Long-acting beta-adrenoceptor agonist

Salmeterol—an example of long-acting β₂ adrenoreceptor agonist

Long-acting β adrenoceptor agonists (LABAs, more specifically, long-acting β₂ adrenergic receptor 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 (albuterol), 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, β adrenoceptor agonists can improve symptoms.^[1][2] In children this benefit is uncertain and they may be potentially harmful.^[2] They should not be used without an accompanying steroid due to an increased risk of severe symptoms, including exacerbation in both children and adults.^[3][4][5][6] At least with formoterol, an increased risk appears to be present even when steroids are used^[7] and this risk has not been ruled out for salmeterol.^[8]

Agents

Some of the currently available long-acting β₂ adrenoceptor agonists include:
INN: Trade (brand) name

• arformoterol: Brovana (some consider it to be an ultra-LABA)^[9]
• bambuterol: Bambec, Oxeol
• clenbuterol: Dilaterol, Spiropent
• formoterol: Foradil, Oxis, Perforomist
• salmeterol: Serevent
• Protokylol

Ultra-LABAs

Several long-acting β adrenoreceptor agonists have a duration of action of 24 hours, allowing for once-daily dosing. They are considered to be ultra-long-acting β adrenoreceptor agonists (ultra-LABAs)^[10] and are now approved.

• indacaterol: approved by the European Medicines Agency (EMA) on November 30, 2009,^[11] and by Russian FDA-equivalent under the trade name Onbrez Breezhaler. In the United States. it was approved by the Food and Drug Administration (FDA) under the trade name Arcapta Neohaler on July 1, 2011)^[12]
• olodaterol: approved in some EU countries and Russia, and by the United States FDA on July 31, 2014 under Striverdi Respimat^[13]
• vilanterol is the ultra-LABA not available by itself but only as a component of combination drugs:
  • with fluticasone furoate: Breo Ellipta (U.S.), Relvar Ellipta (EU, RU). This second medication in this combination is the synthetic inhaled corticosteroid fluticasone furoate. This product was approved by the FDA on May 2013 as once-daily inhaled therapy for the treatment of chronic obstructive pulmonary disease (COPD)
  • with umeclidinium bromide: Anoro Ellipta. Umeclidinium bromide is a long-acting muscarinic antagonist.^[14] This combination was approved by the FDA on December 18, 2013^[15] for the long-term maintenance treatment of COPD. On March 28, 2014, it was approved in European countries^[16] and in Russia^[17] under the same trade name

Ultra-LABAs under development

• abediterol (codenamed LAS100977)^[18][19]
• salmefamol (salbutamol and para-methoxyamphetamine (PMA) hybrid)

Failed agents

• carmoterol (formerly TA-2005):^[19] development terminated^[20]
• PF-610355: development terminated^[21]

Concerns

While the use of inhaled LABAs are still recommended in asthma guidelines for the resulting improved symptom control,^[22] 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).^[23] This seems to occur because although LABAs relieve asthma symptoms, they also promote bronchial inflammation and sensitivity without warning.^[24]

On February 18, 2011, the FDA issued a safety alert for long-acting β agonists.^[25]

References