The enzyme carbonic anhydrase facilitates the reaction between carbon dioxide and water to form carbonic acid, which then breaks down to hydrogen (H+) and bicarbonate (HC03~) ions. This process is fundamental to the production of either acid or alkaline secretions and high concentrations of carbonic anhydrase are present in the gastric mucosa, pancreas, eye and kidney. Because the number of H+ available to exchange with Na+ in the proximal tubule is reduced, sodium loss and diuresis occur. But HC03~ reabsorption from the tubule is also reduced, and its loss in the urine leads within days to metabolic acidosis, which attenuates the diuretic response to carbonic anhydrase inhibition. Consequently, inhibitors of carbonic anhydrase are obsolete as diuretics, but still have specific uses. Acetazolamide is the most widely used carbonic anhydrase inhibitor.
Reduction of intraocular pressure. This action is due not to diuresis (thiazides actually raise intraocular pressure slightly). The formation of aqueous humour is an active process requiring a supply of bicarbonate ions, which depends on carbonic anhydrase. Inhibition of carbonic anhydrase reduces the formation of aqueous humour and lowers intraocular pressure. This is a local action and is not affected by the development of acid-base changes elsewhere in the body, i.e. tolerance does not develop. In patients with acute glaucoma, acetazolamide can be taken either orally, or intravenously. Acetazolamide is not recommended for long-term use because of the risk of hypokalaemia and acidosis, but brinzolamide or dorzolamide are effective as eye drops, well tolerated, and thus suitable for chronic use in glaucoma.
High-altitude (mountain) sickness. This condition may affect unacclimatised people at altitudes over 3000 metres especially after rapid ascent; symptoms range from nausea, lassitude and headache to pulmonary and cerebral oedema. The initiating cause is hypoxia: at high altitude, the normal hyperventi-latory response to falling oxygen tension is inhibited because alkalosis is also induced. Acetazolamide induces metabolic acidosis, increases respiratory drive, notably at night when apnoetic attacks may occur, and thus helps to maintain arterial oxygen tension; 125-250 mg b.d. may be given orally on the day before the ascent and continued for 2 days after reaching the intended altitude, and 250 mg b.d. is used to treat established high-altitude sickness. (Note that this is an unlicenced indication in the UK). Dexamethasone may be used as an alternative or in addition, 2mg 6-hourly for prevention, and 4 mg 6-hourly for treatment.
The drug has two other uses. In periodic paralysis, where sudden falls in plasma K+ occur due to its exchange with Na+ in cells, the rise in plasma H+ caused by acetazolamide provides an alternative cation to K+ for exchange with Na+. Acetazolamide may be used occasionally as a second-line drug for tonic-clonic and partial epileptic seizures.
Adverse effects. High doses of acetazolamide may cause drowsiness and fever, rashes and paraesthesiae may occur, and blood disorders have been reported. Renal calculi may develop, because the urine calcium is in less soluble form owing to low citrate content of the urine, a consequence of metabolic acidosis.
Dichlorphenamide is similar, but a more potent inhibitor of carbonic anhydrase.
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