Tolerance to the Nonbronchodilator Effects of Inhaled β₂-Agonists in Asthma

Abstract

We observed tolerance to the nonbronchodilator actions of the inhaled beta 2-agonist terbutaline in patients with mild asthma, an effect that may be more pronounced in mast cells than in bronchial smooth muscle. This property of beta-agonists may constitute a drawback to their regular use in patients with asthma.

Beyond the dogma: novel 2-adrenoceptor signalling in the airways

“…Asthma deaths, adverse events and effect of glucocorticoids Long-term use of b 2 -adrenoceptor agonists is common in the management of asthma and airways hyperresponsiveness (AHR), which is defined as an increase in the sensitivity of the ASM to constrictor stimuli [129][130][131][132]. Similarly, the ability of short-and long-acting b 2 -adrenoceptor agonists to protect the airways against bronchoconstrictor stimuli and to promote bronchodilatation may be partially lost with time following long-term use [2,129,131,[133][134][135][136][137][138][139][140].…”

“…Similarly, the ability of short-and long-acting b 2 -adrenoceptor agonists to protect the airways against bronchoconstrictor stimuli and to promote bronchodilatation may be partially lost with time following long-term use [2,129,131,[133][134][135][136][137][138][139][140]. Indeed, there is a greater tendency for bronchodilator tolerance to develop to longacting b 2 -adrenoceptor agonists compared to their short-acting counterparts, which may relate to some aspect of their prolonged duration of agonism [141,142].…”

The pharmacogenetics of asthma: a candidate gene approach

“…Clinically, desensitization is typically termed tachyphylaxis, which refers to a loss of clinical effectiveness of a therapeutic agent upon repetitive administration. In asthma, chronic ␤-agonist administration has been associated with tachyphylaxis in some 18,19 but clearly not all 20,21 studies. In addition, excessive ␤-agonist use has been associated with increased asthma mortality 22 and morbidity.…”

Ex vivo pharmacologic modulation of basophil histamine release in asthmatic patients

“…On the other hand, salmeterol was found to reduce spontaneous histamine release. We used three patient groups to study the effects of treatment: a small group of nine inhaled corticosteroids-treated patients tested twice, before and after 1 month of salmeterol treatment, in order to show that salmeterol decreased histamine release; a second group of seven patients treated with inhaled corticosteroids and salmeterol tested at a 3-month interval to examine whether tachyphylaxis might occur, as had been observed for the nonbronchodilating activities of salmeterol (38)(39)(40); and a larger group of 21 patients receiving long-term treatment with inhaled corticosteroids and salmeterol. First, salmeterol was shown to reduce spontaneous but not anti-IgEinduced histamine release, confirming that salmeterol, a long-acting P,-agonist, has similar in vitro and ex vivo properties.…”

“…However, some studies have been inconclusive (37), and tolerance of the nonbronchodilator effects of salmeterol has been observed (38)(39)(40). Twenty control subjects and 78 asthmatic patients with variable disease severity were studied to examine 1 ) whether the spontaneous and anti-IgE release of histamine from blood basophils was correlated with the severity of asthma and its stability, and 2) the e x vivo effects of inhaled corticosteroids or salmeterol on histamine release from the basophils of asthmatic patients.…”