ZONA BAJA

After the introduction of oral acetazolamide, the search began for a topically active CAI that would reduce IOP without the adverse effects associated with the oral CAIs. One group of topical CAIs to be developed that demonstrated good clinical potential was the thienoth- iopyran-2-sulfonamides, such as dorzolamide. Initially,

topical CAIs were thought to gain access to the ciliary body through both local ocular penetration and systemic absorption. Many studies have shown, however, that local penetration is the major route.Topical CAIs alter aqueous humor composition; this includes lowering pH, decreasing bicarbonate levels, and increasing posterior chamber ascorbate levels limited to the eye receiving the dose.

Dorzolamide (Trusopt)

Pharmacology

Dorzolamide was the first commercially available topical CAI to show significant ocular hypotensive activity in humans.The addition of an alkyl amino side group allows this compound to alternate between an acidic and basic form. This property enhances both lipid and water solu- bility, thereby allowing increased corneal and scleral penetration.

When used as monotherapy, the usual dose is one drop of dorzolamide 2% (approximately 30 mL) every 8 hours. The plasma concentration of free drug is approximately 1/200th of the amount required for systemic pharmaco- logic effects. However, the concentration in the ciliary processes (2 to 10 mcmol/l) is equivalent to that produced by systemic CAIs.

Inhibition of isoenzyme II in the ciliary processes by dorzolamide is thought to be responsible for decreasing aqueous humor secretion. Dorzolamide also inhibits membrane-bound isoenzyme IV, which is currently being investigated for its role in the production of aqueous humor.

Although effective, topical dorzolamide 2% does not appear to inhibit aqueous humor formation to the same extent as systemic acetazolamide. This may, in part, be a result of incomplete inhibition of one or two carbonic anhydrase isoenzymes responsible for aqueous humor production. In normal humans, dorzolamide 2% reduces aqueous humor flow during the day and at night during sleep 13% and 9%, respectively, although not as effectively as does systemic acetazolamide (24% suppression). The additive effect of dorzolamide on aqueous humor flow in glaucoma patients was studied in patients who had been receiving long-term timolol. Dorzolamide further reduced aqueous flow by 24% ± 11%.There appears to be no addi- tive effect of dorzolamide with latanoprost on the rate of aqueous humor flow in normal subjects.

Topical dorzolamide does not appear to cause a change in retinal circulatory variables, including venous diameter and volumetric blood flow rate, after a single dose in normal subjects. The drug also does not have any apparent effect on retrobulbar hemodynamics as determined by color Doppler imaging. In some studies, however, improvements in retinal, choroidal, and retrobul- bar blood flow as determined by various assessment meth- ods and hemodynamic markers demonstrate that dorzolamide alone or in combination therapy may improve ocular blood flow in patients with glaucoma and ocular

hypertension.The clinical significance of this has not been elucidated.

Clinical Uses

Dorzolamide is indicated for the treatment of elevated IOP in patients with ocular hypertension and open-angle glaucoma.The drug is commercially available as a 2.0% solu- tion (Trusopt). It is supplied as a sterile, isotonic, buffered, slightly viscous solution with a pH of approximately 5.6. BAC 0.0075% is added as a preservative.

When administered twice daily and three times daily, 2.0% dorzolamide reduces IOP 21.8% to 24.4% and 22.2% to 26.2%, respectively. The maximal ocular hypotensive effect occurs 2 hours after administration. Although twice-daily administration reduces IOP, dosing three times daily produces better overall ocular hypotensive effect.

Monotherapy with three-times-daily 2% dorzolamide and twice-daily timolol 0.5% or betaxolol 0.5% demon- strated peak IOP changes of 23%, 25%, and 21%, respec- tively.Additive effects on IOP occur when dorzolamide is added to timolol gel solution.

Dorzolamide was also evaluated in open-angle glau- coma or ocular hypertension patients as monotherapy and when used with timolol and/or pilocarpine for up to 2 years. At 2 years the mean decrease in IOP was approx- imately 23% for monotherapy patients and 31% to 36% for adjunctive therapy patients. Although dorzolamide was reasonably well tolerated, most patients required adjunc- tive therapy within 6 months.

Topical dorzolamide and oral acetazolamide do not produce additive effects, and their concomitant use is not indicated for glaucoma therapy.

Dorzolamide has been compared with acetazolamide for the prevention of IOP spikes after YAG laser capsulo- tomy. One drop of topical dorzolamide 2% and one 125-mg dose of acetazolamide 1 hour before capsulotomy are comparable in preventing elevations of IOP. Dorzolamide is also effective in preventing IOP spikes after argon laser trabeculoplasty or laser iridotomy.

Because dorzolamide inhibits carbonic anhydrase II in the corneal endothelium, the long-term effects of dorzol- amide on corneal endothelial cell density and thickness have been of interest. Patients with glaucoma or ocular hypertension have been evaluated for 1 year by corneal specular microscopy and ultrasonic pachymetry, and dorzolamide has demonstrated good long-term tolerability. Side Effects

Dorzolamide is generally well tolerated. Ocular side effects include local irritation, possibly related to pH and tonicity. Stinging (7%), burning or foreign body sensation (12%), and blurring of vision (9%) are among the most common. Others include superficial punctate keratitis and headache. A severe sterile purulent conjunctivitis developing over weeks to months was described in seven patients and resolved on discontinuation of dorzolamide. Because all CAIs are sulfonamides, local sensitization has

been reported in approximately 4% of patients as lid or conjunctival allergies.

Because dorzolamide may inhibit corneal endothelial carbonic anhydrase, it may potentially cause some corneal edema or decompensation. There is generally little or no change in corneal thickness and endothelial cell count. However, nine patients with corneal endothe- lial compromise developed irreversible corneal edema within 3 to 20 weeks (mean, 8 weeks) after treatment began. All patients had undergone previous intraocular surgery, including four patients who had undergone corneal transplantation. A hypersensitivity reaction caus- ing a marginal keratitis was reported with topical dorzol- amide, which resolved upon drug discontinuation.

Systemic side effects reported with oral CAIs have generally not been seen with topical CAIs. Paresthesias, electrolyte imbalance, and CNS side effects, including malaise and fatigue, have not been reported with dorzol- amide. Bitter taste is experienced in approximately 25% of patients taking topical dorzolamide. Three cases of nephrolithiasis have been attributed to topical dorzo- lamide. Onset was from 21 days to 8 months after treat- ment began. Two patients, however, had previously received systemic CAIs. Because there may be an increased risk of developing nephrolithiasis, a careful history of renal calculi should be obtained.

Because a potential exists for an additive systemic effect with other CAIs, the concomitant use of topical dorzolamide with an oral CAI is not recommended. The safety of dorzolamide use has not been established in pregnancy, lactation, or in children. However, the drug has been studied in children with glaucoma who were previ- ously on oral acetazolamide. Dorzolamide was effective and did not cause any adverse reactions or intolerance. Contraindications

Dorzolamide is administered topically but can be absorbed systemically. Although there is risk of systemic hypersensitivity reactions to dorzolamide, a nonantibiotic sulfonamide, in patients allergic to sulfonamide antibiotics, the risk appears to be low.

The use of dorzolamide has not been studied in patients with severe renal impairment (CrCl < 30 ml/min).The drug, therefore, should be used cautiously in such patients. Likewise, dorzolamide should be used with caution in patients with hepatic impairment. Because of potential additive systemic effects, dorzolamide should be avoided in patients taking an oral CAI.

Brinzolamide (Azopt)

Pharmacology

Brinzolamide, a heterocyclic sulfonamide, is a topical CAI suspension that has a high affinity for the carbonic anhy- drase II isoenzyme.Because the ocular hypotensive effect of the drug is equivalent whether dosed twice or three times daily, brinzolamide 1% may be administered twice daily.

Clinical Uses

Brinzolamide is indicated for the treatment of elevated IOP in patients with ocular hypertension or open-angle glaucoma. The drug is commercially available as a sterile 1.0% aqueous suspension with a pH of approximately 7.5. BAC 0.01% is added as a preservative.

The efficacy and safety of brinzolamide 1%, either two or three times daily, were evaluated in 572 patients with open-angle glaucoma or ocular hypertension against timolol 0.5% twice daily and dorzolamide 2.0% three times daily. Mean IOP changes were –3.8 to –5.7 mm Hg, –4.2 to –5.6 mm Hg, and –4.3 to –5.9 mm Hg for two- and three-times-daily brinzolamide and dorzolamide dosing, respectively. The mean IOP changes for timolol 0.5% ranged from –5.6 to –6.3 mm Hg (Figure 10-15). Brinzolamide was well tolerated, with 1.8% (twice daily) and 3% (three times daily) of patients reporting ocular discomfort versus 16.4% with dorzolamide. Complaints of blurred vision were higher with brinzolamide (5–6%) than dorzolamide (1%) or timolol (0%).

A meta-analysis of randomized clinical trials reported peak ocular hypotensive effect on IOP of 17% (19% to 15%) and trough effect of 17% (19% to 15%).

Side Effects

Both brinzolamide and dorzolamide exhibit similar taste abnormalities. A single case report of the development of metabolic acidosis from topical brinzolamide has been described after twice-daily dosing. Other adverse events are negligible for brinzolamide except for some blurring of vision, attributable to its suspension vehicle.

Contraindications

Brinzolamide has the same contraindications and precau- tions as dorzolamide.

Timolol 0.5% and Dorzolamide 2% (Cosopt)

A combination product of timolol 0.5% and dorzolamide 2% is available (Cosopt). This fixed-combination dosed twice daily is equivalent to dorzolamide 2% three times daily and timolol 0.5% twice daily dosed separately. Moreover, the combination product is more convenient, requiring one bottle and fewer drops per day than sepa- rate bottles. The combination product used twice daily has been compared with monotherapy with either dorzol- amide 2% three times daily or timolol 0.5% twice daily. The mean reduction in IOP was 27.4% (–7.7 mm Hg), 15.5% (–4.6 mm Hg), and 22.2% (–6.4 mm Hg) for the combination product, dorzolamide, and timolol, respec- tively (Figure 10-16). The dorzolamide–timolol combina- tion was compared with either individual component in patients not controlled on timolol twice daily alone. The combination product was more effective than either timolol 0.5% twice daily or dorzolamide 2% three times daily for up to 3 months. The most frequently reported ocular side effect was ocular burning or stinging, with the overall adverse effects being similar for the combination product and dorzolamide, but less for timolol.

The ocular hypotensive effect of Cosopt has been compared with that of latanoprost. Mean diurnal IOP changes of –7.1 ± 3.8 mm Hg and –7.1 ± 3.3 mm Hg for Cosopt and latanoprost, respectively, were found. Both agents are equally effective in lowering IOP, although latanoprost is better tolerated than is Cosopt. Both treat- ments also show similar efficacy in regards to percentage of patients achieving target pressures.

The substitution of brinzolamide for dorzolamide in addition to concomitant administration of timolol demon- strates equivalent IOP reduction but less ocular burning

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Mean IOP change (mm Hg)

−3 −4 −5 −6 −7 Month 1 8:00 AM Month 1 10:00 AM Month 2 8:00 AM Month 2 10:00 AM Month 2 6:00 PM Month 3 8:00 AM Month 3 10:00 AM Month 3 6:00 AM Brinzolamide 1% BID Brinzolamide 1% TID Dorzolamide 2% TID Timolol 0.5% BID

Figure 10-15 Mean intraocular pressure (IOP) change (mm Hg) for the various treatment groups by visit and time of day for a 3-month treatment period. Each value represents the least-squares mean of the change from baseline diurnal IOP, and all were significant. (Adapted from Silver LH, Brinzolamide Primary Therapy Study Group. Clinical efficacy and safety of brinzol- amide [Azopt], a new topical carbonic anhydrase inhibitor for primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol 1998;126:400–408.)

and stinging.Additional studies have also shown that brin- zolamide and dorzolamide are both safe and effective when added as adjunctive therapy to the combination of latanoprost and a β-blocker.

Clinical Advantages of Topical Carbonic Anhydrase Inhibitors

Topical CAIs offer distinct advantages over other inhibitors of aqueous humor formation. Compared with β-blockers, CAIs reduce the nocturnal aqueous flow rate by 25%.β-Blockers lack the ability to suppress aqueous formation below the already reduced flow rate that occurs during sleep. In contrast to systemic CAIs, topical CAIs lack most of the systemic side effects while produc- ing a comparable ocular hypotensive effect. None of the topical CAIs, however, has the ability to reduce IOP to the level achieved by 500 mg of oral acetazolamide. Topical agents are used in place of systemic CAIs for chronic treatment of primary and secondary open-angle glauco- mas. Other recently developed medications have proba- bly relegated the position of topical CAIs to second- or third-line therapy. Cosopt may simplify therapy and improve compliance for patients who require treatment with both timolol and dorzolamide.