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dorzolamide-timolol eye drops generic cosopt

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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.

Seizure Disorders

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.

Other Uses

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.

Dosage and Administration


Carbonic anhydrase inhibitors are usually administered orally. For parenteral therapy, acetazolamide sodium is preferably administered IV; IM administration may be used but is painful. Brinzolamide is applied topically to the eye as an ophthalmic suspension. Dorzolamide hydrochloride is applied topically to the eye as an ophthalmic solution.


Dosage of carbonic anhydrase inhibitors should be adjusted according to the patient's requirements and response. When acetazolamide is used as a diuretic, the drug should be given intermittently. In the treatment of glaucoma, epilepsy, or other conditions in which the effectiveness of the carbonic anhydrase inhibitors is independent of their diuretic effects, administration of the drugs is continuous. When acetazolamide is used in the prophylactic management of epilepsy, it should be kept in mind that adding, withdrawing, or replacing one anticonvulsant with another should be accomplished gradually. In addition, anticonvulsants should be discontinued very gradually because sudden withdrawal can precipitate status epilepticus.


The incidence and severity of many adverse reactions to carbonic anhydrase inhibitors are dose related and usually respond to a lowering of dosage or withdrawal of the drug. Because all adverse effects do not occur with the same frequency and/or severity with all of these drugs, many patients unable to tolerate one carbonic anhydrase inhibitor may be able to tolerate another. Serious adverse effects are infrequent, especially during short-term therapy.

While systemic absorption of brinzolamide or dorzolamide occurs following topical administration to the eye, use of topical carbonic anhydrase inhibitors have not been associated with adverse effects resulting from systemic carbonic anhydrase inhibition to date.

GI Effects

GI disturbances including anorexia, nausea, vomiting, diarrhea, weight loss, altered taste and smell, constipation, dryness of the mouth, excessive thirst, and abdominal distention may occur during therapy with systemically administered carbonic anhydrase inhibitors.

Nervous System Effects

CNS disturbances such as drowsiness, sedation, headache, confusion, depression, fatigue, lassitude, malaise, irritability, nervousness, excitement, dizziness, vertigo, and seizures have been reported with systemically administered carbonic anhydrase inhibitors. Paresthesia, characterized as numbness and a tingling sensation, may occur in the extremities, tongue, and/or the mucocutaneous junctions of the lips or the anus. Muscular weakness, ataxia, tremor, and flaccid paralysis have been reported in patients receiving these drugs.

Hypersensitivity Reactions

Hypersensitivity reactions common to all sulfonamide derivatives occur rarely in patients receiving carbonic anhydrase inhibitors. One patient died of cholestatic jaundice after taking 13 g of acetazolamide in 26 days. The jaundice was attributed to drug-induced hypersensitivity and hepatitis. Other hypersensitivity reactions which may occur include fever, rash and skin eruptions including exfoliative dermatitis and urticaria, and pruritus.

Hematologic Effects

Bone marrow depression manifested by aplastic anemia, thrombocytopenia or thrombocytopenic purpura, leukopenia, agranulocytosis, and hemolytic anemia has been reported with systemically administered carbonic anhydrase inhibitors. Fatalities resulting from aplastic anemia have been reported following therapy with acetazolamide or methazolamide. In one patient, fatal bone marrow depression with leukopenia, thrombocytopenia, and anemia occurred after therapy with 500 mg of acetazolamide twice daily for 14 weeks.

Renal and Metabolic Effects

Dysuria, crystalluria, renal colic, and sulfonamide-like renal lesions have been reported during therapy with systemically administered carbonic anhydrase inhibitors. Renal calculi have also occurred, possibly because of reduced excretion of citrate combined with unchanged or increased calcium excretion. Renal calculi may occur more frequently in patients with hypercalciuria. Phosphaturia also has been reported. One clinician has suggested that 24-hour urinary calcium determinations be performed before initiating therapy with a carbonic anhydrase inhibitor and that patients with hypercalciuria who must be treated with one of these drugs should be cautioned to reduce dietary intake of calcium and increase fluid intake.

One case of renal failure (anuria) occurred in a patient after taking 500 mg of acetazolamide twice daily for 2 weeks. The patient recovered after treatment with sodium bicarbonate (4 g orally initially, followed by 2 g every 6 hours) and forced fluids.

Rarely, hypokalemia may occur, especially in patients taking dichlorphenamide, and is especially likely if brisk diuresis occurs or in patients with hepatic cirrhosis or who are receiving other drugs that increase potassium excretion. Ingestion of potassium-rich foods may reduce or prevent potassium depletion; however, administration of a potassium supplement may be necessary in patients whose serum potassium concentrations are below about 3 mEq/L or who are receiving digitalis glycosides. When selecting a potassium supplement for a patient receiving a carbonic anhydrase inhibitor, the fact that plasma chloride concentrations may be elevated should be kept in mind.

Elevation of blood glucose, possibly caused by hypokalemia, and glycosuria have been reported rarely in diabetics and prediabetics receiving acetazolamide.

Uric acid excretion is decreased during therapy with systemically administered carbonic anhydrase inhibitors, and gout may be exacerbated. Elevated serum uric acid concentrations return to pretreatment levels when the drugs are discontinued. The possibility of hyponatremia should also be considered.

Reduced plasma bicarbonate concentrations and, in some instances, elevated plasma chloride concentrations may result in metabolic acidosis during long-term therapy with systemically administered carbonic anhydrase inhibitors. However, severe acidosis occurs rarely, if at all, with dosages of the drugs used to lower intraocular pressure. If necessary, acidosis may be corrected by administration of sodium bicarbonate.

In patients with hepatic cirrhosis, hypokalemia and/or elevations in blood ammonia concentrations caused by systemically administered carbonic anhydrase inhibitors may precipitate hepatic coma or precoma. Disorientation occurs in patients with cirrhosis receiving carbonic anhydrase inhibitors, possibly because of elevations of blood ammonia or increased cerebral carbon dioxide tension and decreased oxygen consumption.

Other Adverse Effects

Myopia has been reported in patients receiving carbonic anhydrase inhibitors; this effect is transient and subsides when dosage is reduced or the drug withdrawn.

Acetazolamide has been implicated in hirsutism which occurred in a 30-month old child after 1 year of treatment with 5 mg/kg daily. The excessive growth of hair on the back and legs was reported to be diminishing 1 year after acetazolamide was discontinued.

Other adverse effects which may occur in patients receiving carbonic anhydrase inhibitors are hepatic insufficiency, melena, hematuria, hearing dysfunction or tinnitus, globus hystericus, polyuria or increased urinary frequency, hyperpnea, cyanosis, and elevations in serum bilirubin concentrations.

Precautions and Contraindications

Electrolyte balance should be monitored in patients receiving systemically administered carbonic anhydrase inhibitors. (See Cautions: Renal and Metabolic Effects.) Systemically administered carbonic anhydrase inhibitors should be used with caution in patients with respiratory acidosis or those with severe loss of respiratory capacity caused by pulmonary infection, obstruction, emphysema, or advanced pulmonary disease. One manufacturer states that dichlorphenamide is contraindicated in patients with severe pulmonary obstruction. Respiratory acidosis may be precipitated or increased in these patients. Administration of these drugs may be especially hazardous in patients with elevated pCO2 values or those in whom blood pH is below 7.2.

Periodic hematologic determinations should be performed in patients receiving systemically administered carbonic anhydrase inhibitors. If blood dyscrasias occur, the drug should be discontinued and appropriate therapy instituted.

Since systemically administered carbonic anhydrase inhibitors may cause hyperglycemia and glycosuria in patients with diabetes mellitus, the drugs should be used with caution in these patients.

Use of acetazolamide for the prevention of acute high-altitude sickness (mountain sickness) in climbers attempting a rapid ascent does not obviate the need for prompt descent if severe forms of acute altitude sickness such as high-altitude pulmonary or cerebral edema occur.

Systemically administered carbonic anhydrase inhibitors are contraindicated in patients with hepatic disease or insufficiency, especially those with cirrhosis because of the risk of developing hepatic encephalopathy. Systemically administered carbonic anhydrase inhibitors are also contraindicated in patients with depressed serum concentrations of sodium and/or potassium and in patients with adrenocortical insufficiency, hyperchloremic acidosis, or severe renal disease or dysfunction.

Patients receiving oral or parenterally administered carbonic anhydrase inhibitors should be warned that the ability to perform tasks requiring mental alertness and/or physical coordination may be impaired.

Pregnancy, Fertility, and Lactation


Teratogenic and embryocidal effects have been demonstrated in rats and mice receiving carbonic anhydrase inhibitors in doses 10 times those recommended in humans. Acetazolamide can cause fetal toxicity when administered to pregnant women. Acetazolamide, administered orally or IV, has been shown to be teratogenic (defects of the limbs) in mice, rats, hamsters, and rabbits, and premature delivery and congenital anomalies have been reported in neonates born to women receiving the drug. If acetazolamide is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the possible hazard to the fetus.


Acetazolamide had no effect on fertility in male or female rats receiving the drug orally at up to 4 times the maximum recommended daily human dose (1 g in a 50-kg patient).


Because of the potential for serious adverse effects in nursing infants, the manufacturer states that a decision should be made whether to discontinue nursing or therapy with the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Systemically administered carbonic anhydrase inhibitors increase excretion of lithium, and patients receiving lithium should be observed for impairment of responsiveness to that drug whenever a carbonic anhydrase inhibitor is administered.

Alkalinization of the urine produced by systemically administered carbonic anhydrase inhibitors may decrease the rate of excretion of some drugs such as amphetamines, procainamide, quinidine, or possibly tricyclic antidepressants and the effects of the drugs may be enhanced and/or prolonged. Since the rate of excretion of weak acids, including phenobarbital and salicylates, is increased when the urine is alkaline, the effectiveness of these drugs may be reduced during therapy with carbonic anhydrase inhibitors. In addition, metabolic acidosis induced by systemically administered carbonic anhydrase inhibitors may potentiate salicylate toxicity, and some evidence suggests that toxicity observed in some patients receiving concomitant therapy may result from either the carbonic anhydrase inhibitor or salicylate or from both drugs. Methenamine compounds, such as methenamine, methenamine hippurate, and methenamine mandelate require an acid urine in order to be effective and may be inactive in the alkaline urine produced by the carbonic anhydrase inhibitors.

Carbonic anhydrase inhibitors may augment the effects of other diuretics such as the thiazides. Results of one study indicate that acetazolamide competes with and displaces chlorthalidone from erythrocyte binding sites. Although it appears that this effect may alter the response to chlorthalidone, the clinical importance has not been determined.

Rarely, systemically administered carbonic anhydrase inhibitors may interfere with the hypoglycemic response to insulin or oral antidiabetic agents, possibly by causing hypokalemia. In patients receiving digitalis glycosides, hypokalemia may predispose the patient to digitalis toxicity and possibly fatal cardiac arrhythmias may result. Other drugs, including most diuretics, corticosteroids, corticotropin, and amphotericin B also cause increased excretion of potassium, and patients receiving one of these drugs concurrently with a systemically administered carbonic anhydrase inhibitor may experience severe hypokalemia.

Severe osteomalacia has been reported in 2 patients receiving acetazolamide and phenytoin or primidone. It has been postulated that acetazolamide hastens bone demineralization and accentuates the deleterious effects of phenytoin and related drugs on calcium metabolism.



After oral administration, acetazolamide, dichlorphenamide, and methazolamide are absorbed from the GI tract. The approximate onset, peak, and duration of action in lowering intraocular pressure following a single dose of the carbonic anhydrase inhibitors are as follows:

Drug (route) Onset (hours) Peak (hours) Duration (hours)
Acetazolamide (oral tablets) 1 1-4 8-12
Acetazolamide (oral extended-release capsules) 2 3-6 18-24
Acetazolamide (IM) unknown unknown unknown
Acetazolamide (IV) 2 minutes 0.25 4-5
Dichlorphenamide (oral) 0.5-1 2-4 6-12
Methazolamide (oral) 2-4 6-8 10-18

Some systemic absorption of brinzolamide or dorzolamide occurs following topical application to the eye.


Carbonic anhydrase inhibitors are distributed throughout the body in those tissues containing high concentrations of carbonic anhydrase especially the erythrocytes and renal cortex. The drugs also enter the aqueous humor of the eye.

For information on the pharmacokinetics of specific carbonic anhydrase inhibitors, see the individual monographs in 52:10.

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