Pharmacology of Airway Control

1. Introduction
2. Airway Physiology Recap
3. Bronchodilators
   • Short-Acting β₂ Agonists (SABAs)
   • Long-Acting β₂ Agonists (LABAs)
   • Short-Acting Muscarinic Antagonists (SAMAs)
   • Long-Acting Muscarinic Antagonists (LAMAs)
4. Anti-Inflammatory Drugs
   • Inhaled Corticosteroids (ICS)
   • Oral Corticosteroids
   • Leukotriene Receptor Antagonists
   • Methylxanthines
   • Biologic Therapies
5. Inhalers and Spacers
6. Stepwise Treatment of Asthma
7. Stepwise Treatment of COPD
8. Acute Severe Asthma Management
9. Summary
10. Drug Summary Table
11. Quiz

• Asthma is often driven by Th2 (T helper 2, a type of lymphocyte that drives allergic inflammation) pathways, with eosinophilic airway inflammation. This "type 2-high" asthma (the pattern of eosinophil-rich, allergic-type inflammation) responds to corticosteroids (steroid drugs), but "type 2-low" asthma (asthma without that pattern) responds poorly. COPD (chronic obstructive pulmonary disease) is largely a smoking-related neutrophilic and emphysematous airway disease with limited steroid response.
• The three main classes of inhaled drug are β₂ agonists (short-acting SABAs and long-acting LABAs), muscarinic antagonists (short-acting SAMAs and long-acting LAMAs) and inhaled corticosteroids (ICS). Muscarinic antagonists are drugs that block acetylcholine at muscarinic receptors. Biologic therapies (injected antibody drugs) are added for severe disease.
• The 2024 asthma guideline from NICE, the British Thoracic Society (BTS) and the Scottish Intercollegiate Guidelines Network (SIGN) builds treatment for people aged 12 and over around combination ICS-formoterol (an inhaled corticosteroid plus formoterol, a LABA that works quickly). It is usually started as needed for symptom relief ("AIR", anti-inflammatory reliever therapy). If asthma is not controlled, treatment moves to "MART" (maintenance and reliever therapy).
• In COPD, if a short-acting bronchodilator (a drug that widens the airways) is not enough, NICE uses LABA + LAMA when there are no asthmatic features. Asthmatic features are signs that the person will respond to steroids, such as a raised eosinophil count. When they are present, NICE uses LABA + ICS. Triple therapy (LABA + LAMA + ICS) follows only if symptoms or exacerbations (sudden worsenings) continue on dual therapy.

Introduction

Up to 5.4 million people in the UK are treated for asthma, and around 3 million have COPD (about 2 million of them undiagnosed). Their pharmacology shares many drug classes, but the relative emphasis differs considerably. This article focuses on those drug classes; the underlying respiratory physiology is covered in Respiratory System.

Airway Physiology Recap

Two opposing autonomic inputs control the calibre of bronchial smooth muscle:

• Parasympathetic (vagus) outflow: releases acetylcholine, which acts on M₃ muscarinic receptors (M₃ is one subtype of acetylcholine receptor) on bronchial smooth muscle to cause bronchoconstriction (narrowing of the airways) and mucus secretion. This is the dominant input, and it is active all the time ("tonic").
• Circulating adrenaline: acts on β₂-adrenergic receptors on bronchial smooth muscle to cause bronchodilation (widening of the airways). There is no direct sympathetic innervation (nerve supply) of bronchial smooth muscle in humans.

The main disease processes differ between the two conditions:

• Asthma: inflammation is often Th2-driven and eosinophilic. It causes swelling of the airway lining (mucosal oedema), plugs of mucus that block airways, smooth muscle that over-reacts to triggers (hyperreactivity), and bronchoconstriction that can be reversed. Inhaled corticosteroids are the cornerstone of treatment because they directly target the inflammation.
• COPD: smoking-related neutrophilic inflammation, emphysema and chronic bronchitis. The bronchoconstriction has a substantial parasympathetic component, which is one reason why muscarinic antagonists are central to COPD treatment. A Cochrane review found that tiotropium (a long-acting muscarinic antagonist) reduced exacerbations compared with a long-acting β₂ agonist. ICS have a smaller role. They are used for people with asthmatic features (such as a raised eosinophil count) and as part of triple therapy (see below).

Bronchodilators

Short-Acting β₂ Agonists (SABAs)

Salbutamol (Ventolin) and terbutaline are the standard SABAs. They activate β₂ receptors on airway smooth muscle. These are G_s-coupled receptors (linked to G_s, a signalling protein inside the cell), so activation raises cyclic AMP (cAMP, a messenger inside the cell) and produces bronchodilation. Onset within minutes, duration 4-6 hours.

Used for symptom relief (as a "reliever"). In asthma, a SABA is only prescribed alongside an ICS (see below). In COPD, a SABA or SAMA is the first treatment for breathlessness. SABAs are also used in acute exacerbations of asthma and COPD, typically by nebuliser (a device that turns a liquid drug into a mist to breathe in), and before exercise.

Side effects arise mainly from β₂ activation in non-airway tissues, with a smaller contribution from off-target β₁ stimulation at high doses:

• Tremor (shaking), from β₂ activation in skeletal muscle.
• Tachycardia and palpitations (a fast heart rate and awareness of the heartbeat). There are two causes. Vasodilation triggers a reflex rise in heart rate, and high doses also activate β₁ receptors in the heart.
• Hypokalaemia (low blood potassium): β₂ activation drives potassium into cells. This is why nebulised salbutamol is used to treat hyperkalaemia (high blood potassium).
• Hyperglycaemia (high blood glucose).
• Lactic acidosis (a build-up of lactic acid in the blood) at high doses.

A critical pre-clinical point: SABA overuse is a marker of poor asthma control and an independent risk factor for asthma deaths. NICE, BTS and SIGN now advise that a SABA should never be prescribed for asthma without an ICS. SABA monotherapy (a SABA used on its own) is no longer recommended.

Long-Acting β₂ Agonists (LABAs)

The LABAs include salmeterol, formoterol, indacaterol, vilanterol: duration 12-24 hours.

Two important properties:

• Formoterol has both a fast onset and a long duration, allowing it to be used as both a maintenance and a reliever (the basis of the MART regimen below). Salmeterol has a slower onset and is maintenance-only.
• LABAs must never be prescribed without a concurrent inhaled corticosteroid in asthma: LABA monotherapy was associated with increased asthma deaths in early trials. Modern combination inhalers (ICS-LABA fixed-dose combinations, which put both drugs in one device) mean that every dose of LABA comes with an ICS.

Short-Acting Muscarinic Antagonists (SAMAs)

Ipratropium bromide is the standard SAMA. It blocks M₃ receptors on airway smooth muscle, opposing vagal bronchoconstriction. Onset is slower than salbutamol (~30-60 minutes for full effect) but it is a useful add-on to SABA in:

• Acute severe asthma not responding to nebulised salbutamol alone.
• COPD exacerbations.

Ipratropium is a quaternary ammonium compound: it carries a permanent positive charge, so it crosses membranes poorly and little is absorbed into the blood. Dry mouth is common. Urinary problems, such as urinary retention (difficulty emptying the bladder), and blurred vision are uncommon. Acute angle-closure glaucoma (a sudden rise in pressure inside the eye that can damage sight) has been reported with nebulised ipratropium, particularly when given with nebulised salbutamol. The eyes must be protected from the mist. NICE notes that anticholinergic medicines (drugs that block acetylcholine), such as ipratropium, need a mouthpiece rather than a face mask when nebulised.

Long-Acting Muscarinic Antagonists (LAMAs)

The LAMAs (tiotropium (Spiriva), glycopyrronium, umeclidinium and aclidinium) provide once- or twice-daily bronchodilation. Tiotropium binds all muscarinic receptor types, but it shows "kinetic selectivity": it stays bound to M₁ and M₃ receptors for longer than to M₂. Its very slow release from M₃ receptors gives it a long duration of action. LAMAs are a mainstay of COPD maintenance treatment, usually combined with a LABA.

Side effects are similar to ipratropium, plus increased risk of urinary retention in older men and worsening of angle-closure glaucoma if the drug reaches the eyes.

Anti-Inflammatory Drugs

Inhaled Corticosteroids (ICS)

The cornerstone of asthma maintenance. Beclometasone, budesonide, fluticasone and mometasone are the principal UK ICS. They cross cell membranes and bind glucocorticoid receptors (receptors for cortisol-type steroids) in the cytoplasm. This changes gene transcription. Production of cytokines (signalling proteins released by immune cells) and other inflammatory mediators (chemicals that drive inflammation) falls, and production of β₂ receptors rises.

ICS take days to weeks to achieve full effect; they are preventer drugs (taken regularly to stop symptoms developing), not reliever drugs.

Local side effects:

• Oral candidiasis (thrush): reduced by rinsing the mouth after each inhalation and using a spacer (a large chamber attached to the inhaler, described below).
• Hoarse voice (dysphonia).

Systemic side effects are uncommon at standard inhaled doses but become relevant at high doses or in children:

• Adrenal suppression.
• Growth retardation in children (slight; outweighed by benefits of asthma control).
• Reduced bone mineral density with prolonged high-dose use.
• Increased pneumonia risk in COPD. NICE advises discussing this risk. In COPD, ICS are used for people with asthmatic features, or as part of triple therapy when symptoms or exacerbations continue on dual therapy.

Oral Corticosteroids

Prednisolone is used for:

• Acute exacerbations of asthma and COPD: typically a 5-day course.
• Severe asthma not controlled on inhaled therapy.

The general side effects of long-term steroids (covered in Immunosuppression and Disease-Modifying Therapy) limit long-term use. The modern strategy is to find a "steroid-sparing" combination of ICS, LABA, LAMA and biologic therapy that achieves control without continuous oral steroids.

Leukotriene Receptor Antagonists

Leukotrienes are inflammatory mediators made from arachidonic acid (a fatty acid in cell membranes) by the lipoxygenase enzyme pathway (see NSAIDs: non-steroidal anti-inflammatory drugs). They cause bronchoconstriction, mucus secretion, oedema and eosinophil recruitment.

Montelukast blocks the type 1 cysteinyl-leukotriene receptor (CysLT₁). It is used as add-on therapy in asthma, particularly in:

• Exercise-induced asthma.
• Allergic rhinitis (allergic inflammation of the nose lining, such as hay fever) in people who also have asthma.
• Aspirin-sensitive asthma.

Side effects: gastrointestinal (GI) upset, headache. Neuropsychiatric effects are effects on mood, sleep and behaviour, such as depression, sleep disturbance and suicidal thoughts. In 2019 the Medicines and Healthcare products Regulatory Agency (MHRA) issued a reminder about this risk. The MHRA strengthened its warnings in 2024: montelukast should be stopped if new or worsening neuropsychiatric symptoms appear.

Methylxanthines

Theophylline (oral) and aminophylline (IV form) are non-selective phosphodiesterase inhibitors (they block the enzymes that break down cAMP) and adenosine receptor antagonists (they block receptors for adenosine, a signalling molecule). They have bronchodilator and weak anti-inflammatory effects. They have a narrow therapeutic index (the toxic dose is close to the effective dose), so plasma levels must be monitored.

Side effects (often the limiting factor): GI upset, tachyarrhythmias (fast abnormal heart rhythms), seizures, hypokalaemia. Theophylline is broken down by liver enzymes, including CYP1A2 (one of the liver's drug-metabolising enzymes), so it has many drug interactions. Drugs that inhibit liver enzymes, such as ciprofloxacin and the macrolide antibiotics erythromycin and clarithromycin, raise theophylline levels. Drugs that induce (speed up) liver enzymes, such as rifampicin, lower them. Smoking lowers them too.

Theophylline is now reserved for difficult-to-control asthma and as a second-line drug in COPD, because of these limitations. In COPD, second-line means it is used only after short-acting and long-acting inhaled bronchodilators have been tried, or when a person cannot use inhaled therapy.

Biologic Therapies

Severe asthma, particularly with high blood eosinophils or evidence of allergic phenotype, can now be treated with biologics:

• Omalizumab: an anti-IgE (immunoglobulin E) monoclonal antibody, meaning a laboratory-made antibody aimed at a single target; severe allergic asthma.
• Mepolizumab, reslizumab, benralizumab: anti-interleukin-5 (IL-5, a signalling protein that drives eosinophils) or anti-IL-5 receptor; severe eosinophilic asthma.
• Tezepelumab: blocks thymic stromal lymphopoietin (TSLP, a signalling protein involved in airway inflammation); severe asthma in people aged 12 and over. NICE bases its criteria on exacerbations or oral steroid use rather than on a phenotype.
• Dupilumab: blocks interleukin-4 (IL-4) and interleukin-13 (IL-13) signalling; severe asthma with type 2 (Th2) inflammation. It is also used for atopic dermatitis (eczema) and for chronic rhinosinusitis with nasal polyps (long-term inflammation of the nose and the air spaces around it). NICE recommended it in March 2026 as an add-on for some people with uncontrolled COPD (see below).

Biologics have transformed prognosis in severe asthma but are expensive and used after specialist assessment.

Inhalers and Spacers

Inhaled drug delivery depends critically on technique. The major device types:

• Pressurised metered-dose inhalers (pMDIs): the classic blue and brown inhalers. The patient must breathe in at the same time as pressing the canister (actuation). They are often used poorly.
• Dry powder inhalers (DPIs): activated by the patient's inspiratory effort; require sufficient inspiratory flow.
• Soft mist inhalers: produce a slow-moving mist that improves lung deposition (the amount of drug that settles in the lungs).
• Nebulisers: reserved for acute exacerbations and patients unable to use other devices.

Spacers are large-volume reservoirs attached to pMDIs that:

• Reduce the need for hand-breath coordination.
• Reduce oropharyngeal deposition (drug settling in the mouth and throat), and therefore thrush, dysphonia and systemic absorption with ICS.
• Increase lung deposition.

Spacers should be used routinely with pMDI corticosteroids and in any patient with poor inhaler technique, particularly children and the elderly.

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