Bronchial asthma is characterized by periodic, recurrent, reversible airway obstruction. These episodes occur due to bronchospasm, swelling of the bronchial mucosa and formation of mucus plugs.
It’s an inflammatory disease where there is a non-specific bronchial hyperreactivity, meaning that the bronchial smooth muscle is very sensitive to various stimuli. This hyperreactivity occurs due to chronic airway inflammation.
Two types of asthma exist: extrinsic (allergic) asthma, where there is a type I hypersensitivity reaction, and intrinsic (non-allergic), where there is no hypersensitivity. Asthmatic attack in people with extrinsic asthma occurs when they inhale whatever they’re allergic to, like dust or pollen. Asthmatic attack in people with intrinsic asthma can be provoked due to cold air, viruses, stress and other factors.
In extrinsic asthma do two things occur when the mast cells bind the antigen: in the immediate phase does bronchospasm occur, which causes the characteristic asthmatic attack. In the late phase will there be airway inflammation, together with lesser bronchospasm.
Pharmacokinetics of bronchial pharmacology
It’s preferable to administer anti-asthmatic medication by inhalation, because the drug directly reaches the site where it is needed -> onset is quicker and fewer systemic side effects. A particle size around 1 µm is preferred.
Bronchodilators don’t fix the underlying problem that is airway inflammation, however they do treat the symptoms.
β2 agonists are the most efficacious bronchorelaxants. They provide relief of bronchospasm within 3 minutes of inhalation. They should only be used during attacks and not regularly, as both tachyphylaxis and tolerance may develop. We have short-acting, long-acting and very long-acting types.
|Short-acting β2 agonists
|Long-acting β2 agonists
|Very long-acting β2 agonists
(up to 24 hours)
|Terbutaline||Salmeterol (onset: 30 min)||Vilanterol|
Indacaterol and olodaterol are mainly used in COPD and not in asthma. Salmeterol needs 30 minutes to kick in and therefore shouldn’t be used for acute attacks.
Theophylline is both an adenosine receptor antagonist and a non-selective phosphodiesterase inhibitor. The latter means that it causes cAMP and cGMP levels to increase intracellularly. It causes bronchorelaxation. Its clinical use is declining because:
- It has a narrow margin of safety
- Clearance differs considerably between persons
- It has multiple drug interactions
- It causes symptoms like convulsions, arrhythmia and hypotension
Muscarinic receptor antagonists decrease the acetylcholine-mediated component of bronchospasm. Their efficacy depends on the actual vagal tone. If there is no vagal tone is there no acetylcholine to block. Ipratropium, oxitropium and triotropium are often used. They may be used together with β2 agonists.
These drugs actually treat the underlying problem of airway inflammation. They decrease the bronchial hyperreactivity, which reduces the frequency and intensity of bronchospasms, but they can’t stop the spasms if they occur. They are the prophylactic component of asthma treatment, while the bronchodilators are the acute component.
Corticosteroids and glucocorticoid receptor agonists are often used. They alter gene expression, which decreases the formation of cytokines, prostaglandins and mast cells. They have a slow onset of action.
These steroids are also inhaled. They have significant first pass metabolism, which limits the systemic effects. They have few side-effects.
Frequently used inhaled steroids are:
- Beclomethasone dipropionate
- Fluticasone propionate
- Mometasone furoate
In more severe cases can systemic corticosteroids be used as well, like hydrocortisone, prednisolone and methylprednisolone, but they have serious side-effects.
Another type of anti-inflammatory drug used is auto-leukotriene drugs. Recall from topic 23 that leukotrienes cause bronchoconstriction, bronchial swelling and increased mucus secretion, so inhibiting their action will obviously have a beneficial effect on asthma. Leukotrienes also attract neutrophils, so inhibiting them will reduce inflammation as well.
A lipoxygenase inhibitor called zileuton was previously used, but it turned out it was toxic for the liver so it’s not used anymore.
Nowadays we use leukotriene antagonists like zafirlukast, montelukast and pranlukast. They’re competitive antagonists for the CysLT1 receptor.
The third group of anti-inflammatory drugs are the cromone compounds sodium cromoglycate and nedocromil sodium. They stabilize mast cells so that they’re less likely to degranulate, and inhibit chemotaxis. They’re also given by inhalation, but they’re much less effective than glucocorticoids.
The last group of anti-inflammatory drugs are the biological therapies – the antibodies. Omalizumab binds to the Fc part of IgE molecules, so that they can’t bind to and sensitize mast cells. Mepolizumab binds to and inactivates IL-5, which is essential for activating eosinophils. Benralizumab binds to and inactivates the IL-5 receptor on eosinophils so that the eosinophils can’t be activated by IL-5. Dupilumab binds to the receptor for IL-4 and IL-13.
These biological therapies are very effective and safe, but they’re very expensive and therefore only used in severe cases.
This is a normal treatment plan for asthma. Here you can see which treatments should be used for the different severities of asthma. RABA = rapid acting β2-agonist, LABA = long-acting β2-agonist
Treatment of COPD
The symptoms of COPD are, by definition, not very reversible by bronchodilators. We use them anyway. Here’s what can be done:
- Very long acting β2-agonists + long-acting muscarinic receptor antagonists
- Inhaled steroids have little effect
- In acute exacerbations are systemic steroids used
- Antibacterial therapy is necessary
23. Pharmacology of eicosanoids. Drugs acting on smooth muscle
25. Drug treatment of allergic rhinitis. Antitussives, expectorants and mucolytics