Overview
This lecture sets up the pharmacology of asthma “preventers” and “relievers” by separating the two processes drugs are aimed at: the chronic inflammatory process of the airway wall, and the bronchoconstriction of airway smooth muscle. It defines asthma, works through the Th2-driven immune response and the sensitisation step that primes mast cells, catalogues the mediators released (pre-formed and newly synthesised, with the arachidonic acid pathways in detail), then turns to the receptors and second messengers that set bronchial tone, and closes with the management principle that inflammation is the primary target and bronchodilators are reserved for symptoms.
What asthma is
Asthma is chronic airway inflammation characterised by three features:
- inflammatory cell infiltration with airway wall thickening and remodelling
- increased mucous production, which aids obstruction
- airway hyper-responsiveness, leading to excessive bronchial smooth muscle constriction in response to numerous stimuli
The lecture also frames asthma as primarily an inflammatory illness with bronchial hyperreactivity, bronchospasm and mucous overproduction. Asthmatic bronchospasm results from a combination of release of mediators (histamine, leukotrienes and others) and an exaggerated response to their effects.
How the airway becomes obstructed. Comparing a normal with an obstructed bronchus, the normal airway has smooth muscle, blood vessels, an open lumen and a mucous lining. In the obstructed airway the same structures show contracted smooth muscle with decreased lumen diameter, blood vessels infiltrated by immune cells, inflammation and swelling, and excess mucus. Obstruction is therefore the sum of three things narrowing the lumen: smooth-muscle contraction, mucosal inflammation and swelling, and mucus hypersecretion.
The asthmatic immune response: Th2 versus Th1
The difference between an atopic and a non-atopic person is which way the naive CD4+ T cell is polarised after an antigen-presenting cell in the airway epithelium presents allergen.
- Atopic: B-cell-matured dendritic cells polarise naive CD4+ Th cells to Th2 cells. Exposure to IL-10 and IL-4 gives an activated Th2 lymphocyte producing Th2 cytokines including IL-13. Downstream this activates eosinophils (releasing MBP, ECP, leukotrienes, cytokines), mast cells (histamine, leukotrienes, cytokines) and plasma cells (IgE). The result is airway oedema, goblet cell hyperplasia, subepithelial fibrosis and smooth muscle hyperresponsiveness, that is, asthma.
- Non-atopic: exposure to IL-12 gives an activated Th1 lymphocyte producing IFN-γ, a low-level IgG response as a physiologic response, and a normal airway.
Pathogenesis flow. Antigen is taken up by a dendritic cell and presented to a naive T lymphocyte (Th-0). Th-0 then differentiates down one of two mutually inhibitory arms:
- IL-12 promotes the Th1 arm, which releases IFN-γ, lymphotoxin and IL-2, giving cell-mediated immunity and neutrophilic inflammation.
- The Th2 arm (IL-12 inhibitory on this branch) acts via IL-4/IL-13, IL-9/IL-4, IL-3 and IL-3/IL-5/GM-CSF to drive IgE production and activation of mast cells, then basophils and eosinophils. These release mediators of inflammation (histamine, prostaglandins, leukotrienes, enzymes), producing bronchial hyperresponsiveness and airway obstruction, hence asthma symptoms.
What Th2 activation does in the airway. Airways Th2 lymphocyte activation provokes:
- synthesis and release of proinflammatory cytokines (for example IL-4, IL-5 and IL-13) to prime B lymphocytes
- maturation of dendritic cells
- increased recruitment of inflammatory cells (eosinophils, basophils, mast cells, macrophages, lymphocytes)
- rising IgE levels, which correlate with worsening asthma symptoms
Released chemical mediators also activate neural pathways, provoking vagal efferent release of ACh onto airway smooth muscle and so bronchoconstriction. This is the neural link between the inflammatory and the bronchoconstrictor limbs of the disease.
Sensitisation: priming the system
- B cells initiate an IgE response, driven by IL-4, IL-5 and IL-13 plus allergen.
- Allergen-specific IgE crosslinks onto two IgE receptors expressed on mast cells (also basophils and eosinophils).
- Allergen re-encounter signals the synthesis and release of cell-specific inflammatory mediators.
- The airways become inflamed and hyper-reactive.
Downstream effects of inflammatory mediators in the airway wall
Allergen crosses the epithelium; beneath it, mast cells and basophils (via IgE) and macrophages and dendritic cells release cytokines and chemokines, with Th2 cells and eosinophils making up the inflammation compartment. The inflammatory mediators (leukotrienes, prostaglandins, purines, histamine, proteases, PAF, protons and others) fan out to five downstream effects:
- mucous hypersecretion, mucous plugs and gland hyperplasia in the lumen
- epithelial shedding and sub-epithelial fibrosis
- sensory nerve activation and plasticity, with plasma leakage and oedema
- vasodilation and angiogenesis of blood vessels
- parasympathetic nerve activation and plasticity, causing bronchoconstriction and bronchial hyperreactivity in smooth muscle
Mediators in asthma
Pre-formed, before mast cell stimulation. Stored in the cytoplasmic secretory granules of mast cells and basophils, and released during allergic or inflammatory reactions:
- histamine
- chemotactic factors
- neutral proteases
- acid hydrolases
- heparin
IL-5 also rapidly primes basophils for enhanced histamine release and leukotriene C4 (LTC4) generation.
Synthesised at the time of mast cell stimulation:
- arachidonic acid and its metabolites (eicosanoids)
- leukotrienes
- prostanoids
These are released from activated inflammatory cells (for example neutrophils, macrophages) through phospholipase A2 (PLA2) action.
The arachidonic acid pathways
Membrane phospholipids are converted by phospholipases to arachidonic acid, which then splits down two branches:
- 5-Lipoxygenase pathway: leukotriene B4 (chemotaxis); leukotrienes C4, D4 and E4.
- Cyclooxygenase pathway: prostacyclin (vasodilation); prostaglandin E1 (vasodilation); thromboxane A2 (vasoconstriction and bronchoconstriction); PGD2 (vasodilation, bronchoconstriction).
Leukotrienes C4, D4 and E4 are the “slow reacting substance of anaphylaxis” (SRSA) and are the ones most relevant to asthma. They contract respiratory smooth muscle and increase vascular permeability, which gives inflammatory cell infiltration and lung oedema; the diagram also labels them with vasodilation and bronchoconstriction.
Leukotriene B4 is involved in all types of inflammation. Its effect is chemotactic: it attracts inflammatory cells to the site, where toxic ROS products and enzymes are induced and damage the host’s own tissues. The 5-lipoxygenase step is marked as the point to inhibit to reduce LTB4-driven chemotaxis.
Prostanoids (COX branch). PGD2 causes bronchoconstriction and vasodilation, with increased permeability and inflammatory cell infiltration. Thromboxane TXA2 causes bronchoconstriction. The cyclooxygenase step is marked as the point to inhibit to reduce these prostanoid effects.
Cross-talk between the branches. Cyclooxygenase products such as PGE1 can attenuate the lipoxygenase pathway, shown as negative feedback from PGE1 back onto the lipoxygenase branch.
Warning
The exact clinical significance and mechanism of this negative-feedback arrow is shown graphically only on the slide and is not spelled out in the accompanying text.
Aspirin, NSAIDs and drug-induced rhinitis
Drug-induced rhinitis is characterised by symptoms of rhinitis (nasal obstruction, rhinorrhoea and sneezing) and facial flushing.
In nonallergic rhinitis with eosinophilia syndrome (NARES), asthma is triggered within 1 to 3 hours of ingestion of aspirin and other NSAIDs (for example ibuprofen).
Important
Mechanism: PGE1 is a down-regulator of lipoxygenase activity. Aspirin and other NSAIDs inhibit COX, reducing PGE1 levels, which removes that inhibition and allows activation of the lipoxygenase pathway, producing increased amounts of pro-inflammatory leukotrienes.
Triggers
Once airway cells have become sensitised, re-exposure to allergen can trigger an asthma attack. Non-allergens can also trigger asthma:
- exercise
- cold air
- medicines
- irritant chemicals
- infections
- pollution and others
Regulation of bronchial tone
Muscarinic (M2 and M3), histaminergic and leukotriene receptors form important bronchoconstrictor pathways; the β2-adrenoceptor pathway is the opposing bronchodilator pathway.
β2-adrenoceptor agonist mechanism (bronchodilation).
- A β-agonist binds the β2-AR.
- The receptor couples via Gs to activate adenylate cyclase (AC).
- AC converts ATP to cAMP (PDE converts cAMP to AMP as the off-pathway).
- cAMP activates protein kinase A.
- PKA produces three effects, together giving bronchodilation: increased conductance of Ca2+-activated K+ channels, giving rapid efflux of K+ and membrane hyperpolarisation; decreased IP3 and Ca2+; and decreased myosin light chain kinase (MLCK).
Bronchoconstrictor pathways on the same cell.
- Mast cells below the smooth muscle release inflammatory mediators such as histamine, and cysteinyl leukotrienes (LTC4, LTD4, LTE4) which act on the G-protein-coupled CysLT receptor-1 on the smooth muscle cell.
- The M3 receptor couples via Gq to activate PLC-β, producing IP3 and DAG, which drive Ca2+ release and contraction.
- The M2 receptor couples via Gi, inhibiting the cAMP pathway and so opposing bronchodilation.
- On the opposing side, an adrenergic bronchodilator acting on β2-AR via Gs raises cAMP, which inhibits contraction.
Summary of bidirectional control of bronchial tone.
- Bronchodilation arm: β2AR agonist activates AC, which converts ATP to cAMP, promoting bronchodilation. PDE breaks cAMP down to AMP; theophylline inhibits PDE, preserving cAMP and promoting bronchodilation.
- Bronchoconstriction arm: acetylcholine and adenosine both promote bronchoconstriction. Muscarinic antagonists inhibit the acetylcholine input.
Assessment and classification of severity
Lung function is monitored with spirometry and peak flow. The flow-volume loop plots flow (L/sec) against volume (L), with expiratory limb parameters (PEF, FEF25/50/75%, FEV1/FVC landmarks) and inspiratory limb parameters (PIF25/50/75%).
Example classification of asthma severity by clinical symptoms, age 12 years and over. Normal FEV1:FVC ratio is 80% at 20 to 39 years, 75% at 40 to 59 years and 70% at 60 to 80 years.
| Intermittent | Mild persistent | Moderate persistent | Severe persistent | |
|---|---|---|---|---|
| Symptoms | ≤2 d/wk | >2 d/wk but not daily | daily | throughout the day |
| Nighttime awakenings | ≤2×/mo | 3-4×/mo | >1×/wk but not nightly | often 7×/wk |
| SABA use for symptom control (not prevention of EIB) | ≤2 d/wk | >2 d/wk but not daily, and not more than once on any day | daily | several times per day |
| Interference with normal activity | none | minor limitation | some limitation | extremely limited |
| Lung function | normal FEV1 between exacerbations, FEV1 >80% predicted, FEV1:FVC normal | FEV1 >80% predicted, FEV1:FVC normal | FEV1 >60% but <80% predicted, FEV1:FVC normal | FEV1 <60% predicted, FEV1:FVC reduced >5% |
| Step | 1 | 2 | 3 | 4 or 5 |
SABA monotherapy is not advocated (McCracken et al, 2017, JAMA 318(3):279-290).
Management
Key points: asthma severity varies over time, so treatment needs to be flexible. The goals of treatment are to reduce symptoms using the minimum of medication, which requires patients to self-monitor symptoms and adjust medication following a set treatment plan; therapy should provide effective anti-inflammatory and bronchodilatory control.
Summary approach, in order of priority:
- Primary: manage inflammation as the underlying problem, even in mild asthma.
- Secondary: reserve bronchodilators mainly for symptomatic use.
Several pharmacological points of attack exist:
- reduce bronchial responsiveness in all patients with anti-inflammatories
- relax airway smooth muscle with β-agonists and muscarinic antagonists, preferably long-lasting versions
- prevent mast cell activation with leukotriene receptor antagonists (mast cell stabilisers are considered largely ineffective in asthma)
Historical and device context
Historical asthma remedies included smoking a cigar at bedtime as a “preventive” during the hay asthma season, with Indian tobacco or lobelia inflata preferred by some patients, and the “Cigares de Joy” advertised for immediate relief in asthma, cough, bronchitis, hay fever, influenza and shortness of breath. Himrod’s Powder was a burned-and-inhaled powder marketed as a cure for bronchial asthma, used at least three times daily, with warnings of dryness of throat, rapid pulse and blurring of vision; its active constituent was stramonium, whose chief constituent daturine resembles atropine, which explains the antimuscarinic warning symptoms.
Current inhaler device types shown: MDI with spacer, MDI, Diskus, Handihaler, Twisthaler, Autohaler, Aerolizer, Flexhaler, Neohaler, Respimat, Pressair, Turbuhaler, Ellipta.
Resources given: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14e, Chapter 36 Pulmonary Pharmacology (AccessMedicine, Med Library); Rau’s Respiratory Care Pharmacology, 11th edn, 2024 (Med Lib reserve).
Exam-style SAQ given in the lecture
Paul is an 11 year old boy with a history of mild asthma. His medication currently includes a salbutamol inhaler, 100 µg per metered dose, 2 puffs when required for wheezing.
(a) Briefly describe the mechanisms of action of the above medicine.
(b) Outline adverse effects that you might predict from the mechanisms of action of the above medicine.
(c) Following a review of recent guideline changes, Symbicort 100/6 metered dose inhaler (a combination of budesonide 100 µg, a glucocorticoid, and formoterol 6 µg, a long-acting beta agonist), 2 puffs twice daily, is substituted for the salbutamol inhaler. Discuss possible reasons for this substitution.
(d) What information and advice relating to the changes in medication would you give to Paul?
Self-test
- Define asthma using the three characteristic features given in the lecture.
- List the three changes in the airway wall and lumen that narrow the lumen in an obstructed airway.
- Distinguish the atopic from the non-atopic airway response to allergen, naming the polarising cytokine, the T cell subset and the outcome in each.
- Describe the steps by which airway cells become sensitised so that a later allergen encounter triggers an attack.
- Explain how the inflammatory limb of asthma produces bronchoconstriction through a neural route.
- Distinguish pre-formed mediators from those synthesised at the time of mast cell stimulation, giving examples of each.
- Describe the two branches of arachidonic acid metabolism and name the products of each given in the lecture.
- Which leukotrienes make up the slow reacting substance of anaphylaxis, and what are their effects?
- Explain how LTB4 differs in action from LTC4/D4/E4, and where the lecture marks the point of drug inhibition to reduce it.
- Predict what happens to leukotriene production when a patient with NARES takes aspirin, and explain the mechanism.
- Describe the steps from β2-adrenoceptor binding to bronchodilation, including the three downstream effects of protein kinase A.
- Distinguish the roles of M2 and M3 muscarinic receptors on airway smooth muscle.
- What is the effect of theophylline on bronchial tone, and by what mechanism?
- List the non-allergen triggers of asthma given in the lecture.
- What is the normal FEV1:FVC ratio at ages 20-39, 40-59 and 60-80 years?
- A patient aged over 12 has daily symptoms, nighttime awakenings more than once a week but not nightly, daily SABA use, some limitation of activity, and FEV1 70% predicted with a normal FEV1:FVC. Which severity class is this, and which step?
- State the primary and secondary recommendations of the summary approach to asthma, and list the pharmacological points of attack.
- Integrative: using the two limbs of the disease, explain why anti-inflammatory therapy is primary and bronchodilators are reserved for symptomatic use, and why SABA monotherapy is not advocated.
Answers
Reveal answers
- Chronic airway inflammation characterised by inflammatory cell infiltration with airway wall thickening/remodelling; increased mucous production aiding obstruction; and airway hyper-responsiveness leading to excessive bronchial smooth muscle constriction in response to numerous stimuli.
- Contracted smooth muscle reducing lumen diameter; inflammation and swelling of the mucosa with blood vessels infiltrated by immune cells; and excess mucus.
- Atopic: the naive CD4+ cell is exposed to IL-10/IL-4 and becomes an activated Th2 lymphocyte producing Th2 cytokines including IL-13, driving eosinophils, mast cells and plasma cells (IgE), giving airway oedema, goblet cell hyperplasia, subepithelial fibrosis and smooth muscle hyperresponsiveness, that is, asthma. Non-atopic: exposure to IL-12 gives an activated Th1 lymphocyte producing IFN-γ, with a low-level IgG physiologic response and a normal airway.
- B cells initiate an IgE response under IL-4, IL-5 and IL-13 plus allergen; allergen-specific IgE crosslinks onto two IgE receptors on mast cells (also basophils and eosinophils); on allergen re-encounter the cells synthesise and release cell-specific inflammatory mediators; the airways become inflamed and hyper-reactive.
- Released chemical mediators activate neural pathways, provoking vagal efferent release of acetylcholine onto airway smooth muscle, which causes bronchoconstriction. The airway wall diagram shows the same idea as parasympathetic nerve activation and plasticity producing bronchoconstriction and bronchial hyperreactivity.
- Pre-formed mediators are stored in cytoplasmic secretory granules of mast cells and basophils and released during allergic or inflammatory reactions: histamine, chemotactic factors, neutral proteases, acid hydrolases, heparin. Newly synthesised at the time of stimulation: arachidonic acid and its metabolites (eicosanoids), leukotrienes and prostanoids, released from activated inflammatory cells through phospholipase A2 action.
- Membrane phospholipids are converted by phospholipases to arachidonic acid. The 5-lipoxygenase branch gives leukotriene B4 (chemotaxis) and leukotrienes C4, D4 and E4. The cyclooxygenase branch gives prostacyclin (vasodilation), prostaglandin E1 (vasodilation), thromboxane A2 (vasoconstriction and bronchoconstriction) and PGD2 (vasodilation, bronchoconstriction).
- LTC4, LTD4 and LTE4. They are the ones most relevant to asthma: they contract respiratory smooth muscle and increase vascular permeability, giving inflammatory cell infiltration and lung oedema, and are labelled with vasodilation and bronchoconstriction.
- LTB4 is involved in all types of inflammation and acts chemotactically, attracting inflammatory cells to the site where toxic ROS products and enzymes are induced and damage the host’s own tissues, whereas LTC4/D4/E4 act mainly as SRSA on smooth muscle and vascular permeability. The lecture marks the 5-lipoxygenase step as the place to inhibit.
- Leukotriene production increases. PGE1 is a down-regulator of lipoxygenase activity; aspirin inhibits COX and reduces PGE1 levels, which allows activation of the lipoxygenase pathway and increased amounts of pro-inflammatory leukotrienes. Asthma is triggered within 1 to 3 hours of ingestion of aspirin or other NSAIDs such as ibuprofen.
- The agonist binds β2-AR, which couples via Gs to activate adenylate cyclase; AC converts ATP to cAMP; cAMP activates protein kinase A; PKA increases conductance of Ca2+-activated K+ channels (rapid K+ efflux and membrane hyperpolarisation), decreases IP3 and Ca2+, and decreases MLCK. Together these give bronchodilation. PDE converting cAMP to AMP is the off-pathway.
- M3 couples via Gq to activate PLC-β, producing IP3 and DAG, which drive Ca2+ release and contraction. M2 couples via Gi and inhibits the cAMP pathway, so it opposes bronchodilation.
- Theophylline promotes bronchodilation by inhibiting PDE, so cAMP is not broken down to AMP and cAMP levels are preserved.
- Exercise, cold air, medicines, irritant chemicals, infections, pollution and others.
- 80% at 20-39 years, 75% at 40-59 years, 70% at 60-80 years.
- Moderate persistent asthma, step 3 (daily symptoms, nighttime awakenings more than once a week but not nightly, daily SABA use, some limitation, FEV1 greater than 60% but less than 80% predicted with normal FEV1:FVC).
- Primary: manage inflammation as the underlying problem, even in mild asthma. Secondary: reserve bronchodilators mainly for symptomatic use. Points of attack: reduce bronchial responsiveness in all patients with anti-inflammatories; relax airway smooth muscle with β-agonists and muscarinic antagonists, preferably long-lasting versions; prevent mast cell activation with leukotriene receptor antagonists (mast cell stabilisers are considered largely ineffective).
- Asthma is primarily an inflammatory illness in which Th2-driven inflammation, IgE-mediated mast cell activation and mediator release produce both the airway wall changes (oedema, mucus, fibrosis, remodelling) and the hyperresponsiveness that makes smooth muscle over-constrict; bronchodilators act only on the smooth muscle limb and so relieve symptoms without touching the underlying process. Treating the inflammation reduces bronchial responsiveness in all patients, which is why anti-inflammatory therapy is primary and bronchodilators are reserved for symptomatic use, and why SABA monotherapy is not advocated.