Bases of respiratory pharmacology

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Regulation of bronchial tone

Bronchial smooth muscle lacks direct sympathetic innervation, but responds avidly to circulating catecholamines and exogenous drugs through a high density of β₂adrenergic receptors. In contrast, parasympathetic control is the main physiological determinant of airway tone, mediated by the vagus nerve and the body's muscarinic receptors.

• β₂ Adrenergic Pathway (Bronchodilator): Coupled to G_s protein. Agonist binding stimulates adenylate cyclase (AC), elevating cyclic adenosine monophosphate (cAMP). This activates protein kinase A (PKA), which catalyzes the phosphorylation of myosin light chain kinase (MLCK), inactivating it, and promotes cellular calcium efflux, inducing deep muscle relaxation.
• Muscarinic Cholinergic Pathway (Bronchoconstrictor): The release of acetylcholine activates M₃ receptors coupled to G_q protein, activating phospholipase C (PLC) that generates inositol triphosphate (IP₃) and diacylglycerol (DAG). IP₃ induces the rapid release of calcium from the sarcoplasmic reticulum, causing immediate muscle contraction.

The molecular affinity constant of the ligands and the dissociation kinetics of these receptors determine the duration and selectivity of the bronchodilation effect:

Desensitization Mechanism of the β_{2 Receptor}

Continuous and prolonged exposure to β₂ agonists induces receptor phosphorylation by G protein-coupled receptor kinases (GRKs) and subsequent binding of β-arrestin. This process promotes the uncoupling of the G_s protein and the internalization of the receptor into cellular endosomes (downregulation). Clinically, this manifests as drug tolerance, a phenomenon that is prevented by co-administration of corticosteroids.

Inflammatory phenotypes: Asthma vs. COPD

The immune response of the respiratory mucosa defines the optimal pharmacological profile of intervention:

• TYPE 2 INFLAMMATION (ASTHMA) Orchestrated by Th2 lymphocytes, type 2 innate lymphoid cells (ILC2), eosinophils and mast cells. Key cytokines: IL-4 (IgE induction), IL-5 (eosinophil maturation and recruitment) and IL-13 (bronchial hyperreactivity and remodeling). It responds with high sensitivity to glucocorticoids.
• NON-TYPE 2 INFLAMMATION / COPD Predominance of neutrophils, alveolar macrophages and CD8+ T lymphocytes. Driven by mediators such as IL-8, tumor necrosis factor alpha (TNF-α) and leukotriene LTB₄. It is characterized by marked resistance to corticosteroids due to the inactivation of histone deacetylase 2 (HDAC2) by oxidative stress.