Why are long-acting beta-adrenoceptor agonists long-acting?
- PMID: 7912202
- DOI: 10.1183/09031936.94.07030569
Why are long-acting beta-adrenoceptor agonists long-acting?
Abstract
The extended duration of bronchodilation due to formoterol and salmeterol greatly exceeds that of short acting beta 2-adrenoceptor agonists, such as salbutamol or terbutaline. This extended duration and their capacity to "reassert" airway smooth muscle relaxation in vitro despite repeated washing has prompted considerable debate on the underlying mechanism(s). The comparative pharmacology, and molecular modelling of these drugs and of the beta 2-adrenoceptor and its ligand binding core have cast doubt on the exosite/exoceptor model previously proposed to explain the behaviour of salmeterol. We present evidence supporting a unifying hypothesis that the duration of action both of formoterol and salmeterol is determined principally by their physicochemical interactions with membrane lipid bilayers (plasmalemma diffusion microkinetic model), rather than putative distinct exosite/exoceptor binding sites in or near the beta 2-adrenoceptor. This model provides a clearer understanding of the pharmacological profile of these drugs (rate of onset, duration, "reassertion", interaction with hydrophilic and hydrophobic beta 2-adrenoceptor antagonists), and explains why in human airway smooth muscle in vitro a true relaxation-concentration response may not exist for salmeterol.
Similar articles
-
Long acting inhaled beta-adrenoceptor agonists the comparative pharmacology of formoterol and salmeterol.Agents Actions Suppl. 1993;43:253-69. doi: 10.1007/978-3-0348-7324-6_22. Agents Actions Suppl. 1993. PMID: 8103622
-
Extent of salmeterol-mediated reassertion of relaxation in guinea-pig trachea pretreated with aliphatic side chain structural analogues.Br J Pharmacol. 1996 Mar;117(6):1009-15. doi: 10.1111/j.1476-5381.1996.tb16690.x. Br J Pharmacol. 1996. PMID: 8882590 Free PMC article.
-
Pharmacological similarities and differences between beta2-agonists.Respir Med. 2001 Aug;95 Suppl B:S7-11. doi: 10.1053/rmed.2001.1139. Respir Med. 2001. PMID: 11534896 Review.
-
Relaxation kinetics of formoterol and salmeterol in the guinea pig trachea in vitro.Lung. 1996;174(3):159-70. doi: 10.1007/BF00173308. Lung. 1996. PMID: 8830192
-
Pharmacological basis for duration of effect: formoterol and salmeterol versus short-acting beta 2-adrenoceptor agonists.Lung. 1996;174(1):1-22. doi: 10.1007/BF00167947. Lung. 1996. PMID: 8746998 Review.
Cited by
-
Clinical pharmacokinetics of AZD3199, an inhaled ultra-long-acting β2-adrenoreceptor agonist (uLABA).Drug Des Devel Ther. 2015 Feb 5;9:753-62. doi: 10.2147/DDDT.S66049. eCollection 2015. Drug Des Devel Ther. 2015. PMID: 25709399 Free PMC article. Clinical Trial.
-
Estimation of the dissociation rate of unlabelled ligand-receptor complexes by a 'two-step' competition binding approach.Br J Pharmacol. 2010 Nov;161(6):1311-28. doi: 10.1111/j.1476-5381.2010.00931.x. Br J Pharmacol. 2010. PMID: 20946109 Free PMC article.
-
Inhaled β2-agonists in asthma management: an evolving story.Breathe (Sheff). 2016 Dec;12(4):375-377. doi: 10.1183/20734735.017116. Breathe (Sheff). 2016. PMID: 28210324 Free PMC article.
-
Different effects of salmeterol, formoterol and salbutamol on cholinergic responses in the ferret trachea.Br J Pharmacol. 1995 Apr;114(7):1478-82. doi: 10.1111/j.1476-5381.1995.tb13373.x. Br J Pharmacol. 1995. PMID: 7606351 Free PMC article.
-
Formoterol. An update of its pharmacological properties and therapeutic efficacy in the management of asthma.Drugs. 1998 Feb;55(2):303-22. doi: 10.2165/00003495-199855020-00016. Drugs. 1998. PMID: 9506248 Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Miscellaneous
