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62 EW CORNEA April 2012 Pharmaceutical focus Although not an ideal situation for allergy sufferers, in most short- term courses of treatment, preservatives will not harm the ocular surface W hen one-quarter of the U.S. population is affected by a disease state and 90% of those patients exhibit ocular manifestations, it's safe to say ophthalmologists will see a good number of patients on a fairly rou- tine basis for treatment. When that disease state is allergic conjunctivitis and the most common topical treat- ments include preservatives known to adversely affect the ocular surface, it's not as clear-cut. Ocular allergies are usually sea- sonal or occasionally perennial, but more chronic forms include atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC), the latter two being more difficult to treat as well. VKC is more typically present in children, with AKC mostly affecting men under age 50. Current medical treatments range from antihistamines, mast cell stabilizers, combination antihis- tamine/mast cell stabilizers, decongestants, nonsteroidal anti- inflammatory drugs (NSAIDs), steroids, and vasoconstrictors. Most of the prescription medications use Brand name/marketer benzalkonium chloride in various strengths (see Table 1), a preservative reported to harm the ocular surface when used in chronic diseases such as glaucoma. "Fundamentally, the issue is that we don't have a good test to determine which patient is going to have a problem with the preserva- tive and which won't," said Ira J. Udell, M.D., chairman, ophthalmol- ogy department, North Shore Long Island Jewish Health System, Great Neck, N.Y. That does not imply ophthal- mologists should ignore the status of the corneal surface when they're evaluating allergy patients, he said. "The preservative is going to irritate the surface as soon as it hits it and will do so chronically over time," said Leonard Bielory, M.D., medical staff, Robert Wood Johnson University Hospital; professor, Rutgers University Center for Envi- ronmental Prediction; and director, STARx Allergy & Asthma Center, New Brunswick, N.J. "For instance, people think they've developed an allergy to a topical glaucoma med that is not actually an allergy to the med but a secondary irritation that has developed to the preservative." (For more on allergic reactions to topical medications, see sidebar.) In seasonal or perennial con- junctivitis, "the mast cells remain below the conjunctival surface so you have the integrity of that sur- face protecting the allergic trigger Generic name/recommended dosing Combined antihistamine/mast cell stabilizers Bepreve/ISTA (Irvine, Calif.) Elestat/Allergan (Irvine, Calif.) Lastacaft/Allergan Pataday/Patanol/Alcon (Fort Worth, Texas) Zaditor/Alcon Antihistamines Emadine/Alcon Livostin/Novartis (Basel, Switzerland) Optivar/Meda Pharmaceuticals (Somerset, N.J.) Mast cell stabilizers Alamast/Vistakon (Jacksonville, Fla.) Alocril/Allergan Bepotastine besilate ophthalmic solution 1.5%/BID Epinastine HCL ophthalmic solution 0.05%/BID Alcaftadine ophthalmic solution 0.25%/QID Olopatadine hydrochloride solution 0.2%/QID Ketotifen fumarate ophthalmic solution 0.025%/BID Emedastine difumarate ophthalmic solution 0.05%QID Levocabastine hydrochloride ophthalmic suspension 0.05%/QID Azelastine hydrochloride ophthalmic solution 0.05%/BID Pemirolast potassium ophthalmic solution 0.1%/QID Nedocromil 2%/BID Preservative use in allergy medications Allergic reactions by Michelle Dalton EyeWorld Contributing Editor A ccording to Dr. Bielory, although numerous adverse reactions to topical medications may occur, only 10% or so are a true allergic reaction. And even those allergies are typically in response to the active ingredient rather than the preservative, he said. In a recent paper, he cited a study that found even a single exposure to benzalkonium chloride 0.005% could produce precorneal tear film instability.1 Dr. Udell suggested doing a washout on these patients, with the caveat that physicians should "always try to withdraw medications you think might be the culprit first and see if it makes a difference," he said. Prepare the patient that withdrawal may result in increased discomfort. He's also noted in these situations that it may be necessary to put the patient on a steroid to get him/her back to the original baseline, "then start adding in drops selectively based on what you think is the least noxious agent," he said. "Once you start getting secondary effects of toxicity or irritation from the preservative or active agents of the drugs themselves, you start to lose perspective on why you put the patient on the drug in the first place." Although rare, in cases of true allergic reaction to the topical drug, it's essential for clinicians to get patients back to the baseline condition (as bad as that condition might have been) before revising treatment strategies. One pearl to alert clinicians that the patient may be having a true allergic reaction—it will be delayed. The allergic response is not the typical one seen where 15 minutes after an allergen exposure the patient begins to react, Dr. Bielory said. Instead, think of it as the "poison ivy reaction," where it will take a couple of days before the reaction begins. "In cases of true allergy to a medication, the irritation will be perpet- ual as long as you're continuing to add the med on a daily basis," he said. Working with an allergist may be beneficial in these cases, he said. Reference 1. Hong J, Bielory L. Allergy to ophthalmic preservatives. Curr Opin Allergy Clin Immunol. 2009;9(5):447-53. cells; the conjunctival surface of allergic patients appears to be more porous," Dr. Bielory said. In the more chronic forms, mast cells move Preservative used Benzalkonium chloride 0.005% Benzalkonium chloride 0.01% Benzalkonium chloride 0.005% Benzalkonium chloride 0.01% Benzalkonium chloride 0.01% Benzalkonium chloride Benzalkonium chloride 0.15 mg Benzalkonium chloride 0.125 mg Lauralkonium chloride 0.005% Benzalkonium chloride 0.01% to the surface of the conjunctiva and further accentuate allergic inflam- mation. "When there is a defect in the epithelial junction between cells of the conjunctiva, there will be cracks for allergens and pollutants to get through the deeper layers of the sub- stantia propria; when one has aller- gic inflammation it increases the gaps between the cells and causes further leakage that exacerbates the allergic response, creating a vicious cycle," he said. Dr. Bielory's general rule of thumb is to prescribe medications with preservatives for most seasonal sufferers, "unless the surface is really raw. Someone with the potential for a leaky surface, such as a chronic seasonal [patient], may already have a defect that's occurring," he said, although he noted there have not been any clinical studies to confirm his observations. There is no doubt preservatives adversely affect the ocular surface, Dr. Udell said, noting that the pre-