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Susceptibility to Tolerance and ß2-Adrenoceptor Polymorphism
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Daniel K C Lee, MBBCh, MRCP, MD Department of Respiratory Medicine, Ipswich Hospital, Heath Road, Ipswich IP4 5PD, Suffolk, England, Graeme P Currie, Aberdeen Royal Infirmary, Scotland, Catherine M Jackson, Tayside Centre for General Practice, Scotland, Kean C Khoo, Llandough Hospital, Wales, Brian J Lipworth, Asthma and Allergy Research Group, University of Dundee, Scotland
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dkclee{at}doctors.org.uk Daniel K C Lee, et al.
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Salpeter and colleagues examined the development of tolerance to the effects of regular ß2-agonist therapy in patients with asthma (1). However, the authors failed to mention the important influence of ß2- adrenoceptor polymorphism on the propensity for desensitization of response following regular ß2-agonist use. In particular, patients with the homozygous arginine-16 ß2-adrenoceptor genotype have been shown to have poorer outcomes of asthma control following regular albuterol use (2). In asthmatic patients who were washed out of the effects of ß2- agonist therapy, acute systemic ß2-adrenoceptor-mediated responses to a single bolus of inhaled albuterol were enhanced in subjects expressing the homozygous arginine-16/glutamine-27 haplotype, which in turn suggested a greater propensity for desensitization of response on chronic exposure (3). In asthmatic patients receiving concomitant inhaled corticosteroids, the greatest degree of desensitization of response for protection against bronchoconstriction was observed in association with the arginine-16 polymorphism, especially with the homozygous arginine-16/glutamine-27 haplotype, following regular exposure to long-acting ß2-agonist therapy (4). In the same study, there was greater tolerance with formoterol compared to salmeterol, which occurred in patients expressing the arginine -16 polymorphism, for protection against bronchoconstriction. This phenomenon may be explained by a higher degree of ß2-adrenoceptor intrinsic activity in the former compared to the latter, whereby prolonged 24-hour receptor occupancy would result in enhanced agonist-induced receptor down-regulation and desensitization of response (5). Thus, while it is tempting to evaluate mean data from the meta- analysis of Salpeter and colleagues, it is more clinically relevant to consider individual responses, particularly as susceptibility to tolerance is genetically determined by ß2-adrenoceptor polymorphism. Indeed in the real life clinical situation, one sees an individual rather than an average patient. Daniel K C Lee, MBBCh, MRCP, MD, Department of Respiratory Medicine, Ipswich Hospital, Heath Road, Ipswich IP4 5PD, England, UK Graeme P Currie, MBChB, DCH, MRCP, MD, Department of Respiratory Medicine, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZN, Scotland, UK Catherine M Jackson, MBChB, MRCGP, Tayside Centre for General Practice, University of Dundee, Kirsty Semple Way, Dundee DD2 4BF, Scotland, UK Kean C Khoo, MBBCh, MRCP, Department of Respiratory Medicine, Llandough Hospital, Penlan Road, Penarth CF64 2XX, Wales, UK Brian J Lipworth, BMedSci, MBChB, MD, FRCP, FRCPE, Asthma and Allergy Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK References 1. Salpeter SR, Ormiston TM, Salpeter EE. Meta-analysis: respiratory tolerance to regular beta2-agonist use in patients with asthma. Ann Intern Med. 2004;140:802-13. 2. Israel E, Drazen JM, Liggett SB, Boushey HA, Cherniack RM, Chinchilli VM et al. The effect of polymorphisms of the beta2-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med. 2000;162:75-80. 3. Lee DK, Bates CE, Lipworth BJ. Acute systemic effects of inhaled salbutamol in asthmatic subjects expressing common homozygous beta2- adrenoceptor haplotypes at positions 16 and 27. Br J Clin Pharmacol. 2004;57:100-104. 4. Lee DK, Currie GP, Hall IP, Lima JJ, Lipworth BJ. The arginine-16 beta2-adrenoceptor polymorphism predisposes to bronchoprotective subsensitivity in patients treated with formoterol and salmeterol. Br J Clin Pharmacol. 2004;57:68-75. 5. Linden A, Bergendal A, Ullman A, Skoogh BE, Lofdahl CG. Salmeterol, formoterol, and salbutamol in the isolated guinea pig trachea: differences in maximum relaxant effect and potency but not in functional antagonism. Thorax. 1993;48:547-53. Conflict of Interest:None declared |
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