Bad Medicine

Before leaving Beta receptors let's talk about another issue related to it. Asthma, is a common inflammatory long-standing disease of the lung airways. The reason behind why asthma is common now can be the topic of the next article inshallah. What I want to talk about today is asthma treatment, particularly, Beta agonists.. may we presribe them to treat asthma exacerbations?

Pathophysiology

The pathophysiology of asthma can be devided into the following steps :

• After exposure to an allergy-inducing antigen called Allergin, the patient's cells produce IgE antibodies specific to that antigen.
• This happens due to overexpression of Th2 cells, compared with Th1.
• Th2 Cells produces cytokines like IL-4, IL-5 and IL-13, which stimulates production of IgE antibodies.
• After production of the antibodies, they bind to receptors on mast cells, preparing to getting exposed again to the antigen.
• After second exposure to the antigen, allergen-specific IgE antibodies on the mast cell surface undergo cross-linking, leading to rapid release of histamin and other compounds like prostaglandin D2.
• Histamine and prostaglanding release leads to bronchoconstriction, and increased thickness of airway wall due to edema.
• Later, influx of inflammatory cells like basophils and neutrophils can lead to delayed bronchoconstriction.

Now, after we have quickly reviewed asthma, let's discuss its treatment options.

Beta agonists

From what we have reviewed in the previous article, we know that beta receptors activation cause bronchodilation, and widening of the airway. Thus, it's logical to prescribe long-acting beta agonists to control asthma exacerbations, right?

Unfortunately, medicine is always unexpected! All cells in our body has some kind of regulation to the concentration of receptors to any biological compound.

Picture this: You're at home, with the ability to control a satellite dish on your roof, adjusting its radius. You're watching TV and notice the signal is a little weak. What do you do? Most likely, you'd increase the dish's radius to capture more signals and boost the reception.

Later, the signal becomes excessively strong, stronger than it needs to be. What then? You'd reduce the dish's radius to receive fewer signals, bringing the reception back to a normal level.

Our body's cells regulate the number of receptors on their surfaces in a similar fashion. Cells require a sort of brakes to tell them when to halt production of a particular receptor, or when to ramp up production of another. Consider the beta receptor as an example: the cell produces these receptors and presents them on its surface. Once presented, the receptors bind to catecholamines in the bloodstream. When a sufficient number of catecholamines have bound, the cell recognizes that it has produced enough beta receptors and gradually slows down production.

Conversely, if the cell hasn't encountered catecholamines for an extended period, it concludes a decrease in beta receptors on its surface and initiates the production of more, ensuring the receptor count is restored to the appropriate level.

Tolerance

Now.. What happens when we prescribe a long acting beta agonist like salmetrol? On short term, we will activate beta receptors, dilating the smooth muslces lining the airway, and decreasing the mucous secretion, which will lead to the desired result, which is eliminating the episode and releiving the symptoms of the exacerbation.

But on long term, beta receptors will be activated continuously, more than usual, a lot more! Thus: cells will guess that it over-produced beta receptors, and that it must cut down the production of beta receptors gradually. After long period of taking salmetrol, concentration of beta receptors become very low, which puts the patient in risk of serious, life-threatening exacerbations!

This study is the focus of today's article. The study compared the number and severity of life-threatening asthma exacerbations in patients taking a placebo with those taking long-acting beta agonists.

The study is a meta-analysis, that analyzed the results of 19 clinical trials, each of them is 3 months at least. Number of participants were 33,826.

The study found that long-acting beta-agonists increased exacerbations requiring hospitalization (OR, 2.6 [95% CI, 1.6 to 4.3]) and life-threatening exacerbations (OR, 1.8 [CI, 1.1 to 2.9]) compared with placebo. Hospitalizations were statistically significantly increased with salmeterol and formoterol.

The study concluded that long-acting beta-agonists increase severe and life-threatening asthma exacerbations, as well as asthma-related deaths.

The effect of tolerance cannot be underestimated! If there are no beta receptors in a patient's cells, the medication will not work, no matter how much you increase the dose. This has led the FDA to warn against the use of beta agonists in asthma treatment, limiting their use to a second line treatment if low to moderate doses of corticosteroids are insufficient to control the disease. Beta agonists are strictly prohibited for use as inhaled medications to control acute asthma exacerbations, as this has led to a number deaths.

References

1. Hashmi MF, Cataletto ME. Asthma. [Updated 2024 May 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430901/
2. Principles of Pharmacology – Study Guide, 16. Receptor Regulation, Available from https://open.lib.umn.edu/pharmacology/chapter/receptor-regulation/
3. Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med. 2006 Jun 20;144(12):904-12. doi: 10.7326/0003-4819-144-12-200606200-00126. Epub 2006 Jun 5. PMID: 16754916.
4. Swanson's Family Medicine Review, 6th edition, Page 147