In this entry, I would like to discuss the implications of some recently published basic science research on the function of beta agonists -- the most common class of quick-relief inhalers that includes albuterol. While the research was done with mice, it has implications on human asthma treatment, particularly in light of recent controversies of the risks of long acting beta agonists (LABAs) in asthma treatment.
How beta agonists work and what do mice have to do with this?
Beta agonists get their name from their mechanism of action -- the complete name is Beta adrenergic receptor agonists. Drugs have their effects on cells in two main ways: a) by getting into the cell through the cell wall and acting directly to change the machinery of the cell and b) by engaging a receptor on the cell surface - a sort of messenger on the surface of the cell that communicates the message to the inside of the cell.
Beta agonists work in the second way; they bind the beta adrenergic receptor on the cell surface, which leads to a message that is communicated to the inside of the cell to change cell function. Now a key point regards which cells have these receptors, as these are the cells that should be affected by beta agonists. While there are several cell types that have beta adrenergic receptors, an important cell in the lung is the airway smooth muscle cell.
Airway smooth muscle surrounds the large airways (breathing tubes) of the lung. In asthmatics, this smooth muscle is overgrown and overly responsive. When it is stimulated, it constricts, leading to asthma symptoms, most importantly wheeze and shortness of breath as air has a harder time getting in and out of narrowed breathing tubes. The response of beta adrenergic receptor binding by beta agonists is to relax the airway smooth muscle, which improves symptoms of wheeze as air can move more easily in and out of the lung.
While mice do not naturally get asthma like humans, they can be treated experimentally to be asthmatic. Researchers can also manipulate the way mice get asthma in ways that we can not in humans, so a lot of research to understand more about human asthma has been carried out in mice. Recent research in mice who are genetically deficient in (do not have) beta adrenergic receptors showed that these mice, paradoxically, did not develop asthma. In addition, normal asthmatic mice that were treated with a beta blocking drug (the opposite of a beta agonist drug) showed less asthma than those not treated. One would think that mice who either do not have beta adrenergic receptors or whose receptors are blocked would have worse asthma, as any stimulation of these receptors typically is thought to relax smooth muscle and improve asthma. This research, though performed in mice, challenges our thinking about the development of asthma as it shows that normal function of these receptors is necessary for asthma to develop. When one would think that getting rid of them would make asthma worse, it made it better.
Implications for asthma treatment
These findings inform the current controversy surrounding the suggested harmful effects of long-term use of long-acting beta agonists (LABAs, e.g. salmeterol, formoterol) in asthmatics. This is the paradox: LABAs improve asthma symptoms by opening up airways on the short term yet may put patients at risk of worse asthma down the road by making asthmatic airways more sensitive. Even more tantalizing from a scientific point of view is the possibility that blocking beta adrenergic receptors may be beneficial in humans as it seems to be in mice. This paradoxical approach applied to the same biochemical pathways has been used in the treatment of heart failure in humans.
For now, these findings are provocative but not ready for prime time in terms of changing asthma treatment. By no means am I recommending that my patients toss out medications that make them feel better based on this research. However, the findings shed light on a possible mechanism by which medications that are helpful in the short term could be harmful in the long term, especially if used injudiciously and without careful monitoring.
Published On: April 24, 2009