Medications for Allergy

Allergic rhinitis is an IgE-mediated inflammatory disease of the nasal mucosal membranes characterized mainly by sneezing, rhinorrhea, nasal pruritis, and congestion. It is the most common form of rhinitis, affecting 20 to 40 million Americans annually, and it is considered one of the most prevalent chronic diseases in the United States. It is also well documented that allergic rhinitis can negatively impact the quality of life and contribute significantly to loss of work productivity.

Allergic rhinitis may be categorized as seasonal “hay fever” or perennial (when symptoms persist year-round). Often, patients may react to multiple allergens and have seasonal exacerbation of symptoms in addition to perennial rhinitis. Tree, grass, and weed pollens are common seasonal allergens because they become airborne in large concentrations during a particular season of the year. Important perennial allergens include house dust mites, indoor molds, animal dander, and occupational allergens.

Management overview

Treatment options for allergic rhinitis include allergen avoidance, use of pharmacological agents for prevention and control of symptoms, and allergen immunotherapy for desensitization of patients in whom avoidance strategies and pharmacotherapy have failed to produce a satisfactory response.

Allergen avoidance

Whenever possible, environmental control measures should be emphasized as a fundamental part of the treatment plan. For instance, patients with pollen or outdoor mold allergies should remain in closed environments whenever possible. Patients sensitive to dust mites should enclose all mattresses and pillows with allergen-proof casings and eliminate carpeting, if possible, to reduce exposure; bedclothes should be frequently laundered in hot water to remove allergens. Although not always feasible, patients with animal allergies should consider removal of pets from home.

Antihistamines

Antihistamines (H1-antagonists) are typically prescribed as first-line agents for allergic rhinitis. They exert their actions by competitively antagonizing histamine at the H1- receptor sites and thereby suppress symptoms attributable to histamine release, such as sneezing, rhinorrhea, nasal itching, conjunctival itching, and lacrimation.

Antihistamines, however, are generally not effective in alleviating nasal congestion.

First-generation antihistamines

Various 1st-generation antihistamines are widely available with and without prescription. Although effective and economical, the usefulness of these agents is limited by their sedative and anticholinergic properties due to penetration of the central nervous system and poor receptor specificity.

All 1st-generation antihistamines are sedating to some degree and may cause performance impairment in 10% to 40% of users. In general, the ethanolamines (e.g., diphenhydramine) and phenothiazines (e.g., promethazine) are the most sedating. The ethylenedi-amines (e.g., pyrilamine) cause moderate sedation, and the alkylamines (e.g., chlorpheniramine, brompheniramine) are considered the least sedating. The use of lst-generation antihistamines at bedtime, which are less expensive, and newer nonsedating agents during the day has been advocated as a cost-saving strategy. This therapeutic approach may not be cost-effective, however, as residual effects of the bedtime dose may result in daytime sedation and performance impairment.

The anticholinergic effects of 1st-generation antihistamines (dry mucous membranes, urinary retention, blurred vision) may preclude their use in certain patients. Elderly patients are especially sensitive to these adverse effects. These older agents should be used cautiously in patients with narrow angle glaucoma or prostatic hypertrophy or in those taking other medications that may potentiate these side effects.

Although 2nd-generation antihistamines are generally prescribed due to ease of dosing and favorable side-effects profile, clinicians should be cognizant of available non-prescription antihistamines, as many patients may be self-managing with over-the-counter products (see Table 1).

Table 1 Selected 1st-generation antihistamines

Note: available OTC, often in combination with various decongestants, analgesics, and antitussives

Cromolyn sodium

Cromolyn sodium [Rynacrom(UK), Nasalcrom, Prevalin (Netherlands)] stabilizes mast cells and thereby prevents the degranulation of chemical mediators upon antigen presentation. Intranasal cromolyn ameliorates symptoms such as sneezing, rhinorrhea, and nasal pruritis but lacks efficacy for nasal congestion. Cromolyn is generally less efficacious than intranasal corticos-teroids. Therapy adherence may be problematic, as it necessitates frequent dosing (3 to 4 times daily). However, cromolyn may be safely administered, even to very young children, with negligible side effects. Intranasal cromolyn is now available without prescription. Patients should be advised to initiate therapy with cromolyn before the start of the allergy season or in anticipation of allergen exposure.

Ipratropium bromide

Ipratropium bromide [Atrovent, Apovent] is a well-tolerated topical anti-cholinergic agent that is available in a 0.03% nasal formulation. It is indicated for rhinorrhea associated with allergic and nonallergic perennial rhinitis. (A 0.06% formulation is approved for rhinorrhea associated with the common cold.) This agent quickly and effectively reduces nasal hypersecretion but has no effect on other symptoms of rhinitis such as sneezing and congestion. The most commonly reported adverse effects are nasal dryness and epistaxis. The recommended dose of intranasal ipratropium bromide is 2 sprays per nostril 2 to 3 times daily.

Conclusion

Pharmacotherapy remains the mainstay of management in patients with allergic rhinitis. Given the wide selection of available agents, the ideal regimen should be individualized to reflect disease severity and specific symptoms. Factors such as the potential for side effects, risk for drug interactions, ease of administration, and cost should also be considered. Most importantly, patients should be routinely followed to assess therapeutic response and to monitor for side effects or complications.

The use of intranasal corticosteroids is increasingly becoming first-line therapy for many patients with allergic rhinitis, especially those with moderate to severe symptoms or those with perennial allergic rhinitis in which nasal symptoms predominate. Intranasal corticosteroids specifically inhibit the allergic inflammatory processes that contribute to the late-phase response of nasal congestion. When used prophylactically, they can also inhibit the early-phase response to allergens. Overall, they are effective in relieving sneezing, nasal itching, rhinorrhea, and congestion.

Table 3 lists available intranasal corticosteroids, along with dosing information and comparative costs. In general, these agents are considered more cost-effective for use as monotherapy than 2nd-generation antihistamines. A recent meta-analysis found intranasal corticosteroids to be more effective than oral antihistamines in reducing nasal blockage, nasal discharge, sneezing, nasal itch, postnasal drip, and total nasal symptoms. No significant difference was detected for nasal discomfort, nasal resistance, and eye symptoms. No particular product has demonstrated clinical superiority, selection of drug should be based on factors such as response, ease of administration, cost, and formulation.

Table 3 Intranasal corticosteroids

Application site irritation (e.g., nasal irritation, burning, or sneezing after administration) is the most commonly encountered side effect. Patients complaining of local irritation may be switched to various aqueous formulations. Although rare, mucosal erosion and septal perforations have been reported with long-term use. To minimize septal irritation, patients should be instructed to direct the spray upwards and toward the lateral portion of the nose. Periodic examination of the nasal septum should be performed.

Although systemic effects from intranasal corticosteroids at recommended doses are considered minimal, there are some concerns regarding long-term exposure. Reports of posterior subcapsular cataract formation have been linked with the use of intranasal or inhaled corticosteroids; however, more recent prospective trials did not reveal evidence of posterior subcapsular cataract formation or elevation in intraocular pressure.

In 1998, the FDA’s advisory committees on pulmonary and allergy drugs and on metabolic endocrine drugs convened to assess data suggesting that intranasal corticosteroids may have an effect on growth velocity in children. Consequently, a new class labeling for pediatric use of inhaled and intranasal corticosteroids was mandated. At this time, the long-term significance of growth velocity reduction on final adult height is unknown. The FDA recommends routine monitoring of growth in pediatric patients using intranasal corticosteroids and titration to the lowest effective dose to minimize systemic risks.

Patient education is essential in ensuring proper use and compliance to intranasal corticosteroid therapy. Patients should be instructed on instillation techniques and informed about the possible delay in symptomatic response. Assessment of maximal response may require a therapeutic trial of several weeks. The drug should be administered regularly on a daily basis, rather than as needed for rescue relief.

For patients with severe disease, the combined use of intranasal corticosteroids and antihistamines may be necessary to control symptoms. The use of oral corticosteroids should be reserved for patients with severe exacerbations or intractable disease due to high risk of systemic adverse effects.

Nasal congestion is a common complication of allergic rhinitis. Congestion resulting from initial allergen exposure is usually limited; generation of other inflammatory mediators (e.g., leukotrienes) contributes, however, to the prominence of congestion in the late-phase inflammatory response period.^. Consequently, many patients will require a decongestant in addition to antihistamine therapy. Decongestants are also useful in clearing nasal passages at the onset of intranasal corticosteroid therapy to improve drug delivery.

Decongestants exert their effects by activation of alpha-adrenergic receptors in the vascular smooth muscle of the respiratory mucosa, thereby causing vaso-constriction in the turbinates. Oral formulations such as pseudoephedrine and phenylpropanolamine are available alone or in combination with various antihistamines. Decongestants may produce unwanted side effects, such as excitation of the central nervous system (e.g., insomnia, restlessness, agitation), tachycardia, urinary retention, and elevations in blood pressure. These agents should be administered cautiously in patients with hypertension, hyperthyroidism, diabetes mellitus, cardiovascular disease, or urinary obstructive diseases.

Topical decongestants (e.g., oxymetazoline, xylometazoline) [Nasal] can rapidly improve symptoms with minimal systemic effects. However, overuse may lead to the development of rhinitis medicamentosa (rebound congestion associated with nasal hyperreactivity, mucosal swelling, and tolerance). For this reason, topical decongestants are contraindicated for chronic nasal congestion, and their use should be limited to 3 to 5 days of therapy.

Second-generation antihistamines

The newer antihistamines are devoid of anticholinergic and sedative effects with the exception of cetirizine, which may be mildly sedating in some patients. The low incidence of side effects is attributed to their high selectivity for peripheral H1-receptors and low propensity to cross the blood-brain barrier. Three 2nd-generation antihista-mines for oral administration are currently available in the United States: cetirizine, fexofenadine, and loratadine. All appear effective in mitigating the symptoms of allergic rhinitis. Table 2 lists available agents and dosages.

Table 2 Second-generation antihistamines

Cardiotoxicity associated with astemizole and terfenadine is the most serious side effect associated with the 2nd-generation antihistamines. Serum accumulation of these agents may deleteriously prolong the QT interval. Serious ventricular arrhythmias (including Torsades de pointes), cardiac arrest, and death have ensued as a result of overdoses and concomitant use of medications that impair the metabolism of terfenadine and astemizole (potent inhibitors of cytochrome P450 3A4 isoenzymes, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, indinavir, fluoxamine). These reactions and interactions have not been associated with the currently available agents. (Both terfenadine and astemizole have since been voluntarily withdrawn from the US market; terfenadine has been replaced with its nonarrhythmogenic metabolite, fexofenadine.)

Azelastine is a new topically administered 2nd-generation antihistamine that has demonstrated efficacy in improving both early- and late-phase symptoms of allergic rhinitis. Symptomatic response may be seen as early as 30 minutes after dose. In comparative trials, intranasal azelastine appears equally as efficacious as oral antihistamines but generally less effective than corticosteroids in relieving nasal symptoms. The most commonly reported adverse effects are bitter taste, application site irritation, and somnolence. Azelastine is administered 2 sprays per nostril twice daily.

It is well-known that people in certain parts of the planet are far more likely to suffer from allergic rhinitis than in other parts, though it is not so clear why that happens. In Denmark, just over one in every 100 visits to a family physician involves seasonal allergic rhinitis, though in Britain the figure is one in 50 and in Australia almost one in 10. The disease is more of an urban than a rural phenomenon, a fact which has led many researchers to point a finger at air pollution as an aggravating condition.

Air pollution may indeed play a role in the increased incidence of this condition, perhaps because gases such as ozone and nitrous oxide are harming epithelial cells, the bloodless surface covering of human tissues, glands, and organs. But one study suggested that the role of air pollution may have been exaggerated. The children of Leipzig, despite breathing the notoriously polluted and sulfur dioxide-laden air of former East Germany, were found to have lower rates of rhinitis than children in the western, alpine city of Munich.

Physicians and rhinologists have traditionally divided allergic patients into those whose symptoms were seasonal and those who suffered all year round. Yet a single patient with a number of seasonal reactions to allergens that peak at different times of year may appear to have a year-round allergy. In any case, an individual with severe perennial symptoms should receive different drug treatments from an individual with mild seasonal symptoms.

For the person who suffers moderate, occasional allergic rhinitis symptoms, there are a variety of pharmacological allies available. Allergen avoidance is, as always, the ideal solution, but it may prove practically impossible for allergy sufferers who have no choice but to share the air they breathe with allergenic pollen. It helps, however, to know when the pollen count of a particular allergenic plant is going to begin climbing, and when it will peak, in order to begin therapy beforehand.

Treatment may include the use of non-sedating oral antihistamines, or topical antihistamines or so-called mast cell stabilizers to the nose and eyes. Mast cells act as receptors for the allergenic pollen, and for the antibody immunoglobulin E which the body uses to defend itself. Its reaction to these signals is to release substances such as histamine that worsen rhinitis symptoms.

Oral antihistamines, which are used to prevent this histamine reaction, offer a number of alternatives in terms of speed of onset and duration of effect for the treatment of milder seasonal rhinitis, available under names such as terfenadine, cetirizine (Zyrtec), astemizole (Hismanal) and acrivastine (Semprex). Topical antihistamines such as levocabastine (Livostin) and azelastine (Astelin), however, are becoming more widely used because their effect can be concentrated on the most affected organ. Topical sodium cromoglycate, long used in treatment of allergic rhinitis symptoms, still has a place today because the absence of significant side effects permits regular use without worry.

Those who suffer from more severe forms of seasonal allergic rhinitis should be treated according to whether they are primarily eye sufferers or primarily nose sufferers. If their symptoms are mostly in the nose, they should receive topical nasal steroids before the beginning of the pollen season to minimize early damage to cells and inflammation, which would release aggravating substances such as histamines and tryptase. Eye treatment may also be necessary for mostly nasal sufferers.

If the eye is the source of most discomfort, choices are limited to the topical use of sodium cromoglycate in conjunction with nasal steroids to lessen general irritation. The only readily-available alternative to that is an oral antihistamine.

Should allergic rhinitis be really severe and treatment beyond the limits of such drugs, the patient will probably need to see a specialist who may, in a crisis, recommend short-term systemic corticosteroids. Immunotherapy may also be considered at this juncture. These more drastic treatments represent the weapons of last resort against seasonal allergic rhinitis at present, but with allergic mechanisms better understood every year, it may not be that way for long.

Most intranasal corticosteroids (CS) take a few days to work with the exception of the newer, more potent agents fluticasone and mometasone. Regardless, the maximum effect requires 1-2 weeks and possibly up to 3 weeks. Patients should be encouraged to contact their healthcare provider if no benefit is seen in this time. Often anti-allergy therapy is prescribed on a presumptive basis. Patients may be on intranasal CS therapy and not be aware of which allergens they are sensitive to. Skin prick allergy testing can easily assess allergy status. Once specific allergens are identified, appropriate environmental controls can be instituted.

When a patient exhibits intolerance to a specific intranasal corticosteroids product, an excipient in the formulation may be the cause. A suggested intervention would be to switch to an alternative product. For example, an alcohol-free product could be recommended over a product containing alcohol. Additional reinforcement should target instructions on proper nasal CS administration, and nasal conditioning (moisturizing). Often overlooked are patient-specific nasal behaviors. For example, a patient may be reporting nosebleeds, and through further inquiry reveals he is a frequent nose-picker; another patient may irrigate the nose with hydrogen peroxide. If nosebleeds remain problematic for the patient, referral to an Ear, Nose and Throat Specialist may be warranted. To facilitate tailoring patient therapy, Table 8 compares various intranasal corticosteroids available in the U.S.

Conclusion

Allergic rhinitis is characterized by acute and late phase reactions. Inflammation plays a dominant role in maintaining the late phase and contributes to the increased risk of complications. Intranasal steroids have been proven effective treatment for allergic rhinitis and are superior to oral antihistamines. Therefore, first-line treatment of allergic rhinitis should be intranasal steroids in patients with allergic rhinitis of perennial or seasonal pattern with persistent or moderate symptoms. Environmental control measures should target allergens relevant to the individual. Pharmacists are in a unique position to provide balanced information and take patient-specific factors into consideration when evaluating an individual patient for specific therapy for allergic rhinitis.

Intranasal corticosteroid sprays are most effective when used consistently. Some patients may not be prepared to use nasal sprays and this unfamiliarity coupled with negative preconceptions can hamper successful therapy. Both pharmacists and physicians need to educate the patient that intranasal corticosteroids work best when taken on a regular basis. Proper administration technique is very important to minimize adverse effects (bleeding and nasal septal perforation) and to optimize outcomes. The spray should target the nasal turbinates. Table 7 outlines the most important information to convey to the patient administering aqueous nasal sprays. Patient adherence is enhanced with fewer daily doses and a convenient dosing schedule. Providing written material along with verbal instruction further improves adherence. There is a growing body of published literature describing a circadian rhythm to airway biology and pathophysiology as it relates to asthma. The circadian pattern in allergic rhinitis is less clear. For now, patients should be instructed to administer the intranasal corticosteroids (CS) spray at a convenient time. However, nighttime admin-istration can worsen the dripping of the spray liquid down the back of the throat. Patients who cannot tolerate this sensation should administer the dose during the day.

Researchers are trying to identify variables that can impact patient adherence. Study models take into consideration prior experience with the class of agents, adverse effects, patient perceptions of risk and benefit, and interference with usual routines. Patients may not tolerate an individual product’s odor, taste, or sensation upon administration. There appear to be differences among the various products in this regard. In one study, several of the sensory attributes of Nasacort AQ (odorless and tasteless) were preferred over those of Flonase and Nasonex (both of which contain phenylethyl alcohol).

Patients with allergic rhinitis are at significantly greater risk for acute and chronic sinusitis. Chronic inflammation is recognized as playing a larger role in the pathophysiology of chronic sinusitis. Currently, there is no intranasal CS approved by FDA for acute therapy of sinusitis. Nevertheless, patients should be instructed to continue using their intranasal steroids while undergoing treatment for their sinusitis. Symptoms may improve more rapidly and to a greater degree with no increase in adverse events.

Patients with allergic rhinitis should be cou nseled to modify their environment to minimize exposure to relevant allergen triggers.Implementing targeted environmental control measures makes sense when the clinical signs and symptoms match allergy skin testing results. Some environmental control measures are more effective than others (baits are more effective than sprays for cockroach control). A greater challenge is the feasibility of implementing these effective measures. For example, a patient allergic to tree pollen (or any other seasonal allergen) would be best served by avoiding the outdoors and keeping outdoor air from infiltrating the indoor space. Performing such extreme measures is not likely nor necessary given available treatments. Protective facemasks may be effective when the grass/tree allergic patient needs to be outside for long periods (doing yard work). Keeping windows closed and using air conditioning in the spring/summer can substantially reduce indoor allergen exposure and provide symptom relief. Perennial allergies to indoor allergens pose greater challenges to avoidance than outdoor allergens. Common allergens inside the home include dust mites, cockroaches, pet dander (cats/dogs/hamsters), and mold.

Practical and likely to be beneficial environmental control measures are detailed in Table 6. Website addresses are provided to guide the reader to additional resources. Some strategies may have a beneficial impact on more than one allergen. For example, controlling indoor moisture can help reduce dust mite, cockroach, and mold allergen burden. Cockroach antigen remains present after extermination and cleaning with warm bleach-water solution removes this residue. Combined strategies (pharmacologic, environmental, and behavioral) are more likely to be successful against any specific allergen than single interventions.

Rhinitis can be caused by nonallergic stimuli. Differentiating allergic rhinitis from these often more serious causes is important. Allergic rhinitis is often misdiagnosed as a viral rhinitis, perhaps due to the similar clinical presentation.Other etiologies of rhinitis exist that can be differentiated from one another (Table 5). A successful treatment plan must include patient/provider education, relevant nonpharmacologic modalities and drug therapy.

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