THERAPEUTIC INSIGHTS
Glaucoma Meds and BAK
Can reformulated products improve comfort and compliance for glaucoma patients?
Coordinated by Bobby Christensen, O.D., F.A.A.O., written by Michael Chaglasian, O.D.,

We are well aware of the many challenges we face with glaucoma patients in trying to control the disease and prevent progressive loss of vision. But one related problem that we potentially overlook is the contribution of chronic glaucoma medications to the development of ocular surface disease. Even when we identify topical medications as an associated risk factor for dry eye syndrome (DES), the options for change are limited. This is due to the chronic nature of the disease and the scarcity of products that are gentle to the cornea and conjunctiva.

How significant is this problem? While there are limited references in the literature docu- menting glaucoma and DES, a recent survey of 1,077 glaucoma patients indicated the incidence (patient-reported) of dry eye in that group is 38%. We'll examine the role a common ophthalmic preservative plays in this problem.

BAK and glaucoma

Glaucoma patients typically remain on their eye drops for years — often a decade or more. So the potential for the therapeutic agent or the preservatives to cause toxic effects is significant. Of course the development of ocular surface disease is multifactorial and results from many underlying causes or conditions. For patients who are on topical medications, a significant contributing factor in the development of DES is the preservative benzalkonium chloride (BAK).

BAK is the most widely-used preservative in topical ophthal-mic medications; Alcon claims that 72% of products include it. BAK is a quaternary ammonium compound with detergent-like surfactant properties. It has been shown effective in protecting multi-dose containers from microbial contamination; thus it's achieved widespread use.

Hitting the ocular surface

In recent years, scientists have explored the role of BAK and its effects on ocular surface disruption. They've found that BAK:

► Decreases corneal epithelial cell integrity
► Compromises the epithelial barrier
► Impairs corneal healing
► Causes a secondary increase in corneal and conjunctival inflammatory cells
► Causes a loss of goblet cells
► Reduces tear function
► Decreases Tear Film Break Up Time (TBUT).

Further research is necessary to determine the exact incidence rates of these conditions in association with BAK. Some researchers have linked the effects to longer duration of exposure to the preservative, concentration and use of other products containing this preservative (as most glaucoma patients do).

My clinical experience leads me to believe there is some percentage of patients with DES who show reduced compliance to their glaucoma medications due to dryness exacerbated by BAK. However, despite the side effects listed above, the lack of alternatives leaves BAK as the number one preservative for topical medications.

Current therapies

Current topical therapy for glaucoma includes four different therapeutic classes. Prosta-glandin analogs (PGA) are now the most frequently used, due to their efficacy and low incidence of side effects. Second-line agents for patients who require additional therapy include the carbonic anhydrase inhibitors, alpha adrenergic agonists and beta blockers. Manufacturers use BAK in nearly all versions of these agents with the exception of two: Alphagan P (brimonidine 0.1%, Allergan) and Timoptic XE (timolol maleate 0.5%, Merck).

Because all three of the products in the prostaglandin family contain BAK, currently there's no option for patients whose ocular surface may show signs of toxicity and could benefit from a product free of that preservative. Virtually all of these patients remain on the PGA, potentially aggravating their symptoms of dryness. Dry eye therapy may help alleviate some of these symptoms, but it would be preferable to remove one of the underlying causes and still maintain good IOP control. A BAK-free formulation of an effective IOP-lowering medication that is well tolerated in multi-dose packaging would be a welcome addition to our armamentarium.

A BAK-free future

A BAK-free version of Travatan (travoprost 0.004%, Alcon Labs) is currently in development and awaiting FDA approval. This PGA product uses a new ionic, buffered preservative system that includes sorbitol, zinc and borate. The system works well in the bottle to prevent contamination. After dosing, it comes in contact with ions such as potassium and sodium in the tear film, which cause the preservative system to become inactive. Thus it is safe and gentle on the eye.

In a three-month clinical study on more than 650 patients, Alcon reports that the new formulation had a mean IOP reduction equal to the existing product (Lewis, et al). Dosing, administration and other contraindications remain the same. Keep in mind that the conjunctival hyperemia seen in the PGA class of glaucoma agents is caused by the active prostaglandin molecule and not by the BAK.

Photographic assay studies conducted earlier this year compared the effects of the new Travatan, Xalatan (latanoprost, Pfizer), Systane (Alcon) and gentamicin on live/dead immortalized human corneal epithelial cells following 25 minutes of exposure to each drug. Travatan without BAK demonstrated significantly less toxicity to the cells compared with latanoprost and gentamicin (Norcom, et al). Finally, in a separate study, researchers performed in vivo confocal examination of rabbit corneas and examined them for any changes in epithelial cell dropout, morphology or thickness. Results showed that the new formulation doesn't cause corneal epithelial toxicity (Whitson, et al).

Comfort = compliance

Compliance is always an issue in a chronic disease like glaucoma. While there are many strategies to improve patient compliance, if the medication contributes to patient discomfort, perhaps the most logical approach would be to make the drug as safe and well-tolerated as possible. After all, if the patient experiences reduced symptoms and improved comfort, it will be easier for him or her to comply with treatment.

We need both advantages

All therapies have risks and benefits. In glaucoma, therapeutic options for our patients who also have ocular surface disease are somewhat limited. It would be quite advantageous to have a product in the prostaglandin class that can help improve the signs and symptoms of dry eye disease and still have excellent IOP-lowering capability.

Dr. Chaglasian is Chief of Staff at Illinois Eye Institute, Illinois College of Optometry. He is a member of Alcon's Speakers Bureau and has participated in the company's educational programs.