Rapid Onset of Tolerance to the Bronchoprotective Effect of Salmeterol

Bhagat, Rajesh; Kalra, Sanjay; Swystun, Veronica A.; Cockcroft, Donald W.

doi:10.1378/chest.108.5.1235

Cited by 155 publications

(82 citation statements)

References 28 publications

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“…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].…”

Section: Long-term Use Of B 2 -Adrenoceptor Agonistsmentioning

confidence: 99%

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

Giembycz

Newton²

2006

European Respiratory Journal

132

118

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b 2 -Adrenoceptor agonists evoke rapid bronchodilatation and are the mainstay of the treatment of asthma symptoms worldwide. The mechanism of action of this class of compounds is believed to involve the stimulation of adenylyl cyclase and subsequent activation of the cyclic adenosine monosphosphate (cAMP)/cAMP-dependent protein kinase cascade.This classical model of b 2 -adrenoceptor-mediated signal transduction is deeply entrenched, but there is compelling evidence that agonism of b 2 -adrenoceptors can lead to the activation of multiple effector pathways, which now compels researchers in academia and the pharmaceutical industry alike to think beyond the traditional dogma. Therefore, the regulation by b 2 -adrenoceptor agonists of responses, including airways smooth muscle tone and the secretory capacity of the epithelium and pro-inflammatory/immune cells, may be highly complex, involving both cAMPdependent and -independent mechanisms that, in many cases, may act in concert.In this article, the current status of b 2 -adrenoceptor-mediated signalling in the airways is reviewed in the context of understanding mechanisms that may underlie both the beneficial and detrimental effects of these drugs in asthma symptom management.

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Section: Long-term Use Of B 2 -Adrenoceptor Agonistsmentioning

confidence: 99%

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

Giembycz

Newton²

2006

European Respiratory Journal

132

118

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“…This led to widespread use of LABA along with low dose ICS, mostly in fixed dose formulations. This continued despite the observations made by Bhagat et al [20] that the long term use of LABA along with low dose ICS led to tolerance. The underlying reason for the same was unrevealed by animal studies showing that ICS in optimal doses is critical to avoid pro-inflammatory effects of β 2 agonists and if threshold of total β 2 agonist exposure is crossed, ICS may fail to protect against these adverse effects of β 2 agonists [21][22][23][24].…”

Section: Low Dose Ics Along With Labamentioning

confidence: 91%

“…Animal studies have already shown that β 2 agonists can be proinflammatory if used for long time [21][22][23]. Clinically also, Bhagatet al [20] have shown that Long Term use of LABA with low dose ICS may lead to tolerance.…”

Section: Step Down In Asthmamentioning

confidence: 99%

Flaws in GINA Guidelines and the Solutions Thereof

Gupta¹

2017

Austin J Allergy

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Asthma continues to be the commonest chronic respiratory illness and its prevalence is on the rise. Further, its control remains poor in spite of the wide availability and practice of GINA guidelines. Based on literature, the author is of the opinion that asthma can be better controlled with "Step in-Step down approach" (Initiating treatment of asthma with optimal dose of ICS along with LABA, withdrawal of LABA first during step down and finally reducing dose of ICS once control of asthma is sustained) rather than the Step up-step down approach" suggested by GINA.

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“…6) However, many asthmatics can not be sufficiently managed by b 2 AR agonist therapy, and continuous use of inhaled b 2 AR agonist might induce receptor tolerance that limits the efficacy of these drugs and ultimately results in a loss of bronchoprotective effect. [7][8][9] One of the potential mechanisms that limit the therapeutic efficacy of b 2 AR agonists is desensitization and degradation of ASM b 2 ARs following either acute or chronic exposure to b 2 AR agonists. The badrenergic system has a very tight negative feedback mechanism as an adaptive response to either stimulation or blockade of the receptors.…”

mentioning

confidence: 99%

“…10) It is then followed by a decrease in receptor density and receptor gene expression, which is known as downregulation, and this process develops within hours of stimulation. 7,11,12) Overall, desensitization and downregulation of b 2 ARs could eventually lead to the loss of pharmacological effect of the b 2 AR agonists 13) and potentially increase exacerbation of asthma control. 14,15) On the other hand, in the cardiac system, Burniston et al 16) have found that the administration of b 2 AR agonist tends to be detrimental to cardiac and skeletal muscles even at low doses by directly and indirectly inducing apoptosis of these two kinds of cells through b 2 ARs.…”

mentioning

confidence: 99%