Pharmacology of Airway Control

Core

Introduction

Asthma and COPD between them affect more than 8 million people in the UK. 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 on bronchial smooth muscle to cause bronchoconstriction and mucus secretion. This is the dominant tonic input.
• Circulating adrenaline: acts on β₂-adrenergic receptors on bronchial smooth muscle to cause bronchodilation. There is no direct sympathetic innervation of bronchial smooth muscle in humans.

The pathophysiological dominance differs:

• Asthma: Th2-driven eosinophilic inflammation produces mucosal oedema, mucus plugging, smooth muscle hyperreactivity, and reversible bronchoconstriction. 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 why muscarinic antagonists are often more effective than β₂ agonists. ICS have a smaller role and are reserved for patients with eosinophilia or asthmatic overlap.

Bronchodilators

Short-Acting β₂ Agonists (SABAs)

Salbutamol (Ventolin) and terbutaline are the standard SABAs. They activate G_s-coupled β₂ receptors on airway smooth muscle, raising cAMP and producing bronchodilation. Onset within minutes, duration 4-6 hours.

Used for symptomatic relief ("reliever") in mild intermittent asthma, in acute exacerbations of asthma and COPD (typically by nebuliser), and as exercise pre-medication.

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

• Tremor (skeletal muscle β₂).
• Tachycardia and palpitations (mixed: peripheral vasodilation with reflex tachycardia, plus high-dose β₁ activation).
• Hypokalaemia: β₂ activation drives potassium into cells, the basis of using nebulised salbutamol in hyperkalaemia.
• Hyperglycaemia.
• Lactic acidosis 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 guidance now recommends moving away from SABA monotherapy.

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) ensure compliance with this rule.

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.

It is a quaternary ammonium compound and so is poorly absorbed systemically; side effects (dry mouth, urinary retention, blurred vision) are uncommon at standard doses. Glaucoma can be precipitated by direct contact with the eye, so masks rather than mouthpieces are used in nebulised delivery in glaucoma patients.

Long-Acting Muscarinic Antagonists (LAMAs)

The LAMAs: tiotropium (Spiriva), glycopyrronium, umeclidinium, aclidinium: provide once- or twice-daily bronchodilation. Tiotropium binds M₃ receptors with much greater selectivity than ipratropium and is the cornerstone of COPD pharmacology.

Side effects are similar to ipratropium, plus increased risk of urinary retention in older men and worsening of glaucoma if directly aerosolised onto the eye.

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 cytoplasmic glucocorticoid receptors, modifying transcription to reduce production of cytokines and inflammatory mediators while upregulating β₂-receptor expression.

ICS take days to weeks to achieve full effect; they are preventer, not reliever, drugs.

Local side effects:

• Oral candidiasis (thrush): reduced by rinsing the mouth after each inhalation and using a spacer.
• 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: ICS in COPD should be limited to those with eosinophilia or frequent exacerbations.

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 chronic 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 arachidonic acid-derived mediators (the lipoxygenase branch: see NSAIDs) that cause bronchoconstriction, mucus secretion, oedema and eosinophil recruitment.

Montelukast blocks the cysteinyl-leukotriene receptor (CysLT₁). Used as add-on therapy in asthma, particularly:

• Exercise-induced asthma.
• Allergic rhinitis with concurrent asthma.
• Aspirin-sensitive asthma.

Side effects: GI upset, headache. Concerns about neuropsychiatric effects (depression, sleep disturbance, suicidal ideation) prompted MHRA warnings in 2020.

Methylxanthines

Theophylline (oral) and aminophylline (IV form) are non-selective phosphodiesterase inhibitors and adenosine receptor antagonists with bronchodilator and weakly anti-inflammatory effects. They are narrow-therapeutic-index drugs requiring plasma level monitoring.

Side effects (often the limiting factor): GI upset, tachyarrhythmias, seizures, hypokalaemia. Many drug interactions via CYP1A2 metabolism: macrolides and ciprofloxacin raise theophylline levels; rifampicin and smoking lower them.

Theophylline is now reserved for difficult-to-control asthma and as second-line in COPD because of these limitations.

Biologic Therapies

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

• Omalizumab: anti-IgE monoclonal; severe allergic asthma.
• Mepolizumab, reslizumab, benralizumab: anti-IL-5 (or anti-IL-5 receptor); severe eosinophilic asthma.
• Dupilumab: anti-IL-4/IL-13; severe asthma with type 2 inflammation, also used for atopic dermatitis and chronic rhinosinusitis with nasal polyps.

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. Require coordination of breath and actuation; often poorly used.
• 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.
• 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 (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.

Stepwise Treatment of Asthma

The 2024 NICE/BTS/SIGN joint guideline (NG245) simplified asthma management considerably. The pre-clinical version for adults and young people aged 12 and over:

1. Newly diagnosed asthma: start with as-needed low-dose ICS-formoterol ("AIR" therapy: anti-inflammatory reliever) for symptom relief.
2. If symptoms remain or the patient is highly symptomatic at presentation, move to low-dose ICS-formoterol as both maintenance and reliever (MART).
3. If still uncontrolled, increase to moderate-dose ICS-formoterol MART.
4. Specialist review for further escalation: high-dose ICS, addition of LAMA, leukotriene receptor antagonist, theophylline.
5. Severe disease: biologic therapy guided by phenotype (allergic, eosinophilic, type 2 high).

The legacy "blue inhaler / brown inhaler" stepwise model (SABA only → add ICS → add LABA) is being phased out, although patients on stable older regimens may continue them.

For children under 12, the algorithm differs: a SABA reliever plus paediatric low-dose ICS, with stepwise addition of LTRA, LABA and specialist review.

Stepwise Treatment of COPD

NICE 2019 (updated) algorithm:

1. SABA or SAMA as required.
2. If symptoms or exacerbations persist, add LABA + LAMA dual therapy.
3. If asthmatic features or steroid responsiveness (raised eosinophils, history of atopy, FEV₁ reversibility), add ICS → LABA + LAMA + ICS (triple therapy).
4. Smoking cessation, pulmonary rehabilitation and vaccination throughout.

Acute exacerbations: increased bronchodilator use, oral steroids (5 days), antibiotics if there are features of bacterial infection (sputum purulence, fever).

Acute Severe Asthma Management

The standard package for acute severe asthma:

Acute severe asthma: standard sequence

1. Oxygen, high flow, target SpO₂ 94-98%
2. Salbutamol nebulised (5 mg, repeat as needed; can be continuous)
3. Hydrocortisone IV or oral prednisolone
4. Ipratropium nebulised (added to salbutamol if severe)
5. Magnesium sulfate IV (specialist; aminophylline is a further-line option)
6. Escalate to ICU: intubation if needed

The contrast with COPD exacerbation is important: in COPD, controlled oxygen titrated to SpO₂ 88-92% is standard (because of the small but real risk of CO₂ retention in chronic CO₂-retaining patients), and ipratropium is given with air rather than oxygen as the driving gas.

One additional pre-clinical safety point: beta-blockers (especially non-selective ones) can precipitate severe asthma and are contraindicated. Cardioselective beta-blockers (atenolol, bisoprolol) are still relative contraindications.

Summary

• Bronchial smooth muscle is constricted by parasympathetic M₃ activity and dilated by circulating adrenaline at β₂.
• Bronchodilators: SABAs (salbutamol), LABAs (salmeterol, formoterol), SAMAs (ipratropium), LAMAs (tiotropium).
• Anti-inflammatories: ICS (beclometasone, budesonide, fluticasone), oral steroids in exacerbations, LTRAs (montelukast), methylxanthines (theophylline), biologics (omalizumab, mepolizumab, dupilumab).
• Asthma: front-line ICS-formoterol MART; never use LABA without ICS; SABA monotherapy is now discouraged.
• COPD: front-line LABA + LAMA; ICS only with eosinophilia or asthmatic features.
• Acute severe asthma: oxygen, salbutamol, hydrocortisone/prednisolone, ipratropium, magnesium, escalation.
• Beta-blockers are contraindicated in asthma; spacers improve ICS delivery and reduce side effects.

Drug Summary Table

Reviewed by: Dr. Marcus Judge

Quiz

Preview the Pharmacology of Airway Control quiz