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Understanding the Impact Of BAK on Glaucoma Patients
Long a staple of topical ophthalmic drug formulations, including the prostaglandin analogues, this preservative can have an adverse effect on the ocular surface when used long-term. Here's how to recognize and treat BAK-induced inflammatory dry eye.
By Robert J. Noecker, M.D., M.B.A., and Francis Mah, M.D.

Most ophthalmic preparations must contain preservatives to inhibit microbial growth and maintain the drug's integrity and efficacy. However, many preservatives have cytotoxic effects. Short-term users may have no problems, but patients who use a commercial preparation for long-term treatment of a chronic disease can have significant complications, particularly if they use several drugs that contain the preservative.

Benzalkonium chloride (BAK) is among the most common preservatives used in ophthalmic preparations for dry eye disease and glaucoma — two diseases that are often treated concurrently and for an indefinite length of time. Research has shown that in cell culture, animal and human studies, BAK causes greater cytotoxic effects than some of its alternatives, such as stabilized oxychloro complex.¹ Not only do these effects typically create immediate changes, but more concerning are the effects that manifest slowly over a long period, which can lead to a great deal of misunderstanding and underdiagnosis.

BAK does an excellent job of inhibiting bacterial growth, but its detergent nature causes short- and long-term side effects. In the short term, the preservative breaks up the tear film and can cause brief corneal epitheliopathy that may last a few minutes. Normal tear film returns to an intact and comfortable state once the BAK dissipates.

The real problems occur over the course of months to years, and of course, patients with glaucoma use their medications for many years. Prostaglandin analogues, the mainstays of glaucoma therapy, contain BAK. Commercially prepared latanoprost (XALATAN*) has the highest level of BAK of all the prostaglandin analogue drugs. If a patient diagnosed with glaucoma has existing dry eye disease or experiences dry eye symptoms later, he could start using an artificial tear preparation that contains BAK as well, raising the preservative load on the eye even more.

BAK kills bacteria; the same mechanism that eradicates microbes is also toxic to many cell types of the eye. The ocular effects are dose-dependent and can range from apoptosis to necrosis. The local inflammation causes changes that can mimic the appearance of dry eye signs and symptoms. The discomfort associated with dry eye decreases patients' quality of life, and it also reduces their desire to comply with treatment.

If the problem is treated as environmental dry eye or allergic conjunctivitis without reducing the BAK load on the eye, the ocular surface inflammation will continue or be temporarily masked. BAK induces inflammatory surface changes, which we can treat in much the same way as we treat dry eye, but we must acknowledge the role BAK plays in the process.

Diagnostic Barriers

There are several overriding clinical issues in the diagnosis of BAK-related dry eye among patients treated for glaucoma. The first is that, unlike the initial dryness reaction to drops with BAK, the inflammatory problem creeps up very subtly. Patients may not attribute the gradual changes to their eye drops, and their doctors often do not make the connection either. Patients frequently walk away with artificial tears to help neutralize the problem.

The second issue is the problem of induced dry eye, typically among patients who are more likely to develop dry eye independent of glaucoma treatment. These are often older patients, mostly women who are postmenopausal — quite similar to the typical dry eye population. It is natural to conclude that this is a simple case of inflammatory dry eye disease. A study by Tsai and colleagues² shows that patients with dry eye have higher rates of glaucoma, and in our Pittsburgh clinic, we have seen ocular surface disease symptoms in 30% to 50% of patients receiving glaucoma therapy. As a result, doctors identify the cause in only about 10% of preservative-induced inflammatory dry eye cases.³

The first step toward more accurate diagnosis of the disease origin is simply to understand the effects of BAK. When we see a patient who has been receiving glaucoma therapy for a long time, that's a red flag that it may be a significant contributor to the patient's dry eye symptoms and corneal epitheliopathy. The likelihood increases if the patient uses several preserved preparations.

Testing and Treatment

Like other people with inflammatory dry eye, patients with BAK-related symptoms may complain of excessive blinking, foreign-body sensation, stinging and burning and blurred vision. Fluorescein, rose bengal or lissamine green staining is essential for patients with inflammatory dry eye to rule out allergic conjunctivitis and to gauge the severity of the signs. If corneal staining is present, the patient certainly needs therapy for inflammatory dry eye, including anti-inflammatory medication and artificial tears. Physicians also may see conjunctival injection, punctate changes in the cornea, or blood vessels growing in the lid margin and the cornea.

However, to treat this inflammatory dry eye for the long term, we must consider the underlying cause of the problem. Patients using preparations that contain BAK require additional steps for treatment. If possible, we need to minimize or remove at least one underlying cause — one of the BAK-containing drops contributing to the patient's symptoms. There are a number of alternatives to substitute that contain lower amounts of BAK or an alternative preservative. As long as the drug lowers the pressure to the desired target pressure, a change in preparation is the best way to decrease the load of BAK on the eye and to eliminate an underlying cause of dry eye.

If this approach is unsuccessful, other laser or surgical interventions may be necessary to reduce the patient's need for chronic glaucoma medication.

Goals: Prevention and New Drugs

Inflammatory dry eye related to BAK may take years to develop and years to reverse, so prevention is most important. Thankfully, there are now several options for treating glaucoma that contain no BAK or a relatively low amount of the preservative.

In the United States, timolol is available as a preservative-free preparation, but the single-use vials are expensive, hard to obtain and awkward to use. Some alternative medications include travoprost 0.004% preserved without BAK, which is currently being reviewed by the FDA, and may soon be available as TRAVATAN^® Z solution, and brimonidine. Pharmaceutical companies are now working on other preservative-free or alternatively preserved glaucoma medications, which we hope to see soon. These medications have the potential to be more biocompatible and safer for the ocular surface in long-term glaucoma treatment. This is all part of our profession's growing awareness of BAK-induced inflammatory dry eye. We know the problem exists, we're beginning to treat the underlying problem, and new alternatives will help us achieve our goals with far better results.

References

1. Noecker R. Effects of common ophthalmic preservatives on ocular health. Adv Ther. 2001;18:205-215.

2. Tsai JH, Derby E, Holland EJ, Khatana AK. Incidence and prevalence of glaucoma in severe ocular surface disease. Cornea. 2006;25:530-532.

3. Yu JY, Wu E, Kahook MY, Noecker RJ. Assessment of Prevalence of Dry Eye Among Glaucoma Patients. Poster accepted for presentation at American Academy of Ophthalmology, Nov. 11-12, 2006. Las Vegas, NV.

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