase inhibition in peripheral neurons, which alters membrane excitability. This effect is dose-dependent and nearly universal at standard therapeutic doses. It typically affects the hands, feet, and face and usually diminishes with time but may persist throughout treatment. It is not a sign of nerve damage.
How does acetazolamide prevent altitude sickness?
At high altitude, reduced atmospheric oxygen triggers reflex hyperventilation, which causes respiratory alkalosis (elevated blood pH). This blunts further ventilatory response. Acetazolamide causes mild metabolic acidosis by blocking renal bicarbonate reabsorption, which counteracts the respiratory alkalosis and allows deeper, more effective breathing. This accelerates acclimatisation to altitude.
Can acetazolamide be used for idiopathic intracranial hypertension?
Yes, acetazolamide is a first-line pharmacological treatment for idiopathic intracranial hypertension (pseudotumour cerebri). By reducing cerebrospinal fluid production through CA inhibition in the choroid plexus, it lowers intracranial pressure and alleviates symptoms such as headache and visual disturbances. Weight loss is equally important in overweight patients.
Sources
- EMA: Acetazolamide Summary of Product Characteristics 2023
- Wilderness Medical Society Guidelines on AMS 2022
- Friedman DI: Idiopathic Intracranial Hypertension Treatment. Neurology 2023