Salbutamol and other β2-adrenoceptor agonists
BronchoconstrictionBronchodilatorsSelectivity of β2-agonistsLong-acting β2-agonists (LABA)Limitations

β2 agonists like salbutamol cause airway smooth muscle relaxation by increasing intracellular cAMP levels. They are fairly specific to airway smooth muscle, especially when inhaled. They have no direct effects on inflammatory processes or cough reflexes. For some asthma patients, occasional relief with a β2 agonist as required is sufficient to control their disease. More persistent cases require add-on therapies, such as inhaled glucocorticosteroids.

Why the airways contain smooth muscle is a bit of a mystery, since bronchoconstriction doesn’t appear to have many adaptive advantages. Bronchoconstriction occurs prior to cough, and this narrowing of the airways probably helps to generate increased shear forces to remove mucus. This brief bronchoconstriction is produced by firing of cholinergic parasympathetic nerves innervating the airways and quickly reverses. Prolonged bronchoconstriction – as seen in asthma and other inflammatory airway diseases – causes airflow limitation and can be life-threatening. Part of the bronchoconstriction seen in such diseases may be mediated by cholinergic mechanisms, but a significant proportion is caused by a vast number of inflammatory mediators. Reversing this type of bronchoconstriction can’t be achieved with a single receptor antagonist and another approach is required.

The current pharmacological approach to treating bronchoconstriction that is caused by multiple mediators is physiological antagonism. Rather than giving a drug that blocks the receptors for inflammatory mediators (there are too many), we simply appose bronchoconstriction using β2-agonists which cause airway smooth muscle to relax. Most mediators that cause bronchoconstriction do so by binding to G-protein coupled receptors (GPCR) that initiate signalling via the DAG and PLC pathways which lead to increased concentrations of intracellular calcium and contraction in airway smooth muscle (Figure 1). β2-adrenoceptors are also GPCR, but they couple instead adenylate cyclase, increasing the concentration of the second messenger cyclic AMP (cAMP). cAMP causes smooth muscle relaxation through several mechanisms, including promoting the lowering of intracellular calcium concentrations and decreasing the sensitivity of the contractile apparatus to calcium.


Figure 1: Many inflammatory mediators cause bronchoconstriction by acting on specific receptors, all of which are linked to increases in intracellular Ca2+ and contraction via the PLC and DAG pathway. β2 agonists and adrenaline act at β2-adrenoceptors and signal via increases in cAMP, which cause relaxation instead. This mechanism of action is sometimes described as functional (or physiological) antagonism. All the bronchoconstrictor mediators are still present, binding to their receptors and trying to cause contraction, but β2 agonists have the opposite effect, limiting or completely reversing bronchospasm.

Selectivity of β2-agonists
Prior to the development of β2-selective agonists, treatment options were limited to adrenaline and isoprenaline. Adrenaline binds to all α- and β-adrenoceptors causing not only bronchodilation (β2) but increased heart rate (β1) and vasoconstriction (mainly α1). Because of the cardiovascular effects, adrenaline is generally not used today, even in status asthmaticus. Isoprenaline on the other hand has affinity for both β1 and β2 receptors, limiting the cardiovascular side effects to tachycardia. Modern β2-selective agonists have the obvious advantage that they have the highest affinity for β2-adrenoceptors in the airways. However, there are some β2 receptors in the heart, so some tachycardia is still seen when β2 agonists are used, especially when used in heroic doses in status asthmaticus. Other common side-effects such as tremor are related to β2 receptors on other cells types and unavoidable.

Long-acting β2-agonists (LABA)
One of the few improvements that have been made to β2-agonists over the last 30 years is their duration of action. Conventional short-acting β2-agonists (SABA) produce effects that last 4-6 hours, whereas more recent long-acting β2-agonists (LABA) last 8-12 hours. LABA such as salmeterol are ideal for patients who suffer nocturnal symptoms, and may need to be prescribed when symptoms aren’t adequately controlled by SABA. Because asthma treatment guidelines are designed to wean patients onto the minimal required maintenance mediation, LABA are not used in the first instance in mild asthma. Patients are also more aware of their symptom frequency when they use SABA to abort attacks, rather than LABA which may mask them.


  • β2-agonists only produce bronchodilation; they have no effect on the inflammatory processes that underlie the pathology of the asthma syndrome, or other inflammatory lung diseases. These must be targeted with anti-inflammatory drugs such as glucocorticosteroids.
  • A problematic property of airway smooth muscle is that it is more difficult to relax the more contracted it is. Drugs like salbutamol have less of an effect in vitro when airway smooth muscle is contracted maximally with contractile agonists such as acetylcholine. This may partly explain why nebulised β2-agonists have limited effects in severe bronchoconstriction.
  • Excess mucus production causes two problems for the delivery of β2-agonists. Firstly, mucus lining the airways adds an additional barrier for the drug to diffuse through. Secondly, plugging of airways with mucus will prevent any inhaled drug from reaching the lower airways. There are no treatments for severe airway mucus plugging.
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