The World Health Organization (WHO) defines quality of life (QoL) as “an individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards, and concerns” (WHO, 2012).

Health care providers who prescribe a specific therapy may unintentionally exert a negative influence on their patients’ QoL. An excellent example of unintentional harm is the negative impact of ophthalmic therapeutic on ocular surface health. Camp et al (2015) conducted a study to assess the impact of glaucoma medications on dry eye QoL. One group of patients took glaucoma medications on a regular basis, and individuals in the control group took no glaucoma medicines. At their initial visit, all participants completed the Dry Eye Questionnaire 5 (DEQ5) and the Impact of Dry Eye on Everyday Life (IDEEL).

Analysis of the data revealed that subjects taking glaucoma drops had significantly more dry eye signs and symptoms than controls. Investigators noted a positive correlation between the number of drops taken and the percentage of dry eye symptoms reported by the subjects. One-third of patients using glaucoma drops had severe ocular surface symptoms (i.e., reporting a DEQ5 score of 12 or greater). By comparison, 25% of controls reported symptoms.

The authors noted that use of multiple glaucoma medications was associated with a proportional increase in the severity of dry eye symptoms. This finding may result from the use of preservatives, especially benzalkonium chloride (BAK), which is commonly used in topical glaucoma medications (Camp et al, 2015).

Possible Side Effects

BAK is a quaternary ammonium detergent introduced as a germicide early in the 20th century (Rosin and Bell, 2013). It acts by disrupting the lipid membranes of cells. The first ophthalmic use of BAK was as a preservative in hard contact lens solutions. It is an excellent germicidal agent but has numerous side effects, including conjunctival inflammation and fibrosis, tear film instability, corneal cytotoxicity, anterior chamber inflammation, trabecular meshwork (TM) cell apoptosis, cataract development, and macular edema (Rosin and Bell, 2013; Steven et al, 2018).

Stevens and colleagues (2012) utilized laser flare photometry to evaluate anterior chamber inflammation associated with BAK use. They recruited 28 subjects who had untreated ocular hypertension for the study. After obtaining baseline anterior chamber photometry (ACP) on both eyes, they randomly assigned a BAK-preserved beta-blocker for one eye and a preservative-free beta-blocker in the fellow eye. After one month of treatment, ACP measurements were repeated. Flare values were higher in both groups, but values in the BAK-treated eyes were higher than those in the preservative-free treated eyes, and the difference was statistically significant (Stevens et al, 2012). This suggests that BAK has the potential to cause intraocular inflammation.

Another potential, unfortunate side effect of BAK is loss of TM tissue secondary to apoptosis (Stevens et al, 2012). Throughout life, attrition of TM cells occurs, and is believed to be caused by apoptosis. At 20 years old, the TM of each eye contains an estimated 763,000 cells but normally loses approximately 6,000 cells per year (Baleriola et al, 2008). By 80 years old, the total number of cells has fallen to 403,000 per eye. DNA fragmentation is a typical feature of apoptotic cell death and can be quantified using TUNEL assay.

Ammar and Kahook (2011) used this technology to evaluate cell loss in cultured human TM cells exposed to glaucoma medications preserved with either BAK or polyquad. Those preserved with BAK demonstrated a dose-dependent reduction in TM cell viability. They noted an association between BAK and increased levels of MMP-9, a matrix metalloproteinase implicated in the pathogenesis of glaucoma.

Understanding that the formulation of ocular agents including preservatives may influence long-term vision, comfort, and function can help practitioners make prescribing decisions. CLS

References

1. World Health Organization. The World Health Organization Quality of Life (WHOQOL). 2012 Mar 1. Available at https://www.who.int/tools/whoqol . Accessed March 7, 2022.
2. Camp A, Wellika SR, Tzub JH, et al. Dry eye specific quality of life in veterans using glaucoma drops. Cont Lens Anterior Eye. 2015 Jun;38:220-225.
3. Rosin LM, Bell NP. Preservative toxicity in glaucoma medication: clinical evaluation of benzalkonium chloride-free 0.5% timolol eye drops. Clin Ophthalmol. 2013:7:2131-2135.
4. Steven DW, Alaghband P, Lim KS. Preservatives in glaucoma medication. Br J Ophthalmol. 2018 Nov;102:1497-1503.
5. Stevens AM, Kestelyn PA, de Bacquer D, Kestelyn PG. Benzalkonium chloride induces anterior chamber inflammation in previously untreated patients with ocular hypertension as measured by flare meter: a randomized clinical trial. Acta Ophthalmol. 2012 May;90:e221-e224.
6. Baleriola J, García-Feijoo J, Martínez-de-la-Casa JM, Fernández-Cruz A, de la Rosa EJ, Fernández-Durango R. Apoptosis in the trabecular meshwork of glaucomatous patients. Mol Vis. 2008 Aug 18;14:1513-1516
7. Ammar DA, Kahook MY. Effects of glaucoma medications and preservatives on cultured human trabecular meshwork and non-pigmented ciliary epithelial cell lines. Br J Ophthalmol. 2011 Oct;95:1466-1469.