Pulmonary corticosteroids and mast cell inhibitors

Definitions & Key takeaways

Pulmonary corticosteroids and mast cell inhibitors are medications used to treat certain lung disorders. Corticosteroids are a class of drugs that reduce inflammation and swelling in the lungs, making it easier to breathe. They are often used to treat conditions such as asthma, chronic obstructive pulmonary disease (COPD), and certain types of lung infections. Mast cell inhibitors, also known as mast cell stabilizers, are a class of drugs that prevent the release of inflammatory mediators from mast cells in the lungs. They are often used to prevent symptoms of asthma and allergic rhinitis. They are less potent than corticosteroids but are generally well-tolerated with fewer side effects.

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Introduction0:00–1:01

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.
But, most of the times, narrowing of the airways actually occurs as a result of inflammation and excessive release of various inflammatory chemical mediators like leukotrienes and prostaglandins.
So, to effectively manage the disease, it’s important to give medications that will control the inflammation. 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 muscle 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.

Pathophysiology1:01–3:11

Allergens from environmental triggers, like air pollutants or cigarette smoke, are picked up by dendritic cells which, present them to a type 2 helper 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 that attract other immune cells to the area.
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 receptor in the smooth muscles and mucus gland 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.
Now, we have 3 ways to control the inflammation in asthma. We can decrease the synthesis of the inflammatory mediators, inhibit their release, or prevent mast cell activation.

Mechanism of Action3:11–4:28

The most common way to stop the synthesis of prostaglandin and leukotriene is through the use of corticosteroids. These medications are synthetic versions of glucocorticoid, or cortisol, which is the stress hormone produced in the adrenal cortex.
When these medications reach immune cells, they can pass through the cell membrane because they are steroids, which means they are lipophilic.
Once inside, they inhibit the synthesis of all inflammatory cytokines. In mast cells, they increase the production of annexin-1 proteins that inhibit the enzyme phospholipase A2.
This stops the conversion of membrane phospholipid into arachidonic acid and decreases the synthesis of leukotrienes and prostaglandins.
Corticosteroids also downregulate the enzyme cyclooxygenase-2, which reduces the production of prostaglandins. Finally, they also inhibit the proliferation of Th2 cells, which reduces the production of IL-4 and IL-5, further reducing the activity of mast cells and eosinophils.
This way, corticosteroids effectively inhibit the inflammatory process at multiple stages. Depending on the route of administration, corticosteroid therapy for asthma can be divided into two broad categories; inhaled therapy and systemic therapy.

Corticosteroid therapy4:28–6:27

Inhaled therapy uses nebulized corticosteroids, which means it’s an aerosolized mist. It’s the first line therapy for chronic asthma because its actions localized in the lungs, so there’s fewer systemic side-effects.
Inhaled corticosteroids are often used alongside a bronchodilator like leukotriene receptor antagonist or a beta-2 agonist to control the disease more effectively.
Fluticasone, budesonide, beclomethasone, dexamethasone and mometasone are some of the commonly used inhaled glucocorticoids.
Among them, dexamethasone and fluticasone are the longer acting and more potent medications. Systemic corticosteroid therapy is usually given when bronchodilator therapy and inhaled corticosteroid therapy fails to control the symptoms.
In general, prednisolone is the medication of choice. Oral prednisolone is used to treat the symptoms of severe chronic asthma, while intravenous prednisolone is used in acute asthma attacks.
Systemic side-effects of corticosteroids include susceptibility to infections, growth retardation in children, easy bruising, hyperglycemia, or high blood sugar, and weight gain.
These side effects are less common with inhaled corticosteroids unless they’re used at high doses. However, inhaled corticosteroids weaken the immune response in the mouth and throat, which makes oropharyngeal candida infections more common.
Mouth rinsing after using the medication or using a spacer, a device that allows the medication to enter the back of the throat slowly, so most of goes to the lungs, can be used to prevent this complication.
Systemic therapy could cause pituitary-adrenal suppression, where less cortisol is produced. So when it’s time to stop treatment, it’s important to reduce the dose gradually to give the adrenal gland time to ramp up cortisol production.

Mast cell stabilizers6:27–7:14

Moving on! The next group is the mast cell stabilizers, like cromolyn and nedocromil.
These medications inhibit the release of prostaglandins and leukotrienes from mast cells. They’re usually administered as an aerosol through an inhaler since they are not well absorbed in the GI tract.
Once inhaled, they act locally and stabilize the mast cell membrane, which prevents the release of inflammatory mediators.
This way they produce a mild anti-inflammatory effect at the site of inflammation. Mast cell stabilizers are usually very safe and well-tolerated, that’s why, cromolyn was used as a long time prophylactic medication for mild to moderate asthma.
But, compared to the inhaled steroids, mast cell stabilizers have a very short duration of action, which is why they are rarely used now-a-days.
Finally, the last medication is the anti-IgE antibody, omalizumab. It’s a modified monoclonal antibody that is administered by the subcutaneous route.

Omalizumab7:14–8:06

Omalizumab binds to the IgE antibodies in the bloodstream so they can’t stimulate the FcεR1 receptors on mast cells. This decreases the activation of mast cells, which in turn reduces the synthesis and release of various inflammatory mediators like leukotrienes and prostaglandins.
Omalizumab’s main drawback is that it’s a very expensive medication, so it's typically used if the person does not respond to other medications.
It’s particularly effective in treating allergic asthma which often present with very high levels of IgE antibody. Side effects are usually mild and include susceptibility to infections, and pain, redness, and swelling at the site of injection.

Memory Palace8:06–10:15

We want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharmacology facts!
Let’s start with a sailboat with a large mast for mast cells. On the bow of the ship is our corticosteroids.
Since they all have “son” in their name, let’s use a group of boys to represent them. First, let’s have 2 of the boys doing math problems on a whiteboard for dexamethasone and beclomethasone.
The mother is there playing the flute for her sons which represent mometasone and fluticasone. Lastly, there is a pair of conjoined twins who are best buds, for budesonide.
They are surrounded by a misty fog to help you remember they are the inhaled corticosteroids. Next is a boy dressed as a shark, the most fearsome predator of the sea, for prednisolone.
In the shark costumes mouth is an IV bag to help you remember it’s a peroral or intravenous medication used for systemic treatment.
For side effects, let’s have a candy mushroom by the inhaled corticosteroids since they cause oropharyngeal candidiasis, which is a fungal infection.
For systemic side effects, we have a tiny elf for growth retardation, and he’s eating handfuls of sugar for hyperglycemia.
This makes him kind of fat, representing weight gain, and he bumps into things a lot, so he’s got a black eye to represent easy bruising.
For the next group of drugs, let’s look at the middle of the, boat which is full of holes. These holes allow inflammatory mediators to be released from the mast cell, so let’s put 2 chrome plating over these to represent cromolyn and nedocromil, the 2 drugs that block mediator release.
However they’re nailed on rather poorly, and it looks like they’re about to fall off, so remember! They are very short acting and are rarely used.
Finally, at the prow is the engine that starts, or activates, our mast cell boat. But resting on top of it, is a lizard with an omega sign on its back for omalizumab.
This lazy lizard is preventing mast cell activation and It’s sneezing uncontrollably to help you remember it’s very effectiveness in allergic asthma.
He’s resting on top of a pile of cash because this drug can be very expensive. On his rump, there’s a big red bump with a bandaid on it to help you remember there can be painful swelling at the injection site.

Review10:15–10:46

All right, as a quick recap, treatment of asthma involves stopping the underlying inflammatory process by reducing the release of inflammatory mediators like leukotrienes and prostaglandins.
This is done by using corticosteroids, which stops the synthesis of these mediators, mast cell stabilizers, which inhibit mediator release, or anti-IgE antibody that inhibits mast cell activation.
These medications are used typically used alongside bronchodilators for asthma prophylaxis. But wait, there’s more: Here’s a mind map with all of the mnemonics.

Mind Map10:46–10:58

Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers after the credits.