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BAK is the preservative used in the vast majority of prescription eyedrops (excluding, obviously, the unpreserved ones like Restasis and Xiidra) such as corticosteroids, antibiotics, antihistamines, etc. Historically, it has been used in the vast majority of glaucoma eyedrops; this latter has been changing, because of the well documented and profound effects on glaucoma patients, but even that single trend away from BAK in one single drug group has been happening far too slowly.
BAK is also the preservative used in a large number of over-the-counter eyedrops, including allergy and decongestant drops, many combination drops, and even some lubricant drops intended solely for dryness. These products have no warning on their labels specific to the effects of the preservative, so people who self-treat minor eye irritations over the long term without guidance from an eye doctor on what's safe (this happens commonly - they think it's not worth seeing a doctor about) can experience lasting harm without any way to know or prevent it.
The excerpt below from the Iatrogenic (i.e. medically caused) dry eye report summarizes what we know about all the different ways BAK can harm us:
TFOS DEWS II Iatrogenic Dry Eye Report
4.3.2.1 Role of preservatives and excipients
References in this excerpt:
[118] 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(1):39–42.
[122] Labbé A, Terry O, Brasnu E, Van Went C, Baudouin C. Tear film osmolarity in patients treated for glaucoma or ocular hypertension. Cornea 2012;31(9):994–999.
[125] Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res 2010;29(4):312–334.
[126] Uter W, Lessmann H, Geier J, Schnuch A. Is the irritant benzalkonium chloride a contact allergen? A contribution to the ongoing debate from a clinical perspective. Contact Dermat 2008;58(6):359–363.
[127] Herreras JM, Pastor JC, Calonge M, Asensio VM. Ocular surface alteration after long-term treatment with an antiglaucomatous drug. Ophthalmology 1992;99(7):1082–1088.
[128] Chung SH, Lee SK, Cristol SM, Lee ES, Lee DW, Seo KY, et al. Impact of short-term exposure of commercial eyedrops preserved with benzalkonium chloride on precorneal mucin. Mol Vis 2006;12:415–421.
[129] Kahook MY, Noecker R. Quantitative analysis of conjunctival goblet cells after chronic application of topical drops. Adv Ther 2008;25(8):743–751.
[130] Göbbels M, Spitznas M. Corneal epithelial permeability of dry eyes before and after treatment with artificial tears. Ophthalmology 1992;99(6):873–878.
[131] Baudouin C, Aragona P, Messmer EM, Tomlinson A, Calonge M, Boboridis KG, et al. Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. Ocul Surf 2013;11(4):246–258.
[132] Clouzeau C, Godefroy D, Riancho L, Rostène W, Baudouin C, Brignole-Baudouin F. Hyperosmolarity potentiates toxic effects of benzalkonium chloride on conjunctival epithelial cells in vitro. Mol Vis 2012;18:851–863.
[133] Sarkar J, Chaudhary S, Namavari A, Ozturk O, Chang JH, Yco L, et al. Corneal neurotoxicity due to topical benzalkonium chloride. Investig Ophthalmol Vis Sci 2012;53(4):1792–1802.
[134] Martone Gianluca, Frezzotti Paolo, Tosi Gian Marco, Traversi Claudio, Mittica Vincenzo, Malandrini Alex, et al. An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology. Am J Ophthalmol 2009;147(4):725–735.
[135] Denoyer A, Godefroy D, Célérier I, Frugier J, Riancho L, Baudouin F, et al. CX3CL1 expression in the conjunctiva is involved in immune cell trafficking during toxic ocular surface inflammation. Mucosal Immunol 2012;5(6):702–711.
[136] Lee HJ, Jun RM, Cho MS, Choi KR. Comparison of the ocular surface changes following the use of two different prostaglandin F2α analogues containing benzalkonium chloride or polyquad in rabbit eyes. Cutan Ocul Toxicol 2015;34(3):195–202.
[137] Galletti JG, Gabelloni ML, Morande PE, Sabbione F, Vermeulen ME, Trevani AS, et al. Benzalkonium chloride breaks down conjunctival immunological tolerance in a murine model. Mucosal Immunol 2013;6(1):24–34.
[138] Pisella PJ, Debbasch C, Hamard P, Creuzot-Garcher C, Rat P, Brignole F, et al. Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study. Investig Ophthalmol Vis Sci 2004;45(5):1360–1368.
[139] Baudouin Christophe, Liang Hong, Hamard Pascale, Riancho Luisa, Creuzot-Garcher Catherine, Warnet Jean-Michel, et al. The ocular surface of glaucoma patients treated over the long term expresses inflammatory markers related to both t-helper 1 and t-helper 2 pathways. Ophthalmology 2008;115(1):109–115.
[140] Zhivov A, Kraak R, Bergter H, Kundt G, Beck R, Guthoff RF. Influence of benzalkonium chloride on langerhans cells in corneal epithelium and development of dry eye in healthy volunteers. Curr Eye Res 2010;35(8):762–769.
[141] Brignole-Baudouin F, Riancho L, Liang H, Nakib Z, Baudouin C. In vitro comparative toxicology of polyquad-preserved and benzalkonium chloride-preserved travoprost/timolol fixed combination and latanoprost/timolol fixed combination. J Ocul Pharmacol Ther 2011;27(3):273–280.
[142] Labbé A, Pauly A, Liang H, Brignole-Baudouin F, Martin C, Warnet JM, et al. Comparison of toxicological profiles of benzalkonium chloride and polyquaternium-1: an experimental study. J Ocul Pharmacol Ther Off J Assoc Ocul Pharmacol Ther 2006;22(4):267–278.
[143] Kahook MY, Noecker RJ. Comparison of corneal and conjunctival changes after dosing of travoprost preserved with sofZia, latanoprost with 0.02% benzalkonium chloride, and preservative-free artificial tears. Cornea 2008;27:339–343.
BAK is also the preservative used in a large number of over-the-counter eyedrops, including allergy and decongestant drops, many combination drops, and even some lubricant drops intended solely for dryness. These products have no warning on their labels specific to the effects of the preservative, so people who self-treat minor eye irritations over the long term without guidance from an eye doctor on what's safe (this happens commonly - they think it's not worth seeing a doctor about) can experience lasting harm without any way to know or prevent it.
The excerpt below from the Iatrogenic (i.e. medically caused) dry eye report summarizes what we know about all the different ways BAK can harm us:
- Causes damage to the goblet cells and mucous (sticky) layer of the tear film
- Causes damage to the lipid layer
- Increases tear osmolarity
- Causes inflammation and leads to an inflammatory vicious cycle
- Is more damaging to people who already have dry eye (poorer tissue defenses)
- Is toxic to trigeminal nerve endings
- Reduces nerve density and corneal sensitivity (meaning people who don't seem to have symptoms from the BAK may have damage all the same)
TFOS DEWS II Iatrogenic Dry Eye Report
4.3.2.1 Role of preservatives and excipients
....BAK may cause or aggravate DED through various mechanisms such as its toxic and proinflammatory effects, as well as its detergent properties, which have been well demonstrated in numerous experimental and clinical investigations [125]. Goblet cells produce soluble mucins and contribute to tear film stability and immune defenses. These cells are extremely sensitive to toxic and inflammatory stress, decreased in density in humans after short exposure to BAK or BAK-containing timolol [127]. MUC1 and MUC16 were found to be reduced after exposure to BAK in human corneal and limbal epithelial cells. Transmission electron microscopy revealed alteration of the mucus layer after exposure to 0.01% BAK for 5 or 15 min, whereas more prolonged exposure (60 min) to 0.01% BAK destroyed the mucous layer [128]. These toxic effects were also found by Kahook and Noecker, who reported significantly lower densities of goblet cells in animals receiving BAK-containing latanoprost compared to preservative-free artificial tears, even though the specific effects of latanoprost alone were not addressed [129].
In addition, as a tensioactive compound, BAK is also a detergent for the lipid layer of the tear film. Thus, while an unpreserved betablocker did not impact upon tear stability, decreased TBUT was observed with a preserved betablocker [118]. Increased tear osmolarity was also observed in patients receiving preserved eyedrops compared to those who received unpreserved topical medication [122]. Following the loss of its protective properties, the impaired tear film not only results in dry eye symptoms and corneal damage, but also may convey cytotoxic inflammatory mediators throughout the ocular surface. Hence, increased corneal epithelial permeability has been shown in dry eye with additional impairment when using artificial tears containing BAK compared to nonpreserved eyedrops [130]. Tear film alterations may therefore stimulate a series of biological changes in the ocular surface, leading to subsequent neurogenic inflammation and further impairment of the tear film, creating a vicious cycle [131].
BAK causes disruption of the tight junctions of the corneal epithelium, an effect that has led to BAK being considered an enhancer of drug penetration into the anterior chamber [125]. The cytotoxic effects of BAK have been shown to be increased experimentally when cells are previously subjected to a hyperosmotic stress mimicking dry eye in vitro. Therefore, BAK can cause some level of toxicity in normal or glaucomatous eyes, which can be compensated by tissue defenses, but causes a much greater level in dry eyes, consistent with clinical findings. However, as BAK may progressively cause tear instability and hence hyperosmolarity, this compound is likely to change the conditions of its own tolerance and result in increasing toxicity levels [132].
Additionally BAK has shown neurotoxic effects to the trigeminal nerve endings [133], consistent with the results of a large study comparing the effects of preserved and unpreserved antiglaucoma drugs on corneal nerves using in vivo confocal microscopy (IVCM) [134]. The density of superficial epithelial cells and the number of sub-basal nerves were reduced in the preservative-containing groups, and stromal keratocyte activation and bead-like nerve shaping were higher in the glaucoma preservative therapy groups than in the control and preservative-free groups. Moreover, this study identified decreased corneal sensitivity, based on esthesiometry, in all preserved groups compared to control or unpreserved prostaglandin and betablocker groups. This neurotoxic property of BAK could thus contribute to apparent tolerance in some patients receiving BAK-containing eyedrops.
Experimental data also demonstrated direct proinflammatory effects of BAK with the release of inflammatory cytokines or increased expression of receptors to chemokines and cytokines [135,136]. Additionally, BAK breaks down conjunctival immunological tolerance in a murine model [137]. In humans, using immunocytological and flow cytometry methods, higher expression of HLA-DR, a marker of inflammation, occurred in impression cytology specimens over the ocular surface with preserved eyedrops [138]. Other inflammation-related markers, such as ICAM-1, interleukin (IL)-6, IL-8, IL-10, CCR4 or CCR5, were also found to be overexpressed in glaucoma patients and even more with multiple therapies and preserved eyedrops [139]. A significant infiltration of the central cornea with dendritic inflammatory cells is observed with IVCM in healthy volunteers receiving BAK-containing eye drops compared to a non-preserved solution [140].
New preservatives recently developed as alternatives to BAK, such as Polyquad®, Purite® and sofZia®, result in significantly lower cytotoxic effects [125,136,141–143]. However, their possible effects on the tear film and tolerance in dry eye patients have not been fully investigated.
In addition, as a tensioactive compound, BAK is also a detergent for the lipid layer of the tear film. Thus, while an unpreserved betablocker did not impact upon tear stability, decreased TBUT was observed with a preserved betablocker [118]. Increased tear osmolarity was also observed in patients receiving preserved eyedrops compared to those who received unpreserved topical medication [122]. Following the loss of its protective properties, the impaired tear film not only results in dry eye symptoms and corneal damage, but also may convey cytotoxic inflammatory mediators throughout the ocular surface. Hence, increased corneal epithelial permeability has been shown in dry eye with additional impairment when using artificial tears containing BAK compared to nonpreserved eyedrops [130]. Tear film alterations may therefore stimulate a series of biological changes in the ocular surface, leading to subsequent neurogenic inflammation and further impairment of the tear film, creating a vicious cycle [131].
BAK causes disruption of the tight junctions of the corneal epithelium, an effect that has led to BAK being considered an enhancer of drug penetration into the anterior chamber [125]. The cytotoxic effects of BAK have been shown to be increased experimentally when cells are previously subjected to a hyperosmotic stress mimicking dry eye in vitro. Therefore, BAK can cause some level of toxicity in normal or glaucomatous eyes, which can be compensated by tissue defenses, but causes a much greater level in dry eyes, consistent with clinical findings. However, as BAK may progressively cause tear instability and hence hyperosmolarity, this compound is likely to change the conditions of its own tolerance and result in increasing toxicity levels [132].
Additionally BAK has shown neurotoxic effects to the trigeminal nerve endings [133], consistent with the results of a large study comparing the effects of preserved and unpreserved antiglaucoma drugs on corneal nerves using in vivo confocal microscopy (IVCM) [134]. The density of superficial epithelial cells and the number of sub-basal nerves were reduced in the preservative-containing groups, and stromal keratocyte activation and bead-like nerve shaping were higher in the glaucoma preservative therapy groups than in the control and preservative-free groups. Moreover, this study identified decreased corneal sensitivity, based on esthesiometry, in all preserved groups compared to control or unpreserved prostaglandin and betablocker groups. This neurotoxic property of BAK could thus contribute to apparent tolerance in some patients receiving BAK-containing eyedrops.
Experimental data also demonstrated direct proinflammatory effects of BAK with the release of inflammatory cytokines or increased expression of receptors to chemokines and cytokines [135,136]. Additionally, BAK breaks down conjunctival immunological tolerance in a murine model [137]. In humans, using immunocytological and flow cytometry methods, higher expression of HLA-DR, a marker of inflammation, occurred in impression cytology specimens over the ocular surface with preserved eyedrops [138]. Other inflammation-related markers, such as ICAM-1, interleukin (IL)-6, IL-8, IL-10, CCR4 or CCR5, were also found to be overexpressed in glaucoma patients and even more with multiple therapies and preserved eyedrops [139]. A significant infiltration of the central cornea with dendritic inflammatory cells is observed with IVCM in healthy volunteers receiving BAK-containing eye drops compared to a non-preserved solution [140].
New preservatives recently developed as alternatives to BAK, such as Polyquad®, Purite® and sofZia®, result in significantly lower cytotoxic effects [125,136,141–143]. However, their possible effects on the tear film and tolerance in dry eye patients have not been fully investigated.
[118] 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(1):39–42.
[122] Labbé A, Terry O, Brasnu E, Van Went C, Baudouin C. Tear film osmolarity in patients treated for glaucoma or ocular hypertension. Cornea 2012;31(9):994–999.
[125] Baudouin C, Labbé A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the good, the bad and the ugly. Prog Retin Eye Res 2010;29(4):312–334.
[126] Uter W, Lessmann H, Geier J, Schnuch A. Is the irritant benzalkonium chloride a contact allergen? A contribution to the ongoing debate from a clinical perspective. Contact Dermat 2008;58(6):359–363.
[127] Herreras JM, Pastor JC, Calonge M, Asensio VM. Ocular surface alteration after long-term treatment with an antiglaucomatous drug. Ophthalmology 1992;99(7):1082–1088.
[128] Chung SH, Lee SK, Cristol SM, Lee ES, Lee DW, Seo KY, et al. Impact of short-term exposure of commercial eyedrops preserved with benzalkonium chloride on precorneal mucin. Mol Vis 2006;12:415–421.
[129] Kahook MY, Noecker R. Quantitative analysis of conjunctival goblet cells after chronic application of topical drops. Adv Ther 2008;25(8):743–751.
[130] Göbbels M, Spitznas M. Corneal epithelial permeability of dry eyes before and after treatment with artificial tears. Ophthalmology 1992;99(6):873–878.
[131] Baudouin C, Aragona P, Messmer EM, Tomlinson A, Calonge M, Boboridis KG, et al. Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. Ocul Surf 2013;11(4):246–258.
[132] Clouzeau C, Godefroy D, Riancho L, Rostène W, Baudouin C, Brignole-Baudouin F. Hyperosmolarity potentiates toxic effects of benzalkonium chloride on conjunctival epithelial cells in vitro. Mol Vis 2012;18:851–863.
[133] Sarkar J, Chaudhary S, Namavari A, Ozturk O, Chang JH, Yco L, et al. Corneal neurotoxicity due to topical benzalkonium chloride. Investig Ophthalmol Vis Sci 2012;53(4):1792–1802.
[134] Martone Gianluca, Frezzotti Paolo, Tosi Gian Marco, Traversi Claudio, Mittica Vincenzo, Malandrini Alex, et al. An in vivo confocal microscopy analysis of effects of topical antiglaucoma therapy with preservative on corneal innervation and morphology. Am J Ophthalmol 2009;147(4):725–735.
[135] Denoyer A, Godefroy D, Célérier I, Frugier J, Riancho L, Baudouin F, et al. CX3CL1 expression in the conjunctiva is involved in immune cell trafficking during toxic ocular surface inflammation. Mucosal Immunol 2012;5(6):702–711.
[136] Lee HJ, Jun RM, Cho MS, Choi KR. Comparison of the ocular surface changes following the use of two different prostaglandin F2α analogues containing benzalkonium chloride or polyquad in rabbit eyes. Cutan Ocul Toxicol 2015;34(3):195–202.
[137] Galletti JG, Gabelloni ML, Morande PE, Sabbione F, Vermeulen ME, Trevani AS, et al. Benzalkonium chloride breaks down conjunctival immunological tolerance in a murine model. Mucosal Immunol 2013;6(1):24–34.
[138] Pisella PJ, Debbasch C, Hamard P, Creuzot-Garcher C, Rat P, Brignole F, et al. Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study. Investig Ophthalmol Vis Sci 2004;45(5):1360–1368.
[139] Baudouin Christophe, Liang Hong, Hamard Pascale, Riancho Luisa, Creuzot-Garcher Catherine, Warnet Jean-Michel, et al. The ocular surface of glaucoma patients treated over the long term expresses inflammatory markers related to both t-helper 1 and t-helper 2 pathways. Ophthalmology 2008;115(1):109–115.
[140] Zhivov A, Kraak R, Bergter H, Kundt G, Beck R, Guthoff RF. Influence of benzalkonium chloride on langerhans cells in corneal epithelium and development of dry eye in healthy volunteers. Curr Eye Res 2010;35(8):762–769.
[141] Brignole-Baudouin F, Riancho L, Liang H, Nakib Z, Baudouin C. In vitro comparative toxicology of polyquad-preserved and benzalkonium chloride-preserved travoprost/timolol fixed combination and latanoprost/timolol fixed combination. J Ocul Pharmacol Ther 2011;27(3):273–280.
[142] Labbé A, Pauly A, Liang H, Brignole-Baudouin F, Martin C, Warnet JM, et al. Comparison of toxicological profiles of benzalkonium chloride and polyquaternium-1: an experimental study. J Ocul Pharmacol Ther Off J Assoc Ocul Pharmacol Ther 2006;22(4):267–278.
[143] Kahook MY, Noecker RJ. Comparison of corneal and conjunctival changes after dosing of travoprost preserved with sofZia, latanoprost with 0.02% benzalkonium chloride, and preservative-free artificial tears. Cornea 2008;27:339–343.
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