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Typical Antihistamine


Consumers used to have to make a decision when allergy symptoms struck. They could put up with the combined misery of sneezing, itchy eyes, and a runny nose, or they could struggle blearily against the head-drooping drowsiness brought on by taking an antihistamine. Now, however, consumers can banish allergy symptoms without having to schedule a siesta. They need only drop by their local supermarket to pick up a nonsedating antihistamine.

Their choices include Allegra, Zyrtec, and Clarinex, which are available by prescription, and Claritin, which is available over the counter. Although antihistamines can cut down on sneezing, eye itching, and nasal secretions, they're not much good at clearing a stuffy nose. So these drugs are also offered with a decongestant ingredient such as pseudoephedrine hydrochloride.

Millions of consumers casually take these medications today, but nonsedating antihistamines had a bumpy start. The first of this class of drug to go on the market was Seldane (terfenadine), which was introduced in 1985 by Hoechst Marion Roussel. The company is now known as Sanofi-Aventis.

In the body, terfenadine is normally metabolized into fexofenadine--the active ingredient responsible for the antihistamine's activity--by converting a methyl into a carboxylate group. But metabolism of terfenadine can be hindered by liver disease, grapefruit juice, and other medications such as the antibiotic erythromycin. When terfenadine builds up in the bloodstream as a result, it blocks cardiac potassium channels, leading to serious and sometimes fatal heart rhythm abnormalities.

The Food & Drug Administration initially judged that terfenadine's benefits outweighed its risks because the drug doesn't cause sleepiness--a significant safety advantage for people who used antihistamines. But the agency pushed Hoechst Marion Roussel to develop an antihistamine based on fexofenadine itself, which lacks terfenadine's risks. After the safer alternative Allegra (fexofenadine hydrochloride) was approved in July 1996, FDA announced that it would withdraw its approval for terfenadine products. Hoechst Marion Roussel then pulled Seldane from the market.

Other nonsedating antihistamines approved by FDA include Hismanal, which was approved in 1988 but withdrawn from the market in 1999 because of cardiovascular and other safety problems; Claritin, approved in 1993; Zyrtec, approved in 1995; and Clarinex, approved in 2002.

THE NUMBER OF people who could benefit from these drugs is staggering. In the U.S. alone, more than 35 million people suffer from seasonal allergies, reports the American Academy of Allergy, Asthma & Immunology.

Their symptoms result from an excessive immune response to the proteins found in allergens such as pollen or mold. When a susceptible person inhales pollen, the immune system begins pumping out immunoglobulin E (IgE) antibodies that are specific for the pollen proteins. The antibodies then fasten onto the surface of mast cells--connective tissue cells that are abundant in the nose, eyes, lungs, and gastrointestinal tract.

When this unlucky person is again exposed to pollen grains, the IgE antibodies latch onto the new batch of allergens and also begin cross-linking. These interactions trigger a release of histamines and other chemical messengers from the mast cells attached to the antibodies.

The histamine molecules then bind to receptors on cells in blood vessels, the gastrointestinal tract, and the respiratory tract--collectively known as peripheral H1 receptors. In turn, this coupling leads blood vessels to dilate and leak fluid, smooth muscle to constrict, and mucus secretion to increase. Sneezing, a runny nose, and red, itchy, watery eyes are the inelegant result.

Antihistamines block the interaction between histamine molecules and their target cells by binding to the cell receptors themselves. But the interaction between antihistamines and H1 receptors can have two very different effects. Binding of antihistamines to peripheral H1 receptors reduces allergy symptoms. But H1 receptors also exist in the central nervous system, and antihistamines that bind to them cause sedation, cognitive impairment, and other effects. In fact, the sedative effect can be so strong that such products are sometimes used as sleeping aids.

The first generation of antihistamines, which includes compounds such as Benadryl and Chlor-Trimeton, bind to both types of H1 receptor and are termed nonselective. Thus patients who take these compounds have to put up with sleepiness if they want relief of allergy symptoms.

The second- and third-generation antihistamines, on the other hand, are nonsedating because they selectively bind to peripheral H1 receptors. They are considerably less likely to bind to the H1 receptors in the central nervous system because they are much less capable of crossing the blood-brain barrier.—SOPHIE ROVNER


The Top Pharmaceuticals
That Changed The World
Vol. 83, Issue 25 (6/20/05)
Table Of Contents

Fexofenadine Hydrochloride

Allegra structure


  • 15343-40-8

CAS Registry

  • ,-Dimethyl-4-
    acid hydrochloride

Other Names

  • Allegra
  • Telfast
  • carboxyterfenadine hydrochloride
  • terfenadine carboxylate hydrochloride


1996, Hoechst Marion Roussel

Sales Volume

  • $1.87 billion globally in 2004, including $1.49 billion in the U.S.