Mechanism of action of albuterol
Pro Research Analysisby 
Searched over 200M research papers
Mechanism of Action of Albuterol
Introduction to Albuterol and Its Enantiomers
Albuterol, a widely used bronchodilator, is commonly administered to relieve symptoms of asthma and chronic obstructive pulmonary disease (COPD). It exists as a racemic mixture composed of two enantiomers: (R)-albuterol and (S)-albuterol. These enantiomers exhibit distinct pharmacological properties, influencing their therapeutic and adverse effects.
Bronchodilatory Effects of (R)-Albuterol
Beta2-Adrenergic Receptor Activation
(R)-Albuterol primarily exerts its bronchodilatory effects by activating beta2-adrenergic receptors on airway smooth muscle cells. This activation leads to the stimulation of adenylate cyclase, increasing cyclic AMP (cAMP) levels, which in turn causes relaxation of the smooth muscle and bronchodilation1 7. Additionally, (R)-albuterol has been shown to decrease intracellular calcium concentrations, further contributing to muscle relaxation2 7.
Anti-Inflammatory Properties
(R)-Albuterol also exhibits anti-inflammatory effects. It can suppress the production of inflammatory mediators such as granulocyte macrophage-colony stimulating factor (GM-CSF) via pathways involving inducible nitric oxide synthase (iNOS)6. This anti-inflammatory action is specific to (R)-albuterol and is not observed with the (S)-enantiomer3 6.
Pro-Constrictory and Pro-Inflammatory Effects of (S)-Albuterol
Activation of Pro-Constrictory Pathways
In contrast to (R)-albuterol, (S)-albuterol has been associated with pro-constrictory effects. It increases the expression and activity of Gialpha-1 proteins and intracellular calcium concentrations, which can lead to bronchoconstriction1 2. These effects are dose-dependent and can counteract the bronchodilatory effects of (R)-albuterol when both enantiomers are present in racemic albuterol1 2.
Pro-Inflammatory Pathways
(S)-Albuterol has been shown to activate pro-inflammatory pathways, including the activation of phosphatidylinositol 3'-OH-kinase (PI3K) and nuclear factor kappaB (NF-kappaB)1. It also increases the production of histamine and interleukin-4 (IL-4) in mast cells, contributing to inflammation and potentially exacerbating asthma symptoms5.
Clinical Implications of Racemic Albuterol
Efficacy and Safety Concerns
The presence of (S)-albuterol in racemic albuterol formulations can diminish the overall therapeutic efficacy of the drug. (S)-albuterol's pro-constrictory and pro-inflammatory effects can negate the beneficial bronchodilatory and anti-inflammatory actions of (R)-albuterol3 10. This has led to the development and use of levalbuterol, a formulation containing only (R)-albuterol, which may offer improved therapeutic outcomes with fewer adverse effects10.
Beta2-Adrenergic Receptor Tolerance
Chronic use of racemic albuterol can lead to beta2-adrenergic receptor tolerance, reducing the drug's effectiveness over time. This tolerance is mediated through mechanisms upstream of protein kinase A and can be reversed by corticosteroids, which enhance the receptor's responsiveness4.
Conclusion
Albuterol's mechanism of action is complex due to the distinct effects of its enantiomers. While (R)-albuterol provides bronchodilatory and anti-inflammatory benefits, (S)-albuterol can induce bronchoconstriction and inflammation. Understanding these differences is crucial for optimizing asthma and COPD treatment, potentially favoring the use of levalbuterol over racemic albuterol to minimize adverse effects and improve patient outcomes.
Sources and full results
Most relevant research papers on this topic
(S)-Albuterol activates pro-constrictory and pro-inflammatory pathways in human bronchial smooth muscle cells.
(S)-albuterol activates pro-constrictory pathways and pro-inflammatory pathways in human bronchial smooth muscle cells, potentially explaining the detrimental effects of chronic racemic albuterol in airway diseases like bronchial asthma.
In Vitro Study(S)-Albuterol increases intracellular free calcium by muscarinic receptor activation and a phospholipase C-dependent mechanism in airway smooth muscle.
(S)-albuterol increases intracellular free calcium in airway smooth muscle, potentially contributing to bronchial hyperresponsiveness, while (R)-albuterol decreases it, potentially affecting asthma treatment.
In Vitro Study
Highly CitedModulation of T-cell function by (R)- and (S)-isomers of albuterol: anti-inflammatory influences of (R)-isomers are negated in the presence of the (S)-isomer.
The (R)-isomer of albuterol has anti-inflammatory effects, while the (S)-isomer can stimulate proliferation in T-cells, potentially acting as an inverse agonist.
In Vitro StudyHighly CitedSteroids completely reverse albuterol-induced beta(2)-adrenergic receptor tolerance in human small airways.
Steroids can prevent or reverse beta(2)-adrenergic receptor desensitization in human small airways, potentially improving the efficacy of bronchodilators in asthma and chronic obstructive pulmonary disease.
In Vitro StudyHighly Cited(S)-Albuterol Increases the Production of Histamine and IL-4 in Mast Cells
(S)-albuterol may have adverse effects in asthma control by activating mast cells to produce inflammatory mediators like histamine and IL-4, while (R)-albuterol has no effect on mast cell mediator release.
In Vitro Study(R)-albuterol elicits antiinflammatory effects in human airway epithelial cells via iNOS.
(R)-albuterol exhibits antiinflammatory effects in human airway epithelial cells via iNOS, a novel pathway for beta2-adrenergic agonists.
In Vitro StudyEffects of albuterol isomers on the contraction and Ca2+ signaling of small airways in mouse lung slices.
(R)-albuterol induces greater airway relaxation than racemic albuterol, with (S)-albuterol being responsible for reduced efficacy in asthma patients.
In Vitro StudyInhaled albuterol/salbutamol and ipratropium bromide and their combination in the treatment of chronic obstructive pulmonary disease
Combination albuterol-ipratropium therapy was once an innovative treatment for COPD, but newer treatments have surpassed its advantages in improving airflow and simplifying therapy.
Systematic ReviewAlbuterol modulates its own transepithelial flux via changes in paracellular permeability.
Albuterol mainly crosses the epithelium via the paracellular pathway, but can modulate its own permeability through changes in tight junction leakiness, influenced by the (2)-adrenergic receptor signaling.
In Vitro StudyContrasting properties of albuterol stereoisomers.
(S)-albuterol may intensify allergic bronchospasm and promote eosinophil activation in asthmatic airways, making levalbuterol a potential asthma treatment option.
Highly Cited