Carbonic anhydrase inhibitors.
Acetazolamide is the prototype carbonic anhydrase inhibitor — a sulfonamide-derived drug used in glaucoma, idiopathic intracranial hypertension, altitude sickness, and certain forms of metabolic alkalosis. Related agents include methazolamide (oral) and dorzolamide and brinzolamide (topical eye drops). The drugs contain a sulfonamide group but lack the N4 arylamine.
- Oral
Acetazolamide(Diamox),methazolamide.- Topical (ophthalmic)
Dorzolamide,brinzolamide.- Mechanism
- Inhibition of
carbonic anhydrase, reducing bicarbonate reabsorption (kidney) and aqueous humour production (eye). - Indications
- Glaucoma, idiopathic intracranial hypertension, altitude sickness, some metabolic alkalosis.
Acetazolamide
Acetazolamide inhibits carbonic anhydrase, the enzyme that interconverts CO2 and H2O with HCO3− and H+. The enzyme is widespread; the clinical effects come from inhibition in specific tissues.
In the proximal renal tubule, inhibition reduces bicarbonate reabsorption — producing a mild diuresis and a metabolic acidosis. This is why acetazolamide is used to correct metabolic alkalosis in selected patients (for example, contraction alkalosis from aggressive diuresis).
In the eye, inhibition of carbonic anhydrase in the ciliary body reduces aqueous humour production, lowering intraocular pressure. This is the basis of its use in glaucoma, particularly acute angle-closure glaucoma where rapid IOP reduction is needed.
The same effect on cerebrospinal fluid production underlies its use in idiopathic intracranial hypertension (pseudotumour cerebri), where reducing CSF production reduces intracranial pressure.
In altitude sickness, acetazolamide is used both for prophylaxis and for treatment of acute mountain sickness. The induced metabolic acidosis stimulates ventilation, partly compensating for the hypoxic environment and accelerating altitude acclimatisation.
Acetazolamide is also used in some forms of periodic paralysis, in epilepsy as adjunctive therapy in selected cases, and historically as a diuretic before more potent agents became available.
Topical agents
Dorzolamide and brinzolamide are topical carbonic anhydrase inhibitors used as eye drops for glaucoma. They reduce aqueous humour production locally with much less systemic exposure than oral acetazolamide. Common side effects are local — bitter taste (drug drains through the lacrimal duct), conjunctival irritation, transient blurred vision. Combination drops with timolol are widely available.
Adverse effects of oral agents
Acetazolamide is generally well tolerated but has a recognisable cluster of effects:
Paresthesias — tingling around the mouth, in fingers and toes — are common and dose-related; most patients adapt or it resolves on dose adjustment. Metabolic acidosis is expected pharmacology and usually mild. Kidney stones are a recognised risk — the drug alters urine pH and promotes calcium phosphate stone formation. Hypokalemia can occur. Fatigue, malaise, and altered taste (carbonated drinks may taste flat) are common. Rare but important: aplastic anemia, agranulocytosis, severe cutaneous adverse reactions including SJS/TEN (rare but reported).
The sulfa allergy question
Acetazolamide contains a sulfonamide group but lacks an N4 arylamine. The cross-reactivity question follows the general pattern for non-antibiotic sulfonamides — low rates in published data. Most prescribers are comfortable using acetazolamide in patients with a typical sulfa antibiotic allergy label. Decisions in patients with severe past reactions are individualised.
Acetazolamide does have its own reaction pattern, including some severe cutaneous reactions reported in pharmacovigilance data, particularly in patients with certain HLA backgrounds — though specific HLA associations for acetazolamide are less established than for other classes. The patient with a previous severe reaction to a sulfa antibiotic and a planned course of acetazolamide is a case for individualised judgement.
Topical carbonic anhydrase inhibitors have very low systemic exposure and are usually well tolerated even in patients with sulfa allergy labels, though the prescribing information typically carries an inherited caution.