Epinephrine Was First an Asthma Treatment

This is the first in an occasional series on the origin of commonly used medicines.

When epinephrine was first discovered at the turn of the 20th century, it was essentially a drug without a disease.

In 1894, two British researchers — physician George Oliver and physiologist Edward Albert Sharpey-Schafer — discovered that the extract of the adrenal glands increased heart rate and blood pressure in animals, according to a feature in The Lancet Respiratory Medicine.

Over the next 5 years, researchers around the world tried to isolate the active component of adrenal extract, according to Hugh Sampson, MD, director emeritus of the Jaffe Food Allergy Institute at Mount Sinai Hospital in New York City.

Eventually, Japanese biochemist Jokichi Takamine isolated the “pure, stable, crystalline” form of the compound, according to The Lancet paper. He named the compound “adrenalin,” for its origin in the adrenal glands, which are located just above the kidneys. His employer, now known as Parke-Davis (a subsidiary of Pfizer), quickly patented the hormone.

“Because Parke-Davis patented the name [adrenalin], people were a bit nervous about using that particular name, and that’s why I guess in the U.S. it became known as epinephrine,” Sampson told MedPage Today. “My U.K. colleagues are adamant that it should be called adrenaline, not epinephrine.”

Once it was identified, researchers then got to work on finding a condition for epinephrine to treat. Around 1900, American physician Solomon Solis-Cohen started testing crude epinephrine extract on patients with asthma and hay fever, according to The Lancet.

Researchers saw good results treating asthma with epinephrine, even if they didn’t understand exactly how it worked. In one case report from 1920, a 30-year-old woman with nightly asthma attacks saw their frequency reduced with epinephrine injections.

Over time, experts disentangled the exact mechanisms by which epinephrine worked in asthma, and eventually, treatments became more specific, Sampson said.

“When I was a resident, we still used subcutaneous epinephrine in the treatment of status asthmaticus, whereas now, we have all these nebulized forms of the drug, which are more specific,” said Sampson, who was a resident in the 1980s.

Essentially, epinephrine targets a mix of alpha- and beta-adrenergic receptors, which are widely distributed throughout the body, said Corinne Keet, MD, PhD, a pediatric allergist and immunologist at the University of North Carolina School of Medicine at Chapel Hill. Beta adrenergic receptors — specifically, beta-2 receptors — are involved in bronchodilation, she said, while alpha adrenergic receptors are involved in vasoconstriction.

“It’s helpful when we’re treating anaphylaxis to have the full range of the activity on the receptors that epinephrine acts on, but it’s not as helpful when we’re treating something like asthma,” Keet said.

Focusing in on the bronchodilating effects of epinephrine led to the development of an important class of drugs for asthma — the beta-2 adrenergic receptor agonists such as albuterol. These drugs, which can be either short- or long-acting, essentially relax the muscles of the airways to help patients breathe easier.

For treating anaphylaxis, clinicians want both the bronchodilating effects exerted on the beta adrenergic receptors, but also the vasoconstricting effects of alpha adrenergic receptors, Keet said.

That’s because in an allergic reaction, mast cells are activated, releasing histamine and a variety of other mediators that lead to a drop in blood pressure, bronchoconstriction, and swelling.

“Vasodilation leads to lower blood pressure, and to permeability of the blood vessels, which leads to swelling of the tissues, the airway, and the skin,” Keet said. “It also causes bronchoconstriction of the airways that leads to wheezing and coughing … and increased mucous production.”

But epinephrine, she said, “counteracts all of those things,” opening up the airways, increasing blood pressure, increasing cardiac output, and stabilizing mast cells.

While epinephrine was used intramuscularly throughout the 20th century for treating anaphylaxis, the highly recognizable “EpiPen” brand, today made by Mylan Pharmaceuticals, wasn’t approved by the FDA until 1987. (Generic formulations of EpiPen weren’t approved until 2018.)

Other automated devices for delivering epinephrine, including the Auvi-Q, are now available as well — offering relief to those with food allergies and their families, particularly as such conditions have been on the rise with the turn of the 21st century, Sampson said.

“It gives people some confidence that should they experience one of these reactions,” Sampson said, “they would have an emergency plan, and they would have medication to reverse it.”

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