Long-acting beta-adrenoceptor agonist

Long-acting beta-adrenoceptor agonists (LABAs, more specifically β₂-agonists) are usually prescribed for moderate to severe persistent asthma patients or patients with chronic obstructive pulmonary disease (COPD). They are designed to reduce the need for shorter-acting β₂-agonists such as salbutamol, as they have a duration of action of approximately 12 hours in comparison with the 4- to 6-hour duration of salbutamol, making them candidates for sparing high doses of corticosteroids or treating nocturnal asthma and providing symptomatic improvement in patients with COPD. With the exception of formoterol, long-acting β₂-agonists are not recommended for the treatment of acute asthma exacerbations because of their slower onset of action compared to salbutamol. Their long duration of action is due to the addition of a long, lipophilic side-chain that binds to an exosite on adrenergic receptors. This allows the active portion of the molecule to continuously bind and unbind at β₂ receptors in the smooth muscle in the lungs.

Medical uses

When combined with inhaled steroids, beta-adrenoceptor agonists can improve symptoms.^[1][2] In children this benefit is uncertain and they may be potentially harmful.^[2][3] They should not be used without an accompanying steroid due to an increased risk of severe symptoms, including exacerbation in both children and adults.^[4][5][6][7] At least with formoterol, an increased risk appears to be present even when steroids are used^[8] and this risk has not been ruled out for salmeterol.^[9]

Agents

Some currently available long-acting beta-adrenoceptor agonists are:

• Salmeterol
• Formoterol
• Bambuterol

Three ultra-long-acting beta-adrenoceptor agonists that have a duration of action of 24 hours, allowing for once-daily dosing^[10] are now approved.

• Indacaterol (approved by the European Medicines Agency (EMA) under the trade name Onbrez on November 30, 2009,^[11] and by the United States Food and Drug Administration (FDA) under the trade name Arcapta Neohaler, on July 1, 2011^[12])
• Olodaterol (approved in some European countries and by the United States Food and Drug Administration (FDA) on July 31, 2014 under Striverdi^[13])
• Vilanterol (combination of the synthetic inhaled corticosteroid fluticasone furoate (FF) and the long-acting beta2-adrenergic agonist vilanterol trifenatate was approved by US Food and Drug Administration (FDA) in May 2013 as once-daily inhaled therapy for the treatment of chronic obstructive pulmonary disease (COPD). The product is called Breo Ellipta in the United States and Relvar Ellipta in Europe.^[14]
• Carmoterol (Under Development)^[15]
• LAS100977 (Under Development)^[15]
• PF-610355 (Under Development)^[15]
• Salmefamol (Salbutamol + PMA hybrid).

Concerns

While the use of inhaled LABAs are still recommended in asthma guidelines for the resulting improved symptom control,^[16] further concerns have been raised, by a large meta-analysis of the pooled results from 19 trials with 33,826 participants, that salmeterol may increase the small risks of asthma deaths, and this additional risk is not reduced with the additional use of inhaled steroids (e.g., as with the combination product Fluticasone/salmeterol).^[17] This seems to occur because although LABAs relieve asthma symptoms, they also promote bronchial inflammation and sensitivity without warning.^[18]

References

In 2011, the FDA issued a safety alert for Long-Acting Beta-Agonists (LABAs):

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm201003.htm