STUDIES OF CLINICAL IMPACT
BAK does not appear to have any necessary effect on the efficacy of glaucoma medications, as demonstrated in studies with various nonpreserved and alternatively preserved preparations of glaucoma drops.3,4 Animal models and laboratory models have been used to isolate the effects of BAK alone on mammalian cells and tissues. These studies have shown a significantly deleterious effect of BAK on these cells that is both time and dose dependent.5,6 Studies performed with glaucoma medications with and without BAK have shown changes that can be attributed to the BAK alone.1,7 Research performed in humans has also provided information that correlates with the changes seen in experimental settings,8,9 although comorbidities such as other ocular conditions and systemic conditions make it difficult to isolate BAK's effect. Nonetheless, even with the wide variation seen in human studies, there is a large body of evidence demonstrating changes in the ocular surface of people using BAK-containing eye drops.10,11
SIGNS AND SYMPTOMS
An argument can be made that there is no apparent difference in signs or symptoms in patients using eye drops that contain higher amounts of BAK compared to those using drops with less BAK. This stance, however, may neglect the possibility that BAK may be causing the signs and symptoms associated with an abnormal ocular surface. In addition, the changes that occur are time dependent and insidious in nature. Unlike hyperemia or allergic reactions that may be relatively obvious to the doctor, both in time of onset and intensity, BAK-induced changes can be difficult to isolate and verify.12
The use of BAK appears to cause subconjunctival inflammation similar to that seen in patients with dry eyes and ocular surface disease of other types. What this may translate into clinically is hyperemia, chemosis, and staining on the ocular surface. The corresponding corneal changes due to damage to epithelial cells appear as punctate erosions that are visualized with fluorescein, Lissamine Green (Accutome, Inc., Malvern, PA), or rose bengal. Changes in the eyelids may manifest as neovascularization of the margin and alterations in the meibomian glands.
The patients in whom these changes are most apparent are those with preexisting ocular surface disease, namely those with dry eyes (common in women) and meibomian gland disease or rosacea (common in men). Other patients, such as those with compromised corneal sensation or herpetic eye disease, may experience significant changes in their corneal surface (eg, delayed wound healing and significant epithelial defects) when higher amounts of BAK are applied to the ocular surface. Recently, the use of glaucoma medications was cited as a major risk factor for graft failure after corneal transplants.13
CONCLUSION
The long-term clinical impact of the chronic use of glaucoma medications with high amounts of BAK on the ocular structures of a previously normal eye cannot be determined at this time. There is, however, a plethora of anecdotal evidence that patients with preexisting ocular surface disease do poorly in terms of tolerating drugs with high concentrations of BAK. Although the primary goal of glaucoma therapy is to lower IOP, clinicians must take into account the impact of therapy on the patient's long-term outcome, and they must choose agents that will not compromise the future success of other medical or surgical therapies.
Robert J. Noecker, MD, MBA, is Director of the Glaucoma Service and Associate Professor/Vice Chair at the Department of Ophthalmology at the University of Pittsburgh. He has received research support and is a consultant to Allergan, Inc., and he is on the speakers' bureaus for Allergan, Inc., and Alcon Laboratories, Inc. Dr. Noecker may be reached at (412) 647-5753; noeckerrj@upmc.edu.
1. Noecker RJ, Herrygers LA, Anwaruddin R. Corneal and conjunctival changes caused by commonly used glaucoma medications. Cornea. 2004;23:490-496.
2. Herrygers LA, Noecker RJ. Effect of preservatives in chronic ocular therapy. Clinical & Surgical Ophthalmology. 2003;1/21:3:88-94.
3. Katz LJ. Twelve-moth evaluation of brimonidine-Purite versus brimonidine in patients with glaucoma or ocular hypertension. J Glaucoma. 2002;11:119-126.
4. Lewis RA, Katz GJ, Weiss MJ, et al; Travoprost BAC-Free Study Group. Travoprost 0.004% with and without benzalkonium chloride: a comparison of safety and efficacy. J Glaucoma. 2007;16:98-103.
5. Burnstein NL, Klyce SD. Electrophysiologic and morphologic effects of ophthalmic preparations on rabbit cornea epithelium. Invest Ophthalmol Vis Sci. 1977;16:899-911.
6. Gasset AR, Ishii Y, Kaufman HE, Miller T. Cytotoxicity of ophthalmic preservatives. Am J Ophthalmol. 1974;78:98-105.
7. de Jong C, Stolwijk T, Kuppens E, et al. Topical timolol with and without benzalkonium chloride epithelial permeability and autofluorescence of the cornea in glaucoma. Graefes Arch Clin Exp Ophthalmol. 1994;232:221-224.
8. Baudouin C, Pisella PJ, Fillacier K, et al. Ocular surface changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology. 1999;106:556-563.
9. Pisella PJ, Lala E, Parier V, et al. Effect of preservatives on the conjunctiva: a comparative study of beta-blocker eye drops with and without preservatives in glaucoma patients [in French]. J Fr Ophthalmol. 2003;26:675-679.
10. Broadway DC, Grierson I, O'Brien C, Hitchings RA. Adverse effects of topical antiglaucoma medication. I: The conjunctival cell profile. Arch Ophthalmol. 1994;112:1437-1445.
11. Sherwood MB, Grierson I, Millar L, Hitchings RA. Long-term morphologic effects of antiglaucoma drugs on the conjunctiva and Tenon's capsule in glaucomatous patients. Ophthalmology. 1989;96:327-335.
12. Pisella PJ, Pouliquen P, Badouin C. Prevalence of ocular symptoms and signs with preserved and preservative-free glaucoma medication. Br J Ophthalmol. 2002;86:418-423.
13. Price MO, Thompson RW Jr, Price FW Jr. Risk factors for various causes of failure in initial corneal grafts. Arch Ophthalmol. 2003;121:1087-1092.
No, it will not matter
By Eve J. Higginbotham, MD
The introduction into clinicians' therapeutic armamentarium of additional medications free of benzalkonium chloride (BAK) will make essentially no difference. In reality, several factors outside our control as physicians that relate to our choice of medications for patients and the use of medications by our patients are far more significant than whether or not the preservative in the drug is suitable for their eyes. Although my colleague Robert Noecker, MD, raises some very good points in his argument, the circumstances of everyday practice must be strongly considered.
CLASS
Class is more important than the influence of preservatives to the interplay between any given antiglaucoma medication and its observed side effects. Years ago, when clinicians had more limited therapeutic choices such as pilocarpine and epinephrine, the issue of preservatives was not quite as important as it is today. The ocular redness associated with these medications was often considered a small price in preserving vision, given the surgical alternatives available at the time.
In rabbit studies conducted by my laboratory at the University of Illinois in the 1980s, it was clear that rabbits pretreated with pilocarpine were much more likely to express myofibroblasts in their postsurgical conjunctival tissue compared with animals pretreated with either timolol or artificial tears.1 Although epinephrine required less frequent use to achieve its optimal dosage for reducing IOP, the redness that resulted from its administration adversely impacted patients' instillation of this drug as prescribed. Thus, it was no surprise that the use of timolol grew soon after its introduction in the late 1970s. Nevertheless, the use of pilocarpine and epinephrine continued for much of the 1980s despite the well-known side effects of these medications. Clinically, prostaglandins, other miotics such as carbachol, and the alpha agonist brimonidine tartrate can also cause ocular injection more often than beta blockers. These observations suggest that the class of drug will influence the occurrence of conjunctival hyperemia in any given patient.
INDIVIDUAL REACTION
The impact of any given drug on the ocular surface may go beyond class when we consider the differences in hyperemia among the three prostaglandin analogs currently in common use. In the study conducted by Parrish and colleagues,2 patients on latanoprost evidenced less hyperemia compared with other compounds within this general class. This is a remarkable observation given that the concentration of BAK is greater in latanoprost versus bimatoprost and travoprost. Thus, the compound itself may impart a reaction in some patients that may not be evident in others.
ANTIFIBROTICS
The preservative BAK may play a role in the adverse reaction of the cells within the conjunctiva. This point is important when considering the health of the tissue prior to filtration surgery, but it is not of great significance given the potency of antifibrotic agents. The actions of mitomycin C and 5-fluorouracil are powerful. Although the potential influence of antiglaucoma medications on the outcome of filtration surgery can be significant, the use of antifibrotic agents mitigates this detrimental impact.3 This point may be the most debatable in my argument, because the array of combinations of medications is variable as is the response of patients to topical medications. It is important to remind ourselves, however, that a single application of either of the aforementioned antifibrotic agents is enough to influence the outcome of filtration surgery in patients who are at high risk for failure.
INSURERS
My last point relates to the more practical issues related to managing patients in an era when the ultimate selection of a medication depends on the formularies of insurance plans. Undoubtedly, some formularies may not include the newer medications with alternative preservatives such as Purite (Allergan, Inc., Irvine, CA), no preservatives such as with timolol, or less BAK, and other insurers may only permit the use of these agents with justification. Ultimately, patients may be the ones to choose their medication, and they may not consider the value of a different preservative when faced with higher cost. Certainly, some will select the older, cheaper drug.
CONCLUSION
That newer drugs may be “better” for conjunctival health may not make a difference in clinical practice. We surgeons have the opportunity to reduce the negative impact of preserved antiglaucoma medications on filtration surgery by using potent antifibrotic agents. Moreover, it may be more important to consider a different class of medication or compound than to choose a different preservative. Considering that preservative-free timolol has been available for years and the use of this medication has not penetrated clinical practice significantly, the future of these other emerging agents is predictable. Most important is that our patients adhere to the prescribed regimen regardless of the concentration of BAK.
Eve J. Higginbotham, MD, is Dean and Senior Vice President for Academic Affairs at the Morehouse School of Medicine, Atlanta, Georgia. She has served on the speakers' bureaus for Pfizer, Inc., Alcon Laboratories, Inc., and Allergan, Inc. Dr. Higginbotham may be reached at (404) 752-1720; ejhigginbotham@msm.edu
1. Young TL, Higginbotham EJ, Zou XL, Farber MD. Effects of topical glaucoma drugs on fistulized rabbit conjunctiva. Ophthalmology. 1990;97:1423-1427.
2. Parrish RK, Palmberg P, Sheu WP; XLT Study Group. A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, randomized, masked-evaluator multicenter study. Am J Ophthalmol. 2003;135:688-703.
3. Broadway DC, Grierson I, O'Brien C, Hitchings RA. Adverse effects of topical antiglaucoma medication. II. The outcome of filtration surgery. Arch Ophthalmol. 1994;112:1446-1454. Comment in: Arch Ophthalmol. 1995;113:849-850.
