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Introduction
Background
Efficacy
Usage
Side Effects
Conclusion
References

Carbonic Anhydrase Inhibitors

Zinaria Y. Williams, MD

Introduction

Oral carbonic anhydrase inhibitors (CAIs) were introduced for the treatment of glaucoma in 1954 by Becker¹ and Grant.² Their chronic use has become limited because they are poorly tolerated and because of their potential for severe and life-threatening systemic side effects. The most commonly used oral CAIs are acetazolamide and methazolamide.

Topical CAIs were developed to achieve the IOP-lowering effects of oral CAIs without the serious adverse effects. These drugs are better tolerated by patients and are effective in reducing aqueous production. The currently available topical CAIs are dorzolamide and brinzolamide.

Background

Carbonic anhydrase (CA) is an enzyme that catalyzes the hydration of carbon dioxide into bicarbonate and the dehydration of bicarbonate into carbon dioxide:

CA is found in many tissues in the body and plays an important role in pH regulation, carbon dioxide expiration, gastric acidity, muscle contraction, renal acidification, normal brain development and aqueous humor production. CA is located within the cell membrane of the pigmented and nonpigmented epithelium of the ciliary body.³ The enzyme produces bicarbonate ions that are actively transported across the epithelial cell membrane into the posterior chamber. The osmotic gradient that results allows water to move passively into the posterior chamber in the process of aqueous production.

Inhibition of CA prevents bicarbonate formation and its secretion into the posterior chamber. This reduces aqueous production and decreases intraocular pressure (IOP).

Efficacy

CAIs are sulfonamide derivatives that lower IOP by decreasing aqueous production. They have no effect on aqueous outflow. Greater than 90% of the CA enzyme activity must be inhibited to reach a reduction in IOP. The chemical structure of dorzolamide and brinzolamide is different from the oral CAIs to increase the drug's solubility for corneal penetration.

Dorzolamide provides a mean decrease in IOP by 18% to 22% (4.5 mm Hg to 6.1 mm Hg).⁴ A 1-year study comparing dorzolamide, timolol and betaxolol reported no statistically significant difference in IOP at 2 hours following instillation. However, at 5 hours and 8 hours post-instillation, timolol was found to be more effective in lowering the IOP.⁵

Dorzolamide is additive or near additive when used in combination with beta-blockers and alpha-adrenergic agonists. The IOP-lowering effect of a dorzolamide-timolol combination is greater than that of either of the two medications as monotherapy. In one study, the mean IOP reduction from baseline was 27% to 33% for the combination, 15% to 20% for dorzolamide and 22.2% to 22.6% for timolol.⁶ When the dorzolamide-timolol combination drop was compared to the concomitant administration of dorzolamide plus timolol, the IOP-lowering effect was comparable.⁷

The ocular hypotensive ability of dorzolamide is equivalent to brimonidine.⁸ A combination of the two drugs provides a significant reduction in IOP greater than brimonidine alone. The dorzolamide-timolol combination, however, achieves a more pronounced decrease in IOP than the dorzolamide-brimonidine combination.⁹

Brinzolamide's effectiveness in reducing IOP is equivalent to that of dorzolamide. As with dorzolamide, this formulation also has an additive effect when combined with timolol.¹⁰

Acetozolamide is more effective than topical dorzolamide in decreasing aqueous production and reducing IOP. Oral acetazolamide results in a 30% reduction in aqueous flow (2.2 µL/min to 3.2 µL/min) compared to a 17% reduction (2.7 µL/min) with dorzolamide. When acetazolamide is added to dorzolamide, the aqueous flow is reduced even further.¹¹ Methazolamide has fewer side effects but is not as effective as acetazolamide.

Usage

Dorzolamide hydrochloride 2% ophthalmic solution (Trusopt, Merck, Whitehouse, NJ) is dosed three times a day. The solution is clear and viscous. Dorzolamide can be used on a long-term basis for the treatment of ocular hypertension and glaucoma. Dorzolamide offers less of an ocular hypotensive effect than acetazolamide, but has fewer side effects. This drug can be used in monotherapy, but has a greater effect on IOP when used in combination with a beta-blocker or an alpha-adrenergic agonist. Dorzolamide 2% and timolol 0.5% (Cosopt, Merck, Whitehouse Station, NJ) is a fixed drug combination that offers twice a day dosing that is more effective than either drug individually. The combined drug is well tolerated and provides a convenient alternative, resulting in improved patient compliance.

Brinzolamide 1% (Azopt, Alcon, Fort Worth, TX) is an ophthalmic suspension that has a more physiologic pH than dorzolamide (7.5 compared to 5.6, respectively). This white suspension must be shaken to best utilize the readily suspended and slow settling brinzolamide precipitate. The drug is also dosed three times a day and can be used chronically to treat glaucoma and ocular hypertension. This drop is better tolerated by patients because of the lower frequency of ocular surface irritation.

Acetozolamide (Diamox, Lederle, Pearl River, NY) is available as a 125-mg or 250-mg tablet, a 500-mg sustained-release (Diamox Sequel, Lederle) capsule and a 500-mg powder for intravenous injection after reconstitution. The long-term use of this medication is associated with many adverse effects caused by the induced metabolic acidosis. Oral CAIs are used on a short-term basis in acute settings of ocular hypertension or as a last resort in the treatment of glaucoma. Acetozolamide is useful for secondary glaucomas such as acute-angle closure, lens particle or phacolytic glaucoma to acutely reduce IOP while buying time until the underlying cause has resolved. For these acute situations, 250-mg four times a day or 500-mg sustained-release capsule twice a day are often used. At this dose, the effect of acetazolamide peaks at 8 hours and lasts 12 hours. When oral administration is not possible due to nausea, vomiting or anesthesia, intravenous injection of 250 mg to 500 mg can be given. Acetazolamide is not metabolized by the liver or kidney.

Acetazolamide is also used in the treatment of idiopathic intracranial hypertension (pseudotumor cerebri) and cystoid macular edema.

Methazolamide (Neptazane, Lederle) is supplied in 25-mg and 50-mg tablets. It is more lipid soluble than acetazolamide and, therefore, less of the drug is needed to achieve an ocular hypotensive effect. IOP can be effectively reduced with 25-mg to 50-mg two to three times a day. Although methazolamide has a slower onset than acetazolamide, the former has a longer duration of action. Methazolamide is metabolized by the liver, which decreases its risk of producing a metabolic acidosis. This medication is slightly better tolerated than acetazolamide at equivalent doses.

Dichlorphenamide (Daranide, Merck) is a lesser-used oral CAI. It is available in a 50-mg tablet with a two to three times a day dosing.

Side Effects

The most common side effects of topical CAIs are a bitter taste, blurry vision, burning and stinging upon instillation and superficial punctuate keratitis. Brinzolamide causes less burning, which is attributed to its near-physiologic pH. Brinzolamide suspension causes more blurry vision than dorzolamide solution. Dorzolamide can induce a transient myopic shift (up to 7 D). Topical CAIs have few serious ocular side effects.

The CA enzyme plays an important role in the metabolic pumping function of the corneal endothelium. Reports of central corneal thickening after administration of dorzolamide without any affect on endothelial cell morphology^12,13 and irreversible corneal edema in patients with endothelial compromise¹⁴ have been published. Thus far, dorzolamide does not appear to sufficiently inhibit CA enzyme outside of the eye to cause significant systemic effects with acute or chronic use.

The allergy rate is approximately 10%. Because all CAIs are sulfonamide derivatives, caution should be used in patients with a known sulfonamide allergy.

The side effects of oral CAIs remain significant and limit their prolonged use. Many patients are unable to take oral CAIs for a long period because of the disagreeable and incapacitating adverse effects. The most common side effects that result in discontinuation of the drug are malaise, fatigue, weight loss, depression, anorexia and decreased libido. Gastrointestinal symptoms including nausea, cramping, diarrhea and metallic taste are also common with chronic CAI therapy. Paresthesias are usually transient. Acute diuresis occurs during the initial treatment, but tends to be short-lived.

Metabolic acidosis occurs with acetazolamide because of the inhibited excretion of hydrogen ions from the kidney. The degree of metabolic acidosis can be severe and may require hospitalization. Patients with severe liver or kidney disease should not be treated with oral CAIs. Patients with sickle cell disease can have exacerbation of their sickle cell crisis by the acidosis. Severe metabolic acidosis due to competitive protein-binding inhibition of acetazolamide by salicylate can occur in patients taking CAIs and aspirin.^15,16

Hypokalemia can develop in patients who are concurrently taking other drugs that cause potassium loss such as thiazide diuretics, steroids and aminoglycoside antibiotics. Potassium supplementation is often required. Hypokalemia must be avoided in patients taking digitalis as it can potentiate digitalis toxicity.

There is an 11- to 15-fold increased risk of renal calculi usually occurring within the first 6 months of treatment. The alkaline urine that results from CAIs leads to the formation of calcium salts that become calcium oxylate and calcium phosphate renal stones. The recurrence rate of stone formation is also high.

Blood dyscrasias such as aplastic anemia, agranulocytosis and thrombocytopenia are rare adverse effects that can have fatal results. Aplastic anemia appears to be an idiosyncratic reaction to CAIs that is not dose- or time-dependent.¹⁷ Periodic complete blood count screening is suggested by some investigators; however, these studies are not predictive of the hematopoietic toxicity.

In consideration of these systemic side effects, the use of oral CAIs should be reserved for use in acute situations when IOP must be maximally lowered. Topical CAIs are not as effective in decreasing aqueous production, but they provide an acceptable reduction in IOP, especially when combined with other topical aqueous suppressants, and have a much safer side effect profile.

Conclusion

Both oral and topical forms of CAIs are effective medications for lowering IOP. However, in consideration of the associated systemic side effects, the use of oral CAIs should be reserved for use in acute situations when IOP must be maximally lowered. Topical CAIs are not as effective in decreasing aqueous production, but they provide an acceptable reduction in IOP, especially when combined with other topical aqueous suppressants, and have a much safer side-effect profile.

References

1. Becker B. Decrease in intraocular pressure in man by a carbonic anhydrase inhibitor, Diamox. A preliminary report. Am J Ophthalmol. 1954;37:13.
2. Grant WM, Trotter RR. Diamox (acetazolamide) in treatment of glaucoma. Arch Ophthalmol. 1954;51:735.
3. Lutjen-Drecoll E, Lonnerholm G, Eichhorn M. Carbonic anhydrase distribution in the human and monkey eye by light and electron microscopy. Graefes Arch Clin Exp Ophthalmol. 1983;220:285-291.
4. Lippa EA, Carlson LE, Ehinger B, et al. Dose response and duration of action of dorzolamide, a topical carbonic anhydrase inhibitor. Arch Ophthalmol. 1992;110:495-499.
5. Strahlman E, Tipping R, Vogel R. A double-masked, randomized 1-year study comparing dorzolamide (Trusopt), timolol, and betaxolol. International Dorzolamide Study Group. Arch Ophthalmol. 1995;113:1009-1016.
6. Boyle JE, Ghosh K, Gieser DK, et al. A randomized trial comparing the dorzolamide-timolol combination given twice daily to monotherapy with timolol and dorzolamide. Dorzolamide-Timolol Study Group. Ophthalmology. 1998;105:1945-1951.
7. Strohmaier K, Snyder E, DuBiner H, et al. The efficacy and safety of the dorzolamide-timolol combination versus the concomitant administration of its components. Dorzolamide-Timolol Study Group. Ophthalmology. 1998;105:1936-1944.
8. Whitson JT, Henry C, Hughes B. Comparison of the safety and efficacy of dorzolamide 2% and brimonidine 0.2% in patients with glaucoma or ocular hypertension. J Glaucoma. 2004;13:168-173.
9. Ozturk F, Ermis SS, Inan UU, et al. Comparison of the efficacy and safety of dorzolamide 2% when added to brimonidine 0.2% or timolol maleate 0.5% in patients with primary open-angle glaucoma. J Ocul Pharmacol Ther. 2005;21:68-74.
10. Michaud JE, Friren B, International Brinzolamide Adjunctive Study Group. Comparison of topical brinzolamide 1% and dorzolamide 2% eye drops given twice daily in addition to timolol 0.5% in patients with primary open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2001;132:235-243.
11. Maus TL, Larsson LI, McLaren JW, Brubaker RF. Comparison of dorzolamide and acetazolamide as suppressors of aqueous humor flow in humans. Arch Ophthalmol. 1997;115:45-49.
12. Wirtitsch MG, Findl O, Kiss B, et al. Short-term effect of dorzolamide hydrochloride on central corneal thickness in humans with cornea guttata. Arch Ophthalmol. 2003;121:621-625.
13. Inoue K, Okugawa K, Oshika T, Amano S. Influence of dorzolamide on corneal endothelium. Jpn J Ophthalmol. 2003;47:129-33.
14. Konowal A, Morrison JC, Brown SV, et al. Irreversible corneal decompensation in patients treated with topical dorzolamide. Am J Ophthalmol. 1999;127:403-406.
15. Cowan RA, Hartnell GG, Lowdell CP, et al. Metabolic acidosis induced by carbonic anhydrase inhibitors and salicylates in patients with normal renal function. Br Med J (Clin Res Ed). 1984;289:347-348.
16. Sweeney KR, Chapron DJ, Brandt JL. Toxic interaction between acetazolamide and salicylate: case reports and a pharmacokinetic explanation. Clin Pharmacol Ther. 1986;40:518-524.
17. Fraundelder FT, Meyer SM, Bagby GC Jr., Dreis MW. Hematologic reactions to carbonic anhydrase inhibitors. Am J Ophthalmol. 1985;100:79-81.