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Bronchodilators: Beta 2-agonists and muscarinic antagonists

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Bronchodilators: Beta 2-agonists and muscarinic antagonists

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Bronchodilators: Beta 2-agonists and muscarinic antagonists

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A 46-year old man presented to his physician with an increasing cough productive of a yellowish sputum. In addition, he reports moderate shortness of breath on exertion. The man has a clinical history significant for substantial smoking in addition to an instance of sustained V-tach a year previous. Physical exam: patient with very shallow breathing and a barrel-shaped chest. Wheezing and distant heart sounds heard on auscultation. What is the mechanism of action of the drug most likely ordered for inhalational therapy for this man?

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Content Reviewers:

Yifan Xiao, MD

In obstructive lung diseases like asthma, where individuals suffer from reversible narrowing of the airways, medications like bronchodilators are helpful in keeping the airways open.

Now, based on their mechanism of action, bronchodilators can be broadly divided into four main groups; β2-agonists, muscarinic antagonists, leukotrienes antagonist and methylxanthines.

In this video, we will focus on the bronchodilators like β2-agonist and muscarinic antagonist which mimics or inhibits the regulatory effects of the autonomic nervous system on bronchial smooth muscle.

So, if we take a look at the lungs, you’ve got the trachea, which branches off into right and left bronchi, and then continues to branch into thousands of bronchioles.

In the bronchioles you’ve got the lumen, the mucosa, which includes the inner lining of epithelial cells, as well as the lamina propria which contains many cells like the type 2 helper cells, B cells, and mast cells.

Surrounding the lamina propria, there is a layer of smooth muscles and submucosa. These muscles are innervated by the nerves of the autonomic nervous system, which means they can’t be controlled consciously.

The autonomic nervous system is made up the sympathetic system which is involved in the “fight or flight” response, like running from angry raccoons, and parasympathetic system which is involved in the “rest and digest” response, like taking a nap after a big dinner.

So let’s say that racoons are chasing you, the sympathetic nerves activates and release norepinephrine which bind to β2 adrenergic receptors on the smooth muscles in the respiratory tract, causing them to relax. The diameter of the airways increase and more oxygen gets to the lungs.

When you’re resting, there’s less need for the extra oxygen, so the parasympathetic nerves release acetylcholine, which bind to muscarinic M3 receptors in the respiratory tract, causing smooth muscle contraction and narrowing the airways.

Now, in conditions like asthma and chronic obstructive lung disease such as emphysema and chronic bronchitis, the respiratory airways becomes narrower which obstructs airflow, leading to wheezing, shortness of breath, and chest tightness.

Now, the main difference between asthma and chronic obstructive pulmonary diseases, or COPD, is that in asthma, the airway narrowing is due to muscle spasms, which is reversible, while in COPD it’s due to chronic inflammatory damage to the airways, which is irreversible.

Now, for asthma, we can use β2-agonists to relax the smooth muscles, or muscarinic antagonists to prevent muscle contraction.

Now, although the airway obstruction in COPD is irreversible, bronchodilators can often prevent the complete closure of the airway during expiration which provides mild symptomatic relief.

Let’s start with the β2-agonists first, which are also known as β2 receptor agonists. These medications come in an aerosolized form and are taken via inhalers.

Once in the lungs, they bind to the β2 adrenergic receptors on bronchial smooth muscle cells. This activates the enzyme adenylyl cyclase which leads to increased cAMP production that ultimately cause relaxation of the smooth muscle.

The effect is both fast, and localized within the lungs, which makes these medications the treatment of choice for quick symptom relief with minimal side effects.

β2-agonists also stimulate the β2 receptors on immune cells like mast cells and decrease the release of inflammatory mediators like leukotrienes and prostaglandins. This, in turn, decreases the inflammation, swelling, and irritation in the respiratory tract.

Ultimately, all these events help dilate the narrowed airways and improve air flow.

Now, based on the duration of action, inhaled β2-agonists can be divided into two broad groups; short acting β2-agonists, or SABA, and long acting β2-agonists, or LABA.

SABAs include medication like albuterol, metaproterenol, and terbutaline.

Inhaled albuterol taken from a pressurized metered dose inhaler, or pMDI, produces bronchodilation within 5 minutes, and lasts for a period of 2 to 4 hours. It’s best used to terminate acute asthma attacks, but less useful for prophylaxis. They are also the medication of choice for exercise induced bronchospasm, a condition where exercises can trigger asthma attacks.

Side effects of SABAs are caused by increased sympathetic stimulation, and include tachycardia, palpitation, muscle tremors, restlessness, and insomnia.

Long acting β2-agonists or LABAs include medications like salmeterol and formoterol.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Regulation of airway inflammation and remodeling by muscarinic receptors: Perspectives on anticholinergic therapy in asthma and COPD" Life Sciences (2012)
  5. "Comparative efficacy of fixed-dose combinations of long-acting muscarinic antagonists and long-acting β2-agonists: a systematic review and network meta-analysis" Therapeutic Advances in Respiratory Disease (2016)
  6. "The Role of Bronchodilators in Preventing Exacerbations of Chronic Obstructive Pulmonary Disease" Tuberculosis and Respiratory Diseases (2016)