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The term allergy was coined in 1906 to explain the unexpected response to diphtheria antitoxin. With nearly 18% of Americans experiencing allergy symptoms for 31 days or more each year, the search for a safe and effective cure for the sneezing, congestion, and rhinorrhea of allergic rhinitis remains an ongoing challenge. A complete cure remains elusive, but symptomatic relief is available, courtesy of antihistamines.
Antihistamines are among the most widely used categories of medicine, in both prescription and OTC forms. In addition to allergic rhinitis, antihistamines are useful in treating forms of conjunctivitis and acute urticaria. The first generation of antihistaminesrepresented by diphenhydramine, chlorpheniramine, and brompheniraminebears the disadvantage of sedation during treatment. Since the 1980s, research has produced a series of second-generation, "nonsedating" antihistamines. Fexofenadine is the second of these agents to attain generic status.
The body's first response to the presence of an allergen is to create memory cells specific to the offending agent. Upon reexposure to the allergen, the immune system is primed for a quick response, and immunoglobulin E (IgE) antibodies are released. IgE not only attaches to the offending agent, but adheres to the body's numerous mast cells. The attachment causes a disintegration of the mast cells, releasing histamine. Histamine moves to H1 receptors and causes dilation and increased permeability of the capillaries.
Stimulation of H1 receptors is associated with the traditional symptoms of allergies. H1 receptors appear in many tissues, however, including the midbrain of the central nervous system. The effect of histamine in the midbrain is the induction of arousal and alertness. First-generation antihistamines, by crossing the blood-brain barrier, block this effect of histamine in the brain and cause drowsiness.
The second-generation antihistamines are designed to be less lipophilic. This property limits their access to the midbrain and results in less sedation. It has been noted, however, that, as doses increase, the likelihood for sedation increases, even with these nonsedating antihistamines.
Terfenadine, an early second-generation antihistamine, had the unfortunate effect of blocking the potassium channel involved in the repolarization of cardiac cells, causing cardiotoxicity in the form of prolonged QT intervals. As a result, terfenadine was removed from the market, almost simultaneously with its first shipment in generic form. Fexofenadine, the active metabolite of terfenadine, does not affect these potassium channels and has not been associated with cardiac toxicity.
Administration and Dosing
Following oral administration, fexofenadine is rapidly absorbed, with an antihistamine effect seen within 1 to 3 hours. Food can diminish the absorption rate but does not seem to have a clinically significant effect on the activity of fexofenadine.
To provide relief of symptoms of allergic rhinitis, the usual dose of fexofenadine for adults and children over the age of 12 is 60 mg twice daily or 180 mg once daily. For children aged 6 to 12, the usual dose is 30 mg twice a day. Higher doses do not appear to provide significant therapeutic benefit.
Safety Profile and Drug Interactions
Whereas second-generation antihistamines cause less sedation, it should be noted that higher doses do seem to cross the bloodbrain barrier and exert some sedative effect. This effect still appears less pronounced than with the first-generation antihistamines, and even less so with the specific agent fexofenadine.
There are few side effects associated with fexofenadine; in fact, during initial trials, more participants stopped taking the placebo due to drowsiness (3.3% for placebo vs 2.2% for fexofenadine). Headache, dizziness, insomnia, and nausea also have been reported rarely. The safety of use of fexofenadine in children under the age of 6 has not been established.
Concurrent administration of erythromycin or ketoconazole can increase blood levels of fexofenadine. This increase is not considered clinically significant, however, nor is this effect associated with any changes in cardiac QT intervals.
The second-generation antihistamines offer relief from allergy symptoms with less sedation than earlier agents. Fexofenadine, the least sedating of this category at standard doses, effectively treats symptoms and offers a wide range of doses, including a once-daily regimen to enhance compliance.
Mr. Middleton is an instructor of pharmacology for Kellogg Community College in Battle Creek, Mich.