CARBONIC ANHYDRASE INHIBITORS FOR THE TREATMENT OF GLAUCOMA

Glaucoma is the leading cause of irreversible blindness. Its leading symptom and the most important initial link of the disease pathogenesis is represented by an increase of intraocular pressure (IOP). Decrease of IOP is a basic notion in the therapy of glaucoma. Drug-induced therapy is currently the most widely spread initial intervention to decrease IOP. Prostaglandin analogues are referred to the basic group of pharmacotherapeutic agents, because they are the most effective and well tolerated. Beta-blocking agents are selected as an alternative. Other medicinal products to treat glaucoma include inhibitors of carbonic anhydrase for systemic (acetazolamide and methazolamide) and local (dorzolamide and brinzolamide) use. Systemic inhibitors of carbonic anhydrase are, on the one hand, more active than non-systemic medicinal preparations, and, on the other hand, have numerous side effects which are not safe for humans. Thus, medicinal preparations for local use are most frequently applied in the therapy of glaucoma. If necessary, they are combined with beta-blocking agents or alpha-adrenergic agonists.

According to the World Health Organization (WHO), a number of patients with glaucoma around the world varies from 60.5 to 105 mil.people.Meanwhile it is expected that a number of patients will be increased by 10 mil.during the next 10 years.In Russia, over 1 mil. of patients with glaucoma have been revealed.However, a true number of patients is twice as high Increase of intraocular pressure (IOP) is the leading symptom of glaucoma and the most important initial link of the disease pathogenesis.Recently, the notion of 'tolerant IOP' has become increasingly common.It means the range of IOP, which is safe for this person.Tolerant IOP is not only subject to individual variations, but can also be changed throughout life and under the effect of certain general and eye diseases.Thus, the individual value of tolerant pressure can be significantly lower than the upper limit of statistically normal IOP.
Decrease in intraocular pressure (IOP) is a basic term in glaucoma therapy.In open-angle glaucoma, it is the basis of treatment, in close-angle glaucoma it is a part of complex therapy, which requires a surgery [2][3][4].Currently, drug-induced therapy is the most widely spread initial intervention to decrease IOP [2][3][4].The basic group of pharmacotherapeutic agents is represented by prostaglandin analogues, as they are the most effective ones (decrease of IOP by 25-33%), well tolerated and they should be instilled into an eye only once a day [2,3,[5][6][7][8].Ophthalmological forms of beta-blocking agents are selected as an alternative (in case of intolerance or other obstacles for indication of prostaglandins) [2,3,8,9].They result in IOP decrease by 20-25% [2].Other agents for glaucoma treatment include carbonic anhydrase inhibitors for systemic (peroral) and local use (decrease of IOP by 20-30%), alpha2-adrenergic agonists, parasympathomimetics, and rho-kinase inhibitors [2,3,10,11].
Ophthalmological agents of carbonic anhydrase inhibitors include dorzolamide (2% eye drops and a combined preparation with 0.5% timolol) and brinzolamide (1% eye suspension and a combined preparation with 0.2% brimonidine) [4].These agents decrease IOP by 15-20% [2].Peroral (systemic) carbonic anhydrase inhibitors are more active and represented by acetazolamide (tablets 125 and 250 mg; sustain-action tablets 500 mg) and methazolamide (tablets, 25 and 50 mg).Acetazolamide is used in an acute attack of glaucoma [4].Today, two generations of drugs from the group of carbonic anhydrase inhibitors are distinguished.The 1 st generation carbonic anhydrase inhibitors include acetazolamide and methazolamide, the 2 nd generation agents involve non-systemic dorzolamide and brinzolamide.
Comparative effectiveness and tolerance of 1 st and 2 nd generation carbonic anhydrase inhibitors in glaucoma are reviewed in a number of studies [12][13][14].
As far as effectiveness of these agents go, it should be noted that acetazolamide produces a more active effect on IOP control as compared with dorzolamide.Thus, in a randomized, double-blind, placebo-controlled study of 40 people at 2 academic sites [12] acetazolamide decreased IOP by 19% in average (P < 0.001), whereas dorzolamide did the same by 13% (P < 0.001).The result was confirmed during a randomized, multi-centered, double blind, parallel cohort study with 215 patients with open-angle glaucoma or eye hypertension.Dorzolamide (2% solution TID) or acetazolamide (250 mg QID) were added to 0.5 timolol maleate ophthalmic gel-forming solution for 12 weeks [13].Control of IOP was statistically better (P = 0.009) in the group of acetazolamide (0.1 ± 0.42 mm Hg) as compared with dorzolamide (1.9 ± 0.43 mm Hg).
During an earlier study involving 105 patients where acetazolamide and dorzolamide were added to timolol in a randomized fashion while treating glaucoma for 12 weeks [14], similar results were obtained: the average IOP was slightly lower (approximately by 1 mm Hg), during intake of acetazolamide it was reduced in a more active way approximately by 1 mm Hg as compared with dorzolamide [14].
Acetazolamide reduced formation of IOP more actively as compared with dorzolamide: by 30% and 17%, respectively.The difference between the action of acetazolamide and dorzolamide was statistically significant (P < 0.001).When acetazolamide was added to dorzolamide, formation of intraocular liquid was additionally reduced by 16% (P < 0.001).In case dorzolamide was added to acetazolamide, no additional decrease of the flow was observed (P = 0.73) [12].However, dorzolamide displayed a significantly better tolerance by patients as compared with acetazolamide in all three studies [13,14].
Acetazolamide was associated with a statistically greater number of systemic adverse events than dorzolamide (dorzolamide 26%, acetazolamide 53%, p < 0.001) and cases of treatment discontinuation due to side effects (dorzolamide 2-8%, acetazolamide 24-25%, p = 0.007) [13,14].In the group of dorzolamide, incidence of systemic adverse reactions was reduced by 50% by week 12 but remained the same in the group of acetazolamide (р < 0.001) [14].A higher rate of adverse events due to administration of acetazolamide 1 st generation carbonic anhydrase inhibitors and its more frequent discontinuation were found in these studies as compared with dorzolamide [13,14].
Thus, as far as 2 nd generation agents go, they are safe enough and have obvious advantages in a clinic because they cause adverse effects to a much lesser extent [4].Regular adverse effects of systemic inhibitors of carbonic anhydrase include paresthesia (of feet and hands), discomfort in the stomach, hypopotassemia, kidney stones and allergic reactions.In case of acetazolamide intake, stomach discomfort and paresthesia occur more frequently than in case of methazolamide [4].With acetazolamide, very rare, but sometimes severe adverse effects are developed (acute renal insufficiency, paralytic ileus, thrombocytopenia, myopia in the highlands, and Steven-Johnson syndrome) [15][16][17][18][19]. Burning and tingling in the eye and such a systemic adverse effect as metallic taste in the mouth are found while using dorzolamide (more frequently) and brinzolamide (less frequently) [4].
It has become a tradition of therapeutic use of the 2 nd generation carbonic anhydrase inhibitors to increase effectiveness of prostaglandins or beta-adrenal blockers.α 2 -adrenoceptor agonists are often used for this purpose apart from 2 nd generation carbonic anhydrase inhibitors.An extensive meta-analysis (26 tests involving 5583 patients) was conducted to estimate effectiveness and safety of brinzolamide and dorzolamide as add-on therapy to analogs of prostaglandin or beta-blocking agents during treatment of patients with glaucoma or eye hypertension, which can't properly control IOP in monotherapy [20].It has been shown that brinzolamide and timolol were not significantly different regarding decrease in IOP as addition to prostaglandins; equal effectiveness of administration was found during comparison with dorzolamide.
As compared with brimonidine (BID), brinzolamide caused a more significant decrease in IOP in the morning (P < 0.0001), but not during the rest of the day, when its effectiveness was equal to that of brimonidine (BID).When brimonidine was used thrice a day, it provided a greater effect than while taking brinzolamide TID (P = 0.02).The study has shown that brinzolamide, dorzolamide and timolol are similarly safe and produce no serious adverse effects.
It has been found out that brinzolamide as addition to prostaglandins or beta-adrenoblockers effectively reduced IOP in patients with refractory glaucoma or eye hypertension without causing significant adverse reactions [20].

LITERATURE REVIEW
In two studies, effectiveness of additional therapy with α 2 -adrenomimetics or 2 nd generation carbonic anhydrase inhibitors combined with prostaglandin preparations has been compared [21].
163 patients with primary open-angle glaucoma, exfoliative glaucoma or eye hypertension with IOP who obtained travoprost 0.004% participated in the double-blind, three-month, randomized, multi-centered, parallel-group clinical study.The patients were randomized to obtain additional therapy with brimonidine 0.15% BID (N = 79) or brinzolamide 1% BID (N = 84).Three months of combined therapy in the group of travoprost+brimonidine was followed by a significant decrease in the average daily IOP from 21,7 ± 0,33 mm Hg to 18,4 ± 0,33 mm Hg.Decrease of IOP in both groups was significant.The intergroup difference was significant in favor of brinzolamide (P = 0.035).Authors conclude that a combination of travoprost and brinzolamide was therapeutically more effective in respect to IOP decrease as compared with a combination of travoprost and brimonidine [21].
A single-center, blind, parallel-group, randomized controlled clinical study involving 120 patients with open-angle glaucoma or eye hypertension was devoted to comparative effectiveness of brimonidine, dorzolamide and brinzolamide in relation to IOP decrease when used as an add-on therapy to prostaglandin analogues [22].

RESULTS
The mean value of IOP was compared every hour at baseline in all groups.After initiation of add-on therapy, the mean IOP was significantly decreased in all examined groups of patients.However, add-on therapy was followed by a significant decrease of the mean IOP in all examined groups of patients.During this study, a mean change of IOP from baseline was greater in the group of brimonidine as compared with dorzolamide and brinzolamide (P < 0.001).Effectiveness of dorzolamide and brinzolamide was nearly the same [22].
When an effect of brinzolamide and timolol IOP on therapeutic effectiveness of latanoprost (prospective, randomized study involving 32 patients with primary open-angle glaucoma, normal tension glaucoma or eye hypertension) was compared at 12 weeks, both brinzolamide and timolol reduced IOP by 2.0 mm Hg in average with equal effectiveness (P < 0.01).The medicinal products had equal safety among patients [23].
In another perspective, 8-week, open-label, crossover clinical study (26 patients with glaucoma or eye hypertension) a significantly better therapeutic effectiveness of latanoprost was obtained with add-on of 1% of brinzolamide (TID) or 0.5% of gel-forming solution of timolol (once every morning).However, only add-on therapy with brinzolamide could significantly reduce IOP at night [24].
2 nd generation carbonic anhydrase inhibitors are frequently used with adrenergic blocking agents and most frequently timolol.In this case, equal therapeutic effectiveness of brinzolamide and dorzolamide is displayed [25].1% brinzolamide was equally effective when administered BID and TID producing an average daily reduction of IOP as compared with baseline within the range of 13.2-21.8%[25].Thus, a dose given twice a day is one of the least expensive add-ons to therapy with beta-blockers in glaucoma and is associated with lesser direct medical costs as compared with dorzolamide [25].
Another study was related to comparative cost of treatment with brinzolamide and dorzolamide in France, Italy, Portugal and Spain among patients with eye hypertension or primary open-angle glaucoma [26].The following results were obtained: provided as monotherapy BID or TID, brinzolamide was as effective as dorzolamide TID.Brinsolamide BID and timolol was as effective as a combination of dorzolamide and timilol BID.Direct medical expenses for patients with brinzolamide were lower as compared with those who were administered dorzolamide.The authors concluded that brinzolamide was a more saving alternative to dorzolamide [26].
In 12-month, double-blind, randomized, multi-centered, parallel-group study (34 institutions and 523 patients with open-angle glaucoma or eye hypertension), safety and effectiveness of 2% solution of dorzolamide were compared (TID) with those of 0.5% maleate timolol and 0.5% of betaxolol hydrochloride (BID) [27].Effect obtained during add-on of dorzolamide to treatment of patients with non-adequate eye hypotensive effectiveness and effect from adding timolol to treatment with dorzolamide were assessed as well.
The following results were obtained during the study: the mean percentage of IOP decrease was obtained at one year of administration of 2% dorzolamide, 0.5% of timolol and 0.5% of betaxolol and amounted to 23%, 25% and 21%, respectively.The authors made a conclusion that an effective decrease of IOP during the course of treatment for up to 1 year when 2% dorzolamide was administered TID was compared with that of 0.5% of betaxolol taken BID [27].
A randomized, open-label, parallel-group study was conducted at 5 sites of Greece to compare a decrease of IOP when dorzolamide was added to timolol [28].The study included 148 patients with not properly controlled open-angle or pseudoexfoliative glaucoma or eye hypertension resulting in an additive effect of decreased daily IOP from dorzolamide among patents obtaining timolol.At three months, a daily IOP was decreased by 20% in the group of dorzolamide plus timolol.At 3 months, the mean daily decrease of IOP by -4.44 mm Hg (P < 0.001) was estimated with the least square method [28].
Similar results were obtained in a study with 17 patients (timolol plus dorzolamide BID).At three months of treatment, IOP was decreased by 15.6% [29].
A retrospective study of an effect of dorzolamide and brinzolamide on the eye function (mainly field of vision) in open-angle glaucoma and eye hypertension was conducted [30].No significant protection effect in relation to occurrence of glaucoma in patients with eye hypertension was found during the European Glaucoma Prevention Study where dorzolamide was compared with placebo.In two other long-term studies, superiority of dorzolamide add-on over monotherapy with timolol and superiority of a combination of dorzolamide and timolol over brinzolamide and timolol in relation to ocular blood flow improvement (retrobulbar color Doppler ultrasonography -CDI values) and preservation of the field of vision in patients with glaucoma found 4-5 years ago were reported [30].
Fixed combinations of various agents reducing IOP have acquired important relevance for treatment of open-angle glaucoma.Fixed combinations reduce a number of daily instillations, increasing treatment compliance and reducing an effect of preservatives on the eye [31].All available publications in relation to fixed combinations of dorzolamide or brinzolamide (in the pharmaceutical market, they are represented by preparations in combination with such a beta-blocker ОБЗОР ЛИТЕРАТУРЫ as timolol) can be conditionally divided into the following groups: 1) studies of effectiveness and side effects of a fixed combination as compared with monotherapy with separate components; 2) comparison of effectiveness and adverse effects of dorzolamide+timolol and brinzolamide+timolol; 3) comparison of dorzolamide+timolol with representatives of other groups (brimonidine+timolol and latanoprost).
Effectiveness and tolerance of dorzolamide/timolol and brimonidine/timolol were approximately similar.It indirectly testifies to almost equal clinical effectiveness of carbonic anhydrase inhibitors and alpha2-adrenergic agonists [39].Dorzolamide/timolol is as effective in relation to IOP decrease as latanoprost therapy [40].Meanwhile, latanoprost was better tolerated by patients.The study confirms validity of clinical recommendations to use prostaglandin preparations in glaucoma as drugs of choice [2,3].
Pharmaceutical characteristics of combinations are paid attention to as well.Fixed combinations of dorzolamide/timolol with preservative (DTFC) and DTFC without preservatives (PF) were compared [41].It is found out that PF DTFC has equivalent effectiveness to that of DTFC.Due to improved tolerance and adherence, it has advantages in patients with glaucoma who suffer from ocular surface diseases [41].

CONCLUSION
In treatment of glaucoma, carbonic anhydrase inhibitors have rather high clinical effectiveness in IOP decrease and (mainly, 2 nd generation carbonic anhydrase inhibitors) low risk of serious side effects.They can be used as alternative agents when it is impossible to administer drugs of choice such as ophthalmic agents belonging to the group of prostaglandins or betablockers.When monotherapy of glaucoma with beta-blocking agents is not effective enough, fixed combinations of brinzolamide or dorzolamide and timolol are applied.Meanwhile, brinzolamide is superior to dorzolamide due to less irritation of the eye and pharmacoeconomic advantages.
The work is prepared within the state assignment of the Ministry of Education of Russia for the research project of 'Development of an innovative agent to treat open-angle glaucoma using selective inhibition of carbonic anhydrase II' (073-00109-22-02).
It is done in cooperation with the scientific department of Pharmacy Institute of the Yaroslavl State Medical University, Yaroslavl.