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.
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.
Minutes after exposure to the allergen, phospholipase A2 gets activated inside the mast cells, which results in the synthesis and release of leukotrienes and the prostaglandins.
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. 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. 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.