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Year : 2018  |  Volume : 26  |  Issue : 2  |  Page : 118-120

Effect of benzalkonium chloride–preserved timolol maleate on dry eye disease in a black African population, southwestern Nigeria

1 Oculoplastics and Ocular Oncology Unit, Department of Ophthalmology, University of Ibadan/University College Hospital, Ibadan, Oyo State, Nigeria
2 Sheikh Zayed Regional Eye Care Centre, Kanifing, Gambia

Date of Web Publication13-Feb-2019

Correspondence Address:
Dr. Oluyemi Fasina
Oculoplastics and Ocular Oncology Unit, Department of Ophthalmology, University of Ibadan/University College Hospital, Ibadan, Oyo State
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/njo.njo_9_18

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Objective: Benzalkonium chloride, a commonly used preservative in many ophthalmic preparations, has been postulated as a cause of ocular surface toxicity, resulting in dry eye disease in patients on long-term treatment with topical medications. This study aims to determine the effect of benzalkonium chloride–preserved timolol maleate on dry eye disease in an African population. Materials and Methods: Information was retrieved from the data generated at a cross-sectional study on the prevalence of dry eye disease conducted in a randomly selected local government area, southwestern Nigeria, and analysis was conducted on participants with glaucoma and using benzalkonium chloride–preserved timolol maleate (cases), and age- and sex-matched controls. Results: One hundred and seventy-four participants were included in this study with a mean age of 65.05 ± 11.65 years. There was no significant association (P > 0.05) between the use of benzalkonium chloride–preserved timolol maleate and tear-film break-up time, Schirmer 1 test, fluorescein staining score, and overall diagnosis of dry eye disease in the patients. Conclusion: Benzalkonium chloride–preserved timolol maleate did not contribute significantly to dry eye disease in the studied population.

Keywords: Benzalkonium chloride, case–control study, dry eye disease, Nigeria, timolol maleate

How to cite this article:
Fasina O, Olaniyan SI. Effect of benzalkonium chloride–preserved timolol maleate on dry eye disease in a black African population, southwestern Nigeria. Niger J Ophthalmol 2018;26:118-20

How to cite this URL:
Fasina O, Olaniyan SI. Effect of benzalkonium chloride–preserved timolol maleate on dry eye disease in a black African population, southwestern Nigeria. Niger J Ophthalmol [serial online] 2018 [cited 2023 Mar 22];26:118-20. Available from:

  Introduction Top

Dry eye disease has been defined by the International Workshop on Dry Eye as a multifactorial disease affecting the precorneal tear film and ocular surface with symptoms of tear-film instability and ocular discomfort.[1] Benzalkoniun chloride (BAC) is a quaternary cationic surfactant, and the most commonly used preservative for ophthalmic topical medications. It has been implicated in contributing to the ocular toxicity and inflammation associated with chronic use of the topical ophthalmic preparations.[2],[3],[4] BAC has a long half-life of about 20 h in the corneal epithelium and conjunctival tissues after instillation[5]; thus, prolonged exposure to the ocular surface tissue leads to inflammatory cell infiltration, increased corneal epithelial cell permeability, and impaired epithelial barrier function.[3],[6],[7] However, it is not conclusively agreed upon that BAC is solely responsible for this dysfunction, as some authors opined that the additive combination of BAC with the active drug may be contributory.[6] Glaucoma is a major blinding disease among Nigerians[8] and BAC-preserved timolol maleate is one of the commonly used topical medications in treating the disease due to its affordability. In addition, dry eye disease has been reported to be fairly common in the general Nigerian population with a prevalence of 19.2%.[9] Hence, we set out to determine if there are an association between the BAC-preserved timolol maleate and dry eye disease among a Nigerian population.

  Materials and Methods Top

A community-based survey on dry eye disease among adults of 40 years and above was conducted at Iseyin Local Government Area of Oyo State, southwestern Nigeria, by a random sampling technique, and details of the methods of this survey had been published.[10] Included for analysis in this study were individuals in the survey with chronic glaucoma who were on treatment with benzalkonium-preserved timolol maleate 0.5% twice daily for a minimum of 3 months (cases), and age- and sex-matched controls. Information on their sociodemographics; history of ocular and systemic diseases and medications; detailed ocular examination including results of Schirmer 1 test, tear-film break-up time, and corneal fluorescein staining score; the administered six-item questionnaire (a part of the Salisbury Eye Evaluation Questionnaire relating to symptoms of dry eye)[11]; and the diagnosis of dry eye disease were retrieved. The diagnosis of dry eye disease was made in the survey by the simultaneous presence of at least one symptom experienced “often or all of the time” and at least one sign in either eye of the participants.

Statistical analysis

Data were analyzed using the Statistical Package for Social Sciences software (SPSS for Windows, version 21.0; SPSS, Inc, Chicago, Illinois, USA). Quantitative data were analyzed using descriptive statistics (means with standard deviation), and Chi-square test was used to measure the association between categorical variables with level of significance set at 5%.

  Results Top

One hundred and seventy-four patients made up of 87 cases and 87 controls were included in this study with a mean age of 65.05 ± 11.65 years. There was no significant difference in the mean age between the cases 65.61 ± 11.87 years and controls 64.48 ± 11.47 years (P = 1.00). The age and sex distribution of the patients are shown in [Table 1].
Table 1 Age and sex distribution of the patients

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There was no significant association (P > 0.05) between the use of BAC-preserved timolol maleate and tear-film break-up time (P = 0.879), Schirmer 1 test (P = 0.254), fluorescein staining score (P = 1.000), and the diagnosis of dry eye disease (DED) (P = 0.168) [Table 2].
Table 2 Bivariate analysis of effect of BAC-containing timolol maleate on dry eye disease

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  Discussion Top

Timolol maleate is commonly used in the treatment of glaucoma, the most common cause of irreversible blindness in Nigeria.[8] Presumably, compliance with long-term use of the topical medications is affected by the discomfort experienced on instillation of the drug by the patients. This could be attributed in part to the ocular surface toxicity induced by the commonly used BAC preservative in the drug[12],[13] or the additive effect of the preservative and active drug.

In this study, no significant association was observed between dry eye disease and use of BAC-preserved timolol maleate among the studied population. This is at variance with the reports of Baudouin et al.[2] and Chhabra et al.[14] Baudouin et al.[2] reported significant deleterious cytotoxicity of BAC with cultured conjunctival cells, although they conducted an in vitro study of the BAC-containing and preservative-free prostaglandin analogs and the limitation of a direct extrapolation of the findings to humans in vivo was expressed by the authors. Our findings also differ from the report of Pisella et al.,[3] and this could be attributed in part to the longer duration of use of benzalkonium-containing antiglaucoma medications by patients in their study. However, a synergistic effect between the active drug and BAC preservative was postulated by Pisella et al.[3] who demonstrated that BAC 0.02% preparation induced a significantly greater conjunctival cell toxicity followed by latanoprost-containing 0.02% BAC, and timolol containing 0.02% BAC, whereas the least toxicity was observed with preservative-free timolol. They opined that different antiglaucoma medications may have varying protective effects on the toxicity of BAC on the conjunctival cells. In addition, a dose-dependent toxic effect of BAC has been documented ranging from slow cell growth reduction at lower concentrations (0.0001%) to outright epithelial cell death at higher concentrations (0.05%).[2],[15],[16] This dose-dependent cytotoxic effect of BAC could not be elicited in this study due to the secondary data that was analyzed, and this is a limitation to this study.

In conclusion, the use of BAC-preserved timolol maleate is not associated with a higher prevalence of dry eye disease in our region, suggesting that the documented toxic effect of BAC on the ocular surface cells may not result into dry eye disease in our patients. However, further studies, possibly crossover designed, using BAC-containing and preservative-free topical mediations are needed and recommended among our patients to evaluate the direct toxic effects of BAC on ocular surface tissue and resultant dry eye disease.

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Conflicts of interest

There are no conflicts of interest.

  References Top

[No authors listed]. The definition and classification of dry eye disease: Report of the definition and classification subcommittee of the International Dry Eye Workshop (2007). Ocul Surf 2007;5:75-92.  Back to cited text no. 1
Baudouin C, Riancho L, Warnet J-M., Brignole F. In vitro studies of antiglaucomatous prostaglandin analogues: Travoprost with and without benzalkonium chloride and preserved latanoprost. Invest Ophthalmol Vis Sci 2007;48:4123-8.  Back to cited text no. 2
Pisella PJ, Debbasch C, Hamard P, Creuzot-Garcher C, Rat P, Brignote F et al. Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: An ex vivo and in vitro study. Invest Ophthalmol Vis Sci 2004;45:1360-8.  Back to cited text no. 3
Kovoor TA, Kim AS, McCulley JP, Cavanagh HD, Jester JV, Bugde AC et al. Evaluation of the corneal effects of topical ophthalmic fluoroquinolones using in vivo confocal microscopy. Eye Contact Lens 2004;30:90-4.  Back to cited text no. 4
Champeau EJ, Edelhauser HF. Effect of ophthalmic preservatives on the ocular surface: Conjunctival and corneal uptake and distribution of benzalkonium chloride and chlorhexidine digluconate. In: Holly FJ, editor. The preocular tear film. Lubbock, TX: Dry Eye Institute, Inc.; 1986.  Back to cited text no. 5
Baudouin C, de Lunardo C. Short term comparative study of topical 2% carteolol with and without benzalkonium chloride in healthy volunteers. Br J Ophthalmol 1998;82:39-42.  Back to cited text no. 6
Ishibashi T, Yokoi N, Kinoshita S. Comparison of the short-term effects on the human corneal surface of topical timolol maleate with and without benzalkonium chloride. J Glaucoma 2003;12:486-90.  Back to cited text no. 7
Kyari F, Gudlavalleti MV, Sivsubramaniam S, Gilbert CE, Abdull MM, Enetekume G et al. Prevalence of blindness and visual impairment in Nigeria: The National Blindness and Visual Impairment Study. Invest Ophthalmol Vis Sci 2009;50:2033-9.  Back to cited text no. 8
Onwubiko SN, Eze BI, Udeh NN, Arinze OC, Onwasigwe EN, Umeh RE. Dry eye disease: Prevalence, distribution and determinants in a hospital-based population. Contact Lens Ant Eye 2014;37:157-61.  Back to cited text no. 9
Olaniyan SI, Fasina O, Bekibele CO, Ogundipe AO. Dry eye disease in an adult population in South-West Nigeria. Contact Lens Ant Eye 2016;39:359-64.  Back to cited text no. 10
Schein OD, Munoz B, Tielsch JM, Bandeen-Roche K, West S. Prevalence of dry eye among the elderly. Am J Ophthalmol 1997;124:723-8.  Back to cited text no. 11
Baudouin C. Allergic reaction to topical eyedrops. Curr Opin Allergy Clin Immunol 2005;5:459-63.  Back to cited text no. 12
Ichijima H, Petroll WM, Jester JV, Cavanagh HD. Confocal microscopic studies of living rabbit cornea treated with benzalkonium chloride. Cornea 1992;11:221-5.  Back to cited text no. 13
Chhabra H, Gupta A, Singh G. A comparative study of benzalkonium chloride-free latanoprost versus benzalkonium chloride-preserved latanoprost on ocular surface health in patients of primary open angle glaucoma. Int J Basic Clin Pharmacol 2017;6:1110-4.  Back to cited text no. 14
Guenoun JM, Baudouin C, Rat P, Pauly A, Warnet JM, Brignole Baudouin F. In vitro study of inflammatory potential and toxicity profile of latanoprost, travoprost, and bimatoprost in conjunctiva derived epithelial cells. Invest Ophthalmol Vis Sci 2005;46:2444-50.  Back to cited text no. 15
De Saint Jean M, Brignole F, Bringuier AF, Bauchet A, Feldmann G, Baudouin C. Effects of benzalkonium chloride on growth and survival of Chang conjunctival cells. Invest Ophthalmol Vis Sci 1999;40:619-30.  Back to cited text no. 16


  [Table 1], [Table 2]

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