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Clinical Update: Glaucoma
Glaucoma Eyedrops: A Fresh Look at Preservatives
Benzalkonium chloride (BAK) is generally regarded as an effective agent for preventing bacterial contamination of glaucoma eyedrops. However, its advantages and disadvantages increasingly are under scrutiny for possible effects on medical and surgical management.
“BAK is a mixed bag,” said Richard A. Lewis, MD, glaucoma specialist in private practice in Sacramento, Calif., and former president of the American Glaucoma Society.
“For years, it was thought that BAK helped penetration so there was better drug effect. In the old days, when pilocarpine was commonly used for glaucoma, it had such poor penetration that BAK was added to get more drug effect. But more recently, prostaglandin eyedrops, such as latanoprost, bimatoprost and travoprost, penetrate so very well that there is no need for BAK to get penetration,” Dr. Lewis said. He suggested that this renders any hazards of the preservative unnecessary. “You don’t need BAK if you can get equal efficacy without the side effects of BAK.”
Five different classes of drugs currently are used for glaucoma treatment, but prostaglandins have become for many clinicians the preferred first-line therapy.
Some ophthalmologists are emphatic about the hazards posed by the preservative. “BAK is bad for the conjunctiva, the cornea and perhaps even the trabecular meshwork,” said John R. Samples, MD, professor of ophthalmology at the Oregon Health & Science University in Portland. “It is a toxic detergent. It attracts monocytes and lymphocytes into the conjunctiva and it makes the tissue thicken up.”
Dr. Samples contends that BAK can have negative consequences that extend from the ocular surface all the way to the posterior pole. “BAK makes dry eye worse in some patients; it is toxic to corneal epithelial cells and, according to our laboratory work, it is toxic to corneal endothelial cells and trabecular cells when it enters the anterior chamber; it gives us a dysfunctional conjunctiva when it comes time to consider filtration; it has a complex role in setting up allergic reactions in the eye. It has even been implicated in the occurrence of cystoid macular edema,” he noted.
Cumulative damage. “There’s some evidence that total lifetime eye exposure to BAK is important in the late-occurring follicular conjunctivitis that appears with long-term use of adrenergic agonists,” added Dr. Samples.
Dr. Lewis agreed. “The greater the exposure to the preservative, the greater the effect and that effect is cumulative. There are a lot of dry eye problems with BAK,” he said. “There are eyelid and conjunctival problems, irritation and redness, with the whole ocular surface affected by these preservatives.” He finds it affects tear function and that even minor exposure may induce cell-growth arrest and death by necrosis or apoptosis.
Surgery made riskier. Dr. Lewis also said that patients who have been on long-term therapy with BAK-preserved eyedrops may pose surgical problems stemming from ocular surface changes and dry eye. “The conjunctiva is more toxic from BAK, which causes increased scar tissue that is more reactive and inflammatory and may affect the success rate of trabeculectomies.”
Dr. Samples added that prior exposure to BAK is more likely to cause bleb failure and that the blebs created by filtration surgery are more likely to scar down, although it is difficult to measure or see. He added that more research is needed in this area.
Association with failure. One French study found that failure of surgical treatment is mainly linked to the duration and the extent of previous medical treatment with preservative-containing glaucoma eyedrops. The study suggested that failure was associated with inflammation of the ocular surface structures.1
The study also compared the toxicity of eyedrops with and without preservatives, and found that ocular symptoms in the conjunctiva, cornea and eyelids were less prevalent with preservative-free eyedrops, adding that “the benefits of reducing microbial contamination through use of preservative are offset by the known ocular side effects of preservatives.”
Medicine or Marketing?
But many in the ophthalmic community regard BAK as a safe preservative that does a good job in protecting against bacteria, according to Alan Sugar, MD, professor and associate chairman of ophthalmology and visual sciences at the University of Michigan, Ann Arbor.
“Recently, there’s been an upswing of interest in the issue of preservatives,” Dr. Sugar said. “Some of the attention is due to marketing. Companies want to market a glaucoma drug that does not have BAK, as a marketing edge. Some of the attention is increased awareness that toxicity can occur, even though in my mind, it doesn’t occur that frequently.”
Richard P. Mills, MD, MPH, agreed. “I find it hard to believe that for most patients a single drop of BAK-containing preservative per day will cause significant surface problems. Certainly that has been my experience after years of observation.”
Toxicity to BAK does develop in some patients, but not in most, according to Dr. Sugar. “For most patients it’s not that big a deal. There’s less to the issue of BAK than meets the eye.”
Dr. Mills, who is in private practice in Seattle, noted that each patient should be approached as a separate case. “Obviously, there are sensitive patients, and, of course, it’s quite another matter when therapy involves multiple drops per day.”
Dr. Lewis recently conducted a study of the prostaglandin drug travoprost, with and without BAK.2 The BAK-free formulation is sold as Travatan Z (Alcon). The study involved 700 open-angle glaucoma or ocular hypertension patients with pressures between 24 and 36 mmHg. In this double-masked, randomized study, the medication was used once in the evening and IOP was measured at three different intervals throughout the day.
“Our study results show that you don’t need BAK for drug penetration,” Dr. Lewis said. “There was equal efficacy with the IOP changes between Travatan with and without BAK. Now, glaucoma specialists have choices.”
Ophthalmic researchers will probably be getting rid of BAK and substituting a more benign preservative whenever possible, according to Dr. Samples. He said this should have been done already. As long as 20 years ago, he analyzed BAK and identified its disadvantages. “It is surprising how often I will encounter older ophthalmologists who recall noting the toxic effects of BAK and discussing it with manufacturers and colleagues.”
Future directions. “The pipeline for development of glaucoma drugs is very rich,” said Dr. Samples. “There are many new classes of glaucoma medications, perhaps four or five, in the pipeline,” he said. “Companies such as Alcon, Allergan, Merck, Ista and Pfizer all have new glaucoma treatments under development.” He added that many companies are looking at modifications of the prostaglandins, and he is hopeful that these will come without the addition of BAK.
Drop the Drops Altogether?
One new treatment approach under development for glaucoma uses a completely different delivery system: injectable medication. Anecortave acetate, for example, is a modified steroid that appears to control high IOP for at least three months with only a single injection, and it is currently under clinical investigation as a glaucoma treatment.3 (Alcon has also been studying anecortave acetate depot suspension to treat wet AMD.)
Dr. Samples views anecortave acetate as a possible solution to the continuing problem of patient compliance with eyedrops. “Now here’s a drug you can inject and you don’t have to worry about compliance anymore.”
“It’s an interesting concept that would take the preservative problem out of the picture,” agreed Dr. Lewis.
Beyond lowering the IOP. Various neuroprotective drugs are also under investigation and ultimately may become used as injectables in the treatment of glaucoma. Glatiramer acetate, a drug currently used to treat multiple sclerosis, is under study as a possible neuroprotective agent to prevent damage to the optic nerve.
In the future, Dr. Lewis said he is hopeful for both better preservatives and new routes of administration. “I want to see drugs that have a longer duration of action so that we get better compliance and less exposure,” he said. “And we need to get beyond ocular pressure-lowering medications to the neuroprotective drugs.”
2 Lewis, R. A. J Glaucoma 2007;161:98–103.
3 Robin, A. L. Anecortave Acetate Lowers IOP in Patients With Glaucoma. Association for Research in Vision and Ophthalmology, 2006; abstract 1541.
Dr. Lewis is a consultant for Alcon and is on the speaker’s bureau for Allergan, Merck and Pfizer. Dr. Samples receives lecture honoraria from Alcon, Allergan and Merck. Drs. Sugar and Mills have no related financial interests.