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Topical Carbonic Anhydrase Inhibitors

Pratap Challa, MD, MS and Joel S. Schuman, MD, FACS

Carbonic anhydrase inhibitors (CAIs) have been used for glaucoma therapy since 1954, following the description of their efficacy by Becker¹ and Grant et al.² Despite the fact that these agents reduce intraocular pressure (IOP), their systemic use has been limited by side effects³ such as malaise, fatigue, weight loss, depression, anorexia, paresthesias, loss of libido, abdominal cramping, gastric burning and irritation, nausea, diarrhea, kidney stones, bone marrow depression, and even potentially fatal side effects such as aplastic anemia. To reduce the adverse effects associated with these agents, creative use has been made of alkalinizing agents, such as bicarbonate or sodium acetate, to decrease the symptom complex related to the metabolic acidosis induced by CAIs.^3–5 Even with this adjunctive therapy, however, oral CAIs have found limited use in the chronic treatment of glaucoma, primarily because they are poorly tolerated by a significant proportion of patients.

As an attempt to capture the beneficial IOP-lowering action of CAIs, while minimizing their adverse effects, topical CAIs that could decrease IOP without producing the harmful consequences of the oral agents underwent considerable investigation. The quest for such a preparation extends back to Grant’s initial publication on acetazolamide, when he found that topical or subconjunctival application of the drug was ineffective in reducing IOP.² Over the ensuing years, several compounds were investigated for this purpose, with little success. Some of the more successful agents include dichlorphenamide, which reduced IOP in rabbits,⁶ ethoxzolamide analogs,^7–11 ethoxzolamide gel and suspension,^10–13 methazolamide, and benzolamide analogs.^8,9 Each of these agents was investigated thoroughly, but was found to be ineffective, hazardous, or too irritating for topical use. Many of these investigations involved Thomas Maren, who also played a key role in the development of CAIs for systemic use.

In 1988, a breakthrough occurred with the introduction of MK-927, a new topical agent specifically formulated for the eye produced by Merck, Sharp, and Dohme Research Laboratories.¹⁴ This agent proved to be effective in humans and to be well tolerated.^14–16 Double-masked, randomized, placebo-controlled, multicenter studies on this drug demonstrated efficacy and safety, with a peak effect approximately 2 hours after topical administration.^15,17–19

Laboratory investigation showed that this agent entered the eye not only through the cornea, but primarily via a nonaqueous, transscleral route at the limbal region.^20,21 Although many of the other agents investigated for this purpose did not penetrate the eye well, topically administered MK-927 resulted in permeation of the drug to the corneal stroma, aqueous, and ciliary processes.¹⁶ Ocular penetration was most likely related to the property of the drug as an ampholyte, capable of ionizing into anionic and cationic forms. Furthermore, a major advantage to topical administration was that the systemic distribution was decreased over oral agents. The plasma concentration of the drug after a single topical ocular administration was less than 1 μM in rabbits, while at least 2 to 10 μM plasma concentration would be required for physiological side effects. This indicated that systemic toxicity should be minimal or absent,^16,22 which has been confirmed in further human studies.^23,24 Therefore, topical CAIs are preferable over systemic agents due to their decreased systemic side effect profiles.

The first commercially available topical CAI was MK-507, or dorzolamide (Figure 15-1), and it was approved by the US Food and Drug Administration (FDA) in December 1994. Marketed under the trade name Trusopt, it is also an ampholyte like MK-927.^14,24 One property of the dorzolamide molecule is that it requires an acidic pH (5.6) for solubilization and favorable ocular bioavailability. The acidic nature of this solution results in the frequent ocular complaints of stinging and burning upon drop instillation. In our experience, patients with dry eyes complain the most with this medication, and the use of artificial tears 5 to 10 minutes prior to using dorzolamide can make the drop more tolerable.

A second topical CAI was approved by the US FDA in April 1998. It was named brinzolamide and is marketed as Azopt.^25,26 This drug has lipophilic properties that improve its corneal penetration but also make it relatively insoluble in solution. The insolubility problem was addressed by making it into a viscous carbomer suspension with a near-physiological pH (7.5). This prolongs the corneal contact time of the drug and thus increases the drug’s bioavailability. However, this also results in the common complaint of blurred vision and occasional stinging after drop instillation.

As discussed in the chapter on systemic CAI medications, the site of action of all CAIs is in the nonpigmented ciliary epithelium where they block CA isoenzymes. The topical CAIs have a much greater affinity for CA II over that of I or IV.^27,28 This is in contrast to acetazolamide, which nonselectively inhibits both types II and IV (both found in the nonpigmented ciliary epithelium) and may be responsible for its slightly greater pressure effect.²⁹

Both dorzolamide and brinzolamide have proven efficacy in reducing aqueous production and IOP in clinical trials.^{24,25,30–33} Both of them appear to have similar effects on IOP, and as monotherapy (dosed tid), their peak effect occurs at 2 to 3 hours postinstillation and results in a 16% to 24% IOP reduction. Their trough activity is also similar with a 13% to 18% pressure reduction at 12 hours.^{24–26,30,33,34} Their activity appears to be comparable to other drugs that decrease aqueous production such as betaxolol^35–37 and brimonidine,^38,39 although the nonselective beta-blocker timolol appears to have a small (5% to 10%) advantage in IOP lowering.³⁷ They are not as effective as the prostaglandin analogs,³⁷ and so they are typically used as adjunctive agents after other medications have been initiated. When added to timolol 0.5% or to maximal medical therapy, twice-daily dorzolamide and brinzolamide provide an additional reduction in IOP of 11% to 20% and 11% to 16% at peak and trough, respectively.^40–42 Therefore, fixed combinations of these medications have been developed and are marketed as Cosopt (dorzolamide/timolol) and Simbrinza (brinzolamide/brimonidine tartrate) in the United States and Azarga (brinzolamide/timolol) in Europe. The IOP effect of the 2 fixed combinations is similar to each other as well as to concomitant administration of each individual medication.^43,44

DOSING

The topical CAIs are useful in treating nearly all of the glaucomas. They have been approved for 3-times-daily dosing, but due to patient compliance issues, many practitioners use them twice a day. In their fixed combination formulations, they are dosed twice daily to avoid excessive beta-blocker dosing. For most patients, twice-daily dosing is reasonable with the understanding that there may be slightly less trough IOP control with dorzolamide.^45,46 With brinzolamide, there does not appear to be any statistically significant difference between twice-daily and 3-timesdaily dosing.^26,47 Therefore, it is reasonable to use these medications twice daily, but in those patients who need the flattest diurnal pressure curve possible, we use dorzolamide 3 times daily. For such patients on Cosopt, we sometimes ask them to take an additional dorzolamide drop at midday between their Cosopt dosing.

OCULAR HEMODYNAMIC EFFECTS OF THE TOPICAL CARBONIC ANHYDRASE INHIBITORS

The topical (and oral) CAIs have been shown in some studies to alter ocular hemodynamics. They can increase the ocular pulse amplitude,⁴⁸ shorten the arteriovenous passage time (this appears to be increased in patients with glaucoma),⁴⁹ increase end diastolic velocity of the short posterior ciliary arteries, and increase retinal oxygen saturation.^50,51 Another study has shown no change in retrobulbar hemodynamics.⁴⁹ It should be noted that these are difficult parameters to measure with current instruments, but if these changes are further validated, then these drugs could potentially have beneficial effects on ganglion cell function. Increased contrast sensitivity has been reported in low-tension glaucoma patients⁵² as has decreased visual field progression in primary open-angle glaucoma.⁵¹ However, it is difficult to tease out whether these beneficial effects are due to the lowering of IOP vs the hemodynamic effects of these medications. Therefore, the clinical significance of these studies is unclear at present, and they warrant further study.

Although the primary site of action for this drug class is at the ciliary epithelium, one must keep in mind that other ocular structures also express CA and that their inhibition can lead to unintended side effects. The CA isoenzyme types I and II are important for corneal endothelial pump function,53–55 and as mentioned before, the topical CAIs are particularly active against type II. This is especially important because these drugs have been optimized for corneal permeation to allow for diffusion to the ciliary body. Moreover, these drugs need to be quite potent due to the high efficiency of this enzyme class; nearly total (99.9%) inhibition is needed to achieve pressure lowering. Hence, topical delivery can result in direct exposure of the cornea with the potential to affect endothelial pump function. This does not appear to be a problem in ocular hypertensive and open-angle glaucoma patients who have normal endothelial cell counts.⁵⁶ However, increased central corneal thickness measurements have been reported in individuals with known corneal guttata^57,58 and even in patients immediately after yttrium-aluminum-garnet casulotomy.⁵⁹ Furthermore, both reversible and irreversible corneal decompensation has been rarely reported with topical CAI use.^60,61 Therefore, topical CAIs should be used with caution in patients with Fuchs’ corneal dystrophy and other endotheliopathies.

The topical CAIs exhibit much fewer systemic side effects compared to oral CAIs. However, serious systemic side effects have been rarely reported with topical CAIs. This includes nephrolithiasis⁶² and thrombocytopenia.⁶³ These drugs should be used with caution in pregnant and lactating women because they have not been sufficiently studied in these groups. Likewise, no formal studies in children have been performed, but retrospective studies suggest that they are well tolerated.⁶⁴ However, one area of concern is that premature and newborn infants may be susceptible to acidosis with these medications. As mentioned previously, these medications can cross into breastmilk and should be used with caution in lactating women.⁶⁵

Less serious side effects, such as abnormal taste, fatigue, headaches, paresthesias, decreased appetite, and malaise, have been reported with topical CAIs, and associated ocular complaints include burning, stinging, blurred vision, pruritus, and irritation.^34,47 Ocular irritation is more common with dorzolamide due to the acidic pH of the solution, and blurriness is more common with brinzolamide due to the suspension’s viscous nature. In general, brinzolamide has been reported to be somewhat better tolerated.^41,47

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