Bronchodilators

Bronchodilators relax airway smooth muscle to widen the lumen of bronchi and bronchioles. The two major pharmacological classes are beta-2 adrenergic receptor agonists (B2AR agonists) and muscarinic receptor antagonists (antimuscarinics).

Beta-2 agonists bind B2-ARs on bronchial smooth muscle → Gs activation → adenylate cyclase → increased cAMP → PKA activation → (1) increased K+ conductance via Ca2+-activated K+ channels (KCa) → hyperpolarisation; (2) decreased IP3 → decreased Ca2+ release from intracellular stores; (3) decreased MLCK → decreased myosin-actin interaction → bronchodilation. B2-AR activation on airway epithelium also increases ciliary beat frequency → improved mucous and allergen clearance. Variability in patient response arises from polymorphisms in B2-AR gene sequences and CYP enzyme genes.

SABAs (short-acting beta-2 agonists) — salbutamol: highly selective for B2-AR (200x more than B1). Inhaled administration. Onset: 5-15 min; duration: 2-5 hours. Indication: rescue/reliever in asthma and COPD. Use lowest dose possible. ADRs: with regular fixed-interval use — receptor downregulation, decreased bronchoprotection, rebound hyperresponsiveness, increased eosinophilic inflammation. At high doses: tremor (peripheral skeletal muscle B2), tachycardia (cardiac B2 or reflex from vasodilation), hypokalaemia (B-AR stimulation of Na+/K+-ATPase in liver and skeletal muscle → K+ uptake from plasma; hypokalaemia → QT prolongation → re-entrant arrhythmia). Tolerance with frequent use.

LABAs (long-acting beta-2 agonists) — salmeterol and formoterol: lipophilic side-chains resist degradation, prolonging T½. Salmeterol: onset 10-20 min; peak 1-2h; duration ~12h; for nocturnal asthma, exercise-induced asthma, and add-on in COPD. Formoterol: onset 1-3 min; peak ~6 min; duration ~12h; for maintenance AND reliever therapy (MART = single inhaler Maintenance And Reliever Therapy using formoterol + budesonide = Symbicort). LABAs must always be combined with ICS — they cannot be used as monotherapy (do not address inflammation).

Muscarinic receptor antagonists: target M3 receptors on bronchial smooth muscle (which cause bronchoconstriction via Gq → IP3 → Ca2+). M1 blockade is unwanted (disrupts neurotransmission); M2 blockade on presynaptic neurons removes negative feedback on ACh release (may worsen bronchoconstriction). Thus, M3 selectivity is desired. In asthma, airway hyper-reactivity correlates with eosinophil presence around airway nerves: eosinophils release MBP (major basic protein) which antagonises presynaptic M2 receptors → increased ACh release → worsened bronchoconstriction.

SAMAs (short-acting muscarinic antagonists) — ipratropium: M3-selective; inhaled; given with B2-agonist; peak onset 30+ min; duration 3-5h; most useful in COPD and emphysema; benefit in acute asthma. ADRs (rare, from muscarinic antagonism): dry mouth, headache, GI motility disorders, urinary retention, blurred vision. Does not cross BBB (no CNS effects).

LAMAs (long-acting muscarinic antagonists) — tiotropium: M3-selective; dry powder or aqueous inhaler; once-daily; T½ 27-45h; mainly GI and renal clearance. Most useful in COPD (with LABA = synergistic effect); less benefit in asthma (add-on at last steps of treatment plan only). Same ADRs as ipratropium.

Cholinergic stimulation plays a major role in COPD bronchoconstriction (neural cholinergic effect is the primary reversible component) — hence SAMAs and LAMAs are important in COPD. In asthma, CysLTs are the primary bronchoconstrictors; cholinergic stimulation is secondary (increased at night → nocturnal asthma → LAMAs indicated at night or late in treatment plan).

Other bronchodilators: montelukast (LTRA — oral, blocks CysLT1R → prevents bronchoconstriction and allergen/exercise-induced response; adjunctive or alternative to ICS; fewer benefits than low-dose ICS; long-term ADRs include suicidality risk in children); mepolizumab (anti-IL-5 monoclonal antibody — reduces eosinophil survival and numbers; SC injection monthly; adjunctive therapy at step 5 of asthma plan; for severe eosinophilic asthma; do not use for acute exacerbations); magnesium sulphate IV (for acute severe asthma — cofactor in cAMP production → bronchodilation; decreases ACh release at motor end plate; physiological Ca2+ antagonist).