Bronchodilators: Leukotriene antagonists and methylxanthines

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Introduction0:00–0:38

In obstructive lung diseases like asthma, 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’ll focus on the leukotriene modifying agents and methylxanthines. 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.

Pathophysiology0:38–3:48

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 T cells, B cells, and mast cells.
Surrounding the lamina propria, there is a layer of smooth muscles and submucosa. The submucosal layer contains mucus-secreting glands and blood vessels.
Now, the molecular pathway that leads to asthma is actually pretty complex but it is often initiated by an environmental trigger.
Allergens from environmental triggers, like air pollutants or cigarette smoke, are picked up by dendritic cells which present them to a type 2 helper T cell or Th2 cell in the lamina propria.
These cells then produce cytokines like IL-4 and IL-5 which causes the inflammatory response. IL-4 is especially important because it leads to the production of IgE antibodies by B cells, and these antibodies bind to FcεR1 receptors on mast cells to activate them.
These mast cells use an enzyme called phospholipase A2 to take membrane phospholipids and make a 20 carbon polyunsaturated fatty acid called arachidonic acid.
Arachidonic acid is then metabolized by two important enzymes: one is cyclooxygenase-2 or COX-2, which makes prostaglandins, another one is 5-lipoxygenase or 5-LOX, which makes leukotrienes.
Now, IL-5 on the other hand, activates eosinophils, which promote an immune response by releasing more cytokines and leukotrienes.
Leukotrienes bind with the leukotriene receptors on the bronchial smooth muscles and cause them to contract. They also bind to receptors on the mucous glands to increase mucus secretion.
Similarly, prostaglandins also bind to their receptors in smooth muscles and mucus glands to cause a similar effect. These mediators also increase the vascular permeability in the airways and attract more immune cells to the area.
The combination of inflammation and bronchospasm cause obstruction of the airway which leads to symptoms like coughing, chest tightness, dyspnea, or difficulty breathing, and wheezing, which is a high-pitched whistling sound during exhalation.
Chronic inflammation also makes the respiratory tract more sensitive to allergens, so these symptoms become easier to trigger.
In this video, we’ll focus on the management of smooth muscle spasms, as relieving the spasms will help in opening up the narrowed airways.
Now, to do that, the role of bronchodilators like leukotriene modifying agents and methylxanthines is very important. Let’s start with the leukotriene modifying agents.

Leukotriene modifying agents3:48–4:11

These medications can be divided into two broad groups. One is leukotriene receptor antagonists, also known as “cysteinyl leukotriene receptor antagonists”.
The other group is leukotriene synthesis inhibitors, which are also known as 5-lipoxygenase inhibitor. Leukotriene receptor antagonists like montelukast and zafirlukast are peroral medications that bind to the leukotriene receptors in the smooth muscles of the respiratory airways and prevent leukotriene from binding.

Leukotriene receptor antagonists4:11–5:18

This weakens smooth muscle contraction in the respiratory tract, decreases mucus secretion, and reduces inflammation. Since they are taken peroral, they have a slower onset of action compared to inhaled bronchodilators like albuterol, which is why they are used for asthma prophylaxis and not during an acute asthma attack.
They are especially effective in preventing exercise or aspirin induced asthma. Since leukotriene receptor antagonists have mild, nonspecific side effects like headache and rash, they are given in combination with other asthma medications like corticosteroids, which can cause immunosuppression, and long acting beta agonists, which can cause arrhythmias.
This will lower the necessary dose of these more dangerous medications, which makes montelukast and zafirlukast great supportive medications.
Next, let’s move on to the leukotriene synthesis inhibitors like zileuton, which is also peroral. After absorption, it enters immune cells like mast cells and inhibits the enzyme 5-lipoxygenase, which stops the synthesis of leukotriene from arachidonic acid.

Leukotriene synthesis inhibitors5:18–5:51

Just like leukotriene receptor antagonists, they are used for asthma prophylaxis and are effective in preventing exercise or aspirin induced asthma.
However, it’s hepatotoxic and is used less frequently. Moving on!

Methylxanthines5:51–7:39

The next group of bronchodilators are the methylxanthines. Caffeine belongs to this family of compounds.
For asthma treatment, the most common medication is theophylline, also known as 1,3-dimethylxanthine. This medication is taken peroral and can enter the smooth muscles in the respiratory tract.
Once there, theophylline inhibits the enzyme phosphodiesterase or PDE, which converts cAMP into an inactive form called 5-AMP.
This increases the level of cAMP within the cell, and triggers smooth muscle relaxation. Besides its use in asthma, theophylline is also used as a bronchodilator in COPD.
Just like coffee, theophylline also blocks adenosine receptors throughout the body. Adenosine is a mediator that causes vasodilation, decreased heart rate, and neurotransmitter release in the brain, but increased smooth muscle contraction in the respiratory tract.
This mechanism could also explain some of theophylline’s bronchodilating effect. However, theophylline has a very narrow therapeutic index of 5-15mcg/ml, so it’s very easy to overdose.
This could cause insomnia, nausea, and vomiting, but the most dangerous side effects include overstimulation of the central nervous system and cardiovascular system, leading to seizure and arrhythmia.
Since methylxanthines are metabolized by a class of liver enzymes called cytochrome p450, medications that inhibit these enzymes like fluoxetine or ciprofloxacin should be avoided.
Due to the dangerous side effects, theophylline is now rarely used. We want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharmacology facts!

Memory palace7:39–9:44

So for the leukotriene modifying agents, let’s use a white train. Now the train stop represents the target receptor, so we’ll put the leukotriene receptor antagonists here.
Since they have “lukast” in their name let’s put a four leaf clover here for montelukast and zafirlukast. Hopefully they’ll make our luck last!
Now the back of the train is still under construction so let’s use it to represent leukotriene synthesis inhibitors. This will be an army lieutenant named Zee, for zileuton, and he’s holding a big rotting liver to represent hepatotoxicity.
Let’s have a track and field athlete, which represents exercise induced asthma, trying to jump over the train with giant springs on his shoes, which represents aspirin induced asthma.
This will help you remember leukotriene modifying agents are effective against both. Now, methylxanthine will be represented by a big mug of coffee.
Bathing inside the coffee mug is the main drug of this group, theophylline, which is represented by Socrates, the father of western philosophy.
Since theophylline is effective in treating COPD, let’s put an angry police officer next to the mug who’s about to arrest him for public indecency.
There are measurement lines that max out at 15 on the side of the coffee mug to represent the low therapeutic window, but the mug is way over filled.
All this coffee is too much for Socrates to handle, so he’s vomiting into the cup. A human heart and brain is also floating inside to help you remember the cardio and neurotoxicity.
Finally, a chrome colored cell is climbing over the side of the mug, trying to get a sip of coffee because methylxanthines are metabolized by cytochrome p450.
All right, as a quick recap, treatment of obstructive lung diseases like asthma includes bronchodilators, which relax the smooth muscle in the respiratory tract and dilate the airway.

Review9:44–11:08

Leukotriene is an inflammatory mediator that causes smooth muscle contraction. So leukotriene modifying agents like zileuton, which decrease its synthesis, or montelukast and zafirlukast, which blocks its receptor are all effective prophylactic medications that result in smooth muscle relaxation.
Smooth muscle relaxation can be achieved in three ways: first is by inhibiting the leukotriene receptors present on smooth muscles; secondly by inhibiting the synthesis of leukotrienes; and lastly by increasing the cAMP level in smooth muscle cells, and by inhibiting the adenosine receptor on smooth muscles.
Leukotriene receptor antagonists like montelukast, zafirlukast inhibit the leukotriene receptors; zileuton inhibits the synthesis by inhibiting the 5-lipoxygenase enzyme; and methylxanthines like theophylline increase the cAMP level and inhibit the adenosine receptors.
Ultimately, all these actions lead to bronchodilation, which helps in dilating the airways in diseases like asthma. Theophylline is also used to treat COPD, but leukotriene antagonists are of no use in COPD.
But wait, there's more: Here's a mind map with all of the mnemonics from the video. Go ahead and pause the video so you can test yourself to see what you remember.

Mind map11:08–11:20

Stay tuned for the answers at the end.