Bronchodilators: Beta 2-agonists and muscarinic antagonists

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Introduction0:00–0:42

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.

Physiology0:42–2:14

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.

Pathology2:14–3:14

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.

Beta2-agonists3:14–4:17

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.

Short acting Beta2-agonists4:17–5:15

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 Beta2-agonists5:15–6:21

Long acting β2-agonists or LABAs include medications like salmeterol and formoterol. Compared to the SABAs, these β2-agonists have a slow onset of action, which is why they’re not used for symptomatic relief during acute asthma attacks.
But because of their long duration of action, which lasts for over 12 hours, inhaled LABAs are used as a twice-a-day prophylactic or maintenance therapy for asthma and COPD.
Side effects of LABAs are similar to the side effects of SABAs, but sometimes they can get exaggerated because of their longer duration of action.
For example, LABAs can turn tachycardias into arrhythmias, which could result in heart failure and death. That’s why LABAs are rarely used as monotherapy.
Instead, in severe asthma, LABAs are added when the symptoms aren’t well controlled by inhaled corticosteroid alone. This combination reduces the dosage needed for both medications, and subsequently their systemic side-effects.

Muscarinic antagonists6:21–7:53

Alright, now let’s move on to the muscarinic antagonists, also known as muscarinic receptor antagonists. These medications are also given via inhalers where they enter the lungs and bind to M3 muscarinic receptors on the tracheal and bronchial smooth muscles.
This blocks acetylcholine from binding to the receptors, leading to less smooth muscle constriction. Now, ipratropium bromide and tiotropium bromide are the most commonly used muscarinic antagonist for asthma and COPD.
Ipratropium bromide is short acting, with a duration of 4-6 hours, while tiotropium bromide is long acting, with a duration of of 24 hours.
In comparison to the β2-agonists, these medications are less effective for asthma but more effective for COPD, where they are the bronchodilators of choice.
However, for severe asthma and COPD, muscarinic antagonists are often given with LABAs because this combination produces an additive effect, leading to stronger and longer lasting bronchodilation.
Side effects of muscarinic antagonists include, tachycardia, dry mouth, restlessness, pupil dilation, and they are contraindicated in individuals suffering from narrow angle glaucoma since they relax the ciliary muscles which worsens the obstruction of aqueous humor drainage.

Memory Palace7:53–9:56

We want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharmacology facts!
Let’s have a 2 headed bee for the β2-agonists, and a 3 armed musketeer carrying a shield in each arm to represent the muscarinic antagonists that block the M3 receptors.
The bee is relaxing with a tall friend and a short friend which represents LABAs and SABAs. His short friend is Albert Einstein which stands for albuterol.
His very self conscious about his height, so he’s wearing a turban on his head for terbutaline, and on top of that is a metal helmet for metaproterenol.
Next to him is a wheezing jogger to help you remember SABAs are used for symptomatic relief during acute asthma attacks and exercise induced asthma.
Next are the LABAs, and there’s a very long salmon for salmeterol, wearing formal wear for formoterol. For indications let’s have a cop for COPD and a no smoking sign for asthma prophylaxis, For side effects of β2-agonists, there’s the angry racoon to represent sympathetic response.
He’s sitting up in bed because he’s too angry to sleep, and his little heart is about to pop out of his chest. Next are the muscarinic antagonists, which will be represented by two tropical palm trees by the musketeer since they have “tropium” in their name.
The shorter tree has a rat in it for the shorter acting ipratropium while the longer tree has ties hanging off of it for the long acting tiotropium.
Since they are more effective for COPD and less effective for asthma, let’s have a very buff cop holding a tiny no smoking sign.
For side effects, let’s have a girl who’s in love with the musketeer. Her hearts beating faster, she’s got dry mouth, and her pupils are dilated.
In fact, her eyes are almost popping out of her head, which represents the contraindication for people with glaucoma! All right, as a quick recap, treatment of obstructive lung diseases like asthma or COPD includes bronchodilators that causes smooth muscles relaxation and dilation of the bronchi.

Review9:56–10:40

This can be done by stimulating the β2 receptors with β2-agonists, or it can be done by inhibiting the muscarinic M3 receptor with muscarinic antagonists.
Short acting β2-agonists like albuterol is useful in treating acute asthma attacks and exercise induced asthma, while long acting β2-agonists and muscarinic antagonists are effective in prophylactic therapy for severe asthma and COPD.

Mind Map10:40–10:56

But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.
Stay tuned for the answers after the credits.