Antibacterial Agent in Some Asthma Medications Linked to Airway Constriction

January 2001

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.