Rationale Treatment and Pharmacotherapy of Allergic Rhinitis
Allergic rhinitis (AR) and perennial nonallergic rhinitis (PNAR) represent conditions affecting millions of individuals across the world. Although the diagnosis of AR might be presumptively based on the types of symptoms and the history of allergen triggers, confirmation requires documentation of specific IgE reactivity. In contrast, PNAR is a condition with similar symptomatology but in which the patient has no identifiable specific allergic sensitivities. This review presents the diverse options of currently available pharmacologic agents for the treatment of AR and PNAR, including intranasal corticosteroids, H1-antihistamines, decongestants, cromolyn sodium, antileukotrienes, anticholinergics, capsaicin, anti-IgE, and intranasal saline. Furthermore, appropriate stepped-up, stepped-down pharmacotherapeutic algorithms are described for the various forms of rhinitis.
With mild intermittent AR, suggested initial pharmacologic therapy consists of an oral H1-blocker, an intranasal H1-blocker, and/or an oral or intranasal decongestant, the last on a strictly short-term or intermittent basis. A leukotriene modifier is also a consideration. If intermittent disease is moderate or severe, initial treatment with an intranasal corticosteroid (INS) is usually preferred to the aforementioned agents. Persistent mild AR is treated in the same manner as moderate or severe intermittent AR. If symptoms are persistent and moderate or severe, INSs should be the first class of medication used. With all grades of severity, appropriate follow-up should take place in a reasonable amount of time, and therapy should be stepped up or stepped down, as indicated. A pharmacologic treatment algorithm for AR is presented in.
Algorithmic considerations for pharmacologic treatment of AR.
Treatment of PNAR has historically depended on the presence of nasal eosinophilia that, if present, predicted a likely beneficial response to INSs. In contrast, treatment of noneosinophilic nonallergic rhinitis has usually targeted those specific nasal symptoms proving most bothersome. Thus empiric treatment with decongestants, oral antihistamines, INSs, intranasal saline irrigation, intranasal ipratropium bromide, and other agents with anticholinergic properties was often undertaken with varying degrees of success. A stepped-up, stepped-down approach based on progress monitoring is also appropriate for PNAR treatment management.
Algorithmic considerations for pharmacologic treatment of nonallergic rhinitis.
- INSs INSs improve all nasal symptoms of AR, including nasal congestion, rhinorrhea, itching, and sneezing. They generally do so to a greater extent than any other currently available pharmacologic agent.The comprehensive clinical effects of INSs are based on a broad mechanism of action. As glucocorticoids diffuse across the cell membrane, they bind to specific intracellular receptors, forming a complex that is then transported into the nucleus, where it binds to glucocorticoid response elements. As a result, transcription of glucocorticoid response element associated genes is either downregulated or, less frequently, upregulated.This leads to a reduction of the nasal mucosa inflammatory cells and their associated cytokines.Currently available INSs include beclomethasone, budesonide, flunisolide propionate, fluticasone propionate, mometasone furoate, and triamcinolone acetonide. All these are delivered in aqueous preparations and have shown efficacy in both seasonal and perennial AR in a large number of well-controlled studies. Although INSs might vary with regard to their sensory attributes (eg, perceived discomfort, taste, or smell) and thus patient acceptance and adherence, there do not appear to be any clear, clinically relevant differences in efficacy between them.Among the reported side effects are nasal burning and stinging, dryness, and epistaxis. These can occur in 5% to 10% of patients,with the only exception being flunisolide, which, because of its excipients, appears to cause a higher incidence of nasal discomfort. Nasal mucosal atrophy does not occur with chronic INS use, in contrast to local skin atrophy, which occurs with dermatologic high-potency corticosteroids. This is evidenced by the findings of 2 separate year-long studies with fluticasoneand mometasone.Local candidiasis, sometimes seen with inhaled corticosteroids, is extremely rare with INSs. In terms of systemic side effects, laboratory evaluations of the hypothalamic-pituitary-adrenal axis by multiple means have shown minimal to no hypothalamic-pituitary-adrenal axis suppression with recommended doses of INS.Osteocalcin, a marker of bone turnover, and eosinophilia were both unaffected by intranasal budesonide, mometasone, and triamcinolone, suggesting that the systemic glucocorticoid burden was clinically insignificant.These results appear to be confirmed by a recent case-control study showing no increased likelihood of bone fractures among octogenarians using INSs, regardless of the dose used.Nevertheless, some concerns have been raised about the effects of INSs on linear growth in children. Intranasal beclomethasone caused a small but significant reduction in linear growth in at least one study with twice-daily dosing. In contrast, no growth delay was observed in children treated over the course of 1 year with mometasone,fluticasone,or budesonide.However, a continuing clinical concern is that no studies have examined linear growth in children receiving a combination of an intranasal and an inhaled corticosteroid, a common clinical scenario. INSs are the single most effective class of medications for AR and are thus recommended as first-line therapy by both national and international taskforces for those with moderate-severe or persistent rhinitis.They are superior to antihistamines, and leukotriene antagonists, and, with limited information, probably equivalentor even superior to combinations of antihistamines and leukotrienes. For the most part, the addition of an antihistamine to an INS does not appear to confer additional clinical benefits over the use of an INS alone. In a European seasonal AR study, nasal fluticasone was compared with placebo and various pharmacologic combinations: fluticasone plus cetirizine, fluticasone plus montelukast, and cetirizine plus montelukast. Fluticasone monotherapy was not inferior to the other 3 active treatment groups in reducing individual nasal symptoms except for nasal pruritus, where addition of cetirizine conferred an additional benefit. In terms of nasal congestion, only those treatment arms containing the nasal steroid were superior to placebo in relieving nasal congestion.
INSs in the treatment of PNAR
Of the currently available INS preparations in the United States, only fluticasone has the US Food and Drug Administration indication for the treatment of nonallergic rhinitis regardless of the presence of nasal eosinophilia. In a large study of patients with PNAR, administration of fluticasone at the lower dose, 200 μg once daily, was as effective as at the higher dose, 400 μg once daily, in achieving symptom reduction.In a separate study in patients with VMR, fluticasone, 200 μg once daily, was significantly superior to placebo in reducing symptoms of nasal obstruction and decreasing inferior turbinate hypertrophy, as assessed by means of computed tomographic (CT) scanning. However, the evidence for benefit of INSs in PNAR is inconsistent. In a different study mometasone, 200 μg once daily, was not significantly more effective than placebo in reducing overall rhinitis symptoms in a cohort of individuals with PNAR during a 6-week treatment period.
Although many chemical mediators can induce one or more symptoms of AR, histamine remains the quintessential mediator of allergic nasal disease, especially during the early-phase response. Acting at the H1-receptors, histamine can induce most of the allergic symptoms (eg, sneezing; itching of the nose, throat, and palate; and rhinorrhea) through stimulation of the sensory nerves, increase in vascular permeability, and mucus production. H1-antihistamines antagonize the H1-receptor on smooth muscle cells, nerve endings, and glandular cells, leading to a reduction in all of the above symptoms. However, they only have a mild effect on nasal congestion. Tolerance to the beneficial effects of H1-antihistamines has not been shown to occur. H1-antihistamines also appear to have supplementary functions, such as inhibition of mediator release from mast cells and basophils.Furthermore, some of the currently available nonsedating antihistamines appear to exert additional anti-inflammatory properties, such as inhibition of TNF-α–induced release of the chemokines IL-8 (fexofenadine)54 and RANTES (desloratadine),as well as a reduction in intercellular adhesion molecule 1 expression on cultured keratinocytes (cetirizine). It is unclear whether these properties are clinically relevant.
Several older or first-generation oral H1-antihistamines are available as over-the-counter (OTC) formulations (diphenhydramine, clemastine, tripelennamine, pyrilamine, brompheniramine, chlorpheniramine, and tripolidine) or as prescription drugs (hydroxyzine, promethazine, and cyproheptadine). These preparations have poor selectivity for the H1-receptor and, as such, inhibit muscarinic receptors, which might result in various degrees of mucous membrane drying, vision blurring, constipation, urinary retention, and tachycardia.
Sedation is a major adverse effect of the older H1-antihistamines. It occurs because they cross the blood-brain barrier and affect the H1-receptors in the central nervous system. The term sedation has been used to include both drowsiness and a global reduction in intellectual and motor performance.Sedating H1-antihistamines have been linked to airand industrial accidents, as well as significant loss of productivity at school and work.A single 50-mg dose of diphenhydramine led to a degree of diminished driving performance, as assessed in a driving simulator, greater than that seen from the ingestion of ethanol leading to an estimated blood alcohol level of 0.1%.61 Similar to the effects of ethanol intake, a discrepancy often exists between self-perception of sedation and objective measures of drowsiness and performance.
Even though dosing for first-generation H1-antihistamines is often undertaken several times a day, the terminal elimination of first-generation antihistamine half-life varies from 9.2 to 27.9 hours, leading to potential daytime deficits, even when administered only at bedtime. One study suggested that tolerance can develop to the sedating properties of diphenhydramine.It also appears that many individuals with chronic urticaria are able to function reasonably normally on high doses of various sedating antihistamines when taken on a daily basis (Kaplan A, personal communication). Unresolved and requiring further study is the extent to which tolerance to sedation really occurs and whether this might be a class effect.
Second-generation oral H1-antihistamines currently available in the United States include the OTC preparation loratadine and the prescription drugs cetirizine, desloratadine, and fexofenadine. In contrast to the older first-generation antihistamines, for which studies showing clinical efficacy are very limited, effectiveness for cetirizine, desloratadine, fexofenadine, and loratadine have been established in a variety of well-designed, double-blind, placebo-controlled studies. These studies have also helped to establish onset of action, peak effect, and duration of action. Such information is lacking with first-generation antihistamines so that current dosing suggestions for agents belonging to this category are based, at best, on the individual antihistamine’s ability to suppress the cutaneous wheal-and-flare response after allergen or histamine introduction into the skin.
Second-generation oral H1-antihistamines have better H1-receptor selectivity and thus less anticholinergic and antiserotonergic side effects. All these agents, with the exception of fexofenadine, have the potential to cross the blood-brain barrier and bind to central H1-receptors, resulting in sedation. This process has been observed in individuals using loratadine and desloratadine at higher than recommended doses. For the second-generation oral agents available in the United States, cetirizine is the only one labeled to cause an increased incidence of sedation at its recommended dose in persons older than 12 years (11% to 14% vs 6% receiving placebo).
Because of variations in their metabolic profiles, certain antihistamines can either interact with specific drugs or foodstuffs, altering their plasma concentrations. For example, coadministration of the antifungal ketoconazole with either fexofenadine or desloratadine can increase the plasma concentrations of these antihistamines by 135% and 40%, respectively. Grapefruit juice, when administered in large quantities (1.2 L), has the potential to decrease plasma levels of fexofenadine, putatively through saturation of organic anion-transporting peptide carriers. The clinical significance of these findings is questionable. Individuals also have significant variations in their ability to break down a specific drug or metabolite through the cytochrome P-450 or N-acetyltransferase pathway, among others. Desloratadine is metabolized slowly by approximately 6% of the general population and 17% of African Americans,71 resulting in increased plasma levels, which, in turn, could increase dose-related adverse effects, such as sedation. However, sedation was not noted to be more frequent in a large cohort taking desloratadine compared with placebo,so that further studies are required to better characterize the real-life significance of these findings.
A few studies have directly compared the clinical effect of different second-generation antihistamines. Although fexofenadine once daily was not inferior to cetirizine once daily in reducing the total symptom score over a 2-week period in 2 separate studies,some short-term environmental exposure unit studies suggested that cetirizine was more effective than fexofenadine in reducing seasonal AR symptoms during both the 5- to 12-hourand 21- to 24-hour postdose period.In a 2-week study looking at both objective and subjective criteria, desloratadine at 5 mg and fexofenadine at 180 mg were equivalent in their ability to improve both peak nasal inspiratory flow and nasal symptoms in 49 patients with seasonal AR.
Despite the frequent finding of therapeutic equivalency between various second-generation antihistamines in clinical trials, individual patients sometimes perceive differences in efficacy among agents of this class. A recent issue has been posed by loratadine, which, because of its OTC status, has become the preferred treatment of allergies by many insurance companies. This special positioning of loratadine, which appears to be less effective than other nonsedating antihistamines,results in higher copayments or noncoverage for other second-generation antihistamines.
Although there is no clear established role for antihistamines in the treatment of PNAR, patients who have sneezing as a predominant symptom might respond favorably to oral antihistamines.5 Also, a single placebo-controlled study comparing flunisolide with a combination of flunisolide and loratadine found that the INS-antihistamine combination was superior to INS alone in reducing both sneezing and rhinorrhea in a group of patients with NARES.Use of first-generation antihistamines might be potentially helpful in reducing rhinorrhea by virtue of their anticholinergic activity.
Currently, azelastine is the only intranasal antihistamine available commercially in the United States, although intranasal olopatadine might become marketed in the near future. Azelastine appears to have a range of anti-inflammatory properties in addition to its H1-receptor effect. These include interference with the vasoactive neuropeptide substance P,inhibition of production of the leukotrienes B4 and C4,and possibly decrease of nuclear factor κB,a transcription factor for multiple proinflammatory substances. The clinical relevance of these effects is unclear.
Dose-ranging trials have shown a therapeutic onset of action within 3 hours after initial dosing and persistence of efficacy over a 12-hour interval. The most common side effects at the recommended dose of 2 sprays per nostril twice a day are bitter taste (19.7% vs 0.6% placebo) and sedation (11.5 vs 5.4% placebo). Azelastine and olopatadine have demonstrated efficacy in seasonal rhinitis, and in recent studies azelastine appears to be slightly superior to cetirizine, desloratadine, and fexofenadine in its ability to reduce total nasal symptoms scores, including nasal congestion. An older study, however, did not find that azelastine was superior to cetirizine in seasonal AR.
In the 2 pivotal studies that established a role for intranasal azelastine in the treatment of nonallergic, noneosinophilic chronic rhinitis, all nasal symptoms, including nasal congestion, were reduced compared with those after placebo.No studies comparing azelastine with other pharmacologic agents have been performed in VMR.
- Decongestants Vasoconstrictors exist in both intranasal and oral form. Topically applied vasoconstrictor sympathomimetic agents belong to the catecholamines (eg, phenylephrine) or imidazaoline family (eg, oxymetazoline), whereas oral vasocontricting agents are primarily catecholamines (pseudoephedrine and phenylephrine). These agents exert their effects through the α1- and α2-adrenoreceptors present on nasal capacitance vessels responsible for mucosal swelling and associated nasal congestion. The reduction in blood flow to the nasal vasculature after administration leads to increased nasal patency in 5 to 10 minutes when applied topically or 30 minutes when administered orally. Nasal decongestion can last up to 8 to 12 hours with intranasal preparations and 24 hours with extended-release oral decongestants. Traditionally, it has been thought that pseudoephedrine cannot ameliorate symptoms of rhinitis other than nasal congestion.However, a recent study comparing once-daily pseudoephedrine with montelukast showed a reduction in rhinitis symptoms other than nasal congestion in both groups.These additional effects might possibly be due to the halo effect, in which improvement in one particular symptom, such as nasal congestion, leads to a more global sense of well-being and thus less perceived severity of other nasal symptoms. Overall, monotherapy with vasoconstrictors has a limited role in the treatment of AR unless nasal congestion presents as the sole or most bothersome symptom. However, when oral decongestants are combined with an antihistamine, all cardinal symptoms of AR are targeted. The adverse affects of topical nasal decongestants include nasal burning, stinging, dryness, and, less commonly, mucosal ulceration. Tolerance and rebound congestion can occur when these agents are used for longer than 1 week and can culminate in rhinitis medicamentosa.Adverse affects of oral decongestants include central nervous system stimulation, such as insomnia (which might occur in a significant portion of individuals), nervousness, anxiety, and tremors, as well as tachycardia, palpitations, and increases in blood pressure. Decongestants can be used in the treatment of PNAR for symptomatic improvement. When administered topically, intermittent dosing is required for the abovementioned reasons.
- Cromolyn sodium and nedocromil sodium Cromolyns inhibit the degranulation of sensitized mast cells, thereby blocking the release of inflammatory mediators. It does not interfere with either the binding of IgE to the high-affinity IgE receptor or with binding of the allergen to its specific IgE. In allergen challenge studies of individuals with AR, cromolyn sodium has proved effective in reducing both the early- and late-phase allergic reaction. Cromolyn is indicated for both seasonal and perennial AR. The onset of relief appears during the first week of treatment, and symptoms often continue to improve as the medication is dosed over the subsequent weeks. The 4% intranasal solution is recommended for adults and children age 2 years and older. The frequency of dosing might lead to adherence problems given the need to initially instill the solution 4 times daily to obtain a beneficial result. However, once symptoms are under control, a less frequent dosing regimen might suffice for adequate symptom control. Topical adverse effects, such as sneezing, nasal irritation, and unpleasant taste, are uncommon, and cromolyn is poorly absorbed systemically and therefore has an excellent safety record. Tolerance to the clinical effects of cromolyn has not been described. The conclusions derived from several older studies about the role of cromolyns in the treatment of PNAR are inconclusive. Given the limited role of histamine in the genesis of symptomatology of patients with PNAR, the role of cromolyns would be expected to be modest. One study revealed no symptom improvement in a group of adults with NARES after a 2-month-long treatment with 4% cromolyn solution.99 In contrast, another group found that 2% disodium cromoglycate was preferred over placebo by a majority of individuals with VMR.
- Antileukotrienes Cysteinyl leukotrienes are potent lipid mediators derived from the enzymatic action on nuclear membrane phospholipids. Initially studied in the lower airway inflammation of asthma, these inflammatory molecules also appear to play a role in the upper airways, as evidenced by the appearance of high concentrations of leukotriene C4 in nasal secretions of atopic individuals after allergen challenge.Furthermore, nasal challenge with leukotriene D4 in healthy human subjects can significantly increase nasal mucosal blood flow and nasal airway resistance.Leukotrienes do not appear to stimulate the sensory nerves present in the nasal mucosa and thus probably do not contribute significantly to nasal itching or sneezing.Although blockage of the leukotriene pathway could be accomplished by means of either inhibition of synthesis through the 5-lipoxygenase inhibitor zileuton or by receptor blockade of the cysteinyl leukotriene 1 receptor with zafirlukast or montelukast, only montelukast is US Food and Drug Administration approved for treatment of AR, in which it has shown clinical efficacy in both seasonal and perennialAR. One of the leukotriene inhibitors, montelukast, results in few side effects, has a pregnancy B category, and is approved in children as young as 6 months. Montelukast, with very limited comparator data, does not appear to be more effective than nonsedating antihistamines and is less effective than INSsin the treatment of AR. In a pediatric perennial AR study, montelukast was inferior to cetirizine in improving nasal and throat itching symptoms, equivalent in reduction of nasal congestion, and superior in terms of night sleep quality.A recent meta-analysis of 11 published studies on the clinical effects of leukotriene receptor antagonists concluded that these agents only had limited effectiveness in the treatment of AR, reducing mean daily rhinitis symptom scores (in absolute terms) 5% more than placebo (95% CI, 3% to 7%). In comparison with the leukotriene antagonists, antihistamines provided 2% (95% CI, 0% to 4%) greater improvement in symptom scores, and INSs provided 12% (95% CI, 5% to 18%) greater improvement in symptom scores.At this time, no published studies have shown a role for leukotriene modifiers in the treatment of PNAR.
- Ipratropium bromide Ipratropium bromide is an intranasally administered antimuscarinic agent that inhibits parasympathetic function within the nasal mucosa, thus controlling the secretory output from serous and seromucous glands. Because of its low systemic absorption, it is relatively free of the side effects usually accompanying the administration of oral compounds with anticholinergic properties, unless administered at higher than recommended doses. Ipratropium has an onset of action within 15 to 30 minutes. Because of its pharmacokinetic profile, the recommended 24-hour dose ranges from 120 to 320 μg administered in 3 to 6 daily applications.Tolerance to the therapeutic effects of ipratropium has not been described. Side effects are usually limited to local irritation, dryness, and epistaxis, which occur in a dose-dependent manner. Ipratropium has shown efficacy in perennial AR and various forms of nonallergic rhinitis, including infectious rhinitis, gustatory rhinitis, and VMR in both childrenand adults.Although ipratropium bromide is primarily effective at controlling watery anterior nasal discharge, several of the above-referenced studies found that it might improve nasal symptoms other than rhinorrhea. However, given ipratropium’s mechanism of action, these findings might be representative of the halo effect (discussed earlier) rather than reflect a true physiologic cause and effect. Ipratropium should primarily be used in the management of isolated anterior rhinorrhea. It has not proved particularly effective in the management of postnasal drip. It might also be prescribed as an adjunct for the treatment of rhinorrhea not fully controlled by other pharmacologic agents.
- Capsaicin Local application of capsaicin, a pungent compound present in red-hot peppers, can induce nasal burning, rhinorrhea, and nasal congestion through stimulation of the nasal C-fibers. With repeated application of capsaicin, C-fibers are thought to become depleted of neuropeptides, leading to reduced nasal hyperreactivity. Several studies have shown symptomatic improvement in patients with VMR treated with capsaicin.A published practical therapeutic approach has suggested induction of local anesthesia, followed by 5 hourly applications of capsaicin. This treatment plan has shown similar efficacy with intermittent treatment over 2 weeks.120 Although some investigators estimate that improvement after a single treatment course might last for more than 1 year,121 more research is required to better define the role and long-term effects of capsaicin therapy. Capsaicin is not currently available in the United States as a standardized preparation.
- Omalizumab (anti-IgE) Omalizumab is one of the more exciting recent developments in the treatment of atopic diseases. It is probably only the first of several mAbs aimed at modulating allergic inflammation. Omalizumab is a humanized mAb that binds to the constant region of the IgE molecule at its IgE receptor-binding portion, thereby effectively hindering IgE’s interaction with the high-affinity IgE receptor present on mast cells, basophils, and dendritic cells. Anti-IgE binds to circulating, but not cell-bound, IgE, forming stable and long-lived anti-IgE–IgE complexes. After initial appropriate dosing, free IgE concentrations decrease in a rapid dose-dependent fashion by 97% to 99%. Omalizumab has been shown to be effective for AR in both allergen challenge studies and clinical trials. Multiple randomized, double-blind, placebo-controlled studies have shown efficacy of omalizumab in seasonaland perennial AR. It remains to be determined how omalizumab compares with other treatment modalities. However, given its cost, the application of omalizumab in the treatment of AR in the absence of other atopic diseases will likely be restricted to a narrowly defined set of circumstances. No published studies have shown a role for omalizumab in the treatment of PNAR.
- Nasal saline irrigation For many years, nasal saline irrigation has been used as an adjunct treatment for various forms of rhinitis, despite the lack of good clinical trial data. In the process of douching, several ounces of isotonic or hypertonic saline are introduced into the nose and nasopharynx by using a variety of devices, such as a bulb syringe, Neti Pot, squeezable plastic bottle with nasal adaptor, or a pulse irrigator combined with a nasal adaptor. The goal is to remove mucus, enhance ciliary clearance and sinus ostial patency, and, perhaps, to remove pollen and other allergenic or irritant material from the nasal and nasopharyngeal mucosa. Limited data suggest that although hypertonic saline is generally more irritating, it might stimulate ciliary transport to a greater degree than isotonic saline, as evidenced by its ability to improve mucociliary transit times of saccharin. In a pediatric study of 44 children with seasonal allergic rhinoconjunctivitis, those rinsing with nasal hypertonic saline 3 times daily during the 7-week peak pollen season had a lower weekly mean rhinoconjunctivitis score during all weeks, although only in a statistically significant manner during weeks 6 and 7, than the control group. In addition, rinsers had a markedly reduced need for oral antihistamines during 5 of the 7 weeks.In a separate prospective study of 211 individuals with sinonasal disease, including AR, “aging rhinitis,” atrophic rhinitis, postnasal drip, and chronic rhinosinusitis, 3 to 6 weeks of hypertonic saline irrigation led to statistically significant improvement in 23 of 30 symptoms by using a nasal disease-specific symptom questionnaire.
- Combination therapy Few studies have assessed the value of using combination therapy, even though in clinical practice, satisfactory control of symptoms is frequently not achieved unless individual pharmacologic agents are used together. The following is a brief summary of selected studies comparing treatment regimens not including an INS (see INS section for combination therapy including an INS). In seasonal AR trials the combinations of loratadine plus pseudoephedrineand fexofenadine plus pseudoephedrine130 were more effective in reducing symptoms than monotherapy with the individual agents. In a group of adults with seasonal AR, a combination of fexofenadine and pseudoephedrine was compared with a combination of loratadine and montelukast. Both treatment arms improved symptoms, rhinoconjunctivitis quality-of-life questionnaire scores, and nasal obstruction in seasonal AR to a similar degree.When montelukast was added to loratadine in patients 15 years or older with seasonal AR, the combination was superior to either agent alone in reducing daytime nasal symptoms in patients.Similarly, treatment of adults with seasonal AR by using a combination of montelukast and certirizine was found to be preferable to treatment with both individual agents alone. However, another study suggested that symptoms of seasonal AR were not better controlled with the combination of montelukast and loratadine than with once-daily fexofenadine.
Pharmacotherapy Allergic Rhinitis
Most cases of allergic rhinitis respond to pharmacotherapy. Patients with intermittent symptoms are often treated adequately with oral antihistamines, decongestants, or both as needed. Regular use of an intranasal steroid spray may be more appropriate for patients with chronic symptoms. Daily use of an antihistamine, decongestant, or both can be considered either instead of or in addition to nasal steroids. The newer, second-generation (ie, nonsedating) antihistamines are usually preferable to avoid sedation and other adverse effects associated with the older, first-generation antihistamines. Ocular antihistamine drops (for eye symptoms), intranasal antihistamine sprays, intranasal cromolyn, intranasal anticholinergic sprays, and short courses of oral corticosteroids (reserved for severe, acute episodes only) may also provide relief.
Second-generation antihistamines Often referred to as the nonsedating antihistamines. They compete with histamine for histamine receptor type 1 (H1) receptor sites in the blood vessels, GI tract, and respiratory tract, which, in turn, inhibits physiologic effects that histamine normally induces at the H1 receptor sites. Some do not appear to produce clinically significant sedation at usual doses, while others have a low rate of sedation.Other adverse effects (eg, anticholinergic symptoms) are generally not observed. All are efficacious in controlling symptoms of allergic rhinitis (ie, sneezing, rhinorrhea, itching) but do not significantly improve nasal congestion. For this reason, some second-generation antihistamines are available as combination preparations containing a decongestant. They are often preferred for first-line therapy of allergic rhinitis, especially for seasonal or episodic symptoms, because of their excellent efficacy and safety profile. They can be used prn or daily.
Topical azelastine and olopatadine are nasal sprays antihistamines that effectively reduce sneezing, itching, and rhinorrhea but also effectively reduces congestion.[60, 61, 62] Used twice per day, especially when combined with a topical nasal corticosteroid, azelastine is effective at managing both allergic and nonallergic rhinitis.
The second-generation oral antihistamines currently available in the United States are cetirizine, levocetirizine, desloratadine, fexofenadine, and loratadine. A limited number of studies comparing these agents suggest no major differences in efficacy. Only cetirizine causes drowsiness more frequently than placebo.Cetirizine, fexofenadine, and loratadine are also available in decongestant-containing preparations.
- Cetirizine (Zyrtec) Competes with histamine for H1 receptors in GI tract, blood vessels, and respiratory tract, reducing hypersensitivity reactions. Once-daily dosing is convenient. Bedtime dosing may be useful if sedation is a problem.
- Levocetirizine (Xyzal) Histamine1-receptor antagonist. Active enantiomer of cetirizine. Peak plasma levels reached within 1 h and half-life is about 8 h. Available as a 5-mg breakable (scored) tab. Indicated for seasonal and perennial allergic rhinitis.
- Pseudoephedrine/fexofenadine (Allegra) Second-generation agent with a rate of sedation not significantly different from that of placebo. Competes with histamine for H1 receptors in GI tract, blood vessels, and respiratory tract, reducing hypersensitivity reactions. Available in qd and bid preparations.
- Loratadine (Claritin) Selectively inhibits peripheral histamine H1 receptors. Tolerated well, with rate of sedation not significantly different from placebo.
- Pseudoephedrine/loratadine (Claritin-D 24 Hour, Claritin-D 12 Hour) Tolerated well, with rate of sedation not significantly different from that of placebo. Some patients may notice anxiety or insomnia owing to pseudoephedrine component.
- Pseudoephedrine/fexofenadine (Allegra-D) Fexofenadine is a nonsedating second-generation medication with fewer adverse effects than first-generation medications. Competes with histamine for H1 receptors on GI tract, blood vessels, and respiratory tract, reducing hypersensitivity reactions. Does not sedate. Pseudoephedrine stimulates vasoconstriction by directly activating alpha-adrenergic receptors of the respiratory mucosa. Induces also bronchial relaxation and increases heart rate and contractility by stimulating beta-adrenergic receptors.
- Desloratadine (Clarinex) Relieves nasal congestion and systemic effects of seasonal allergy. Long-acting tricyclic histamine antagonist selective for H1-receptor. Major metabolite of loratadine, which after ingestion is extensively metabolized to active metabolite 3-hydroxydesloratadin
- Leukotriene receptor antagonists Alternative to oral antihistamine to treat allergic rhinitis. One of the leukotriene receptor antagonists, montelukast (Singulair), has been approved in the United States for treatment of seasonal and perennial allergic rhinitis.When used as single agent, produces modest improvement in allergic rhinitis symptoms
- Montelukast (Singulair) Selective leukotriene receptor antagonist that inhibits the cysteinyl leukotriene (CysLT 1) receptor. Selectively prevents action of leukotrienes released by mast cells and eosinophils. When used as a single agent, has been shown to result in a reduction of seasonal allergic rhinitis symptoms, similar in degree to that of loratadine
The older, first-generation H1 antagonists (eg, diphenhydramine, hydroxyzine) are effective in reducing most symptoms of allergic rhinitis, but they produce a number of adverse effects (eg, drowsiness, anticholinergic effects). They can be used prn, but adverse effects may limit their usefulness when taken on a daily basis. Some patients tolerate the adverse effects with prolonged use, but they may experience cognitive impairment, and driving skills may be affected.Administration at bedtime may help with drowsiness, but sedation and impairment of cognition may continue until the next day. The second-generation antihistamines are nonsedating in most patients and are preferred as first-line therapy. Few adverse effects are reported (cetirizine may cause drowsiness in as many as 10% of patients); therefore, many specialists prefer the use of second-generation agents for allergic rhinitis. Caution patients taking medications with sedative effects about driving and operating heavy machinery.
- Chlorpheniramine (Chlor-Trimeton) First-generation agent, available OTC in the United States. One of the safest antihistamines to use during pregnancy. Competes with histamine on H1-receptor sites on effector cells in blood vessels and respiratory tract.
- Diphenhydramine (Benadryl, Benylin) Common first-generation agent available OTC in the United States. Competes with histamine on H1-receptor sites on effector cells in blood vessels and respiratory tract. For symptomatic relief of symptoms caused by release of histamine in allergic reactions.
- Hydroxyzine (Atarax, Vistaril, Vistazine) Effective first-generation agent but frequently produces sedation. Considerable sedation may occur with higher doses. Antagonizes H1 receptors in periphery. May suppress histamine activity in subcortical region of CNS
- Decongestants Stimulate vasoconstriction by directly activating alpha-adrenergic receptors of the respiratory mucosa. Pseudoephedrine produces weak bronchial relaxation (unlike epinephrine or ephedrine) and is not effective for treating asthma. Increases heart rate and contractility by stimulating beta-adrenergic receptors. Used alone or in combination with antihistamines to treat nasal congestion. Anxiety and insomnia may occur. Expectorants may thin and loosen secretions, although experimental evidence for their efficacy is limited. Numerous preparations are available containing combinations of various decongestants, expectorants, or antihistamines. Alternatively, a separate decongestant and antihistamine can be administered to allow for individual dose titration of each drug.
- Pseudoephedrine (Sudafed) Stimulates vasoconstriction by directly activating alpha-adrenergic receptors of the respiratory mucosa. Available OTC in the United States. Helpful for nasal and sinus congestion.
Nasal steroid sprays are highly efficacious in treating allergic rhinitis.[72, 73, 74, 75, 76] They control the 4 major symptoms of rhinitis (ie, sneezing, itching, rhinorrhea, congestion). They are effective as monotherapy, although they do not significantly affect ocular symptoms. Studies have shown nasal steroids to be more effective than monotherapy with nasal cromolyn or antihistamines.Greater benefit may occur when nasal steroids are used with other classes of medication. They are safe to use and not associated with significant systemic adverse effects in adults (this may also be true for children, but the data are less clear).
Local adverse effects are limited to minor irritation or nasal bleeding, which resolve with temporary discontinuation of the medication. Nasal septal perforations are rarely reported and are less common with the newer corticosteroids and delivery systems. Safety during pregnancy has not been established; however, clinical experience suggests nasal corticosteroids (particularly beclomethasone, which has most experience in use) are not associated with adverse fetal effects.
The nasal steroids can be used prn, but seem to be maximally effective when used on a daily basis as maintenance therapy. They may also be helpful for vasomotor rhinitis or mixed rhinitis (a combination of vasomotor and allergic rhinitis) and can help to control nasal polyps.
- Mometasone (Nasonex) Nasal spray; may decrease number and activity of inflammatory cells, resulting in decreased nasal inflammation. Demonstrated no mineralocorticoid, androgenic, antiandrogenic, or estrogenic activity in preclinical trials. Decreases rhinovirus-induced up-regulation in respiratory epithelial cells and modulate pretranscriptional mechanisms. Reduces intraepithelial eosinophilia and inflammatory cell infiltration (eg, eosinophils, lymphocytes, monocytes, neutrophils, plasma cells).
- Beclomethasone (Beconase AQ, QNASL) Intranasal steroid. Most reliable during pregnancy, as it has been in use for many years with no significant problems observed. May decrease number and activity of inflammatory cells, resulting in decreased nasal inflammation. QNASL available as intranasal dry powder.
- Budesonide inhaled (Rhinocort Aqua) Newer topical steroid considered efficacious and safe for allergic rhinitis. May decrease number and activity of inflammatory cells, resulting in decreased nasal inflammation.
- Fluticasone (Flonase) Newer topical steroid considered efficacious and safe for allergic rhinitis. May decrease number and activity of inflammatory cells, resulting in decreased nasal inflammation.
- Ciclesonide (Omnaris) Corticosteroid nasal spray indicated for allergic rhinitis. Prodrug that is enzymatically hydrolyzed to pharmacologic active metabolite C21-desisobutyryl-ciclesonide following intranasal application. Corticosteroids have a wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids, leukotrienes, cytokines) involved in allergic inflammation. Each spray delivers 50 mcg.
- Fluticasone furoate (Veramyst) Intranasal corticosteroid. Indicated for seasonal and perennial allergic rhinitis. Relieves nasal symptoms associated with allergic rhinitis. Has also demonstrated improvement in allergic eye symptoms. Contains 27.5 mcg/spray
- Triamcinolone (Nasacort AQ) Injectable corticosteroid used to treat inflammatory dermatosis responsive to steroids; decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability
- Azelastine (Astelin) Use prn or on a regular basis. Use alone or in combination with other medications. Unlike oral antihistamines, has some effect on nasal congestion. Helpful for vasomotor rhinitis. Some patients experience a bitter taste. Systemic absorption may occur, resulting in sedation (reported in approximately 11% of patients).
- Olopatadine intranasal (Patanase) For relief of symptoms of seasonal allergic rhinitis. Before initial use, prime product by releasing 5 sprays or until fine mist appears. When product has not been used for more than 7 days, re-prime by releasing 2 sprays. Avoid spraying into eyes.
- Intranasal cromolyns Produce mast cell stabilization and antiallergic effects that inhibit degranulation of mast cells.Have no direct anti-inflammatory or antihistaminic effects. Effective for prophylaxis. May be used just before exposure to a known allergen (eg, animal, occupational). Begin treatment 1-2 wk before pollen season and continue daily to prevent seasonal allergic rhinitis. Effect is modest compared with that of intranasal corticosteroids. Excellent safety profile and are thought to be safe for use in children and pregnancy.
- Cromolyn sodium (Nasalcrom) Available OTC in the United States. Used daily for seasonal or perennial allergic rhinitis. Significant effect may not be observed for 4-7 d. For patients with isolated and predictable periods of exposure (eg, animal allergy, occupational allergy), administer just before exposure. Generally less effective than nasal corticosteroids. Protective effect lasts 4-8 h, frequent dosing is necessary.
- Intranasal anticholinergic agents Used for reducing rhinorrhea in patients with allergic or vasomotor rhinitis. No significant effect on other symptoms. Can be used alone or in conjunction with other medications. In the United States, ipratropium bromide (Atrovent Nasal Spray) is available in a concentration of 0.03% (officially indicated for treatment of allergic and nonallergic rhinitis) and 0.06% (officially indicated for the treatment of rhinorrhea associated with common cold). The 0.03% strength is discussed.
- Ipratropium (Atrovent Nasal Spray 0.03%) Chemically related to atropine. Has anti-secretory properties, and when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. Poor absorption by nasal mucosa; therefore, not associated with adverse systemic effects. Local adverse effects (eg, dryness, epistaxis, irritation) may occur
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