Inhaled β₂-agonists

Mechanism of Action

The pathophysiology of asthma involves IgE-sensitised mast cells releasing inflammatory mediators that are responsible for bronchospasm, such as leukotrienes. Leukotrienes cause bronchoconstriction and attract eosinophils into the lungs; eosinophils also produce leukotrienes 

β₂-agonists primarily work by dilating the bronchi via direct action on β₂-adrenoceptors located on bronchial smooth muscle, leading to smooth muscle relaxation via an increase in cAMP. Other effects of β₂-agonists include the following:

• Inhibition of mediator release from mast cells, such as histamine, leukotrienes and prostaglandin D₂
• Inhibition of TNF-α release from monocytes
• Increase mucociliary clearance via stimulation of ciliary activity

Created in BioRender. Boucher, M. (2026) https://BioRender.com/fj8d3in

Fig 1: Mechanism of Action of Bronchodilators such as β2 agonists, theophylline and muscarinic antagonists

Pharmacokinetics

Although we are discussing these agents in the context of inhalation and β₂-agonists are elicit their bronchodilator effect locally in the lung, estimates suggest that around 80% of the drug administered via inhalation is swallowed and absorbed from the gastrointestinal tract. Plasma concentration data is useful for assessing potential systemic exposure and side effects; however it does not accurately reflect the proportion of drug active within the lung.

Once β₂-agonists have acted locally in the lung, the drug is either rapidly absorbed into the systemic circulation or excreted. This absorption process is reflected in peak plasma concentrations observed for formoterol, where there are two Cmax peaks:

• the first at 5 minutes post-inhalation (reflecting lung absorption)
• the second at around 2 hours (reflecting gastrointestinal absorption).

Inhaled SABA Pharmacokinetics

Short acting agents include salbutamol and terbutaline, which are given via inhalation and act immediately (within 5 minutes), and usually used on an as needed basis. The duration of action of both salbutamol and terbutaline is 3-5 hours.

Terbutaline acts topically in the lung and has a low bioavailability of 16%. Maximum plasma concentrations are reached after ~1.3hrs and terbutaline has a half-life (t½) of approximately 12 hours. 

Salbutamol is not metabolised in the lung. The t½ of salbutamol ranges from 2-7 hours, with the latter associated with inhalation. When ingested orally, salbutamol is well absorbed from the GI tract and is subject to first pass metabolism. 

Available formulations:

Inhaled LABA Pharmacokinetics

Long acting agents such as formoterol also act rapidly (1-3 minutes), however the effect is still significant after 12 hours of dosing. A peak plasma concentration is observed at 5 minutes post inhalation, suggesting absorption into the systemic circulation via the lung.  Formoterol is eliminated by metabolism, catalysed by several CYP450 enzymes such as CYP2D6, -2C19, -2C9 and -2A6. 

Salmeterol acts locally in the lung and the duration of the effect also lasts for 12 hours. There is limited data on the pharmacokinetics of salmeterol due to very low plasma concentrations observed after inhalation.

Due to their longer duration of action, LABAs are generally given regularly twice daily.

Available formulations:

Cautions and Adverse Effects

Unwanted effects are often a result of systemic absorption and include:

• Tremor
• Tachycardia
• cardiac dysrhythmia

These effects tend to be transient. 

Nebulised salbutamol can be used in the treatment of hyperkalaemia [unlicensed in the UK]; therefore in high doses can cause hypokalaemia, this is more likely with nebulised and intravenous salbutamol use. For these reasons, salbutamol use is cautioned in arrhythmias, cardiovascular disease, hypokalaemia, hyperthyroidism and susceptibility to QT prolongation.

β₂-agonists can also cause hyperglycaemia and increase the risk of ketoacidosis, therefore should be used with caution in diabetes mellitus. Furthermore, they may stimulate thyroid activity so caution is required in hyperthyroidism. 

Patients requiring more than two doses of short acting β₂-agonists weekly (not including prophylactic use) should have a review of their asthma control, as this suggests potential poor control of asthma.

With inhalation, there is a very rare risk of paradoxical bronchospasm, often attributed to non-active components in the formulation such as preservatives or propellants. Signs include immediate wheeze and shortness of breath after dosing, which can be treated with a fast-acting inhaled bronchodilator such as salbutamol. If this reaction occurs, therapy should be discontinued and an alternative sought. 

Interactions

When Β₂-agonists are used alongside theophylline and aminophylline (used in the treatment of asthma), hypokalaemia can occur. The same interaction applies for other drugs that can cause hypokalaemia such as diuretics, laxatives and corticosteroids. Furthermore, hypokalaemia may increase the risk of digoxin toxicity. 

Use of Β₂-agonists alongside Β-blockers, especially the non-selective Β-blocker propranolol, antagonises the action of β₂-agonists.

Theoretically, concomitant treatment with other drugs that prolong the QTc-interval may increase the risk of ventricular arrhythmias, such as TCAs, erythromycin and quinidine, although this risk is very rare with β₂-agonists.

Formoterol may interact with MAO-Is and should be avoided for up to 14 days after discontinuation of MAO-I. 

Concomitant use of ketoconazole increases salmeterol exposure through CYP3A4 inhibition, this may lead to increased incidence of side effects such as palpitations and QTc prolongation. 

References

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