Allergic Rhinitis 2002: Treatment Issues and Options

This program was supported by an unrestricted educational grant from Aventis Pharmaceuticals.

Therapeutic Options in Allergic Rhinitis

Christopher G. Massey, PA-C, RRT (Brockton, MA) characterized allergic rhinitis as a systemic disease that entails weakness, malaise, irritability, fatigue, difficulty concentrating, and decreased appetite as well as the familiar symptoms of upper respiratory distress, itchy throat, and watering eyes. This condition is linked epidemiologically and pathophysiologically with asthma and is a strong factor in sinusitis. An international panel of experts, convened by the World Health Organization (WHO) in 1999 to study allergic rhinitis and its impact on asthma (ARIA), recommended a two-tier classification system for allergic rhinitis: persistence and severity. Intermittent disease was defined as occurring a maximum of 4 days per week or lasting for less than 4 weeks, whereas persistent disease was defined as occurring more than 4 days per week and lasting for more than 4 weeks. Severity was defined as mild, moderate, or severe. Mild disease does not involve sleep disturbance, impairment of normal activities, absenteeism, or troublesome symptoms. Moderate disease entails one or more of the foregoing symptoms, and severe disease involves multiple disabilities and symptoms emulating those of asthma.

The nose functions as an airway, provides olfactory sensation, humidifies air en route to the lungs (especially in cold, dry weather), and is involved in mucociliary transport. All of these functions are diminished or lost with significant rhinitis.

The expression of allergic disease is mediated by TH2 cells. One explanation for the increase of TH2 expression is the “hygiene theory.” This posits that in modern societies, the use of sterile foods, clean water, vaccinations against disease, and frequent antibiotic treatment for acute infections has altered the natural balance between TH1 cells, which are important in infection, and TH2 cells. The dominance of TH2 cells predisposes the individual to allergies in a two-phase process. In the sensitization phase following initial exposure to an allergen, antigen-presenting dendritic cells, under the influence of cytokines including interleukins, capture allergenic antigens and present them to TH2 cells, which stimulate B cells to produce plasma cells and ultimately IgE antibodies. These antibodies affix themselves to mast cells and prime them for the second phase, in which the allergic reaction is triggered upon second exposure to the allergen. The early phase of the allergic response to this exposure is a spectrum of symptoms including nasal congestion, rhinorrhea, pruritis, and sneezing. The release of chemotactic factors and the recruitment of inflammatory cells initiates the late-phase reaction, in which nasal congestion in predominant. This is mediated by histamine, leukotrienes, and prostaglandins released by the inflammatory cells.

Histamine is the most widely studied and important chemical mediator of allergic rhinitis of both the early- and late-phase responses to allergen exposure. It induces sneezing and pruritis by stimulation of sensory nerves, rhinorrhea from stimulation of submucosal glands by vagal reflexes, and nasal blockage by decreasing the tone of the capacitance vessels and the leakage of plasma proteins. Because of its major role in the symptomatology of allergic rhinitis, it was an early target for drug development.

Table 1 illustrates the wide variety of pharmacotherapeutic options available for treating allergic rhinitis. Anti-histaminic agents bind to type-1 histamine receptors (H1) to prevent activation of the receptors during allergen exposure. The first generation of these agents (e.g., pyrilamine, diphenhydramine, tripelennamine, chlorpheniramine, brompheniramine), many of which are still available, have unfavorable risk-to-benefit ratios primarily because they are highly lipophilic small molecules that penetrate the blood-brain barrier easily. Thus, while they are effective for relieving acute symptoms, their major side effect is sedation that manifests as drowsiness and both cognitive and motor impairment. The effects on the central nervous system are potentiated by alcohol. In addition, these medications have poor receptor selectivity, thus binding to cholinergic, dopaminergic, muscarinic, and serotonergic receptors. The results are side effects such as dry mouth and urinary retention. Because of their side-effects profile, first-generation antihistaminic agents are no longer recommended for first-line therapy.

Second-generation antihistaminic agents are longer acting and, because they consist of large lipophobic molecules, they do not readily cross the blood-brain barrier. They are as efficacious as first-generation antihistamines. Cetirizine, a representative agent of this class, also has a sedative effect in approximately 14% of patients at recommended therapeutic doses. Widely used examples of this class of drug are fexofenadine, cetirizine, loratadine, and desloratadine.

Intranasal corticosteroids are the most effective agents for treating rhinorrhea associated with allergic rhinitis, and they are recommended as first-line therapy for persistent and moderate-to-severe disease. They affect all aspects of nasal inflammation in both the early- and late-phase responses to allergen exposure. These agents act via a three-step mechanism. First, they bind with cytosolic glucocorticoid receptors (GR). Second, the resulting steroid-GR complex translocates to the cell nucleus where, third, it binds with DNA, thereby inducing or suppressing genes involved in protein synthesis and inflammation. The intranasal corticosteroids act on both early- and late-phase responses to exposure and exert their effects by inducing vasoconstriction, thus reducing mucosal edema, resulting in a reduction in nasal congestion and rhinorrhea. Intranasal steroids inhibit the expression of cytokines and other mediators of inflammation. Fluticasone, mometasone, budesonide, triamcinolone, flunisolide, and beclomethasone are the major products in this drug class.

Short bursts of systemic corticosteroids are occasionally used for short-term treatment of acute exacerbations of allergic rhinitis, but they are rarely used as first-line therapy.

Only one second-generation antihistaminic agent, azelastine HCl, has been approved in topical formulation for the treatment of both seasonal allergic rhinitis in patients above 4 years of age and non-allergic vasomotor rhinitis in patients 12 years and older. Its anti-inflammatory activity consists of reducing eosinophil and neutrophil infiltration, and decreasing leukotriene and bradykinin levels. It also down-regulates intracellular adhesion molecule expression and cytokine expression. This agent successfully treats sneezing, rhinorrhea, itchy nose, postnasal drip, and nasal congestion. Its common side effects, however, are bitter taste and drowsiness.

Decongestants are a-adrenergic agonists that stimulate receptors to induce local vasoconstriction. By so doing, they decrease blood volume in the nasal mucosa capacitance vessels, thus reducing blood supply to the mucosa, decreasing mucosal edema, and improving nasal patency. Of the two currently available decongestants, pseudoephedrine, which is found in most cold remedies and prescribed combination products, is the more effective. Although it is generally recommended for short-term therapy, it is often prescribed for long-term treatment as well. Its effectiveness may be offset by systemic side effects including dizziness, headache, tremor, insomnia, tachycardia, and hypertension. It may aggravate urinary retention in men with underlying prostatic enlargement, and it is contraindicated for patients with glaucoma, hyperthyroidism, or cardiovascular disease.

Mast cell stabilizers, one of which (cromolyn sodium) is now available without prescription, are thought to prevent the release of prechemical and newly formed mediators to prevent degranulation. They are modestly effective agents, but require dosing four to six times daily.

Topical decongestants, whether long-acting (oxymetazoline) or short-acting (phenylephrine), avoid the risks associated with systemic oral decongestants, but have untoward local effects such as rhinitis medicamentosa, a rebound effect from long-term use.

The intranasal anticholinergic ipratropium, a topically active derivative of atropine, has low lipid solubility and does not cross the blood-brain barrier. It is not systemically active except at extremely high doses. It prevents and relieves rhinorrhea by inhibiting parasympathetic transmission to the submucosal glands, but it does not relieve itching or nasal obstruction. It may be more useful in the management of gustatory rhinitis (nasal congestion and runny nose while eating) and cold-air rhinorrhea (“skier’s nose”) than in allergic rhinitis.

Up to 40% of patients with allergic rhinitis may experience ocular symptoms of allergic conjunctivitis, the pathogenesis of which is similar to that of allergic rhinitis. Several treatment options include H1 antagonists, mast cell inhibitors or combinations of the two, topical nonsteroidal anti-inflammatory drugs, and corticosteroids.

Future therapies for allergic rhinitis include leukotriene modifiers used successfully in the setting of asthma. Other choices may include anti-cytokines, monoclonal antibodies that prevent the binding of IgE with mast cells, and specific immunotherapies. Omalizumab, a recombinant human monoclonal antibody directed against IgE, is currently in phase III trials. One form of specific immunotherapy involves antigenic peptides (altered allergens) that interfere with antigen presentation to lymphocytes. Another form is DNA immunostimulation that drives lymphocyte differentiation toward the TH1 pathway.

Table 1. Pharmacotherapy

• Oral H-1-antihistamines
• Topical H1-antihistamines
•l Intranasal glucocorticosteroids
• Systemic glucocorticosteroids
• Oral decongestants
• Mast cell stabilizers
• Combination products
• Intranasal decongestants
• Intranasal anticholinergics
• Intranasal saline
• Ocular therapeutics

Sedating Properties of Antihistaminics and Their Legal Implications

B. Chandler May, MD, JD, MS (Santa Barbara, CA) noted that first-generation antihistamines, of which diphenhydramine is the prototype, induce drowsiness both subjectively (i.e., sedation) and objectively (i.e., cognitive impairment). Because psychometric tests have different sensitivities to the sedating effects of these agents, a battery of tests is necessary to assess their activity. Table 2 lists the standards of performance, the first four of which are reproducible and thus regarded as objective.

The gold standard of psychomotor performance is automotive driving, either actual or simulated. The foremost measure of sensorimotor coordination speed is a test called the choice reaction time. CNS arousal and information processing are best measured by the critical flicker fusion test, in which the subject attempts to determine when four blinking lights fuse into one. A standard physiological test of response to a sedative antihistamine is the multiple sleep latency test. In this test, the time taken to fall asleep is measured over a 2-hour window. Typically, first-generation antihistamines reduce sleep latency (time to sleep onset) from the normal of 10 to 15 minutes to a range of 6 to 7 minutes. This reproducible effect can be seen even after AM-PM dosing, i.e., the administration of non-sedating histamine in the morning and a first-generation sedating antihistamine at night. Sleepiness can also be monitored over a 24-hour period using a motion sensor worn by the subject. This device, known as an “Actiwatch,” overcomes the problems associated with fixed-interval physiologic testing.

Sedation during anesthesia is measured by a bispectral index monitor, which assesses activity in either the left or the right frontal lobe of the brain via a probe taped to the patient’s forehead. The time-averaged EEG signal is converted electronically into a 0 to 100 point scale to reflect the patient’s degree of sedation. Below 80, one is generally considered “asleep.”

A meta-analysis of 73 controlled, double-blind crossover studies distinguished first-generation antihistamines that impair the central nervous system at all doses, second-generation antihistamines that induce dose-related sedation, and third-generation antihistamines that are not associated with sedation at any dose level. For each agent tested, a risk-to-benefit ratio was established. The ratios varied from a high of 60 for first-generation agents to as low as 0.0 for antihistamines of the third generation (Hindmarch I, Shamsi Z. Clin Exp Allergy 1999;29(Suppl III):133; Shamsi Z et al. Eur J Clin Pharmacol 2001; 56:865). Ironically, those agents with the highest risk-to-benefit ratios are generally available without prescription, while those with lowest risk are prescription medications.

Dr. May compared the pharmacology of the four modern second- and third-generation antihistamines currently available in the United States. Loratadine and desloratadine, a metabolite of loratadine, are both long-acting second-generation tricyclic antihistamines. They differ principally in their respective half-lives of 8.4 hours and 27 hours. At recommended doses, somnolence associated with loratadine is 8% and with desloratadine it is 3%. Both of these agents undergo hepatic metabolism and may interact adversely with other drugs using the CYP3A4 metabolic pathway. Cetrizine, another second-generation antihistamine, is a metabolite of hydroxyzine. It is characterized by rapid onset of action and a half-life of 8.3 hours. Sedation occurs in 13.7% of patients at the recommended dose of 10 mg/day. This agent primarily undergoes renal metabolism.

Fexofenadine, a metabolite of terfenadine, is the only true third-generation antihistamine that has been approved by the Food and Drug Administration. It has a half-life of 14 hours and has not been shown to have a sedating effect at any dose level. Dr. May quoted from The Medical Letter of 2001 and 2002: “Fexofenadine may offer the best combination of effectiveness and safety.” Documentation from a British post-marketing surveillance study encompassing responses from over 11,000 patients supports this statement. Using loratadine as the comparator for sedation and using gender- and age-adjusted ratios, the authors demonstrated that the incidence of sedation among widely used antihistamines varied from a low of 0.63 with fexofenadine to a high of 3.53 with cetirizine (Mann RD et al. Brit Med J 2000;320:1184). In other words, for every one patient complaining of sedation on loratadine, there were 0.63 on fexofenadine and 3.35 on cetirizine.

In an even more elaborate study, Weiler and colleagues compared the effects of fexofenadine, diphenhydramine, alcohol, and placebo in the highly controlled environment of the Iowa driving simulator (Weiler JM et al. Ann Int Med 2000;132:354). This double-blind, four-treatment, four-period crossover study involved 40 patients with active seasonal allergic rhinitis. Following a series of tests involving both objective (e.g., following distance, lane maintenance, reaction time, steering instability) and subjective performance outcomes, the investigators concluded that diphenhydramine has a sedating profile similar to that of a blood alcohol level of 0.9%. (Twenty-five states have a 0.08 blood-alcohol level standard for driver intoxication). The effects of fexofenadine approximated those of placebo. Based on evidence of this kind, 32 states plus the District of Columbia now restrict driving while impaired by medication. Penalties for violation include fines of up to $8,000, revocation or suspension of license to drive ranging from 1 month to 2 years, and imprisonment for 1 day to 2 years. Motor vehicle accidents comprise the fifth leading cause of death in the United States. The use of sedating antihistamines increases the risk of accident by a factor of six, contrasted with the four-fold risk increase associated with driving while talking on a phone. From 1% to 3% of highway accidents per year in the United States are attributed to driver sleepiness alone, resulting in 600 to 1,200 out of a total of 41,500 fatalities.

Dr. May concluded his lecture by presenting two cases from appellate courts. The first, State of Washington vs. Ardith Walley, 1997, was that of a driver convicted of negligent homicide while driving under the influence of intoxicating liquor and/or drugs. The driver’s blood-alcohol and diphenhydramine levels 2 hours after the accident were 0.17% and 0.53%, respectively. In the second case (Mittelman vs. Seifert, 1971), the estate of a civil aviation pilot was held libel for damages awarded to the heirs of passengers on a theory of wrongful death. The pilot’s blood alcohol (0.04%) was below the traditional DWI levels for automobile driving, but was compounded by the concomitant use of chloropheniramine, a first-generation sedating antihistamine, taken for treatment of an upper respiratory infection.

Table 2. Measures of Performance

• Psychomotor
• Sensorimotor Co-ordination Speed
• CNS arousal, Information processing
• Physiological
• Memory
• Sensory Skills
• Motor Ability
• Subjective Ratings