Introduction to Respiratory Pharmacology

Asthma is a chronic inflammatory airway disease characterised by inflammatory cell infiltration, airway wall thickening and remodelling, increased mucous production, and airway hyperresponsiveness — leading to excessive bronchial smooth muscle constriction in response to numerous stimuli. GINA defines asthma as a heterogeneous disease characterised by chronic airway inflammation, with respiratory symptoms (wheeze, dyspnoea, chest tightness, cough) that vary over time and in intensity, together with variable expiratory airflow limitation.

In atopic asthma, dendritic cells present allergen to naive T cells → TH2 cell activation → cytokine release (IL-4, IL-5, IL-13) → IgE-producing plasma cells, mast cell priming, basophil and eosinophil recruitment → release of inflammatory mediators (histamine, prostaglandins, leukotrienes, cytokines). These mediators cause: epithelial damage, goblet cell hyperplasia and mucus hypersecretion, subepithelial fibrosis, vasodilation, increased vascular permeability, angiogenesis, and smooth muscle hyperresponsiveness. Non-atopic asthma follows a similar TH1-mediated pathway that does not respond to allergens.

Pre-formed mediators (stored in mast cell/basophil granules before stimulus): histamine, heparin, chemotactic factors, neutral proteases, acid hydrolases. Newly synthesised mediators (produced after stimulus): eicosanoids — metabolites of arachidonic acid via two pathways.

Lipoxygenase pathway produces leukotrienes. Leukotriene B4 (LTB4): chemotaxis of inflammatory cells; releases reactive oxygen species. Cysteinyl leukotrienes (LTC4, LTD4, LTE4 — formerly called SRSA, slow-reacting substance of anaphylaxis): bronchoconstriction via CysLT1 receptor on bronchial smooth muscle; vasoconstriction; increased vascular permeability; oedema.

COX pathway produces prostanoids. PGD2: bronchoconstriction, vasodilation, increased vascular permeability. TXA2: bronchoconstriction, vasoconstriction. PGE1 attenuates the lipoxygenase pathway (negative feedback). NSAIDs inhibit COX → reduce prostanoids (including PGE1) → remove the negative feedback on the lipoxygenase pathway → increased leukotriene production → can trigger asthma or rhinitis in susceptible patients (within 1-3 hours of ingestion).

Bronchoconstriction mechanisms in the airway smooth muscle: (1) M2 muscarinic receptors — parasympathetic ACh stimulation activates Gi → inhibits adenylate cyclase → decreased cAMP → decreased PKA activity → decreased bronchodilation. (2) M3 muscarinic receptors — ACh activates Gq → phospholipase C-beta → IP3 and DAG → increased intracellular Ca2+ → smooth muscle contraction. (3) CysLT1 receptors — cysteinyl leukotrienes activate Gq → IP3 → increased Ca2+ → contraction; these have synergistic effects with M3 receptors.

Bronchodilation occurs via beta-2 adrenergic receptors (B2-ARs) on bronchial smooth muscle: agonist → Gs → adenylate cyclase → increased cAMP → PKA → increased K+ conductance (hyperpolarisation), decreased IP3, decreased MLCK → relaxation. Increased epithelial cAMP also increases ciliary beat frequency and improves mucous clearance.

Treatment goals in asthma: reduce airway remodelling with anti-inflammatories; relax airway smooth muscle with beta-2 agonists and muscarinic antagonists; prevent mast cell activation with LTRAs. SABA monotherapy is not advocated. Mast cell stabilisers are largely ineffective in asthma.