Antibacterial Agent In Some Asthma Medications Linked To Airway Constriction, UF Scientists Find

January 11, 2001

GAINESVILLE, Fla. — A new University of Florida study provides fresh evidence that an antibacterial agent added to some asthma medications can cause airway constriction, potentially blunting the effectiveness of efforts to reverse an asthma attack.

The chemical benzalkonium chloride, or BAC, is added to some albuterol solutions given by nebulizer, the device most frequently used to try to reverse acute episodes of breathing problems in children under 6. Prescribed for people of all ages, albuterol is considered the most

effective medicine for quickly opening the airways. BAC is not added to albuterol administered by metered-dose inhaler, the device typically used by older children and adults.

UF College of Pharmacy researchers found that 10 of 18 adults with asthma experienced a significant drop in breathing capacity when exposed to the preservative during their experiment. They published findings from their study in the January issue of the Journal of Allergy and Clinical Immunology.

The researchers are calling on parents and health-care professionals to choose products that do not contain BAC.

“We suggest that it’s illogical to use a preservative that may counteract the effect of albuterol — the main medicine that you have to reverse an asthma attack,” said Dr. Michael J. Asmus, an assistant professor of pharmacy practice and lead author of the journal article. “Some people might argue that albuterol is a very powerful medicine and wonder how the small effect of the BAC preservative could matter,” he said. “But the potential is that people having asthma attacks won’t get relief from their rescue medicine, possibly leading to the need for hospitalization and aggressive treatment.”

The UF research is the latest experiment to show the airway constriction effects of BAC. Richard Beasley of the Wellington School of Medicine first described problems with BAC in studies in the 1980s.

In the UF experiment, research participants were given up to four 600 microgram doses of BAC, spaced 20 minutes apart. The idea was to mimic the maximum amount of BAC patients would inhale in an albuterol nebulizer solution under emergency department guidelines for reversing an acute asthma attack.

After inhaling one dose, three participants experienced more than a 20 percent drop in their ability to force air out of their lungs, while seven others — including one whose capacity dropped 47 percent — showed such declines after the second or third dose. So that the research participants’ safety would not be endangered, no further doses of BAC were given once a 20 percent drop was observed. At that level, people begin to sense chest discomfort.

The authors noted that they have not tested a combination of albuterol and BAC, so it’s not clear precisely how much the medicine’s effectiveness would be limited by the additive.

“There have been case reports, however, of the medicine not working at all in some people,” said Dr. Leslie Hendeles, a UF professor of pharmacy practice and a clinical pharmacist in the College of Medicine’s pediatric pulmonary division. “When such patients have been given

albuterol with BAC, their asthma attacks have just gotten worse.”

The U.S. market for asthma medications is huge and growing as the number of people with the lung disease continues to climb. An estimated 17 million people have asthma, according to the American Lung Association.

Originally, pharmaceutical companies added BAC to albuterol to battle bacterial growth in containers that held many doses of the drug and therefore would be opened repeatedly, exposing the medicine to contamination. But the amount of BAC in those containers was low, limiting their potential for causing airway constriction, Asmus said.

When some single-dose containers were introduced later, they contained the same amount of BAC as the multidose bottle — thereby exposing patients to 300 micrograms of BAC per dose rather than 50, Asmus said.

Hendeles said the U.S. Food and Drug Administration has not shown interest in asking or requiring companies to remove BAC from their products. “It has not been easy to get attention to this issue because it can be difficult to determine whether patients in the midst of an asthma attack are failing to respond to treatment because their asthma is so severe or because the treatment itself is compromised by the presence of BAC,” Hendeles said.

Now on the market are some single-dose formulations for the nebulizer that do not contain BAC. The antibacterial is not needed because the albuterol solution is prepared in accordance with sterile filling procedures, Asmus said. One of these products is manufactured by California-based Dey L.P., which supported the UF study with grant funds. Hendeles serves on the company’s pharmacy advisory board.

Asmus said he was not surprised by their findings and pointed out the round of experiments actually had been designed to test another preservative, edetate disodium or EDTA. The pharmaceutical company Dey uses that preservative to prevent discoloration of one of its albuterol products.

All of the research participants took part in the three arms of the study, in which they were exposed on different days to BAC, EDTA or a saline solution that served as a placebo. The participants experienced little if any declines in breathing capacity following EDTA. Two participants reacted to the placebo, with one experiencing a 23 percent decline after a single dose and the second experiencing a 22 percent drop after the fourth dose.

The UF researchers are seeking to spread the word to physicians, nurses, pharmacists and parents about the possibility that BAC can limit the effectiveness of albuterol or even worsen an attack. If BAC is present in a medicine, manufacturers must list it on the label but do not have to indicate the amount.

“We tell the parents of young patients that BAC is found only in nebulized albuterol products that come in a screw-cap container,” Hendeles said. “So if you receive the medicine in a bottle with a lid that breaks off, you’re fine.”