Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors block the enzyme that regenerates bicarbonate in the proximal tubule, ciliary body and choroid plexus. They cause a mild, self-limiting diuresis with bicarbonate loss and metabolic acidosis, lower intraocular and cerebrospinal fluid pressure, and stimulate breathing.

Members. Acetazolamide (oral and intravenous), methazolamide, dichlorphenamide, and the topical agents dorzolamide and brinzolamide.

Mechanism. Inhibition of luminal (type IV) and intracellular (type II) carbonic anhydrase reduces bicarbonate reabsorption in the proximal tubule, causing bicarbonate, sodium and potassium loss in urine. The resulting hyperchloraemic acidosis lowers filtered bicarbonate, so diuresis fades within about 3 days. Reduced aqueous humour production lowers intraocular pressure, and reduced cerebrospinal fluid secretion lowers intracranial pressure. Metabolic acidosis stimulates ventilation.

Pharmacokinetics. Acetazolamide is well absorbed, has a half-life of 6 to 9 hours and is excreted unchanged by the kidney. Topical agents reach the eye with small systemic levels.

Region-specific point. Trekkers on Mount Kenya and Kilimanjaro are at risk of acute mountain sickness, for which acetazolamide is a usual preventive in practice.

• Acetazolamide: altitude illness, glaucoma, idiopathic intracranial hypertension, metabolic alkalosis, epilepsy adjunct.
• Methazolamide: glaucoma; lower protein binding.
• Dichlorphenamide: periodic paralysis.
• Dorzolamide, brinzolamide: topical for glaucoma, with few systemic effects.

• Acute mountain sickness prevention: acetazolamide 125 mg twice daily, starting 1 day before ascent and continuing 2 days after reaching the top altitude. Treatment 250 mg twice daily. Children 2.5 mg/kg twice daily (maximum 125 mg). Descent and dexamethasone are used for severe illness.
• Acute angle-closure glaucoma: acetazolamide 500 mg intravenously, then 250 mg orally every 4 to 6 hours, with topical agents and definitive laser therapy.
• Idiopathic intracranial hypertension: acetazolamide 500 mg twice daily, increased to 1 to 2 g twice daily (maximum 4 g daily) as tolerated, with weight loss.
• Metabolic alkalosis in volume overload: acetazolamide 250 to 500 mg once or twice daily, orally or intravenously, for a few days.
• Chronic open-angle glaucoma: dorzolamide 2% drops 3 times daily as an add-on.
• Periodic paralysis: dichlorphenamide 50 mg twice daily, adjusted.
• Selection: use topical agents for long-term glaucoma to limit systemic effects.

Contraindications. Sulphonamide hypersensitivity, hyponatraemia, hypokalaemia, hyperchloraemic acidosis, adrenal insufficiency, severe renal or hepatic impairment, and cirrhosis (risk of hepatic encephalopathy through raised ammonia).

Adverse effects. Paraesthesia of the hands and feet, altered taste (carbonated drinks taste flat), fatigue, nausea, polyuria, metabolic acidosis, hypokalaemia, calcium phosphate kidney stones, transient myopia, and rarely severe skin reactions and bone marrow suppression.

Interactions. High-dose aspirin (salicylate accumulation and central toxicity), topiramate and zonisamide (additive acidosis and stones), lithium, ciclosporin, carbamazepine (raised levels), digoxin (hypokalaemia), and drugs dependent on urinary pH.

Monitoring. Bicarbonate, potassium, sodium and creatinine, and blood count with prolonged use. Check intraocular pressure and visual fields in glaucoma.

Referral and escalation. Rash with mucosal involvement, marked acidosis or jaundice means stopping the drug urgently.

Special groups. Pregnancy: avoid, because of limited safety data. Breastfeeding: compatible at usual doses. Renal impairment: dose every 12 hours with creatinine clearance 10 to 50 mL/min and avoid under 10 mL/min. Older adults: start low. Children: weight-based dosing.