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Glaucoma affects approximately 3 million Americans and 60 million people worldwide.1 This insidious disease can cause a slow, progressive loss of vision and, ultimately, blindness. Ocular surface disease, on the other hand, affects as many as 30 million Americans.2 Although dry eye rarely causes a decline in vision, it can be responsible for significant decrease in quality of life for those affected by it.
When the two conditions collide, physicians encounter the perfect storm of pathologies, combining the potential for blindness and a miserable quality of life for patients. At least 60% of glaucoma patients experience ocular surface disease complaints,3 and often those symptoms go unaddressed by physicians who may be more focused on minimizing damage secondary to glaucoma than treating the ocular surface.
Glaucoma patients, like those with diabetes and hypertension, face a chronic, progressive condition. The disease often requires management with multiple ophthalmic drops to maintain adequate control of intraocular pressure and prevent visual field loss and retinal nerve fiber layer damage. In fact, 40% of glaucoma patients require more than one medication to preserve good control.
Eye care providers who care for glaucoma patients must be aware that concomitant dry eye can affect their patients, and in fact that the drugs they prescribe to preserve these patients’ vision can in some cases be harmful to their ocular surface.
PRESERVATIVES IN GLAUCOMA DRUGS
Preservatives in ophthalmic medications can be divided into two categories: chemical and oxidative. Chemical preservatives such as benzalkonium chloride (BAK) and chlorobutanol tend to have higher toxicity levels than their oxidative counterparts, such as sorbate and polyquaternium-1 (Polyquad, used in Alcon products).4
BAK is among the most commonly used preservatives. BAK acts as a powerful bactericidal and bacteriostatic agent to keep bottles free of contamination. The compound alters cell membrane permeability and causes lysis of cellular contents.5 Unfortunately, however, it can be detrimental to the tear film and to epithelial cells. BAK can cause chronic inflammation, instability of the tear film, loss of goblet cells, and other damage to the ocular surface. The entire mechanism of action of BAK has not been determined. However, events including apoptosis, oxidative stress, and release of proinflammatory cytokines have been confirmed.6
Although care should be taken to avoid excessive use of BAK-preserved drops in the management of glaucoma, it rarely is. Patients predisposed to or experiencing ocular surface disease should be considered at greatest risk for adverse effects from BAK exposure.
BAK may be the most notorious preservative, but chlorobutanol, sodium perborate, and stabilized oxychloro complex (Purite, used in Allergan products) may also cause cytotoxic effects.7 Signs of deleterious effects from preservatives can include superficial punctate keratitis and decreased tear breakup time. Chronic long-term exposure and associated conjunctival scarring can progress into conditions such as drug-induced pemphigoid.8 Ocular surface side effects secondary to topical glaucoma medications are seen frequently and often dose dependent, but they tend to be reversible upon initiation of a nonpreserved therapeutic alternative.8
POURING ON THE TEARS
Overexposure to preservatives may also be observed in glaucoma patients who try to alleviate their ocular surface symptoms with artificial tears. Artificial tear application is arguably the most commonly prescribed treatment for dry eye problems, but tears can be used in excess by patients, thereby exacerbating the condition.
Watch it Now
Sherri Rowen, MD, discusses medications and the ocular surface with Steven Vold, MD, in this episode of Glaucoma Today’s Journal Club.
Education should be provided to patients about the potential side effects of excipients in artificial tears. Excipients are added to formulations in order to safely preserve the solution or to maintain pH or viscosity.
NUMBER AND DURATION OF DRUGS
Many glaucoma drugs have ocular surface side effects such as instillation site irritation, burning, and varying degrees of hyperemia. The prevalence of ocular surface disease increases with the number of IOP-lowering medications and the duration of their use. The cumulative toxic effect to the conjunctiva can lead to diminished surgical success, should surgery be warranted when topical medications fail. Patients with advancing ocular surface disease are at greater risk of bleeding, poor wound healing, and poor bleb formation after trabeculectomy.5 Certain drugs such as alpha-agonists and carbonic anhydrase inhibitors may cause a follicular response that can subject the patient to greater conjunctival scarring, which must be considered when surgery is planned.5
Maintaining normal tear film osmolarity is necessary for both patient comfort and proper cellular function. Hyperosmolar conditions (>308 mOsm/L) have been shown to cause apoptosis of corneal and limbal cells. A study in 2011 by Luo et al found that the cytochrome c–mediated cell death pathway specifically is the route hyperosmolarity triggers to induce apoptosis, and it may be mediated by c-jun N-terminal kinase and the extracellular-regulated kinase/mitogen-activated protein kinases.9
BAK has been shown to cause a hyperosmolar shift in the tear film in in vivo and in vitro studies. Conjunctival epithelial cells tend to be resilient at low hyperosmolarity levels, but, as osmolarity increases with exposure to BAK, cells undergo apoptosis due to oxidative stress. Hyperosmolarity also increases plasma membrane permeability.10 Additionally, BAK and hyperosmolarity tend to have additive effects, meaning low levels of BAK exposed to hyperosmolar tissue become significantly more cytotoxic.8 Glaucoma patients treated with topical IOP-lowering medications who report no ocular discomfort are less likely to exhibit a hyperosmolar tear.11 However, it must also be considered that patients with chronic dry eye may be less symptomatic due to decreased corneal sensitivity.
Alternative treatment options are available for patients with concomitant glaucoma and ocular surface disease. Incidence of ocular surface disease is lower in patients taking preservative-free glaucoma medications. According to recommendations of the Dry Eye WorkShop report,12 preserved medications should be replaced by preservative-free options whenever possible. Additionally, ophthalmic fixed combination drops may offer satisfactory IOP reduction with less preservative exposure than two separate drops.
Compounds with alternative preservatives such as Purite, as found in Alphagan-P 1.0% (brimonidine tartrate; Allergan), and Polyquad, as found in Travatan Z (travoprost; Alcon), may be less harmful to the ocular surface than formulations with harsher, more traditional preservatives.13
In some patients, surgical choices should be considered. Minimally invasive glaucoma surgery, or MIGS, may be an option to eliminate or reduce the number of topical glaucoma medications a patient is taking. Often in the past glaucoma surgical intervention was delayed because of an unfavorable risk:benefit ratio. The hallmark of MIGS is its well-reported exceptional safety profile, making it a viable option relative to bleb-dependent procedures such as trabeculectomy and tube shunts.
Doctors should be cautious about categorizing patients by their primary disease process, to the neglect of others. Equally, physicians must be mindful of their iatrogenic contributions to the patient’s overall wellbeing. While preserving our glaucoma patients’ vision, we must also remember the spirit of the Hippocratic oath: First, do no harm. n
1. Glaucoma Facts and Stats. Glaucoma Research Foundation. http://www.glaucoma.org/glaucoma/glaucoma-facts-and-stats.php. Accessed October 25, 2016.
2. Karpecki PM. The evolution of dry eye. Review of Optometry. January 15, 2015.
3. Banitt M. Preservative-free glaucoma medications. Glaucoma Research Foundation. http://www.glaucoma.org/treatment/preservative-free-glaucoma-medications.php. Accessed October 25, 2016.
4. Lipner M. A clear-eyed view of preservatives in tears. EyeWorld. March 2014.
5. Whitson JT, Varner DL, Netland PA. Glaucoma drugs and the ocular surface. Review of Ophthalmology. November 15, 2006.
6. Baudouin C, Labbé A, Liang H, et al. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res. 2010;29(4):312-334.
7. Noecker R. Effects of common ophthalmic preservatives on ocular health. Adv Ther. 2001;18(5):205-215.
8. Detry-Morel M. Side effects of glaucoma medications. Bull Soc Belge Ophtalmol. 2006;(299):27-40.
9. Luo L, Li DQ, Pflugfelder SC. Hyperosmolarity-induced apoptosis in human corneal epithelial cells is mediated by cytochrome c and MAPK pathways. Cornea. 2007;26(4):452-460.
10. Clouzeau C, Godefroy D, Riancho L, et al. Hyperosmolarity potentiates toxic effects of benzalkonium chloride on conjunctival epithelial cells in vitro. Mol Vis. 2012;18:851-863.
11. Halkiadakis I, Kontadakis GA, Tsiakou D, et al. Effect of glaucoma medication in tear film osmolarity of patients without symptoms of ocular discomfort. J Ocul Pharmacol Ther. 2015;31(6):330-334.
12. 2007 Report of the International Dry Eye WorkShop. Tear Film and Ocular Surface Society website. http://www.tearfilm.org/dewsreport. Accessed October 25, 2016.
13. Radenkovic M, Stankovic-Babic G, Predrag J, et al. Ocular surface disease incidence in patients with open-angle glaucoma [abstract in English]. Srpski arhiv za celokupno lekarstvo. 2016;144(7-8):376-383.
Whitney Hauser, OD
• Assistant professor at Southern College of Optometry, Memphis, Tennessee
• Financial disclosure: board member for Paragon BioTeck and TearLab and a speaker for and/or consultant to Akorn, Allergan, BioTissue, Science Based Health, Lumenis, NovaBay, Shire, and TearScience