The Challenges of Benzalkonium Chloride in Chloride in Glaucoma Care

Glaucoma, a chronic, progressive optic neuropathy that, if left untreated, can cause irreversible vision loss, affects more than 3 million people in North America.^1,2 Historically, topical medications have been the first line of glaucoma treatment, but patients must often administer multiple pharmacologic agents to achieve and maintain their target IOP.^3,4

Several common side effects of topical glaucoma medications mirror signs and symptoms of ocular surface disease (OSD). The incidence of OSD in the general population ranges from 5% to 30%, while up to 78% of patients undergoing treatment with topical IOP-lowering medications demonstrate signs of OSD and up to 50% experience OSD symptoms.^5-8

The preservatives found in many topical medications can induce or exacerbate the signs and symptoms of OSD in patients with glaucoma. The primary role of these preservatives is to maintain the products’ sterility and extend their shelf life.⁹ The most common preservative is benzalkonium chloride (BAK), which is used in approximately 70% of ophthalmic formulations.¹⁰

This article discusses BAK and the role of preservative-free (PF) topical drops (Tables 1 and 2).

THE EFFECT OF BAK ON THE OCULAR SURFACE

BAK is an effective antimicrobial agent that is both lipid and water soluble, which makes it compatible with many formulations. By destabilizing bacterial and fungal cell membranes upon contact, BAK is effective at killing pathogens,⁹ but it also has cytotoxic effects on ocular surface structures, including the cornea, conjunctiva, goblet cells, and meibomian glands. The clinical manifestations of BAK-induced ocular surface toxicity may include pain, discomfort (eg, stinging, burning, foreign body sensation, itching, ocular dryness), tearing, increased staining of conjunctival and corneal epithelial surfaces, decreased tear breakup time, reduced Schirmer scores, a higher prevalence of punctate keratitis, and overall worse scores on the Ocular Surface Disease Index (OSDI).⁹ These BAK-induced signs and symptoms are generally thought to be caused by the stimulation of ocular surface inflammation; inflammatory markers have been detected in all ocular surface structures, including the cornea,¹¹ conjunctiva,¹² goblet cells,¹³ and meibomian glands after BAK exposure (Figure).^14,15

The toxic effects of BAK, however, are not isolated to ocular surface cells. The preservative has also been detected in ciliary epithelial cells,¹⁶ the trabecular meshwork (TM),^16-18 the retina,^15,19 and the optic nerve.¹⁵ In the context of glaucoma, BAK’s effect on the TM is of particular note because this is the primary outflow pathway for aqueous humor. BAK has been found to reduce TM cell viability and elevate extracellular matrix metalloproteinase-9, interleukin-6, and interleukin-8 expression in the TM.¹⁸ BAK also causes oxidative damage to TM cells.^17,18

Whether these changes affect IOP is unclear, but one study found that exposing the TM to the same concentration of BAK found in commercially available topical glaucoma medications caused structural changes to the TM of nonglaucomatous eyes that were similar to those observed in glaucomatous eyes.¹⁸ The study authors concluded that BAK aggravated all characteristics of TM degeneration typical of glaucoma, including trabecular apoptosis, oxidative stress, and induction of inflammatory chemokines.¹⁸ This hypothesis has been supported by studies that have reported flare in the anterior chamber after BAK exposure and a resolution of flare after BAK exposure was halted.^20,21

The severity of BAK-induced OSD has been correlated with both higher concentrations of the preservative and more frequent dosing of topical agents containing it.^7,22,23 Simply stated, the more drops administered per day over time, the greater the cumulative risk and severity of BAK-induced OSD toxicity. Another study showed that patients who had glaucoma for 6 years or more had significantly higher OSDI scores than those whose disease was of a shorter duration.²⁴

WHEN TO CONSIDER A PF FORMULATION

Side effects remain the most common reason for patients’ poor adherence to prescribed therapy, and poor adherence increases their risk of disease progression.²⁵ Although side effects may be caused by the active ingredient as well as preservatives, BAK is notorious for causing OSD-related toxicity.^15,25

PF medications are a valuable treatment option for glaucoma.^25,26 Their effect on IOP is not inferior to that of preserved preparations, indicating that BAK is not required for adequate drug penetration, as was previously thought.²⁷

Whenever possible, patients newly diagnosed with glaucoma should be evaluated for OSD signs and symptoms and receive OSD treatment before topical glaucoma therapy is initiated. Otherwise, asymptomatic patients may develop symptomatic OSD and abruptly discontinue topical glaucoma therapy. PF topical agents are a valuable strategy for glaucoma therapy in this population because they help maintain the health of the ocular surface.

For patients with symptomatic OSD whose glaucoma is being treated with preserved medications, simply switching them to PF formulas can increase the tolerability of therapy and significantly improve their OSD signs and symptoms.²⁸ In one study, a switch to PF formulations not only maintained IOP control but also significantly reduced irritation, burning, stinging, itching, foreign body sensation, tearing, and dry eye sensation.²⁸

In addition, switching those who have been administering BAK-preserved drops to PF formulations can significantly improve their symptoms and lower their IOP.^29,30 The reason for the decrease in IOP is not well understood but may be related to a reduction in inflammation caused by BAK and/or patients’ improved adherence to prescribed medical therapy. 

A CALL TO ACTION

Based on the mounting evidence of BAK’s negative effects on the ocular surface and intraocular structures—and possibly the TM and thus IOP¹⁹—it is advisable that eye care providers prescribe PF solutions when possible.

In my experience, PF medications are less likely to cause OSD signs and symptoms in patients recently diagnosed with glaucoma. The long-term use of BAK-preserved medications should be avoided when possible to prevent the preservative’s significant toxic effects on the ocular surface and TM. n