Consider ocular tissue health when prescribing glaucoma medications

Polytherapy increases the patient’s cumulative exposure to potentially toxic components.

Many glaucoma patients experience ocular surface symptoms such as burning, stinging, red eye and ocular irritation. The appearance of acute symptomatology may just be the tip of the iceberg when considering the overall health of ocular tissue.

In addition, glaucomatous symptoms usually increase over time, requiring multiple drugs to maintain control. A growing body of evidence indicates that preservatives such as benzalkonium chloride (BAK) are probably responsible for much of the chronic inflammation and cellular toxicity responsible for these adverse effects. Thus, it is important for practitioners to consider ocular tissue health during the evaluation and treatment of their glaucoma patients.

The availability of new preservative-free ophthalmic preparations may help maintain the health of various ocular tissues during glaucoma treatment.

Glaucoma and ocular surface diseases

Glaucoma and ocular surface diseases including dry eye are two common conditions treated by ophthalmologists. These often occur concomitantly, and the prevalence may be higher than what clinicians traditionally think. Which disease is responsible here? The answer is that the treatment for one, such as glaucoma, may be contributing to the other, ocular surface disease.

More precisely, it is the preservative present in many eye drops that could be exacerbating pre-existing dry eye conditions. Treatment for glaucoma with one or more topical preservative-containing eye drops may increase subclinical inflammation or aggravate ocular surface disease that may already be present.

In clinical practice, glaucoma treatment may last for decades. Patients are often treated with two or more topical ophthalmic formulations. The Ocular Hypertension Treatment Study reports that 40% of patients were using more than one drug after 5 years, with 9% using three or more drugs.

The Collaborative Initial Glaucoma Treatment Study shows 75% of patients using two or more drugs within 2 years of initial glaucoma treatment. Polytherapy increases the patient’s cumulative exposure to potentially toxic components such as BAK.

Allergy vs. toxicity

An allergic reaction to an ocular drug is the most spectacular expression of inflammation, but hardly the most frequent. Although easy to recognize, only a small percentage of patients have a true allergic response. Toxic side effects of eye drops are much more frequent and the more important manifestation. Sometimes inflammation associated with toxicity may be subclinical, so it is important to monitor for related signs and symptoms.

Measuring tear breakup time is a fast and easy way to monitor the health of the ocular surface. Up to 70% of glaucoma patients may have a decrease in tear breakup time, an indication of toxicity on some level. Decreased tear breakup time is a small sign, but it is the indicator of something occurring deeper in the tissue – inflammation, and its cortege of tear film impairment.

The level of inflammation present in glaucoma patients is directly related to the number and duration of treatments. This inflammation is a toxic, long-term reaction that increases over time. It is a result of a combination of factors including the ocular surface, the environment, behavior, tear film function and drugs put onto the normal ocular surfaces.

Figure 1. ICAM-1 expression ICAM - 1 expression in conjunctival imprints from patients treated with BAK-free beta-blockers, BAK-containing beta-blockers or multiple BAK-containing eye drops. **P < .001 compared to control and unpreserved groups. Adapted from Pisella and colleagues.

Role of inflammation on the trabecular meshwork

Abnormal inflammatory responses due to BAK are also found in deeper tissues. Patients with ocular surface inflammation often have this in the trabecular meshwork as well. The trabeculum of patients using many topical ophthalmic drugs contains more inflammatory cells in those patients using fewer medications before surgery. An increase in IOP may be due to a loss of trabecular cells, resulting in an abnormal matrix in the trabeculum. Chronic inflammation of the meshwork may have an influence on control of IOP, meaning that ocular surface disease may contribute to glaucoma.

Impression cytology is a method of collecting cells in a minimally invasive way to measure inflammatory markers. It is less aggressive than conjunctival biopsies, making it an easier tool to measure subclinical inflammation in glaucoma or dry eye patients with non-obvious inflammation. Measurements of inflammatory markers demonstrate increased inflammation in patients using one or more preserved eye drop (Figure 1).

Mechanisms of filtering surgery failure

Many patients with poor glaucoma control progress to require additional topical treatments and sometimes surgery. The presence of inflammation can be a negative prognosticator for the success of glaucoma surgery, and previous treatment with anti-glaucoma drugs is a risk factor for surgery failure.

Broadway and colleagues identified long-term topical combination therapy as a significant risk factor for the failure of trabeculectomy, related to the induction of subclinical inflammation. Moving beneath the surface, surgical failure may be due to collagen strands that encapsulate the bleb or block aqueous outflow resulting in a flat, inefficient bleb. Reducing the amount and number of topical treatments decreases the amount of preservative-associated toxicity and may improve outcomes related to glaucoma surgery.

Identify the origin of problems

In order to effectively address the problem, it is important that practitioners objectively identify the origin of ocular surface symptoms. Almost all anti-glaucoma drugs contain BAK, a quaternary ammonium compound with cationic surfactant properties that acts as a preservative by disrupting bacterial cell membranes. BAK can be highly toxic, especially after chronic exposure or when used on a concomitantly impaired ocular surface. The majority of complications may be directly related to this preservative. Many in vitro studies demonstrate that BAK alone is a major instigator of inflammation and toxicity in ocular tissues.

BAK also enhances penetration of the drug into the cornea by causing a separation of the epithelial cells. This effect can be toxic to normal healthy tissue, causing inflammation and impregnation of BAK into tissues deeper in the eye (Figures 2a and 2b).

Directly toxic to epithelial cells and goblet cells, chronic exposure to BAK is also toxic to other tissues, including the conjunctiva, cornea and trabecular meshwork. Toxicity is directly related to the amount, concentration and duration of the use of one or more drugs containing BAK. Glaucoma medications are of particular concern due to the fact that administration is required chronically, one or more times daily.

Effects of 15 minutes of contact of BAK on conjunctival cells in vitro. (Control on the right, BAK 0.01% on the left.)

Prostaglandins and inflammation

Prostaglandins are a popular treatment for glaucoma. The presence of BAK and the physiological nature of the prostaglandins may result in a pro-inflammatory state. But new trial evidence indicates that the level of inflammatory markers measured with three prostaglandins is not as high as that of a comparative beta-blocker (Figure 3). The prostaglandin Xalatan (latanoprost, Pfizer) contains a relatively high concentration of BAK (0.02%), but causes mild inflammation on the ocular surface when used alone. However, toxicity over the long term is directly related to duration of treatment and the addition of other drugs containing BAK, a common requirement in glaucoma.

The prostaglandin Travatan Z (benzalkonium chloride-free travoprost, Alcon) contains a proprietary ionic buffer system and is BAK-free. Travoprost without BAK causes less in vitro cytotoxicity and apoptosis than BAK-containing formulations (Figures 3 and 4).

Figure 3. Inflammatory expression Inflammatory expression after prostaglandin monotherapy for at least 1 year. Relative level of inflammation based on the expression of HLA-DR. Adapted from Baudouin and colleagues, in press.

Figure 4. In vitro cytotoxicity of the first BAK-free prostaglandin Rate of apoptosis after exposure to pure drug for 30 minutes, based on YOPRO-1/NR ratio. *P < .0001 vs. Medium, PBS, Travatan Z. § P < .0001 vs. Xalatan. Adapted from Baudouin and colleagues, in press.

It is well-demonstrated that removal of the preservative from an ophthalmic formulation has no effect on the efficacy of the drug. Lewis and colleagues report that travoprost without BAK is equally efficacious and associated with a lower rate of patient-reported hyperemia compared with the BAK containing travoprost solution.

This presents an opportunity to protect the ocular surface, particularly among patients receiving initial treatment for glaucoma. The use of a BAK-free formulation at treatment onset can prevent inflammation that may later be compounded by the addition of other preservative-containing eye drops.

Clinical recommendations

The ocular surface is a concern in glaucoma patients and should not be neglected. There are many simple measures practitioners can use to quickly and inexpensively assess ocular surface health. First, check for signs and symptoms (Table 1). Simply ask the patient about symptoms experienced during treatment. Stinging, burning, itching, dryness or tearing may be indicators of inflammation. The consequence of these side effects is poor compliance, leading to poor glaucoma control.

There are several tests that can help in evaluating health of the ocular surface. Fluorescein staining can easily be used to visualize tear breakup time and indicate areas of corneal damage. Decreases in tear breakup time result in redness, itching and discomfort. Decreases in tear breakup time also signify something deeper – chronic inflammation that may ultimately affect control of IOP. In addition, a slit lamp exam can be used to check for blepharitis.

Practitioners should be aware of the ocular surface in glaucoma patients, and that the present minor inflammatory problem may be a major problem later. Ocular surface disease is not just insufficient tear production, but instability of the tear film is a common cause of dry eye caused or aggravated by BAK.

There are many tear products available. When one is used, it should not contain BAK. For glaucoma medications, if it is possible to remove the preservative without affecting treatment, this is nearly always desirable.

It is a better choice to avoid exposure in patients new to treatment altogether. If all preservatives cannot be eliminated in patients using multiple medications, try to decrease the amount of preservative in one or more of the formulations. Thus, “the lower the better” applies not only to reducing IOP, but also BAK exposure in glaucoma patients.

For more information:

• Christophe Baudouin, MD, PhD, can be reached at Quinze Vingts Hopital, 28 Rue de Charenton, Paris 75012, France; +33-1-49-09-55-08; e-mail: baudouin@quinze-vingts.fr. He is a consultant for Alcon, Allergan and Pfizer France.

References:

• Baudouin C, Hamard P, et al. Conjunctival epithelial cell expression of interleukins and inflammatory markers in glaucoma patients treated over the long term. Ophthalmology. 2004;111:2186-2192.
• Baudouin C, Liang H, 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. 2007 May 25; [E-pub ahead of print].
• Baudouin C, Pisella PJ, et al. Ocular surface inflammatory changes induced by topical antiglaucoma drugs: Human and animal studies. Ophthalmology. 1999;106:556-563.
• Baudouin C, Riancho L, Warnet JM, Brignole F. In-Vitro studies of antiglaucomatous prostaglandin analogues: Travoprost with and without benzalkonium chloride and preserved latanoprost. Invest Ophthalmol Vis Sci.; In press.
• Broadway DC, Grierson I, O’Brien C, Hitchings RA. Adverse effects of topical antiglaucoma medication. II. The outcome of filtration surgery. Arch Ophthalmol., 1994;112:1446-1454.
• De Saint Jean M, Brignole F, et al. Effects of BAK on growth and survival of Chang conjunctival cells. Invest Ophthalmol Vis Sci. 1999;40:619-630.
• Guenoun JM, Baudouin C, et al. In-vitro study of inflammatory potential and toxicity profile of latanoprost, travoprost, and bimatoprost in conjunctiva-derived epithelial cells. Invest Ophthalmol Vis Sci. 2005;46:2444-2450.
• Kass MA, Heuer DK, et al. The Ocular Hypertension Treatment Study: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701-713.
• Lewis RA, Weiss MJ, et al. Travoprost 0.004% with and without benzalkonium chloride: A comparison of safety and efficacy. J Glaucoma. 2007;16:98-103.
• Lichter PR, Musch DC, et al. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology. 2001;108:1943-1953.
• Noecker RJ, Herrygers LA, Anwaruddin R. Corneal and conjunctival changes caused by commonly used glaucoma medications. Cornea. 2004;23:490-496.
• Pisella PJ, Debbasch C, 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;45:1360-1368.
• Tsai JH, Derby E, Holland EJ, Khatana AK. Incidence and prevalence of glaucoma in severe ocular surface disease. Cornea. 2006;25:530-532.
• Yu JY, EU E, Kahook M, Noecker R. The prevalence and significance of ocular surface disease in glaucoma patients. Presented as a poster at the 2006 American Academy of Ophthalmology. Las Vegas, NV.