What is the mechanism of action of albuterol (bronchodilator) in treating bronchospasm in conditions like asthma and chronic obstructive pulmonary disease (COPD)?

Albuterol Mechanism of Action

Albuterol works by selectively stimulating β2-adrenergic receptors on airway smooth muscle, which activates adenyl cyclase to increase cyclic AMP production, ultimately causing smooth muscle relaxation and bronchodilation. 1

Molecular Mechanism

• Albuterol binds with high affinity to β2-adrenergic receptors located throughout the bronchial tree, with the highest receptor density in alveolar regions 2, 1
• The drug stimulates adenyl cyclase, the enzyme that catalyzes the formation of cyclic-3',5'-adenosine monophosphate (cyclic AMP) from adenosine triphosphate (ATP) 1
• The cyclic AMP thus formed mediates the cellular responses that lead to bronchial smooth muscle relaxation 1

Receptor Selectivity

• Albuterol demonstrates preferential β2-adrenergic receptor activity compared to non-selective agents like isoproterenol, producing greater bronchodilation with fewer cardiovascular effects at comparable doses 1
• While β2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, 10-50% of beta-receptors in the human heart are also β2-receptors, which explains some cardiovascular side effects 1
• The (R)-enantiomer of albuterol (levalbuterol) binds to the β2-adrenergic receptor with high affinity, while the (S)-enantiomer binds with 100-fold less affinity 3

Physiological Effects in Airways

Bronchodilators like albuterol act by relaxing airway smooth muscle in both proximal and distal airways, which increases airway luminal diameter and reduces airway resistance 2

Flow and Volume Responses

• Albuterol produces "flow responses" by increasing FEV1 through reduction of airway resistance caused by airway narrowing 2
• The drug also generates "volume responses" by reducing end-expiratory lung volumes, allowing more volume to be exhaled and improving inspiratory capacity 2
• These volume improvements can occur even when there is little or no flow response measured by FEV1, as reduced end-expiratory lung volumes improve the mechanical efficiency of diaphragm contraction and decrease work of breathing 2

Clinical Pharmacology

• Onset of bronchodilation occurs within 5 minutes, with maximum improvement in pulmonary function typically at approximately 1 hour following inhalation 1
• Duration of action is 3-4 hours in most patients, with some patients experiencing effects up to 6 hours 1
• Albuterol is longer acting than isoproterenol because it is not a substrate for cellular uptake processes for catecholamines nor for catechol-O-methyl transferase 1
• Less than 20% of a single albuterol dose is absorbed following nebulizer administration, with most of the absorbed dose recovered in urine within 24 hours 1

Additional Mechanisms Beyond Bronchodilation

• Bronchodilators improve the mechanical functioning of small airways, reducing heterogeneity and preventing or delaying airway closure, which facilitates volumetric responses 2
• In COPD specifically, albuterol reduces dynamic hyperinflation during exercise by allowing increased expiratory time, which decreases operational lung volumes and work of breathing responsible for dyspnea on exertion 2

Important Clinical Caveats

• The magnitude of response varies considerably between patients and even within the same patient from test to test 2
• In more severe COPD, flow responses are smaller due to expiratory flow limitation from small airway collapse, which limits improvements after bronchodilator administration 2
• Paradoxical bronchoconstriction is a rare but serious complication that can occur with albuterol administration, though the true mechanism remains unknown 4
• Albuterol can cause a fall in PaO2 due to pulmonary vascular effects, which distinguishes it from anticholinergic agents 2