L16 Clinical Pharmacology Bronchodilators

Overview

This lecture covers the drug classes used to relax or protect the airways in asthma and COPD, and where each sits in guideline-based management. It starts with why airway calibre matters mechanically, then works through the signalling of bronchial smooth muscle before taking each class in turn: β2-agonists (SABAs and LABAs), muscarinic antagonists (SAMAs and LAMAs), adjunct IV magnesium, leukotriene receptor antagonists, and IL-5 monoclonal antibodies for severe eosinophilic disease. For each class the objectives are route of administration, site and mechanism of action, named examples, limitations and adverse effects, and the step of asthma or COPD management the class belongs to.

Why bronchoconstriction matters: airway mechanics

• Resistance to laminar flow in the conducting airways follows Hagen-Poiseuille’s law: $R=\frac{8\eta L}{\pi r^4}$, where $\eta$ is dynamic viscosity, $L$ is airway length and $r$ is airway radius.
• Because radius is raised to the fourth power, halving the radius of a bronchial structure increases airway resistance 16-fold.
• This is the rationale for targeting smooth muscle tone pharmacologically: small changes in calibre produce large changes in resistance.

Modulators of bronchial smooth muscle contraction

The airway smooth muscle cell integrates several receptor inputs that converge on contraction or relaxation:

• ACh acts on M2 receptors (Gi-coupled) and M3 receptors (Gq-coupled).
• Noradrenaline/adrenaline act on the β2-adrenoceptor (Gs-coupled), which activates adenylyl cyclase (AC) and raises cAMP.
• The Gq arm signals through PLC-β to DAG and IP3, raising intracellular Ca2+ and driving contraction.
• CysLT1 receptors on the muscle cell bind cysteinyl leukotrienes (LTC4, LTD4, LTE4) released, with other mediators such as histamine, from nearby mast cells.

Bronchial tone can be represented as an axis between bronchodilation and bronchoconstriction:

• β2-agonists (salbutamol) act at the β2 receptor, activating AC, which converts ATP to cAMP and shifts tone toward bronchodilation.
• cAMP is broken down to AMP by phosphodiesterase (PDE); theophylline inhibits PDE.
• Acetylcholine and adenosine both promote bronchoconstriction; muscarinic antagonists block the ACh arm and theophylline blocks the adenosine arm.

β2-agonists

Mechanism

• β2-adrenoceptor activation causes smooth muscle relaxation in response to endogenous catecholamines.
• In airway smooth muscle: the β2-agonist raises cAMP, activating PKA, which increases conductance of Ca2+-sensitive K+ (K+Ca) channels, producing hyperpolarisation and relaxation, and so inhibiting bronchial constriction.
• In epithelium: raised cAMP increases ciliary beat frequency, improving mucus and allergen clearance.
• Patient response varies because of polymorphisms in the nucleotide sequence encoding the β2 receptor; this may underlie increased exacerbation risk in asthma and COPD.

SABAs: salbutamol

• Salbutamol is a selective β2-agonist with roughly 200-fold selectivity for β2 over β1.
• Devices shown: Ventolin Evohaler (100 micrograms, metered-dose inhaler) and Ventolin Accuhaler (200 micrograms, dry powder).
• It relaxes airway smooth muscle and reverses bronchoconstriction; its major role is as rescue/reliever therapy in asthma and COPD.
• Acute inhalation counteracts bronchospasm and treats symptoms: onset 5 to 15 minutes, bronchodilator effect lasting 2 to 5 hours. Also used to prevent exercise-induced asthma.
• Use on an as-required (p.r.n.) basis, only advocated as a second-tier approach, at the lowest possible dose.
• Avoid regular fixed-interval use, which is associated with β2-receptor downregulation, decreased bronchoprotection, rebound hyperresponsiveness, decreased bronchodilator response, increased allergic response and eosinophilic airway inflammation.

SABA adverse effects (at high doses, acute or short-term dosing)

• Tremor of peripheral skeletal muscle, from activation of skeletal muscle β2 receptors.
• Increased heart rate and force of contraction: β2 receptors in the heart can still be affected, selectivity is lost at high doses so β1 receptors are hit, and β2-mediated dilation of peripheral vessels lowers diastolic BP causing reflex tachycardia.
• Hypokalaemia, causing myocardial hyperexcitability: stimulation of β2-adrenoceptors in liver and skeletal muscle with frequent use increases Na+/K+-ATPase activity (possibly via cAMP), increasing K+ uptake from plasma. Intensive β2-agonist treatment lowers K+ by 0.4 to 0.9 mmol/L for up to 1 hour. Caution with diuretics.
• Frequent use through the day can produce tolerance.

Important

Beware concomitant β-blocker use. β-blockers such as propranolol block β2-receptor activation and aggravate asthma. No β-blocker is entirely safe in asthma: non-selective agents (propranolol, carvedilol) must not be used in asthmatics, and partially β1-selective (metoprolol, atenolol) and highly β1-selective agents (bisoprolol) require caution in asthma and COPD.

LABAs: salmeterol and formoterol

• Lipophilic side-chains resist degradation and prolong half-life. Structures of formoterol, salmeterol and salbutamol were compared side by side.
• Salmeterol does not produce rapid relief: onset ~10 to 20 minutes, peak effect ~1 to 2 hours, bronchodilator effect ~12 hours, given as regular twice-daily dosing.
• Uses: nocturnal asthma, exercise-induced asthma, and as an add-on in COPD.
• LABAs must not be used as monotherapy relievers and are not approved as rescue inhalers; a SABA such as salbutamol is needed for rapid relief.
• LABAs do not address the underlying inflammation, so they cannot be used without an anti-inflammatory.
• In 2005 the FDA warned that LABAs could potentiate bronchospasm. LABA use is contraindicated without an asthma controller such as an inhaled corticosteroid, and single-ingredient LABAs should only be used in combination with a controller, never alone.

MART therapy and fixed-dose combination inhalers

• MART = single-inhaler Maintenance And Reliever Therapy, exemplified by budesonide-formoterol (Symbicort).
• Formoterol replaces the need for a SABA because it is a potent β2-agonist that is both fast and long acting: onset < 1 to 3 minutes, Cmax ~6 minutes, duration ~12 hours, which suits it to combined maintenance and reliever use.
• Combining with the ICS budesonide means Symbicort is well tolerated with few issues.
• Fixed-dose combination benefits: using a LABA with a steroid allows the steroid dose to be reduced, and the combination has an adjunctive prophylactic role with inhaled glucocorticoids (budesonide, beclomethasone, fluticasone) for better control.
• Examples: Symbicort (budesonide + formoterol), Seretide (fluticasone + salmeterol). Outcomes are better in combination than when the components are taken separately.

Muscarinic receptor antagonists

Rationale and receptor pharmacology

• Parasympathetic stimulation of M1, M2, M3 and M4 receptors causes bronchoconstriction, so antagonism with atropine-like drugs combats bronchoconstriction. Note the risk of systemic impact, since the parasympathetic system innervates eye, salivary and tear glands, heart, larynx/trachea/bronchi/lungs, stomach, pancreas, kidney, blood vessels, gut, bladder and genitalia.
• At the parasympathetic nerve terminal: ganglionic M1 receptors facilitate neurotransmission; neuronal M2 receptors limit further ACh release (negative feedback); on airway smooth muscle M3 receptors mediate contraction while M2 receptors counteract muscle relaxation.
• Consequence: selectively blocking M3 reduces bronchoconstriction, whereas blocking M2 may allow further ACh outflow.

Receptor subtype table (with receptor-drug complex half-life in hours):

Subtype	Locations	Action when stimulated	Ipratropium t½	Tiotropium t½
M1	Parasympathetic ganglia, exocrine glands, mucous glands	Cholinergic neurotransmission	0.11	14.6
M2	Postganglionic cholinergic nerves, airway smooth muscle	Negative feedback reducing ACh release	0.035	3.6
M3	Airway smooth muscle, mucous glands	Bronchoconstriction, mucus secretion	0.26	34.7

Vagal component: COPD versus asthma

• COPD: there is a major reversible bronchoconstrictor component mediated by neural cholinergic effect, which is why SAMAs and LAMAs are advocated.
• Chronic or severe refractory asthma: cholinergic stimulation plays a secondary role, although increased vagal stimulation at night-time may be an important contributor, so LAMAs are generally used as an add-on at night or at Stage 4/5.

ACh and eosinophils in airway sensitisation

• Airway hyper-reactivity correlates with the presence of activated eosinophils specifically around airway nerves.
• Normal state: ACh signalling from the nerve terminal reaches M3 receptors on airway smooth muscle, with inhibitory M2 autoreceptors in place; anticholinergics act here.
• Sensitized/atopic state: an eosinophil bearing muscarinic receptors sits near the nerve terminal.
• Sensitized and challenged with antigen: eotaxin acting via CCR3 recruits eosinophils to the nerve using ICAM-1; eosinophils release major basic protein (MBP), which acts as a muscarinic receptor antagonist at the inhibitory M2 receptor, so ACh release increases and M3 signalling to airway smooth muscle increases.
• Interventions marked on this pathway: dexamethasone and anti-CD11 (recruitment/adhesion), CCR3 antagonist, anti-IL-5, anti-MBP and heparin.

SAMA: ipratropium

• Given by inhalation. Peak spirometric improvement onset 30+ minutes, duration 3 to 5 hours.
• Given with a β2-agonist it has an additive effect.
• Indications: most useful in COPD, with benefit in acute asthma and in emphysema.
• Not systemically absorbed, but can still produce adverse effects (rare, mostly via muscarinic antagonism): dry mouth, headache, gastrointestinal motility disorders (constipation, diarrhoea, vomiting), cardiac effects (tachycardia, palpitations), urinary retention, and ocular accommodation disturbance (blurred vision).
• Generally no CNS effects because ipratropium does not cross the blood-brain barrier.

LAMA: tiotropium bromide

• Once-daily LAMA for maintenance; sparingly soluble in water; administered by dry powder inhalation.
• Two formulations: aqueous solution (5 mg) via the Spiriva Respimat inhaler, and dry powder (18 mg) via the breath-actuated HandiHaler.
• Pharmacokinetics: peak spirometric improvement at 30 to 60 minutes; maximum plasma concentration 5 to 7 minutes after inhalation; effective half-life 27 to 45 hours.
• The majority of the delivered dose is deposited in the GI tract where it is degraded; a smaller amount reaches the lung, from which a significant 17% may become systemically bioavailable. Actively secreted by the renal route.
• Tiotropium does not penetrate the blood-brain barrier to any relevant extent.

Combination therapy in COPD and its real-world benefit

• LABA + LAMA (for example salmeterol/tiotropium) gives a synergistic effect for symptomatic relief in COPD.
• For repeat or severe exacerbations not controlled by LABA + LAMA, add an ICS: budesonide/formoterol (Symbicort) or fluticasone/salmeterol (Seretide), as ICS + LABA + LAMA.
• Indicated for regular treatment of adults with moderate to severe COPD (FEV1 < 50 to 60% of predicted normal) with frequent symptoms despite SABA use and a history of exacerbations.
• Glucocorticoid inhalers should not be used to initiate bronchodilator therapy in COPD.
• Reality check (Parkin et al., 2021): inhaled bronchodilators give only modest benefit in COPD, and combination LABA/LAMA appears to give only minimal benefit relative to monotherapy with one agent. Cardiovascular risks are uncertain, and little is known about the cardiovascular risk of combination versus monotherapy, hence interest in acute coronary syndrome risk on long-acting bronchodilator mono- versus dual therapy.
• Example marketed combinations: umeclidinium/vilanterol 62.5/25 mcg once daily (GSK); indacaterol/glycopyrronium 85/43 mcg once daily (Novartis); olodaterol/tiotropium 2.5/2.5 mcg, 2 actuations once daily (Boehringer-Ingelheim).

Adjunct: IV magnesium sulphate in acute severe asthma

• Mg2+ is a cofactor in numerous enzymatic reactions.
• It decreases ACh release at the motor end plate on bronchial smooth muscle.
• It acts as a physiological Ca2+ antagonist. Caution: hypermagnesaemia is possible with IV dosing.
• It increases adenylyl cyclase production of cAMP.
• Replacement may be useful where plasma Mg2+ has been depleted by frusemide, by disease, or by β2-adrenergic stimulation.

Leukotriene pathway-modifying agents

Pathway

• Membrane phospholipids are acted on by phospholipases to release arachidonic acid, which branches down two routes.
• 5-Lipoxygenase pathway: leukotriene B4 (chemotaxis), and the cysteinyl leukotrienes LTC4, LTD4 and LTE4, which are the target of CysLT1 receptor antagonists.
• Cyclooxygenase pathway: prostacyclin (vasodilation), prostaglandin E1 (vasodilation), thromboxane A2 (vasoconstriction).
• Cysteinyl leukotrienes acting at CysLT1 receptors produce plasma exudation, mucus secretion, bronchoconstriction and eosinophil recruitment; LTRAs block this receptor.

Montelukast

• Orally active LTRA, a receptor antagonist at CysLT receptors, which blocks the effects of the lipoxygenase products.
• Blocks the bronchoconstrictor response to allergen challenge and exercise-induced bronchoconstriction.
• Limitation: it affects only the leukotriene pathway among the many pathways in operation, so the effect may be limited.
• Currently funded by Pharmac, with a TGA warning of possible neuropsychiatric adverse effects.
• Few adverse effects in short-term use. Long-term risks include neuropsychiatric adverse effects: suicidality, nightmares and behavioural problems. The FDA issued a boxed warning in March 2020 about serious mental health side effects with montelukast (Singulair), advising restricted use for allergic rhinitis, with risks including suicidal thoughts or actions.
• Not appropriate for acute asthma exacerbations. Useful as an adjunct or an alternative to inhaled glucocorticoids in patients with inadequate response or intolerance.

Trial evidence for montelukast

Drug and dose	N	ΔFEV1	β2-agonist use	Trial
Montelukast 10 mg HS	408	+13%	−25%	Chronic asthma, >14 years, 12 weeks
Placebo	273	+4.2%	0%	as above
Montelukast 5 mg HS	201	+8.2%	−12%	Chronic asthma, 6 to 14 years, 8 weeks
Placebo	135	+3.6%	+6%	as above
Beclomethasone 200 μg BID	251	+13.1%	−40%	Chronic asthma, 15 to 85 years, 12 weeks
Montelukast 10 mg HS	387	+7.4%	−24%	as above
Placebo	257	+0.7%	0%	as above

FEV1 is forced expiratory volume in one second; negative β2-agonist figures indicate a decreased requirement for β2-agonist with montelukast.

Biologics: IL-5 monoclonal antibodies for severe eosinophilic asthma

• IL-5 binds the alpha (α) chain of the IL-5 receptor (a receptor tyrosine kinase) found on eosinophils and, to a lesser extent, basophils.
• IL-5 is key to maturation, activation, proliferation and survival of eosinophils.
• Mepolizumab is a humanized monoclonal antibody that binds IL-5 with high affinity and specificity, reducing IL-5 availability and biological signalling, reducing the inflammatory cascade formed through eosinophil activation, promoting eosinophil apoptosis and reducing eosinophil numbers within 4 weeks.
• Mechanistically it binds circulating IL-5 and prevents it engaging the IL-5Rα/βc complex on the eosinophil membrane; the blocked intracellular signalling runs via JAK1/JAK2 to STAT-1/3/5, and via MAPK, PI3K and NF-κB, leading to differentiation, cytokine production, degranulation, adhesion and chemotaxis, survival, and regulation of gene transcription.
• Administration: subcutaneous, by pre-filled pen (auto-injector) or pre-filled safety syringe, 300 mg/mL once monthly.
• Do not use to treat acute asthma exacerbations.
• Risk of opportunistic infections such as herpes zoster. Major adverse effects: headaches, nausea, injection-site pain, fatigue, back pain and flu-like symptoms.

Warning

Two transcript flags on the biologics slides: the citation is given as Drug Design, Development and Therapy 2027, 11:3137-3144, a year that appears to postdate the lecture’s other dates but was transcribed exactly as printed; and the second biologics slide is visually identical to the first, likely a duplicate or animation-build pair in the source deck.

Guideline placement of the drug classes

GINA 2024 asthma, adults and adolescents 12+

Management is personalised through a continuous cycle of Assess, Adjust treatment, Review response:

• Assess: confirmation of diagnosis, symptom control and modifiable risk factors (including lung function), comorbidities, inhaler technique and adherence, patient (and for children, parent) preferences and goals.
• Adjust: treat modifiable risk factors and comorbidities, non-pharmacological strategies, asthma medications including ICS (adjusted up or down), education and skills training.
• Review: symptoms, exacerbations, side-effects, lung function, patient satisfaction.

Underpinning this: establish a patient-doctor partnership, and teach and reinforce essential skills, namely inhaler skills, adherence, and guided self-management education with a written asthma action plan, self-monitoring and regular medical review.

Track 1 (preferred controller and reliever, ICS-formoterol as reliever):

1. Steps 1 to 2: as-needed-only low dose ICS-formoterol.
2. Step 3: low dose maintenance ICS-formoterol.
3. Step 4: medium dose maintenance ICS-formoterol.
4. Step 5: add-on LAMA, refer for phenotype assessment, consider high dose maintenance ICS-formoterol, ± anti-IgE, anti-IL5/5R, anti-IL4Rα, anti-TSLP.
   Reliever throughout: as-needed low dose ICS-formoterol.

Track 2 (alternative controller and reliever):

1. Step 1: take ICS whenever SABA is taken.
2. Step 2: low dose maintenance ICS.
3. Step 3: low dose maintenance ICS-LABA.
4. Step 4: medium or high dose maintenance ICS-LABA.
5. Step 5: add-on LAMA, refer for phenotype assessment, consider high dose maintenance ICS-LABA, ± anti-IgE, anti-IL5/5R, anti-IL4Rα, anti-TSLP.
   Reliever: as-needed ICS-SABA, or as-needed SABA.

Other controller options (limited indications, less evidence): low dose ICS whenever SABA taken, daily LTRA, or add HDM SLIT; medium dose ICS, add LTRA, or add HDM SLIT; add LAMA or LTRA, add HDM SLIT-only, or switch to high dose ICS-only; add azithromycin (adults) or add LTRA. As a last resort consider adding low dose oral corticosteroid, weighing side-effects.

Stable COPD (COPD-X Plan, NZ/Australia 2022)

• Severity by typical symptoms and lung function: mild FEV1 ~60 to 80% predicted, moderate ~40 to 59%, severe < 40%.
• Confirm the diagnosis with spirometry: post-bronchodilator FEV1/FVC < 0.70.
• Non-pharmacological plan of care: reduce risk factors (avoid tobacco and pollution, influenza and pneumococcal vaccination); optimise function (exercise, nutrition, GP action plan); optimise treatment of comorbidities (cardiovascular disease, anxiety, depression, lung cancer, osteoporosis); refer symptomatic patients to pulmonary rehabilitation; initiate advanced care planning in moderate and severe disease; manage advanced lung disease with domiciliary oxygen, long-term non-invasive ventilation, surgery or bronchoscopic interventions in severe disease.
• Pharmacological sequence: start with short-acting relievers (SABA or SAMA, as needed); add long-acting bronchodilators (LAMA or LABA, considering a LAMA/LABA combination depending on symptomatic response); then consider adding ICS. Single-inhaler triple therapy (ICS/LABA/LAMA) may suit patients with ≥1 severe exacerbation requiring hospitalisation or ≥2 moderate exacerbations in the previous 12 months plus significant symptoms despite LAMA/LABA or ICS/LABA, or patients already stabilised on LABA + LAMA + ICS.
• At every visit: assess and optimise inhaler device technique, and minimise inhaler device polypharmacy.

Self-test

1. State Hagen-Poiseuille’s law for airway resistance and explain what happens to resistance if airway radius is halved.
2. List the receptor inputs shown on the airway smooth muscle cell and state which G protein each couples to and whether it favours contraction or relaxation.
3. Describe the steps by which a β2-agonist relaxes airway smooth muscle, from receptor to ion channel.
4. Explain how β2-agonists affect the airway epithelium and why this is therapeutically useful.
5. Give the onset and duration of bronchodilation for salbutamol, and state how it should be dosed.
6. Explain what happens if a SABA is used at regular fixed intervals rather than as required.
7. Describe the mechanism by which β2-agonists cause hypokalaemia, and state the size and duration of the fall in plasma potassium.
8. Explain why a patient on high-dose salbutamol may become tachycardic despite salbutamol being β2-selective.
9. Distinguish salmeterol from formoterol in terms of onset of action and consequent therapeutic role.
10. Explain why a single-ingredient LABA must not be prescribed alone in asthma, and what the 2005 FDA warning stated.
11. Describe what MART therapy is and the properties of formoterol that make it possible.
12. Distinguish the airway actions of M2 and M3 muscarinic receptors, and predict the effect of a drug that blocks M2 preferentially.
13. Using the receptor-drug complex half-lives, explain why tiotropium is dosed once daily while ipratropium is short acting.
14. Distinguish the role of the vagal cholinergic component in COPD from that in chronic severe asthma, and state how this changes where LAMAs are used.
15. Describe the steps by which eosinophil recruitment to airway nerves increases acetylcholine release after antigen challenge.
16. Give the onset, duration and main indications of ipratropium, and explain why it rarely causes CNS effects.
17. Describe the disposition of an inhaled dose of tiotropium and state its effective half-life.
18. What is the spirometric cut-off that confirms a diagnosis of COPD, and what are the FEV1 bands for mild, moderate and severe disease?
19. List the pharmacological steps of stable COPD management in order, and state the criteria for single-inhaler triple therapy.
20. Explain what the Parkin et al. 2021 material says about the real-world benefit and cardiovascular uncertainty of long-acting bronchodilators in COPD.
21. List the four mechanisms by which magnesium sulphate may help in acute severe asthma.
22. Describe the arachidonic acid pathway from membrane phospholipid to the cysteinyl leukotrienes, and name the other branch and its products.
23. List the four downstream effects of CysLT1 receptor activation that montelukast blocks.
24. State the main limitation of montelukast’s mechanism and the principal long-term safety concern.
25. Using the trial table, compare the change in FEV1 and β2-agonist use for montelukast 10 mg versus beclomethasone 200 μg BID in adults.
26. Describe the mechanism of mepolizumab and the time course of its effect on eosinophil numbers.
27. State the route, dose frequency and main safety concerns of mepolizumab.
28. Outline GINA Track 1 from Step 1 to Step 5, naming the reliever used throughout.
29. Distinguish GINA Track 1 from Track 2 in terms of controller and reliever.
30. A patient with asthma also has hypertension. Explain which β-blockers are absolutely avoided, which require caution, and why.
31. A COPD patient on a LAMA/LABA combination has had two moderate exacerbations in the past year and remains symptomatic. Explain what change the COPD-X plan supports and why an ICS was not used first.
32. Integrative: a patient with severe eosinophilic asthma is already on high dose maintenance ICS-formoterol with an add-on LAMA. Explain, using the mechanisms in this lecture, how adding an anti-IL-5 antibody targets a part of the disease the bronchodilators and muscarinic antagonists cannot.

Answers

Reveal answers

1. $R=\frac{8\eta L}{\pi r^4}$, where $\eta$ is dynamic viscosity, $L$ airway length and $r$ airway radius. Halving the radius increases resistance 16-fold.
2. ACh at M2 (Gi) and M3 (Gq); noradrenaline/adrenaline at β2 (Gs), which drives AC and cAMP toward relaxation; cysteinyl leukotrienes (LTC4, LTD4, LTE4) at CysLT1. The Gq arm signals through PLC-β to DAG/IP3 and Ca2+, producing contraction; ACh and leukotriene inputs favour contraction, the β2/cAMP input favours relaxation.
3. The agonist activates the β2 receptor, raising cAMP, which activates PKA; PKA increases conductance of Ca2+-sensitive K+ (K+Ca) channels in airway smooth muscle, causing hyperpolarisation and relaxation, and so inhibiting bronchial constriction.
4. Raised epithelial cAMP increases ciliary beat frequency, which improves mucus and allergen clearance.
5. Onset 5 to 15 minutes, bronchodilator effect lasting 2 to 5 hours. Dose as required (p.r.n.), at the lowest possible dose, and only as a second-tier approach.
6. Regular fixed-interval use causes β2-receptor downregulation, decreased bronchoprotection, rebound hyperresponsiveness, decreased bronchodilator response, and increased allergic response and eosinophilic airway inflammation.
7. Stimulation of β2-adrenoceptors in liver and skeletal muscle with frequent use increases Na+/K+-ATPase activity, possibly through cAMP, increasing K+ uptake from plasma. Intensive treatment lowers plasma K+ by 0.4 to 0.9 mmol/L for up to 1 hour, causing myocardial hyperexcitability; caution with diuretics.
8. β2 receptors in the heart can still be activated; at high doses selectivity is lost so β1 receptors are stimulated, increasing rate and force; and β2-mediated peripheral vasodilation lowers diastolic BP, producing reflex tachycardia.
9. Salmeterol has onset ~10 to 20 minutes, peak ~1 to 2 hours and does not give rapid relief, so it is a twice-daily maintenance drug. Formoterol has rapid onset (<1 to 3 minutes, Cmax ~6 minutes) with ~12 hour duration, so it can serve as both maintenance and reliever in MART.
10. LABAs do not treat the underlying inflammation, so they must be paired with a controller such as an inhaled corticosteroid; single-ingredient LABAs should never be used alone and are not approved as rescue inhalers. In 2005 the FDA warned that LABAs could potentiate bronchospasm.
11. MART is single-inhaler Maintenance And Reliever Therapy using budesonide-formoterol (Symbicort). Formoterol is a potent β2-agonist that is fast acting (onset <1 to 3 minutes, Cmax ~6 minutes) yet long acting (~12 hours), so it replaces the need for a separate SABA; pairing with the ICS budesonide makes the combination well tolerated.
12. On airway smooth muscle M3 mediates contraction and mucus secretion, while M2 counteracts muscle relaxation; neuronal M2 receptors provide negative feedback limiting further ACh release. Blocking M2 preferentially removes that feedback and may allow further ACh outflow, so selective M3 blockade is what reduces bronchoconstriction.
13. Tiotropium forms long-lived receptor-drug complexes (M1 14.6 h, M2 3.6 h, M3 34.7 h), with the longest at M3, and has an effective half-life of 27 to 45 hours, supporting once-daily dosing. Ipratropium’s complexes are very short lived (M1 0.11 h, M2 0.035 h, M3 0.26 h), giving a duration of only 3 to 5 hours.
14. In COPD there is a major reversible bronchoconstrictor component mediated by the neural cholinergic effect, so SAMAs and LAMAs are advocated as core therapy. In chronic or severe refractory asthma cholinergic stimulation is secondary, although increased night-time vagal stimulation may contribute, so LAMAs are used as an add-on at night or at Stage 4/5.
15. After antigen challenge, eotaxin acting through CCR3 recruits eosinophils to the airway nerve via ICAM-1; the eosinophils release major basic protein, which antagonises the inhibitory M2 autoreceptor; loss of that negative feedback increases ACh release and increases M3 signalling on airway smooth muscle. Airway hyper-reactivity correlates with activated eosinophils around airway nerves.
16. Peak spirometric improvement at 30+ minutes, duration 3 to 5 hours; most useful in COPD, with benefit in acute asthma and emphysema, and an additive effect when given with a β2-agonist. It does not cross the blood-brain barrier, so CNS effects are generally absent.
17. Most of the delivered dose is deposited in the GI tract where it is degraded; a smaller amount reaches the lung, from which about 17% may become systemically bioavailable. It is actively secreted renally. Maximum plasma concentration is at 5 to 7 minutes after inhalation and the effective half-life is 27 to 45 hours.
18. Post-bronchodilator FEV1/FVC < 0.70 on spirometry. Mild FEV1 ~60 to 80% predicted, moderate ~40 to 59%, severe < 40%.
19. Start with short-acting relievers (SABA or SAMA) as needed; add a long-acting bronchodilator (LAMA or LABA), considering a LAMA/LABA combination depending on symptomatic response; then consider adding an ICS. Single-inhaler triple therapy suits patients with ≥1 severe exacerbation requiring hospitalisation or ≥2 moderate exacerbations in the previous 12 months plus significant symptoms despite LAMA/LABA or ICS/LABA, or those already stabilised on LABA + LAMA + ICS.
20. Inhaled bronchodilators give only modest benefit in COPD, and combination LABA/LAMA appears to give only minimal benefit over monotherapy. Cardiovascular risks are uncertain and little is known about the cardiovascular risk of combination relative to monotherapy, which is why acute coronary syndrome risk on mono- versus dual therapy is of interest.
21. It is a cofactor in numerous enzymatic reactions; it decreases ACh release at the motor end plate on bronchial smooth muscle; it acts as a physiological Ca2+ antagonist; and it increases adenylyl cyclase production of cAMP. Replacement may also correct depletion caused by frusemide, disease or β2-adrenergic stimulation.
22. Phospholipases release arachidonic acid from membrane phospholipids. The 5-lipoxygenase branch yields leukotriene B4 (chemotaxis) and the cysteinyl leukotrienes LTC4, LTD4 and LTE4. The cyclooxygenase branch yields prostacyclin (vasodilation), prostaglandin E1 (vasodilation) and thromboxane A2 (vasoconstriction).
23. Plasma exudation, mucus secretion, bronchoconstriction and eosinophil recruitment.
24. It affects only the leukotriene pathway among the many pathways in operation, so the effect may be limited. The main long-term concern is neuropsychiatric adverse effects (suicidality, nightmares, behavioural problems), subject to an FDA boxed warning issued in March 2020 and a TGA warning.
25. Beclomethasone 200 μg BID gave ΔFEV1 +13.1% and a 40% reduction in β2-agonist use; montelukast 10 mg HS gave ΔFEV1 +7.4% and a 24% reduction; placebo gave +0.7% and 0%. The inhaled steroid outperformed montelukast on both measures.
26. IL-5 binds the α chain of the IL-5 receptor on eosinophils and to a lesser extent basophils and is key to their maturation, activation, proliferation and survival. Mepolizumab is a humanized monoclonal that binds IL-5 with high affinity and specificity, reducing IL-5 availability and signalling through the IL-5Rα/βc complex, reducing the eosinophil-driven inflammatory cascade, promoting eosinophil apoptosis and reducing eosinophil numbers within 4 weeks.
27. Subcutaneous by pre-filled pen (auto-injector) or pre-filled safety syringe, 300 mg/mL once monthly. It must not be used for acute asthma exacerbations, carries a risk of opportunistic infections such as herpes zoster, and commonly causes headaches, nausea, injection-site pain, fatigue, back pain and flu-like symptoms.
28. Steps 1 to 2 as-needed-only low dose ICS-formoterol; Step 3 low dose maintenance ICS-formoterol; Step 4 medium dose maintenance ICS-formoterol; Step 5 add-on LAMA, refer for phenotype assessment, consider high dose maintenance ICS-formoterol ± anti-IgE, anti-IL5/5R, anti-IL4Rα, anti-TSLP. The reliever throughout is as-needed low dose ICS-formoterol.
29. Track 1 uses ICS-formoterol as both controller and reliever. Track 2 uses maintenance ICS then ICS-LABA as controller, with as-needed ICS-SABA or as-needed SABA as reliever, and begins at Step 1 with taking ICS whenever a SABA is taken.
30. Non-selective β-blockers, propranolol and carvedilol, must not be used in asthmatics because they block β2-receptor activation and aggravate asthma. Partially β1-selective agents (metoprolol, atenolol) and highly β1-selective agents (bisoprolol) require caution in asthma and COPD. No β-blocker is entirely safe in asthma.
31. COPD-X supports adding an ICS, potentially as single-inhaler triple therapy, since the patient has ≥2 moderate exacerbations in the previous 12 months and significant symptoms despite LAMA/LABA. An ICS is not used first because glucocorticoid inhalers should not be used to initiate bronchodilator therapy in COPD.
32. β2-agonists and muscarinic antagonists act on smooth muscle tone, raising cAMP or removing cholinergic drive, and the LAMA additionally addresses the vagal component that is prominent at night; none of them treats the underlying inflammation. Anti-IL-5 therapy removes the cytokine that drives eosinophil maturation, activation, proliferation and survival, reducing eosinophil numbers within 4 weeks. That matters mechanistically because eosinophils recruited to airway nerves release major basic protein, which blocks the inhibitory M2 autoreceptor and increases ACh release onto M3 receptors, and because eosinophil-derived mediators feed the leukotriene-driven bronchoconstriction, mucus secretion and plasma exudation. Removing the eosinophil population therefore attacks the cause of the hyper-reactivity that the bronchodilators only offset symptomatically.