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Asthma & COPD: Pharmacology

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Asthma & COPD: Pharmacology

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Asthma & COPD Treatments

Overview:

Asthma and COPD are obstructive respiratory diseases characterized by airflow obstruction, chronic inflammation, and airway remodeling.

Asthma is defined as intermittent, reversible obstruction and hyper-reactivity with excessive mucus production in the bronchi.

COPD is chronic, progressive, irreversible obstruction; COPD is an umbrella term that includes chronic bronchitis, small airway disease, and emphysema.

Some patients have asthma-COPD overlap syndrome, which involves the airway hyper-reactivity associated with asthma plus elements of COPD.

The shared treatment goals for patients with asthma and/or COPD:

  • We want to open their airways and reduce air trapping, which will relieve dyspnea, and,
  • Reduce airway remodeling and prevent exacerbations.

Treatment of asthma and COPD comprises long-term control and quick-relief medications, and addressing environmental triggers.

Key Terms

Let's begin with some key terms that are used to describe types of treatments and treatment approaches; we focus on asthma in our examples.

Maintenance treatments are used daily, regardless of symptom status, to prevent exacerbations.

Controller treatments are used to both control symptoms and reduce future risk.

Reliever treatments are inhalers used as-needed for quick relief of symptoms; note that they may also be used prior to exercise to prevent exercise-induced bronchoconstriction.

  • This group includes as-needed inhaled corticosteroid-formoterol combinations and short-acting beta-agonists (SABA).

Anti-inflammatory relievers (AIR) are a specific type of reliever treatments that combine a low-dose inhaled corticosteroid (ICS) with a rapid-acting bronchodilator.

  • Examples include budesonide-formoterol, beclometasone-formoterol, and ICS-salbutamol combinations.
  • AIR can also be used prior to exercise and allergen exposure to prevent symptoms and promote bronchodilation.

Maintenance-and-reliever therapy (MART) is an asthma treatment regimen in which the same ICS-formoterol medication is used for both maintenance and symptom relief (at different doses).

  • The ICS is usually budesonide or beclometasone (also spelled beclomethasone).
  • Be aware that this treatment regimen is sometimes called Single-Inhaler Maintenance and Reliever Therapy (SMART).
  • Studies are ongoing as to whether the MART regimen is similarly effective in COPD patients.

Key Drugs & Mechanisms

Bronchodilators

Facilitate bronchial tree opening and improve air flow.

Short- and long-acting beta agonists increase cAMP, which induces bronchodilation.

  • Examples of short-acting beta-agonists (SABA) include albuterol and metaproterenol.
  • Examples of long-acting beta-agonists (LABA) include salmeterol and formoterol. As we'll see, long-acting doesn't necessarily mean slow-acting; for example, formoterol is beneficial in asthma reliever treatments because of its rapid onset of action within 2-3 minutes.

Be aware that beta agonist bronchodilators may cause adverse effects associated with sympathetic activation (tremors, irregular heartbeat).

Muscarinic antagonists promote bronchodilation by blocking acetylcholine binding at M3 receptors; this inhibits bronchoconstriction and reduces mucus secretion.

  • Muscarinic antagonists come in short- and long-acting forms; tiotropium is a long-acting muscarinic antagonist (LAMA) that is used to treat COPD and asthma.
  • Muscarinic antagonists are associated with dry mouth, dizziness, gastrointestinal problems, and cough.

Methylxanthines inhibit phosphodiesterase-4 and block adenosine receptors to induce smooth muscle relaxation.

  • Theophylline can be used to treat asthma; it is not a first-line therapy because the high dosages required to effectively open the airways produce systemic side effects, including seizures.
  • Roflumilast improves exercise tolerance in COPD patients.

Anti-inflammatory drugs

  • Inflammation is a key part of the pathology of asthma and COPD, and promotes infiltration of various immune cells, remodeling, and constriction of the airways.

Inhaled and oral corticosteroids downregulate inflammatory genes to reduce the infiltration of pro-inflammatory mediators and cells.

  • Inhaled corticosteroids are first-line treatment for asthma patients.
  • Oral corticosteroids are associated with systemic toxicity, including increased risk of infection, hypertension, osteoporosis, and ocular disorders. Thus, they are reserved for severe exacerbations and/or patients who are unresponsive to other therapies.

Biological therapies are useful to treat specific types of asthma.
Review asthma phenotypes

  • IgE binding to mast cells triggers release of allergic mediators. Thus, anti-IgE antibodies, such as omalizumab, can be used to reduce exacerbations in severe allergic asthma. They bind free IgE and prevent its binding to mast cell receptors.
  • Interleukin 5 activates eosinophils and promotes airway inflammation. Thus, anti-Interleukin-5 receptor blockers and antagonists, such as mepolizumab, reslizumab, and benralizumab, are used as add-on therapies in severe eosinophilic asthma.

-Anti-leukotrienes can be used to prevent aspirin- and exercise-induced bronchoconstriction; examples include zileuton and montelukast. Leukotrienes are pro-inflammatory mediators that are produced from arachidonic acid.

  • Cromolyn reduces mast cell release of inflammatory mediators; though it may be helpful to prevent asthma exacerbations in some patients, it is generally less effective than inhaled corticosteroids.

Step-wise approach in Asthma Treatment

This approach matches asthma medications with severity; asthma should be monitored over time to determine if treatment needs to be stepped up or down.

We show the step-wise preferred controller and reliever treatment approach for patients 12 and older as recommended by GINA 2023.

The inhaled corticosteroid used in this step-wise approach is budesonide or beclometasone, depending on patient age and other factors.

Reliever: In all 5 steps, as-needed low-dose ICS-formoterol is recommended as a reliver. As mentioned earlier, formoterol is a long-acting beta agonist (LABA) with a rapid onset of action.

Note that ICS-formoterol, an anti-inflammatory reliever, replaces a short-acting beta agonist as the traditional reliever; the rationale for this change is based on substantial evidence that long-term use of short-acting beta agonists can increase asthma severity.

Steps 1 & 2: as-needed-only ICS-formoterol is sufficient. We emphasize that this is an AIR-only approach (anti-inflammatory as reliever).

Steps 3-5 use a MART regimen:
Step 3 comprises a low dose daily maintenance ICS-formoterol.
Step 4 comprises medium dose daily maintenance ICS-formoterol.
Step 5 comprises an add-on long-acting muscarinic antagonist (LAMA) and referral for assessment of asthma phenotype. Patient may need high-dose maintenance ICS-formoterol with targeted biological treatments (anti-IgE, anti-IL5/5R, etc.).

References

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