Pharmacy Times

Behavioral Objectives

SECTION 2
Classification and Diagnosis

Pathophysiology of AC 

Management of AC 

SECTION 3 Conclusion

References

SECTION 4   
Table 1 

Table 2 

Patient Counseling for Proper Administration of Eye Drops 

 

CE Credit Certification

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Contemporary Management 
of Allergic Conjunctivitis

brought to you by 
an unrestricted educational grant from

Leon Behar, PharmD, and Dusan Kostic, PhD

Dr. Behar is Senior Vice President and Director, and Dr. Kostic is Medical Director of the Health Science Center for Continuing Medical Education, New York, NY

Introduction

Ocular allergy is a common problem, affecting up to 22% of the population.¹ As part of the spectrum of allergic diseases, ocular allergy is frequently linked to a personal or family history of allergic rhinitis, atopic dermatitis, asthma, or other allergic conditions.² Because the majority of ocular allergies involve the conjunctiva, the terms “ocular allergy” and “allergic conjunctivitis” (AC) are often used interchangeably. 

The economic burden of AC is substantial. One study found that the annual cost of AC/allergic rhinoconjunctivitis (AR) was $1.9 billion (in 1996 dollars) when it was the primary diagnosis. The cost when AC/AR was a secondary diagnosis was estimated at $4 billion. Thus an estimated $5.9 billion for the overall direct medical expenditures can be attributable to this condition.³

In many cases, conjunctivitis can be the most pronounced or the only clinical manifestation of allergy. In a study of 5,000 children with allergies, ocular disease was the only allergy that could be clinically diagnosed.⁴ The severity of AC ranges from a mild interference with an individual’s quality of life to impaired visual function. Whereas the mildest forms of AC can be successfully treated with over-the-counter (OTC) medications, the more severe forms require careful management by an ophthalmologist.⁵

As the most accessible health care professionals, pharmacists can play an important role in the management of AC. As with other disease states, a clear understanding of the pathophysiology of the disease is necessary to optimize pharmacotherapy. This review addresses the classification and diagnosis, clinical manifestations, and pathophysiology of the most common forms of ocular allergies and describes the latest therapeutic advances in the management of AC. 

Classification and Diagnosis

AC is defined as an inflammation of the conjunctiva in response to the presence of an allergen. The conjunctiva is a thin mucous layer that covers the anterior portion of the eye and the inner surface of the eyelids. This mucous layer is exposed to the external environment and is the most immunologically active tissue of the external eye. 

Depending on the severity of the symptoms and course of the disease, allergic eye disease has been classified into acute and chronic forms (Table 1). 

Table 1.

Seasonal and Perennial AC

Acute AC is caused by airborne allergens and can be seasonal or perennial. Acute AC is considered a mild form of ocular allergy and is rarely associated with permanent visual impairment. However, it can cause considerable discomfort and adversely impact quality of life. 

Seasonal AC (SAC) is the most common form of the disease and represents about half the cases of AC.⁶ The most common cause of SAC is sensitivity to pollen with symptoms usually manifesting throughout the spring and fall. Symptoms include itching, burning, redness, tearing, watery discharge, and eyelid swelling. Typically, both eyes are involved, although symptoms may be more severe in one eye. In addition, ocular symptoms are frequently associated with upper respiratory symptoms. In rare cases, corneal symptoms, including photophobia and blurred vision, are also present. 

Perennial AC (PAC) is much less common than SAC, with a documented prevalence of 0.035%.⁷ The symptoms are similar to those of SAC but are usually milder and more persist-ent. Although the symptoms are pres-ent throughout the year, up to 87% of patients with PAC have seasonal exacerbations, mainly in the fall.⁷ The common cause of PAC is sensitivity to perennial allergens, most commonly dust mites, fungi, or animal dander. In some cases, PAC may result from occupational exposure to other allergens. For example, perennial allergens have been shown to be almost three times more common among flower growers as a result of their exposure to pollen compared with the general population.⁸ 

Atopic Keratoconjunctivitis

Atopic keratoconjunctivitis (AKC) is a serious form of ocular allergy and is usually associated with atopic dermatitis.⁹ A personal and family history of eczema and asthma is very common in patients with AKC. The disease is chronic, with occasional seasonal exacerbations during the winter. AKC usually starts during adolescence and typically persists through the fifth decade of life. Men are more likely to be affected than women. Symptoms include severe itching, burning, and tearing. The eyelids are usually involved, with the presence of itchy red areas and a frequent appearance of scaling and crusting of the eyelids. Cataract develops in 10% to 12% of patients with AKC.¹⁰ Bacterial and viral (most commonly herpes simplex) infections may also occur. AKC with severe corneal involvement can lead to blindness. The triggers for AKC are similar to those responsible for atopic dermatitis and include food allergies and airborne allergens, particularly dust mites and animal dander.

Vernal Keratoconjunctivitis

Vernal keratoconjunctivitis (VKC) is a chronic, potentially vision-threatening disease typically affecting young men.¹¹ The onset of VKC is usually in the prepubescent period; most cases last 2 to 10 years and resolve during puberty. This form of allergic ocular disease is most common in dry warm climates. Most patients with VKC also have a history of eczema or asthma. The disease is characterized by large, cobblestone-like granulations in the upper eyelids and the presence of transient gelatinous yellow-white points (Horner-Trantas dots). Conjunctival scarring and corneal ulceration may develop. The most common symptom of VKC is extreme itching accompanied by a stringy mucous discharge containing eosinophils. Photophobia, lacrimation, burning, and foreign body sensation are additional symptoms associated with VKC.¹¹ As the name implies, the symptoms are most severe during the spring. Ragweed, pollen, and other airborne allergens have been implicated as triggering factors for the development of VKC. Excessive ulceration of the cornea may lead to permanent vision impairment.¹²

Giant Papillary Conjunctivitis 

Giant papillary conjunctivitis (GPC) is caused by foreign bodies and is usually iatrogenic, most often caused by contact lenses, prostheses, or protruding corneal sutures.¹³ The distinguishing feature of GPC is the presence of florid giant papillae on upper tarsal conjunctival surfaces. 

White or clear discharge is typically produced during the morning hours; this exudate becomes thick and stringy over the course of the disease. Symptoms may include itching, blurred vision, and photophobia. Allergic reactions to preservatives or glycoproteins deposited on contact lenses have been implicated in the etiology of GPC, and the condition eventually resolves when the offending foreign body is removed.

Differential Diagnosis

Most signs and symptoms of AC are relatively nonspecific and care should be taken to rule out other ocular conditions. Obtaining a careful and detailed history is often the most important step in evaluating a patient with conjunctivitis.¹⁴ Relevant components of a clinical examination include obtaining a detailed description of symptoms, appearance of the discharge, acuteness of symptom onset, any history of prior episodes, history of allergic disease, exposure to infected individuals, trauma, use of OTC medications and cosmetics, use of contact lenses, and environmental exposures. Common eye conditions that may resemble AC include infective conjunctivitis, blepharitis, dry eye syndrome, and tear duct obstruction.¹⁴

Infective conjunctivitis can be caused by bacterial, viral, fungal, or parasitic infections.¹⁵ Bacterial conjunctivitis is characterized by intensive hyperemia (redness) and the presence of purulent sticky discharge. Viral conjunctivitis is accompanied by a slight redness of the affected eye, the presence of a serous discharge, and, frequently, by lymphadenopathy. The discharge associated with parasitic conjunctivitis is typically mucopurulent. No form of infective conjunctivitis is accompanied by itching, and this symptom is probably the best differentiating factor between AC and the infective forms.^14,15 

Blepharitis is an inflammation of the eyelid margins. Common symptoms include irritation, itching, mild redness, tearing, and a burning sensation. The condition is frequently chronic and is often caused by a bacterial infection. The differentiating characteristic of blepharitis is the presence of a crusted exudate around the base of the eyelashes, sometimes resulting in the loss of lashes.¹⁵
Dry eye syndrome results from reduced tear production and is accompanied by burning and foreign object sensation. It mainly occurs in older individuals, especially in older women, and can be worsened by the use of oral antihistamines, diuretics, hormone replacement therapy, anticholinergics, or psychotropics. This condition is very common in patients with rheumatoid arthritis. Dry eye syndrome as a result of tear duct obstruction is characterized by dry eyes that do not itch.

Pathophysiology of AC

Acute AC is a type I hypersensitivity reaction (ie, mediated by immunoglobulin E [IgE]), resulting in mast cell activation. The chronic forms of conjunctivitis have a more complex pathology, with greater involvement of the cellular immune response, although mast cell activation still plays a central role.¹⁶ Like all allergies, the first stage of AC is marked by allergen sensitization. When deposited on the mucosal epithelium, allergens are processed by Langerhans and other antigen-presenting cells (APCs). T cells are activated through contact with antigen-carrying APCs and subsequently release cytokines that stimulate production of allergen-specific IgE by B cells. These cytokines include interleukin (IL)-4, IL-6, and IL-13. The IgE antibodies bind to high-affinity receptors on the mast cells in the conjunctiva. When the allergen again interacts with conjunctival tissue, it binds to two or more IgE antibodies. This cross-linking of antibodies on the mast cell surface causes cell activation and the release of a variety of preformed mediators contained in mast cell granules. The proinflammatory mediators released by mast cells include histamine, prostaglandins, leukotrienes, and kinins. These mediators cause nerve stimulation, vasodilation, increased vascular permeability, and mucous secretion, leading to itching and burning sensations, eye redness, edema, and the production of discharge. The peak of the initial symptoms of the early phase allergy response occurs about 20 minutes after an allergen challenge and abates by 40 minutes.¹⁷ A late-phase response with reappearance of symptoms frequently occurs 6 or more hours after exposure to the allergen. This phase of the allergic response is partially caused by repeated mast cell degranulation.18 In addition to the inflammatory mediators, mast cells release a number of cytokines that lead to recruitment of nonspecific inflammatory cells to the conjunctiva. Some of these cytokines, including IL-5, IL-6, and platelet-activating factor (PAF), act directly as chemoattractants,¹⁹ whereas others, notably tumor necrosis factor alpha, act indirectly by increasing the expression of endothelial adhesion molecules that facilitate the migration of leukocytes from blood vessels into the conjunctival tissue.²⁰ The recruited cells, including eosinophils, neutrophils, and macrophages, amplify the inflammatory response.²¹ The pathophysiologic role of eosinophils in conjunctival eye disorders has been well documented.²² The presence of eosinophils is characteristic of ocular allergies.²³ Long associated with more severe forms of ocular allergy such as VKC, it has been shown that increased eosinophil infiltration is also found in the conjunctival scrapings of SAC.²⁴ Various authors have suggested that pharmacologic therapy attenuating the negative effect of eosinophils could play an important role in the treatment of ocular allergies.^22,25

Activated eosinophils release highly charged polypeptides that may cause epithelial injury. These proteins are involved in corneal damage that may occur in severe chronic allergic conditions such as AKC. Whereas a type 1 (IgE-mediated) hypersensitivity reaction is the primary mechanism of SAC and PAC, recent studies indicate that T cell–mediated hypersensitivity also plays a role in the development of AKC, VKC, and GPC.²⁶ In AKC, which is associated with systemic atopy, T cells may be recruited from the circulating pool of T cells; however, these cells seem to be produced locally in VKC and GPC.²⁷

Management of AC

The treatment of AC depends on the severity and pathogenesis of the disease.⁵ The most effective and usually least practical treatment involves allergen avoidance. Patients should also be advised to avoid rubbing their eyes, as physical stimulation of the mast cells can cause their further activation.²⁸ Pharmacists should also inform patients that symptomatic relief may be obtained by the administration of cold compresses and that contact lenses should not be worn if conjunctivitis is present or if topical preparations are being instilled. 

Artificial Tear Liquids

Artificial tear substitutes help in the direct removal and dilution of allergens and may provide additional symptomatic relief if administered after refrigeration. These preparations usually contain saline solution combined with wetting and viscosity enhancing agents, such as carboxymethylcellulose, glycerin, hydroxyethyl cellulose, hydroxypropyl methylcellulose, methylcellulose, polycarbophil, polyethylene glycol-400, polysorbate 80, or polyvinyl alcohol. It should be noted that preservatives used in artificial tear preparations may themselves be allergenic, and patients should be advised that they should immediately discontinue use if eye pain, worsening redness, changes in vision, or irritation occur.

Preservative-free preparations are available in single-use containers but at a significantly increased cost. Sodium perborate is a unique disappearing preservative used in certain commercially available preparations (eg, GenTeal Lubricant Eye Drops/Gel; HypoTears Select Eye Drops). The preservative generates a very low level concentration of hydrogen peroxide (0.006%), which is generally imperceptible to the patient. At this concentration, hydrogen peroxide turns into water and oxygen upon contact with the eye, thus minimizing the irritation that may be caused by traditional preservatives. 

Pharmacologic Therapies

Pharmacologic therapies for AC target various stages in the pathophysiologic cascade of the disease (Table 2). Currently, the only therapy targeting the initial binding of allergen-specific IgE molecules to mast cells is allergen immunotherapy. Although this therapy is well-established, particularly for the treatment of allergies caused by ragweed, molds, and animal dander, it is administered by injection in the physician’s office, is usually reserved for more severe cases, and is not universally effective. The next stage in the pathophysiologic cascade is the release of inflammatory mediators by activated mast cells; several topical mast cell stabilizers are available. Histamine is the major inflammatory mediator released by mast cells, and histamine receptor antagonism is a long-established therapeutic approach for the treatment of AC. More recently, dual-action ophthalmic allergy products (eg, olopatadine) with both antihistaminic and mast cell stabilizing activity have become available, as well as multiple-action therapies (eg, ketotifen) which inhibit eosinophil activation in addition to functioning as an antihistamine and mast cell stabilizer. Another class of mediators, prostaglandins, are inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). In cases of severe AC, ophthalmic corticosteroids are occasionally used. Topical vasoconstrictors decrease erythema, one of the end results of the allergic reaction. Although they may provide symptom relief, these agents do not treat the underlying pathophysiologic condition. 

Table 2. 

Topical Mast Cell Stabilizers

Mast cell stabilizers prevent the release of chemical mediators of inflammation from mast cells. Cromolyn sodium is the prototype of this class of agents. Ophthalmic preparations of cromolyn sodium are available as a 4% solution (eg, Opticrom, Crolom) with benzalkonium chloride 0.01% as a preservative. Cromolyn is indicated for the treatment of VKC, vernal conjunctivitis, and vernal keratitis and can be used in adults and children 4 years of age and older. One to two drops are administered four to six times a day. Although cromolyn was originally approved for more severe forms of conjunctivitis, it is now routinely used for treating milder forms of AC because of its excellent safety profile. Several clinical trials established the efficacy of cromolyn for the treatment of VKC and SAC ²⁹; in one trial, cromolyn was more effective than a combination of a topical antihistamine and a decongestant for treatment of VKC.³⁰ One trial suggested that individuals with known ragweed allergy may derive additional therapeutic benefit from using the medication regularly throughout the pollen season.³¹ Patients should be warned that cromolyn does not provide immediate symptomatic relief and that it needs to be used regularly for several days for treatment to be effective. Decreased itching, redness, and discharge are usually evident within a few days, but treatment for up to 6 weeks may be required. Once symptomatic improvement has been established, therapy should be continued for as long as needed to sustain improvement. Transient burning or stinging may occur upon administration of cromolyn. Contact lenses should be removed before administration of the medication. As is the case with all ophthalmic solutions containing benzalkonium chloride or a similar preservative, soft contact lenses should not be worn during treatment with cromolyn. Patients may be instructed to discontinue treatment immediately if increased eye redness, persistent irritation, or changes in vision occur, because those side effects can be signs of an allergy to either the preservative or to the drug itself. A similar warning should be issued to all patients using any ophthalmic preparation containing a preservative or a pharmacologic agent.

Lodoxamide tromethamine (Alomide) is a mast cell stabilizer that demonstrated greater potency than cromolyn in animal models.³² Lodoxamide is available as a 0.1% ophthalmic solution; benzalkonium chloride 0.007% is used as a preservative. Lodoxamide is approved for the same indications as cromolyn; however, lodoxamide can be used in children as young as 2 years of age. The dosage for adults and children older than 2 years of age is one to two drops in each affected eye four times a day for up to 3 months. Patients should be advised that it may take several days to experience relief. In clinical trials, lodoxamide has been shown to provide faster and greater symptom relief than cromolyn.^33,34 The clinical superiority of lodoxamide over cromolyn may be linked to its greater effect on the CD4(+) cells, which are known to play a pivotal role in the pathogenesis of at least some forms of AC.³⁴ As with cromolyn, transient burning or a stinging sensation may occur upon administration, and soft contact lenses should not be worn during therapy. 

Pemirolast potassium (Alamast) is a mast cell stabilizer recently approved in the United States for the prevention of itching associated with AC. Pemirolast can be used in adults and children 3 years of age and older, and it is about 100 times more potent than cromolyn. Pemirolast is available as a 0.1% ophthalmic solution; lauralkonium chloride 0.005% is used as a preservative. One to two drops are administered in each eye up to four times daily. Symptomatic relief may occur after a few days, but frequently requires up to 4 weeks of therapy. Ocular discomfort, burning, dry eye, and foreign body sensation have been reported in fewer than 5% of cases. Headache, rhinitis, and cold/flu symptoms have also been reported.

Nedocromil sodium ophthalmic solution (Alocril) has also been recently approved in the United States for the treatment of itching associated with AC. It is available as a 2% solution containing benzalkonium chloride 0.01% as a preservative. Dosing for adults and children 3 years of age and older is one or two drops in each eye twice a day. Treatment should be continued as long as there is exposure to the allergen, even in the absence of symptoms. Several clinical trials established the effectiveness of nedocromil for treatment of SAC,^35,36 and one trial demonstrated that this agent is more effective than cromolyn for the treatment of VKC.³⁷ Although one study suggested that nedocromil relieves symptoms within 15 minutes of administration,38 onset of action in that study was determined after patients had already been receiving therapy for several weeks. Adverse effects associated with ophthalmic nedocromil are usually mild and transient and include headache (reported in approximately 40% of patients), ocular burning, irritation and stinging, unpleasant taste, and nasal congestion.

In summary, mast cell stabilizers act early in the allergic cascade and have been shown to be effective in a number of ocular allergic diseases. All of the ophthalmic mast cell stabilizers are available by prescription only in the United States. In trials that directly compared the agents from this class, both lodoxamide and nedocromil seemed to exhibit superior efficacy compared with cromolyn. It should be noted, however, that most of those studies used cromolyn 2% as a comparator, and not the currently available 4% solution. A significant drawback of mast cell stabilizers is the slow onset of action and lack of immediate relief. As a result of the generally excellent safety profile of these agents, clinical experience suggests that they can be used for prolonged periods of time while the allergen is present in the environment and for prophylaxis when started prior to exposure to a seasonal allergen. Because the safety of these agents during pregnancy has not been established, they should be used with caution during pregnancy and only if the perceived benefit outweighs any unknown risks. It is not known whether any of these agents are excreted in human milk, thus, care should be exercised when administering mast cell stabilizers to nursing women. 

Topical Antihistamines

Histamine is the main mediator of the type 1 hypersensitivity reaction that causes most forms of AC. Histamine binds to two types of receptors in the conjunctiva; stimulation of H1 receptors results in an itching sensation, whereas activation of H2 receptors seems to be involved in vasodilation.³⁹ All topical antihistamines are H1 receptor antagonists. Although the older topical antihistamines have some beneficial effects, they are not potent enough to be effective as monotherapy and are usually combined with decongestants in OTC preparations (discussed below). Two newer H1 antagonists, levocabastinehydrochloride (Livostin) and emedastine difumarate (Emadine), are potent enough to be effective when administered alone and are available by prescription in the United States.

Levocabastine HCl is a highly selective H1 receptor antagonist with no apparent effects on dopamine, serotonin, adrenergic, or opiate receptors. It is indicated for relief of signs and symptoms of SAC in patients age 12 years and older. Levocabastine HCl is available as a 0.05% suspension; 0.015% benzalkonium chloride is used as a preservative. One drop is administered in each eye up to four times daily. Patients need to be reminded to shake the container prior to administration. In clinical studies, levocabastine HCl was found to be as effective as an antihistamine/decongestant combination and more effective than cromolyn and nedocromil for the treatment of SAC.^40-42 Levocabastine has a rapid onset of action, providing relief from symptoms of conjunctivitis within 10 minutes of administration. The most frequent adverse effects associated with levocabastine are mild, transient stinging and burning and headache. The safety of levocabastine during pregnancy has not been established. The agent is absorbed systemically and has been detected in human milk. 

Emedastine difumarate is a relatively selective H1 antagonist that has no detectable effects on adrenergic, dopaminergic, or serotonin receptors. It is available as a 0.05% solution in a preparation containing benzalkonium chloride 0.01% as a preservative. Emedastine is indicated for the temporary relief of the signs and symptoms of AC in adults and children 3 years of age and older. The recommended dose is one drop in the affected eye up to four times daily. In a double-blind study employing a contralateral eye design and allergen challenge model, emedastine and levocabastine HCl were similarly effective in controlling conjunctival redness.⁴³ Two double-blind, parallel-group studies, one in adults and the other in the pediatric population, compared the two antihistamines for the treatment of SAC in an environmental allergy model. In both studies, after 30 and 42 days of therapy, emedastine was more effective in reducing eyelid swelling, itching, and redness.^44,45 Emedastine was also shown to be superior in controlling the symptoms of AC compared with the topical NSAID ketorolac.⁴⁶ The most common adverse event associated with emedastine therapy is headache, which occurs in up to 11% of patients. The safety of emedastine during pregnancy has not been established. It is currently not known whether ocular administration results in detectable drug concentrations in breast milk. 

In summary, the newer topical antihistamines, levocabastine and emedastine, are potent enough to be used as monotherapy for the treatment of signs and symptoms of AC. Both agents seem to have favorable safety and tolerability profiles. Somnolence or dry eyes, commonly seen with OTC oral antihistamines, are infrequent with topical agents. 

Patient Counseling for Eye Drop Administration 

Agents with Dual Antihistaminic/Mast Cell Stabilizing Effects

Olopatadine (Patanol), recently approved in the United States for the treatment of AC, exhibits a dual mechanism of action: H1 receptor antagonism and mast cell stabilization. It is available as a 0.1% ophthalmic solution with benzalkonium chloride 0.01% as a preservative. Olopatadine is a relatively selective antagonist of H1 receptors, with no detectable effects on alpha-adrenergic, dopamine, muscarinic type 1 and 2, or serotonin receptors. The ophthalmic solution is indicated for the temporary prevention of itching of the eye as a result of AC in adults and children 3 years of age and older. Olopatadine has a rapid onset of action (within 3 minutes), and the reported duration of action is 6 to 8 hours.⁴⁷

In a comparative study of olopatadine versus ketorolac, olopatadine significantly reduced both ocular itching and hyperemia when compared with placebo at all tested time points following allergen challenge.⁴⁸ Conversely, ketorolac did not significantly reduce itching and showed a trend toward increasing hyperemia compared with placebo. Olopatadine was also significantly more tolerable than ketorolac as reported by individuals immediately following drug administration. 

In a comparative trial of olopatadine versus ketotifen fumarate (Zaditor), an agent with a triple mechanism of action (described below), both agents provided symptom control in the majority of treated patients. After 7 days of therapy, hyperemia was controlled in a higher percentage of patients in the olopatadine group. There was no statistically significant difference between the two agents regarding relief of itching, tearing, or mucous discharge at this time point.^49,50 

In published clinical studies,^46,50 olopatadine HCl ophthalmic solution had an excellent tolerability profile; the most commonly reported adverse effect is headache. Symptoms of ocular discomfort, including burning, stinging, and dry eye, have been reported in fewer than 5% of patients.

Agents with Antihistaminic, Mast Cell Stabilizing, and Eosinophil Inhibitory Properties

Two recently approved agents have similar antihistaminic/mast cell stabilizing activity as olopatadine, but also have additional anti-inflammatory activity.

Ketotifen fumarate is a relatively selective, noncompetitive H1 receptor antagonist and mast cell stabilizer that also exhibits direct inhibitory effects on eosinophils. Whereas mast cell stabilizers indirectly inhibit eosinophil chemotaxis by preventing the release of intracellular histamine, ketotifen also has a direct inhibitory effect on eosinophil chemotaxis and degranulation.^51-53 Ketotifen has also been shown to attenuate the response to PAF, a potent eosinophil chemoattractant that induces platelet aggregation and histamine release.⁵⁴ When activated, eosinophils release other mediators of allergic inflammation including leukotrienes and prostaglandins. In addition, activated eosinophils also release several toxins (eg, major basic protein, eosinophil peroxidase, etc) that may cause cellular damage. Indeed, eosinophil activity has been related to the severity of AC.^55,56 Thus, the effects of ketotifen on eosinophil chemotaxis are important for the attenuation of both the immediate and ongoing allergic response. Ketotifen has also been shown to inhibit other proinflammatory medications such as IL-5, E-selectin, Icam-1.^57,58

Ketotifen is available as a 0.025% ophthalmic solution containing benzalkonium chloride as a preservative, and is indicated for the temporary prevention of itching of the eye caused by AC in adults and children as young as 3 years. The recommended dose of ketotifen is one drop in the affected eye twice a day. Ketotifen has a rapid onset of action (within 3 minutes) and an 8- to 12-hour duration of action. In clinical studies, the most commonly reported adverse events with ketotifen were conjunctival infection, headaches, and rhinitis. These effects were generally mild and their occurrence was generally similar to that observed in individuals whose underlying ocular disease was being studied. Of note, burning or stinging were reported at an incidence of less than 5%.

Azelastine hydrochloride (Optivar) is a relatively selective H1 receptor antagonist and a mast cell stabilizer. Azelastine seems to have additional anti-inflammatory effects, primarily by inhibiting migration and degranulation of eosinophils.^48,54,55 Azelastine is available as a 0.05% ophthalmic solution containing benzalkonium chloride 0.0125% as a preservative. Azelastine is approved for the treatment of eye itching associated with AC. The recommended dose is one drop instilled into each affected eye twice a day. In a placebo-controlled clinical study, treatment of experimentally induced AC with azelastine was highly effective, with an onset of action seen within 3 minutes and a duration of effect of 8 to 10 hours.61 In a trial comparing azelastine with levocabastine, the efficacy and tolerability of the two drugs were similar.62 In controlled clinical trials, the most common adverse events with azelastine were transient burning and stinging, headaches, and bitter taste. These effects were generally mild in nature.

NSAIDs

NSAIDs inhibit the activity of cyclooxygenase, an enzyme involved in prostaglandin synthesis. Prostaglandins are potent inflammatory mediators that cause swelling, chemosis, vasodilation, and mucous discharge. 

Ketorolac tromethamine ophthalmic solution 0.5% (Acular) is the only currently available ophthalmic NSAID that is indicated for the temporary relief of ocular itching caused by seasonal AC. The solution contains benzalkonium chloride 0.01% as a preservative. The recommended dose of ketorolac ophthalmic solution is one drop in each eye four times daily. Safety and efficacy in pediatric patients below the age of 12 have not been established. Upon dispensing ketorolac, pharmacists should inform patients that an allergic reaction to the drug is possible, particularly if there is a history of hypersensitivity to any NSAID. The use of ketorolac should be avoided during pregnancy, and care should be exercised when the agent is administered to nursing women. The most common adverse effect seen with ophthalmic ketorolac is transient burning and stinging upon administration, experienced by up to 40% of patients. This high incidence of stinging may significantly compromise adherence to therapy. Other adverse reactions occur rarely and include eye dryness, corneal infiltrates and ulcers, visual disturbances, ocular infections, and superficial keratitis.

Topical Steroids

Therapy with topical steroids is usually reserved for refractory severe cases of AC. The mechanism of action of these agents is somewhat similar to the action of NSAIDs. The primary nonhistamine inflammatory mediators released by the activated mast cells are prostaglandins and leukotrienes. Both are synthesized from arachidonic acid—prostaglandins through the action of cyclooxygenase and leukotrienes through enzymatic activity of lipoxygenase. Although topical steroids are very effective, serious adverse effects, including increased intraocular pressure possibly leading to glaucoma and the development of cataracts, are associated with protracted topical steroid use. In addition, prolonged ophthalmic steroid use may predispose a patient to eye infections. Thus, topical ophthalmic steroids should generally be reserved for short-term acute suppression of symptoms. 

Loteprednol etabonate 0.2% ophthalmic solution (Alrex) is the only ophthalmic steroid that is approved for the temporary relief of the itching and redness of the eye caused by seasonal allergies. Relief begins within approximately 2 hours after administration. Because the solution contains benzalkonium chloride 0.01% as a preservative, soft contact lenses should not be inserted for at least 10 minutes after instilling the agent. Although loteprednol has a good safety profile with minimal risk for increasing intraocular pressure,^63,64 the drug should not be used for longer than 10 days without monitoring intraocular pressure. In clinical studies, the most common adverse events in patients treated with loteprednol were abnormal vision/ blurring, burning, chemosis, discharge, and dry eyes.

Oral Antihistamines

Oral H1 receptor antagonists have been shown to be effective for the treatment of signs and symptoms of SAC and PAC.⁶⁵ Whereas the antihistamines that are available OTC are sedating, certain prescription oral antihistamines are either nonsedating (eg, fexofenadine, loratadine) or minimally sedating (eg, cetirazine). In general, treating AC with topical medications is preferable to using systemic therapy. Both OTC and prescription oral antihistamines can cause dryness of the eyes. In addition, onset of action takes several hours. The advantages of eye drops include the washing out of the allergen(s), minimal systemic exposure, and the soothing effect of some preparations, particularly if refrigerated. Oral antihistamines may, however, be useful in the treatment of AC when it is associated with lid edema, dermatitis, rhinitis, or sinusitis.

Ophthalmic OTC Agents

OTC ophthalmic pharmacologic preparations used for the treatment of signs and symptoms of AC are topical decongestants and antihistamines. Topical decongestants are sympathomimetic vasoconstrictors and are highly effective in reducing erythema. However, their effect is palliative, as they do not disrupt any stage in the allergic cascade, but rather, only act on one of the target tissues. The effects of ocular decongestants last only a short period of time, and rebound erythema and congestion may occur with prolonged use. Decongestants are usually applied one or two drops every 2 hours up to four times a day. Oxymetazoline is a longer-acting agent that is generally administered twice daily. Eye irritation and loss of efficacy is fairly common with overuse of topical decongestants. Adverse effects of topical vasoconstrictors include burning and stinging after administration. The primary contraindication is narrow angle glaucoma. Commonly used decongestant eye drops include naphazoline hydrochloride 0.012%, 0.02%, and 0.03%, tetrahydrozoline 0.05%, phenylephrine hydrochloride 0.12%, and oxymetalozine hydrochloride 0.025%. 

Ophthalmic decongestants are frequently combined with antihistamines in a single topical solution. These combinations are effective in providing rapid relief for itching, redness, and swelling associated with AC and are often the only medication needed if the symptoms are mild and not long-lasting. Adverse effects associated with these preparations are similar to those for topical decongestants alone. The required uniform labeling for these products states that they should not be used by patients with heart disease, high blood pressure, difficulty in urination, or narrow angle glaucoma unless directed by a physician. Common antihistamines available in combination with decongestants include pheniramine maleate 0.3% and antazoline phosphate 0.5%. 

Conclusion

Management of AC usually involves a stepwise approach. Ideally, the allergen would be identified and exposure to it eliminated. However, this is often not possible, and treatment will depend on the severity of the disease. In cases of mild AC, cold compresses and artificial tears may be sufficient to provide relief during an allergic episode. If additional therapy is needed, OTC topical decongestants or decongestant/antihistamine ophthalmic solutions may be useful for a limited period of time. The pharmacist should stress that these agents should not be used for prolonged periods, because rebound erythema may occur. Patients with hypertension or coronary heart disease should avoid topical decongestants because systemic absorption may aggravate these conditions. If symptoms of conjunctivitis are not relieved by the use of OTC medications or reappear upon discontinuation, the patient should be advised to seek medical advice. As with all ophthalmic medications, the pharmacist should counsel the patient regarding proper administration, possible adverse effects, and monitoring for efficacy. When dispensing a mast cell stabilizer, pharmacists should inform patients that symptom relief will take several days and continued use is generally warranted after symptom resolution. Antihistamines or multiple-action products, however, may provide immediate relief. If necessary, palliative OTC treatment may be continued for a few days and then stopped to assess the effectiveness of the prescription therapy. For all ophthalmic solutions, patients should be warned of the potential signs of allergic reaction and the need to discontinue use and notify a physician if a serious reaction occurs. It is important for patients to be able to differentiate between a predictable and mild adverse effect, such as stinging upon administration, versus a serious hypersensitivity reaction. Patients should also be advised not to wear contact lenses while eye redness persists and to remove lenses prior to administering ophthalmic agents. At least 10 minutes should elapse prior to reinsertion of lenses for most preparations. 

With the ever-increasing therapeutic options for managing AC, proper counseling of patients suffering from this condition will allow pharmacists to significantly impact the optimization of pharmaceutical care.

Questions in the quiz are based on the following case:
BD is a 42-year-old woman who presents to the pharmacy requesting a recommendation for an alternative OTC preparation to treat “itchy eyes.” Upon questioning, the pharmacist learns that BD has a history of perennial allergic conjunctivitis, with symptoms (ie, itchy watery eyes, stringy mucous discharge) usually becoming more pronounced in the fall. BD uses the OTC ophthalmic solution of naphazoline HCl, antazoline phosphate (Vasocon-A) two to three times a day on most days, which until recently kept her symptoms at bay. BD also has a history of asthma that has been well controlled with a PRN beta agonist and a low dose of a daily-inhaled corticosteroid, until recently when she has been using her albuterol inhaler more frequently.

BD was self-medicating with diphenhydramine 25 mg every 4 to 6 hours for the past 2 days but discontinued it because it was making her too drowsy to function at work. Other pertinent history includes the use of contact lenses, a long standing history of depression, and generalized anxiety disorder, treated and adequately managed with citalopram 20 mg po qd and buspirone 10 mg po tid.

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References

For a list of references, send a stamped, self-addressed envelope to: References Department, Pharmacy Times, 1065 Old Country Road, Westbury, NY 11590.