Oral carbonic anhydrase inhibitors (i.e., acetazolamide, dichlorphenamide, methazolamide) are used principally as adjuncts for prolonged therapy in patients with open-angle (noncongestive, chronic simple) glaucoma not controlled by miotics alone. Oral carbonic anhydrase inhibitors should be used in conjunction with topical miotics or epinephrine derivatives which, unlike the carbonic anhydrase inhibitors, increase the facility of aqueous outflow. Orally or parenterally administered carbonic anhydrase inhibitors may also be used for short-term administration with miotics and/or osmotic agents such as glycerin, mannitol, or urea to lower intraocular pressure prior to surgery for the correction of acute angle-closure (obstructive, narrow-angle), infantile glaucoma, or glaucoma secondary to intumescent cataract or phacolysis. The drugs should not be used for long-term administration in patients with chronic noncongestive angle-closure glaucoma, because further closure of the angle may occur while worsening of the glaucoma is masked by lowered intraocular pressure.
Oral carbonic anhydrase inhibitors are also used as adjuncts in the short-term treatment of self-limiting secondary glaucomas which may result from anterior uveitis, trauma, iritis, herpes zoster infections, or the glaucomatocyclitic crisis syndrome. Prolonged therapy with oral carbonic anhydrase inhibitors may be of value in the treatment of some chronic secondary glaucomas. In the rare hypersecretion form of glaucoma, these drugs may be effective when used alone.
Carbonic anhydrase inhibitors are of doubtful value in the treatment of severe glaucoma caused by peripheral anterior synechiae and hemorrhagic glaucoma, and one manufacturer of dichlorphenamide indicates that it is contraindicated in these conditions. The manufacturer of methazolamide states that the drug is contraindicated in the treatment of severe or absolute glaucoma.
Topical carbonic anhydrase inhibitors (e.g., brinzolamide ophthalmic suspension, dorzolamide ophthalmic solution) are used topically to reduce elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Topical carbonic anhydrase inhibitors are useful as a first-line agent, especially when a topical β-adrenergic blocking agent cannot be used because of intolerance or a contraindication. In addition, the drugs are useful as a first-line ''add-on'' agent when more than one drug is needed.
Tolerance may develop in patients receiving therapy with a carbonic anhydrase inhibitor for glaucoma; in such cases one of the other drugs in this group may be effective.
Acetazolamide may be used in the management of edema secondary to congestive heart failure or drug therapy. However, carbonic anhydrase inhibitors are much less potent diuretics than are the thiazide diuretics and metabolic acidosis resulting in loss of diuretic effect occurs after 2-4 days of continuous therapy with carbonic anhydrase inhibitors. For these reasons, carbonic anhydrase inhibitors have largely been supplanted by the thiazides.
Acetazolamide is used as an adjunct to other anticonvulsants in the management of centrencephalic epilepsies (e.g., petit mal, unlocalized seizures). Tolerance to the anticonvulsant effects of carbonic anhydrase inhibitors develops quickly, and they may be ineffective for prolonged therapy. Although acetazolamide may be useful in partial, myoclonic, absence, and primary generalized seizures that have not responded adequately to other anticonvulsants, acetazolamide has not been evaluated in controlled clinical studies in specific seizure types and guidelines for appropriate use of the drug are not available.
Acute High- Altitude Sickness
Acetazolamide is used to increase altitude tolerance in the prevention or amelioration of symptoms associated with acute high-altitude sickness (mountain sickness) in climbers attempting rapid ascent and in those who are very susceptible to the condition despite gradual ascent. Acetazolamide has been designated an orphan drug by the US Food and Drug Administration for this use. It should be remembered, however, that whenever possible, gradual ascent and adequate acclimatization (e.g., spending 24 hours at an intermediate altitude, minimizing exertion during the initial 24-48 hours at high altitude) are desirable to prevent acute high-altitude sickness. In controlled studies, prophylactic administration of 250 mg of acetazolamide every 8-12 hours as conventional tablets or 500 mg once daily as extended-release capsules before and during rapid ascent to high altitudes decreased the frequency and/or ameliorated the severity of symptoms of acute high-altitude sickness, including headache, nausea, shortness of breath, dizziness, drowsiness, and fatigue. Pulmonary function (e.g., minute ventilation, expired vital capacity, peak flow) was better in acetazolamide-treated patients, including symptomatic and asymptomatic patients, than in those receiving placebo. Climbers treated with acetazolamide also had less difficulty sleeping. The drug decreases periodic breathing and apnea during sleep and diminishes sleep hypoxemia.
About 50% of untreated, nonacclimatized individuals who rapidly ascend to an altitude of 10,000 feet or higher develop symptoms of acute high-altitude sickness within 6-8 hours. Some individuals develop severe symptoms even with gradual ascent. The syndrome usually responds to rest and supplemental oxygen at night and subsides after 3-4 days, but severe forms of acute altitude sickness (e.g., high-altitude pulmonary and/or cerebral edema) requiring prompt descent and appropriate therapy occasionally occur. The number of individuals at risk of developing acute altitude sickness is increasing as rapid ascents and air travel to areas of high altitude by tourists, without periods of adequate acclimatization, increase. Acetazolamide therapy can hasten acclimatization and may prevent or ameliorate the symptoms of acute altitude sickness in these individuals. Use of acetazolamide does not obviate prompt descent in patients with severe forms of acute altitude sickness. The drug does not prevent acute altitude sickness, but rather shortens the time of acclimatization and has little, if any, effect after symptoms of altitude sickness occur.
Acetazolamide has been used in the treatment of both hyperkalemic and hypokalemic forms of periodic paralysis, and it may be the drug of choice in the hypokalemic form of this condition.
Acetazolamide has been used with good results in the prevention or treatment of alkalosis following open-heart surgery. Correction of the blood pH and diminished respiratory and cardiac distress were reported to occur within 30 minutes after the drug was administered.
Acetazolamide has been used to increase excretion of phenobarbital, lithium carbonate, or salicylates in acute intoxication caused by these drugs. However, because metabolic acidosis results both from salicylate intoxication and acetazolamide administration, use of acetazolamide in the treatment of salicylate intoxication is dangerous and can lead to severe complications; if it is used at all, acetazolamide should probably be used only in adults with respiratory alkalosis and only under the supervision of clinicians experienced in the use of the drug in salicylate overdosage.
Although intracranial pressure may be lowered in some hydrocephalic patients receiving oral acetazolamide or methazolamide, the drugs have not been consistently effective in the treatment of this condition.
In one controlled randomized study in preterm infants with posthemorrhagic ventricular dilatation, infants who received acetazolamide (100 mg/kg daily) and furosemide (1 mg/kg daily) in addition to standard therapy (intermittent removal of CSF) experienced a higher rate of shunt placement and increased neurologic morbidity compared with infants who received standard therapy alone.
Because acetazolamide may inhibit the formation of gastric and pancreatic secretions, it has been used in the treatment of acute pancreatitis and peptic ulcer. Beneficial effects of the drug in these conditions have not been proven.