Antihistamines

Antihistamines represent the primary class of medications used for the treatment of AR over the past 60 years. These medications were developed in the 1940s to decrease histamine-mediated symptoms of AR. Antihistamines used in AR function as competitive antagonists for the histamine-1 (H ₁ ) receptor found on the surface of target cells not only in the nose but also in the lung, conjunctiva, and skin. Not only do these agents compete with histamine in binding to the H ₁ receptor, but they also change the three-dimensional configuration of the receptor, decreasing its affinity for histamine and down-regulating histamine-driven symptoms. This characteristic of deforming the receptor has been termed reverse agonism.

The first antihistamines were limited in their application because of significant adverse effects. Efficacious agents were introduced by the late 1940s, and a large number of medications were introduced over the next 30 years. Each of these early antihistamines belonged to one of six pharmacologic classes based on molecular structure. These six classes and examples of antihistamines in each of these classes are presented in Table 2 . These agents as a group have been commonly referred to as first-generation antihistamines. They tend to have rapid onset of action but relatively brief periods of efficacy because of short serum half-lives.

While these early antihistamines demonstrate good efficacy in the treatment of most symptoms of AR, they are accompanied by clinically important adverse effects that limited their utility. These first-generation agents all have significant lipophilicity and are demonstrated to freely cross the blood–brain barrier. This property allows them to interact with central H ₁ receptors, resulting in central nervous system effects, such as sedation and psychomotor and cognitive impairment. In addition to effects on the histamine receptors centrally, these first-generation agents are poorly selective and exert effects on cholinergic and muscarinic receptors as well. Through effects on these receptors, these agents are also accompanied with anticholinergic effects, such as blurred vision, dry mouth, and increased tenacity of mucus.

In response to the significant adverse event profile of the first-generation antihistamines, newer agents developed over the past 30 years maintain the clinical efficacy of the earlier medications and yet have more advantageous safety profiles . These antihistamines, referred to as second-generation antihistamines, have generally supplanted the use of their earlier counterparts in the treatment of AR. These newer agents have been designed to have lesser lipophilicity, so they do not readily cross the blood–brain barrier. Because they do not have significant interaction with central H ₁ receptors, these second-generation antihistamines provide excellent efficacy at receptors in the nasal mucosa without significant sedation or psychomotor impairment. In addition, these newer drugs do not have significant anticholinergic side effects and therefore are better tolerated than the earlier antihistamines.

Antihistamines have traditionally been used for treating the irritative symptoms of AR, such as sneezing and itching. Older antihistamines with anticholinergic effects can decrease rhinorrhea, although the mucus secretion is often thickened and can be more bothersome for some patients. Newer antihistamines have little effect on rhinorrhea. No oral antihistamines have significant effects on reducing nasal congestion, although some mild benefit in the treatment of nasal congestion has been noted with newer antihistamines, such as desloratadine and levocetirizine. Topical nasal antihistamines, such as olopatadine and azelastine, however, have been demonstrated to have significant benefit in reducing nasal congestion.

Second-generation antihistamines were first employed in the United States in 1985 with the introduction of terfenadine. This medication was widely used until the mid-1990s, when evidence of its effect on liver enzymes and adverse drug interactions led to its withdrawal from the market. Another early second-generation antihistamine, astemizole, was found to have similar effects and was also withdrawn from the market in the mid-1990s.

The next second-generation antihistamine introduced into the United States was loratadine, brought to market in 1993. Loratadine has been widely used in the past 15 years and is currently available over-the-counter (OTC) for treating the symptoms of AR. Loratadine is classified as a nonsedating antihistamine, although at higher doses it can be accompanied by dose-dependant sedation. Loratadine does not have any significant adverse drug reactions or clinically important effects on liver enzymes .

Fexofenadine was developed as an efficacious nonsedating antihistamine in the 1990s and was introduced after its parent compound, terfenadine, was removed from the market. It does not have the same effects on liver metabolism and cardiac toxicity as terfenadine . Fexofenadine is unique in that it appears to be purely nonsedating, even at increased doses. Since 2005, it has been available as a generic preparation in the United States, making it available at a lower cost.

A third second-generation antihistamine, cetirizine, was also introduced in the 1990s. Cetrizine is an active metabolite of the first-generation antihistamine hydroxyzine. It has been demonstrated to have excellent efficacy in the treatment of both respiratory and skin allergy. Cetirizine appears to have some sedative effects, even at the recommended dosage of 10 mg daily . These effects, however, are minimal in most patients in comparison to those of the first-generation antihistamines. Cetirizine was recently released in the United States as an OTC antihistamine.

Desloratadine and levocetirizine, two newer oral antihistamines, have been introduced in the United States market in the past several years. Desloratadine is the primary active metabolite of loratadine. It has a longer half-life than the parent compound, and appears to have a longer duration of action. In addition, desloratadine appears to have some effect on nasal airflow, suggesting that it may have at least mild benefit in the treatment of nasal congestion associated with allergic rhinitis .

Levocetirizine is the S-enantiomer of its parent compound, cetirizine. Studies demonstrate that this S-enantiomer is responsible for most of the clinical effect of cetirizine. Levocetirizine was shown in a 6-month trial to have significant efficacy in the treatment of persistent allergic rhinitis. That is, levocetirizine was not only effective in the treatment of the global symptoms of allergic rhinitis, but also in the treatment of nasal congestion . Levocetirizine appears to be associated with a slight increase in the incidence of sedation, although this effect may be less than that observed with cetirizine.

Topical antihistamines also show benefit in the treatment of allergic rhinitis. Topical agents are used successfully for the treatment of allergic conjunctivitis. These medications will not be reviewed here. One nasal antihistamine, azelastine, is currently available for the treatment of allergic rhinitis. Azelastine shows benefit in reduction of both nasal and eye symptoms, and may have some synergistic benefit when used in conjunction with a topical nasal corticosteroid spray. In recent trials, azelastine used topically has been shown, in comparison to oral cetirizine, to have more rapid and efficacious effects in the treatment of the symptoms of allergic rhinitis, and to bring about significant improvements in quality of life . A second nasal antihistamine, olopatadine, is also currently under review by the US Food and Drug Administration (FDA) as a topical treatment for allergic rhinitis.

Decongestants

Decongestants are used to decrease nasal vascular congestion and improve nasal airflow. These agents, available in both topical and oral forms, work as alpha-adrenergic agonists to reduce blood flow in the venous sinusoids found in the inferior turbinates. They are nonspecific agonists and exert effects in systems other than the nose, often resulting in adverse events and poor patient tolerance.

Oral decongestants are absorbed systemically and work effectively to reduce nasal congestion. They work directly on α ₂ receptors in the nasal mucosa, but also have secondary effects on α ₁ and α ₂ receptors in the central nervous and cardiovascular systems. These agents have relatively short serum half-lives and therefore are often prescribed in time-release formulations. The most commonly used oral decongestant has been pseudoephedrine. However, because it can be converted chemically to methamphetamine, access to pseudoephedrine has been restricted. It is now available either by prescription or by patient request behind the pharmacy counter in limited amounts. In response to these recent regulations, many OTC decongestants have now changed their formulations to include phenylephrine in place of pseudoephedrine. Observations suggest that phenylephrine appears to possess somewhat weaker properties than pseudoephedrine when used orally as a decongestant. Another popular decongestant, phenylpropanolamine, was removed from the United States market in 2001 after it was found to be associated with a marked increase in hemorrhagic strokes in young women .

While oral decongestants are generally safe and well tolerated in healthy patients, there are risks and adverse events associated with their use, especially among susceptible patients. Because these agents have nonspecific effects on α-receptors in the central nervous system, their use is often accompanied by such symptoms as insomnia, jitteriness, nervousness, tremulousness, and restlessness. In addition, because of their effects on the cardiovascular system, patients often experience such symptoms as palpitations, tachycardia, and irregular heartbeat. Oral decongestants also have the potential to raise blood pressure and cause urinary retention. They should be used with caution in patients with cardiac disease and hypertension, and their use should be limited to short-term therapy rather than long-term control of nasal congestion.

Topical vasoconstrictors are also popularly used as decongestant medications. These agents possess excellent efficacy at the end organ, and significantly reduce nasal stuffiness and improve nasal airflow. They also generally have less systemic effect than seen with oral decongestants, although some effects on hypertension and cardiac irritability have been observed. The most popular agents used in the United States are oxymetazoline and phenylephrine, although other agents, such as xylometazoline, are sometimes used. The major adverse event noted with this class of medications is end-organ tachyphylaxis and rebound rhinitis. Due to tolerance that can develop rapidly in susceptible individuals, patients sometimes increase their use of topical vasoconstrictors to many times daily. Frequent use results in hypoxic injury to the nasal mucosa and can lead to a condition known as rhinitis medicamentosa. This disorder is accompanied by severe nasal congestion and dependency on topical vasoconstrictor therapy. Complete withdrawal of these medications, often accompanied by the brief use of systemic corticosteroid medications, is frequently necessary to reverse the rhinitis and reduce the patient’s nasal congestion.