EyeWorld is the official news magazine of the American Society of Cataract & Refractive Surgery.
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February 2011April 2012 Are preservatives essential in glaucoma medications? by Tony Realini, M.D. W ith the exception of a very small number of unit-dose products, virtually all oph- thalmic medications are formulated with preservatives to inhibit microbial contamination. Among the preservatives, benzalko- nium chloride (BAK) is the most widely used, being nearly ubiquitous in ophthalmic preparations. BAK is highly effective in inhibiting the growth of bacteria, fungi, and other microbes. But BAK also has some po- tentially detrimental effects as well. For people with glaucoma and other chronic conditions that require long-term daily eye drop therapy, chronic exposure to BAK can cause significant problems. BAK and the ocular surface "Numerous observational studies have demonstrated that the preva- lence of dry eye in medically treated glaucoma patients is much higher than in the general population," said Christophe Baudouin, M.D., Ph.D., University of Paris. The rates typically fall in the 50-60% range "and have been consistent in study after study," he added. The causal role of BAK in the de- velopment of ocular surface disease has been established by observations that the prevalence of ocular surface disease is higher in people using BAK-preserved drugs versus BAK-free formulations, that the prevalence in- creases with the number of BAK- containing drugs in the medical regimen, and that symptoms often appear after switching from BAK-free to BAK-preserved drugs, he said. "Long-term BAK exposure causes chronic irritation, decreased tear film break-up time, and loss of goblet cells," said Dr. Baudouin. "The osmolarity of the tear film in- SLT continued from page 34 Overall, Dr. Shazly hopes that practitioners come away from the study with the understanding that SLT has a role to play in controlling IOP in pseudophakic patients with ocular hypertension and early glau- coma. "We should not judge the suc- cess early on," he said. "We should wait until the SLT works fully— repeat treatment, additional drops, creases with the number of BAK-pre- served drops that are applied. There is even loss of corneal sensation due to corneal nerve loss." Eyes that are chronically ex- posed to BAK upregulate the expression of many important inflammatory markers, he said, including HLA-DR class II antigens and pro-inflammatory interleukins IL-6, -8, and -10. In addition, BAK is directly toxic to the ocular surface epithelial and goblet cell populations. "BAK dis- rupts tight junctions, which in- creases penetration into the eye. It also induces inflammation, apopto- sis, and epithelial cell turnover," he added. The results of these ocular sur- face effects include discomfort, re- duction in quality of life, reduced adherence to glaucoma medical therapy, and reduced success of subsequent glaucoma filtering proce- dures, he said. Intraocular effects of BAK? "BAK is also capable of entering the anterior chamber," said Dr. Baudouin. "It accumulates in the trabecular meshwork and can kill trabecular meshwork cells." Published reports have sug- gested that BAK can be toxic to the epithelial cells of the ciliary body in culture. Further, the observation that some pseudophakic patients on topical therapy develop macular edema was also ascribed to BAK, leading to the description of "pseudophakic preservative maculopathy." A bigger issue is that of lens opacities. Can BAK cause cataract? A large epidemiologic survey, several case control studies, and two major clinical trials all reported an increase in lens opacification among patients Source: Echo/Cultura/Getty Images using topical glaucoma medications compared to those who did not use topical medications. The cause and effect is not fully characterized, but evidence suggests a possible relation- ship between BAK and cataract for- mation. Alternatives to BAK There are some glaucoma patients for whom minimizing exposure to BAK is desirable. Most important is the small group of patients who have a true allergy to BAK. Also worth considering are patients with pre-existing ocular surface disease who may experience worsening of symptoms with long-term BAK ex- posure. For these patients, there are rela- and surgery should not be applied until the full SKT response is achieved." EW Editors' note: The doctors mentioned have no financial interests related to this article. Contact information Shazly: 617-573-7900, shazlyt@gmail.com Smit: 509-456-0107, barbsmit@hotmail.com tively few BAK-free glaucoma drugs to choose from. Timolol (Timoptic, Aton Pharma, Madison, N.J.) is available in a preservative-free for- mulation packaged in unit-dose for- mat. Brimonidine is available in two concentrations (0.1% and 0.15%) formulated with a proprietary purite preservative (Alphagan P, Allergan, Irvine, Calif.). Travoprost is also available in a BAK-free formulation preserved with a proprietary SofZia system (Travatan Z, Alcon, Fort Worth, Texas). On the horizon is the first preservative-free prostaglandin formulation, if FDA approval is granted (tafluprost, Merck). In addition, non-medical thera- pies can be considered for these pa- tients. Laser trabeculoplasty is a reasonable option, and some pa- tients may benefit from a filtering operation. Is preservation necessary? On the one hand, preservation makes perfect sense. "If you open a bottle of eye drop medication, it grows things that you do not want in your eye," said Gary Novack, Ph.D., San Rafael, Calif. On the other hand, is it neces- sary? "I have bacteria in my eye right now," said Harry Quigley, M.D., professor of ophthalmology, and director, Glaucoma Service, Wilmer Eye Institute, Baltimore. "They aren't hurting me. What evidence is there that an eye infection was ever prevented by preservatives in eye drops?" He noted that the opposite has been observed. Referring to the nu- merous outbreaks of fungal keratitis associated with multipurpose con- tact lens solutions, he pointed out, "Those were preserved solutions. We really have to ask: Are the risks and benefits of BAK and other preserva- tives worth it?" EW Editors' note: The doctors mentioned have no financial interests related to this article. Contact information Baudouin: baudouin@quinze-vingts.fr Novack: gary_novack@pharmalogic.com Quigley: hquigley@jhmi.edu EW GLAUCOMA 35