Therapeutic Options for Glaucoma

Beta-blockers remain a mainstay therapy for the medical management of glaucoma.

BY THOMAS K. MUNDORF, M. D.

Glaucoma is already the second leading cause of blindness in the United States, and a 2004 National Eye Institute (NEI) report warns that ophthalmologists can expect to see a significant increase in the incidence of the disease in coming years. The report, titled "Eye Disease Prevalence, Vision problems in the U.S.," predicted that the number of diagnosed cases of glaucoma in the United States would increase from 2.2 million to 3.6 million by 2020.¹ Similar increases in macular degeneration and diabetic retinopathy, together with glaucoma, will contribute to a predicted increase of almost 70% in the number of legally blind persons worldwide by 2020.²

Facing an ever-growing patient load, ophthalmologists and optometrists are seeking as many options as possible in their medical and surgical approaches to restrain this disease known as the "thief of vision." Here we examine the role of beta-blockers as an option in the medical management of open-angle glaucoma.

Development of Beta-Blockers

Managing glaucoma requires lowering elevated intraocular pressure (IOP) to slow disease progression, as well as prevention of optic nerve damage. Lowering peak IOP has been shown to decrease the risk of progression of both ocular hypertension (OHT) and primary open-angle glaucoma (POAG). Beta-blockers (e.g., timolol maleate), which were first approved in 1978, effectively reduced IOP and quickly displaced miotic and epinephrine compounds as the mainstay of glaucoma therapy. It was found that the blurring of vision and headaches associated with the use of miotics, and follicular conjunctivitis that often result from the chronic use of epinephrine compounds,³ could be avoided by using beta-blockers. This "new" drug class of beta-blockers had some systemic side effects and their use was contraindicated in patients with a history of heart failure or chronic obstructive pulmonary disease (COPD), necessitating careful review of the general health of patients prior to treatment.

However, confidence in beta-blockers increased as this class of treatment was utilized systemically by cardiologists, and they gradually became the gold standard in the management of glaucoma. The class of non-selective beta-blockers has been shown to reduce IOP by approximately 20% to 35% from baseline.⁴

In 1996, prostaglandin analogs (PGAs) such as latanoprost (Xalatan, Pfizer) entered the market, and within 5 years, bimatoprost (Lumigan, Allergan) and travoprost (Travatan, Alcon) followed. This group of ocular medications causes greater reduction in IOP levels than beta-blockers, as well as carbonic anhydrase inhibitors (CAIs), and alpha adrenergic agonists (AAs). In addition to lowering IOP more effectively, the number of filtering procedures declined with the use of this class of medications. PGAs are associated with side effects, including iris discoloration, lash growth, reversible eyelid skin pigmentation, conjunctival hyperemia and ocular irritation.⁵

One Approach May Not Be Enough

PGAs often lower IOP significantly, but PGA treatment is not sufficient for many patients who may need an additional treatment agent or who may not respond to PGAs. As discussed in the Ocular Hypertension Treatment Study, as many as 40% of the study participants on PGA treatment required further IOP-lowering treatments with other hypotensive drugs.⁶ Adding a single second agent to an existing first-line therapy allows the physician to monitor the second agent's efficacy and associated side effects.

While added drugs do not generally have the same efficacy in IOP-lowering potential as they do when used as stand-alone agents, beta-blockers have proven to be effective adjunctives with PGAs. Indeed, Stewart et al. demonstrated that timolol maleate gel or timolol hemihydrate treatment q.d. (a.m. administration) combined with PGA latanoprost treatment q.d. (p.m. administration) were equally safe and effective, resulting in a 16% drop in IOP from baseline when measured at trough level.⁷

Adjunctive Therapies with Beta-Blockers

Combining a beta-blocker like timolol with a PGA as a fixed combination seemed a logical next step. The FDA has not approved any fixed-dose combinations of PGAs and beta-blockers yet, despite their approval in other countries. Clinical studies in the United States continue to evaluate the efficacy of fixed combinations of timolol with each of the PGAs (latanoprost, bimatoprost, and travoprost) to treat glaucoma.

Besides PGAs, beta-blockers have also been combined with other hypotensive drugs to effectively and safely lower IOP. Fixed-dose combinations of timolol and dorzolamide, a carbonic anhydrase inhibitor (Cosopt, Merck), and timolol and brimonidine, an alpha adrenergic agonist (Combigan, Allergan), are available for use in the United States. Cosopt, approved in 1998, lowers IOP through combined actions on aqueous production. Conversely, Combigan, approved in 2007, decreases aqueous production and increases outflow (uveoscleral) to obtain lower IOP.

Various Factors Influence Choices

Glaucoma treatment for individual patients may be influenced by many different factors, including the individual's responses to a drug, medical complications, side effects, ocular discomfort, cost and compliance. It is important for physicians to understand these different issues, particularly how patients respond to individual therapies, before utilizing them in fixed combination. Though fixed combination treatments like Cosopt and Combigan offer the convenience of a simple dosing regimen, similar treatment results can often be achieved by successively adding single agents like beta-blockers (timolol) to another agent, allowing for greater customization of the medical treatment of individual patients that remains cost-effective. Many beta-blockers are available as generics, and even timolol hemihydrate, a beta-blocker with no generic equivalent, is a cost-effective choice.

Beta-blockers are still a mainstay of medical management of glaucoma throughout the world. They are also good choices for management of secondary ocular hypertension, treatment of IOP spikes following laser trabeculoplasty, capsulotomy or retinal repair.

Considering Formulations

Despite similar efficacy and no clinically significant differences in systemic side effects⁸, there are several formulations of beta-blockers with different features that should be considered when prescribing a beta-blocker alone or as adjunctive therapy. A gel formulation of timolol maleate produces ocular retention but also results in increased blurring. Another timolol formulation with penetration enhancer, potassium sorbate, and similar systemic bioavailability to timolol maleate has q.d. dosing but an increased incidence of burning and stinging have been reported.^9-11 Timolol hemihydrate, on the other hand, which is indicated for both q.d. and b.i.d. dosing, has shown less associated blurring and stinging.^{12, 13}

While the FDA has not approved a fixed combination PGA beta-blocker therapy, the addition of a beta-blocker to a PGA is one of the most frequent approaches to effectively lower IOP. As mentioned previously, careful evaluation of the incremental drop in IOP is required before adding a third agent in fixed combination or resorting to laser trabeculoplasty surgery.

Beta-Blockers Are Still a Mainstay

In conclusion, PGAs have supplanted beta-blockers in the management of glaucoma as the first choice for lowering IOP — though beta-blockers are still used extensively. For patients in whom PGAs do not significantly lower IOP or do not lower IOP enough, beta-blockers continue to be extremely valuable in second-line treatment either alone or as adjunctive therapy with PGAs, CAIs or AAs. The choice of therapy is individualized and should be based on the efficacy of the drugs as well as their side-effect profile in the patient, cost, ocular comfort and impact on compliance. Beta-blockers have been proven to be safe and effective in lowering IOP when used as a monotherapy or adjunctively, and will continue to offer a good option for the medical treatment of glaucoma for years to come. OM

Editor's note: Richa Attre, Ph.D., provided editorial assistance in the preparation of this manuscript, funding for which was provided by Vistakon Pharmaceuticals, LLC.

References

1. National Eye Institute. Prevention of Blindness Data Tables; Summary of Eye Disease Prevalence Data. http://www.nei.nih.gov/eyedata/pbd5.tables.asp. Published April 12, 2004. Updated December 2006. Accessed Feb. 26, 2008.
2. Pizzarello L, Abiose A, Flytche T, et al. Vision 2020: The right to sight: A Global Initiative to Eliminate Avoidable Blindness. Arch Ophthalmol. 2004;122: 615-620.
3. Coleiro J, Sigurdsson H, Lockyer J. Follicular conjunctivitis on dipivefrin therapy for glaucoma. Eye. 1988;2:440-442.
4. Soltau JB, Zimmerman TJ. Changing paradigms in the medical treatment of glaucoma. Surv Ophthalmol. 2002;47 Suppl 1:S2-5.
5. Noecker RJ, Herrygers LA, Anwaruddin R. Corneal and conjunctival changes caused by commonly used glaucoma medications. Cornea. 2004;23:490-496
6. Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK 2nd, Wilson MR, Gordon MO. The Ocular Hypertension Treatment Study: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:701-713
7. Stewart WC, Day DG, Sharpe ED, et al. Efficacy and safety of timolol solution once daily vs timolol gel added to latanoprost. Am J Ophthalmol. 1999;128:692-696.
8. Stewart WC. Timolol hemihydrate: a new formulation of timolol for the treatment of glaucoma. J Ocul Pharmacol Ther. 1996;12:225-237.
9. Novack GD, Mundorf T, Crockett RS, et al. A double-masked, active-controlled, randomized, crossover, comfort, ocular safety, and systemic bioavaiability study in healthy volunteers. ARVO Abstracts 2002; abstract:4066.
10. Mundorf TK, Ogawa T, Naka H, et al. A 12-month, multicenter, randomized, double-masked, parallel-group comparison of timolol-LA once daily and timolol maleate ophthalmic solution twice daily in the treatment of adults with glaucoma or ocular hypertension. Clin Ther. 2004;26:541-551.
11. Mundorf T, Ogawa T, Inui N, et al. Timolol LA: a double-masked, active-controlled, randomized, crossover, comfort, ocular safety, and systemic bioavailability study in healthy volunteers. Curr Med Res Opin. 2005;21:369-373.
12. Stewart WC, Leland TM, Cate EA, Stewart JA. Efficacy and safety of timolol solution once daily versus timolol gel in treating elevated intraocular pressure. J Glaucoma. 1998;7:402-407.
13. Stewart WC, Stewart JA, Holmes KT, Leech JN. Differences in ocular surface irritation between timolol hemihydrate and timolol maleate. Am J Ophthalmol. 2000;130:712-716.

Thomas K. Mundorf, M.D., is in private practice, specializing in glaucoma, at the Mundorf Eye Center, Charlotte, N.C. He has received research grants from Aerie, Alcon, Allergan, Ista, Inspire and Novartis. Contact him at (704) 334-3222 or via e-mail at tommundorf@aol.com.