Allergic rhinitis affects millions of Americans and the numbers continue to increase. Fortunately, there exists a wide array of pharmacotherapeutic options with relatively safe side effect profiles for the management of the varying subtypes. Additionally, there are newer agents on the horizon. The efficacies of intranasal corticosteroids, antihistamines, combination topical therapy, leukotriene inhibitors, mast cell stabilizers, anticholinergics, mucolytics, decongestants, and anti-IgE are reviewed.
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AR can be divided into intermittent and persistent symptoms.
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Among the large array of pharmacotherapeutics available for the management of allergic rhinitis, intranasal corticosteroids and oral antihistamines are first line agents for allergic rhinitis.
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Other agents can be added in a symptom-based manner, for example, intranasal anticholinergics for rhinorrhea, intranasal decongestants for nasal obstruction, and intranasal antihistamine for pruritus.
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Anti-IgE antibody is newer class of pharmacotherapeutics that may provide better symptom control as well as downregulate IgE receptors.
Allergic rhinitis (AR) is a very common chronic respiratory disorder thought to be secondary to IgE-mediated type I hypersensitivity of the nasal mucosa to inhaled or, in some cases, to ingested allergens. It affects approximately 15% of Americans and leads to health care costs of two to five billion dollars spent per year. There has been a steady rise in atopic diseases including AR.
AR has also been shown to negatively impact quality of life. Poor sleep quality is associated with AR, and daytime sleepiness can result from antihistamine medications used in the treatment of AR. Decreased concentration in school children has been demonstrated, and studies have shown that AR can lead to decreased productivity. AR is linked to other atopic disease states and is four to six times more likely to develop in those with asthma, which supports the link between the upper and lower airways as described by the unified airway theory. AR, although frequently not life-threatening, can have significant impact on overall health status and daily life of affected individuals.
AR can be divided into seasonal (or intermittent) and perennial (or persistent). Seasonal AR is commonly known as “hay fever,” although it is not caused by hay and does not present with fever. Perennial AR implicates allergen exposure on a more constant basis. AR has two phases: early-phase and late-phase inflammation. The early-phase reaction occurs usually within minutes and results in symptoms mediated by histamine. Sneezing, pruritus, nasal congestion, and rhinorrhea are some of the early-phase symptoms. Late-phase symptoms stem from eosinophils and T-cell mediated cytokines such as interleukin-4 and interleukin-5 and can present with rhinorrhea and nasal congestion.
Management of AR includes avoidance, pharmacotherapy, and immunotherapy. This article discusses the role of pharmacotherapy and reviews the wide spectrum of pharmacologic options available as well as these agents’ efficacy and safety.
Intranasal corticosteroids
Topical application of corticosteroids was introduced in the early 1970s. Intranasal corticosteroids are thought to work mostly locally, thereby avoiding the unwanted side effects that are associated with oral or intravenous corticosteroids such as cushingoid habitus, cataracts, osteoporosis, gastrointestinal irritation, candidiasis, and hyperglycemia, while maintaining the beneficial antiinflammatory effects that corticosteroids offer. The newer formulations of intranasal corticosteroids show even lower amounts of systemic absorption—approximately 1%. There are eight agents available currently for use in the United States ( Table 1 ).
| Generic | Brand |
|---|---|
| Beclomethasone dipropionate | Beconase Aq, Vancenase Aq |
| Budesonide | Rhinocort Aq |
| Flunisolide | Nasalide, Nasarel |
| Fluticasone propionate | Flonase |
| Mometasone furoate | Nasonex |
| Triamcinolone acetonide | Nasacort Aq |
| Newer | |
| Fluticasone furoate | Veramyst |
| Ciclesonide | Omnaris |
Intranasal corticosteroids are understood to be most effective against late-phase mediators in eosinophilic-dominated inflammation with some effect on the acute phase of the allergic response. These agents are useful controller drugs and, therefore, should be used in a chronic manner. However, there are some data supporting its use on an as needed basis. Newer agents have been reported to have an effect as early as 24 hours after administration; however, the benefit from chronic use still seems to outweigh that of as needed use.
Dexamethasone nasal drops were some of the first used topical corticosteroids. Although topically applied, they had significant adverse effects similar to those of systemic corticosteroids, partly due to its long half-life and the lack of first-pass metabolism in the liver. Subsequent drugs that were first-pass metabolized included beclomethasone, which is the most extensively used in airways. Budesonide, fluticasone propionate, mometasone furoate, and triamcinolone acetonide are well studied agents that have even less bioavailability and shorter plasma half-lives than beclomethasone. The newer agents, Food and Drug Administration (FDA) approved in 2006–2007, include ciclesonide and fluticasone furoate.
Most intranasal corticosteroids are poorly lipid soluble, therefore requiring an aqueous solution used in a pump spray to suspend and deliver the drug. There appears to be a dose-dependent response to intranasal corticosteroids. Higher doses result in greater benefit. Overall, the intranasal doses tend to be smaller than those for the lung.
In the treatment of seasonal AR, intranasal corticosteroids are appropriate first-line agents. Studies have demonstrated significant symptomatic relief with the use of intranasal steroids alone. However, for perennial AR, management with sole intranasal corticosteroids has not proven to be as beneficial. Depending on the severity of the disease, short courses of oral corticosteroids, in addition to topical intranasal steroids, improve symptomatic relief more than intranasal steroids alone.
The treatment of AR in children and in pregnant women is very similar to that of nonpregnant adults; however, because of the potential undue consequences in these two populations, practitioners may be advised to be more judicious with the administration of intranasal corticosteroids. Large pediatric studies have not shown significant adverse effects with use of intranasal corticosteroids or significant systemic levels of corticosteroid absorption. In pregnant women, there is always the concern for adverse effects especially to the unborn fetus, particularly cleft lip and palate development. Thus far, there have not been any reported teratogenic effects. Overall, there are not enough studies to support any definitive conclusion regarding the use of these agents in pregnancy. Therefore, careful risk-benefit analysis is recommended for mother and fetus when considering the use of intranasal corticosteroids for the treatment of AR in pregnant women. Of the intranasal corticosteroids, budesonide is the only category B drug.
Patient education regarding how to use these drugs should be highlighted. The correct method to administer a dose can vary from drug to drug and its delivery system. As mentioned previously, patients should be reminded that this medication can take some time to reach a level of maximal benefit, usually on the order of several days. After maximal benefit has been achieved, the drug can be tapered. In some cases, a 14-day course, at the onset of symptoms, is all that is needed to provide relief during an AR episode.
Intranasal corticosteroids have few adverse effects. One randomized, double-blinded, controlled trial looking at pediatric subjects studied mometasone furoate and budesonide versus placebo for a short-term course of 14 days. This study showed no statistically significant difference in lower leg growth rate between groups. Another study looking at intraocular pressures, conducted as a randomized, controlled, double-blinded study comparing placebo, fluticasone propionate, mometasone furoate, and beclomethasone dipropionate for 1 year, showed normal intraocular pressures across all groups. However, in at least one randomized, controlled, double-blinded study, intranasal beclomethasone dipropionate was shown to have a statistically significant decrease in growth-rate for prepubertal children with perennial AR who were followed for 1 year.
Antihistamines
In the 1920s, it was discovered that histamine serves as an important mediator of pathologic allergic disease. Stemming from this basis, antihistamines were some of the first agents geared toward the treatment of atopic conditions ( Table 2 ). The first generation of antihistamines is comprised of six classes of poorly-selective histamine receptor competitive antagonists. These drugs have rapid onset and, although they are quickly efficacious, they wear off rapidly due to their short half-lives. They provide significant relief from AR symptoms such as rhinorrhea. However, this is balanced with a significant side-effect profile. The lack of selectivity for the histamine receptor results in anticholinergic effects due to unintended binding to muscarinic receptors. Consequently, adverse effects include dry mouth, blurred vision, and unwanted mucus thickening. Sedation and cognitive impairment effects stem from central histamine receptor affinity and binding. The first generation antihistamines are lipid soluble and easily cross the blood brain barrier. These medications have limited utility in light of the adverse side effects. This led to the development of second and third generation antihistamines.
| Generic | Brand |
|---|---|
| First generation | |
| Azatadine | Optimine |
| Azelastine | |
| Brompheniramine | Dimetane |
| Chlorpheniramine | Chlor-Trimeton |
| Clemastine | Tavist |
| Dexchlorpheniramine | Polaramine |
| Hydroxyzine | Atarax |
| Promethazine | Phenergan |
| Tripelennamine | Pyribenzamine (PBZ) |
| Second generation | |
| Cetirizine | Zyrtec |
| Fexofenadine | Allegra |
| Loratadine | Claritin |
| Third generation | |
| Desloratadine | Clarinex |
| Levocetirizine | Xyzal |
Second generation antihistamines were developed in an attempt to improve selectivity and the first group of second generation antihistamines were effective at doing so; however, prolonged Q-T effects were observed in the setting of ingestion of other medications using cytochrome P450 hepatic metabolism. This adverse effect was seen in both terfenadine and astemizole, which led to their removal from the market. The next batch of second generation antihistamines did not have the hepatic side effects of the first group of second generation drugs nor the central histamine-mediated and anticholinergic side effects of first generation medications. Loratadine spearheaded this group of nonsedating H1-blockers. Although not sedating at lower doses, dose-dependent sedation has been observed. Its popularity persists since it was introduced in the early 1990s. Concurrently, the development of fexofenadine followed in the footsteps of terfenadine as a nonsedating second generation antihistamine. It stands unique from loratadine due to its truly nonsedating properties even in the context of increasing dosage. Cetirizine is an active metabolite of hydroxyzine, a first generation antihistamine; therefore, it has slight blood brain barrier penetration and causes mild drowsiness. Demonstrable efficacy for AR symptoms as well as urticaria supports cetirizine as a useful drug for both respiratory and dermatologic atopic diseases. Loratadine and cetirizine are now available over-the-counter.
The third generation agents are S-isomers of the older antihistamines. Desloratadine and levocetirizine have minimal side effect profiles; however, they offer increased duration of action. Both agents have been shown to have a positive effect of nasal airflow and reduction in nasal congestion. Therefore, they may offer additional benefit to the treatment of AR when compared with older antihistamines.
There are two topical intranasal antihistamines available in the United States: azelastine and olopatadine. Azelastine is a second generation antihistamine available for the treatment of seasonal AR. Bitter taste is the most common adverse reaction. Olopatadine not only has antihistaminic properties, but it also possesses mast cell-stabilizing and antiinflammatory properties. It is a new treatment approved by the FDA in 2009 for the management of AR with rapid onset and comparable efficacy to intranasal corticosteroid sprays. It is indicated for seasonal AR in patients aged 6 years or older. Both agents are clinically effective on an as needed and continual basis. In a randomized, controlled study looking at children with perennial AR, olopatadine nasal spray twice per day was significantly better than placebo.
Antihistamines
In the 1920s, it was discovered that histamine serves as an important mediator of pathologic allergic disease. Stemming from this basis, antihistamines were some of the first agents geared toward the treatment of atopic conditions ( Table 2 ). The first generation of antihistamines is comprised of six classes of poorly-selective histamine receptor competitive antagonists. These drugs have rapid onset and, although they are quickly efficacious, they wear off rapidly due to their short half-lives. They provide significant relief from AR symptoms such as rhinorrhea. However, this is balanced with a significant side-effect profile. The lack of selectivity for the histamine receptor results in anticholinergic effects due to unintended binding to muscarinic receptors. Consequently, adverse effects include dry mouth, blurred vision, and unwanted mucus thickening. Sedation and cognitive impairment effects stem from central histamine receptor affinity and binding. The first generation antihistamines are lipid soluble and easily cross the blood brain barrier. These medications have limited utility in light of the adverse side effects. This led to the development of second and third generation antihistamines.
| Generic | Brand |
|---|---|
| First generation | |
| Azatadine | Optimine |
| Azelastine | |
| Brompheniramine | Dimetane |
| Chlorpheniramine | Chlor-Trimeton |
| Clemastine | Tavist |
| Dexchlorpheniramine | Polaramine |
| Hydroxyzine | Atarax |
| Promethazine | Phenergan |
| Tripelennamine | Pyribenzamine (PBZ) |
| Second generation | |
| Cetirizine | Zyrtec |
| Fexofenadine | Allegra |
| Loratadine | Claritin |
| Third generation | |
| Desloratadine | Clarinex |
| Levocetirizine | Xyzal |
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