Topical Agents

In 1955, a year after the introduction of oral acetazolamide as an effective ocular hypotensive agent, an unsuccessful attempt to solubilize it for topical treatment was reported.22 The effort to develop a topical agent was revisited in the late 1970s and led to the introduction of several prototype molecules that preceded the approval of dorzolamide in 1995 and brinzolamide in 1998. The availability of these agents has not only dramatically reduced the justification for using oral CAIs but has greatly reduced the side effects associated with the oral agents and has reminded ophthalmologists of the long-term advantage of low pharmacologic tolerance with these nonadrenergic drugs.

6.2.1 Pharmacology. Two topical CAIs that are currently available are dorzolamide and brinzolamide. Dorzolamide (C10H16N2Q4S3 HCl) and brinzolamide (C12H21-N3O5S3) are water-soluble CAIs. Dorzolamide has a substituted amino group (-NHCH2CH3) and thus differs in that respect from the systemic CAIs previously discussed. Both compounds specifically inhibit carbonic anhydrase II, which is found primarily in red blood cells but is also found in ocular tissue such as ciliary processes, corneal endothelium, and Muller cells in the retina.1

6.2.2 Mechanism of Action. The mechanism of action is similar to systemic CAIs. By inhibiting the formation of bicarbonate, the influx of sodium and fluid is reduced, thus reducing IOP. Ingram and Brubaker23 measured the effects of dorzolamide 2% and brinzolamide 1% on aqueous humor formation in a series of 25 normal subjects using fluorophotometry. Compared to the placebo-treated eyes, brinzolamide 1% reduced aqueous production by 0.47 ± 0.20 mL/min (19% ± 10%) during the day and 0.16 ± 0.12 mL/min (16% ± 14%) during the evening. Similarly, dorzolamide 2% reduced aqueous production by 0.34 ± 0.20 mL/min (12% ± 12%) during the day and 0.10 ± 0.13 mL/min (8% ± 14%) at night. As suppressors of aqueous production, the researchers considered the two drugs equivalent.

6.2.3 Indications. The indications for topical CAIs are broader than the indications for systemic agents. In most instances, topical CAIs work well as adjunctive agents rather than first-line agents. However, in special instances when first-line agents may not be well tolerated, particularly in the very young and the elderly, topical CAIs may be considered as first-line agents.

6.2.4 Dorzolamide. Rudimentary attempts at developing a topical CAI included use of acetazolamide-soaked contact lenses,24 as well as new derivatives such as ethox-zolamide gel,25 trifluoro methazolamide,26 and a 6-amino compound.27 Some of these showed transient reductions in IOP in animal models, but there was difficulty achieving adequate ocular penetration to allow the 99% of carbonic anhydrase enzymatic inhibition in ciliary processes required for a sustained IOP effect. Finally, one of the many screened compounds, dorzolamide, was found to be 10 times more effective than acetazolamide at inhibiting carbonic anhydrase isoenzyme II, which is the predominant form in both nonpigmented and pigmented ciliary process epithelium (figure 6.3). Dorzolamide was also twice as effective as acetazolamide in inhibiting isoenzyme II in an in vitro lung preparation.28 Starting in 1990, this compound was tested in glaucomatous monkey and rabbit models,29,30 followed by clinical trials in both normal volunteers and glaucoma patients. At the 2% concentration, the compound was very effective in lowering IOP in both primates and humans. Aqueous dynamics in glaucomatous monkeys showed a 38% reduction in aqueous secretion with no change in outflow facility following single-drop therapy.31 Dorzolamide administered three times daily was compared with twice-daily timolol and twice-daily betaxolol over 12 months in a large, multicenter, prospective, masked trial.32 At peak effect (2 hours), the sustained IOP-lowering effect of dorzolamide was 1 to 2 mm Hg less than timolol solution, but approximately 1mmHg better than betaxolol 0.5%. The IOP effect was maintained for the 12 months of the study, but the difference between the treatment groups at peak disappeared. The trough IOPs, or IOPs measured before the morning dose of medication, while initially very similar, actually increased at 12 months, and again, dorzolamide was intermediate in efficacy between timolol and betaxolol by a small magnitude.

Figure 6.3. Chemical structure of topical carbonic anhydrase inhibitors.

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