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Antagonist Activity of Formoterol and Salmeterol Thorax: First Published As 10.1136/Thx.51.1.54 on 1 January 1996

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Antagonist Activity of Formoterol and Salmeterol Thorax: First Published As 10.1136/Thx.51.1.54 on 1 January 1996 54 Thorax 1996;51:54-58 Evaluation of the 132 adrenoceptor agonist/ antagonist activity of formoterol and salmeterol Thorax: first published as 10.1136/thx.51.1.54 on 1 January 1996. Downloaded from A Grove, B J Lipworth Abstract ist), salmeterol and formoterol, like Background - Salmeterol and formoterol propranolol, exhibited P2 receptor ant- have a lower intrinsic activity at P2 re- agonism as evidenced by their attenuation ceptors than isoprenaline in human bron- of P2 receptor mediated responses. The chus in vitro. The aim ofthe present study degree of P2 blockade with formoterol and was to evaluate in vivo the P2 agonistlant- salmeterol was comparable but less than agonist activity of salmeterol and for- with propranolol. The relevance of these moterol at rest with low endogenous findings at extrapulmonary P2 receptors adrenergic tone, on exercise with raised with regard to airway P2 responses remains endogenous adrenergic tone, and in the unclear and warrants further in- presence of fenoterol, an exogenous full P2 vestigation. receptor agonist. (Thorax 1996;51:54-58) Methods - Eight normal subjects were ran- domised to receive single doses ofplacebo, Keywords: salmeterol, formoterol, 02 agonist/ant- salmeterol 300 sg, formoterol 72 pg, or pro- agonist, intrinsic activity. pranolol 80 mg at weekly intervals. P2 adrenoceptor responses were evaluated at rest, at peak exercise, and after treatment Salmeterol and formoterol are potent long act- with fenoterol 2 4 mg. ing 2 receptor agonists. The potency of these Results - At rest salmeterol and formoterol drugs will determine the dose required to pro- exhibited equivalent P2 agonist activity duce a given effect, but it is important to with regard to decrease in serum potas- appreciate that factors other than potency may sium levels and increase in finger tremor, influence the expression of their 12 agonist with propranolol having no effect. Sal- activity. Both salmeterol and formoterol have meterol and formoterol, like propranolol, a lower intrinsic activity than isoprenaline in http://thorax.bmj.com/ potentiated the hyperkalaemic delta re- human bronchus in vitro, and therefore at sat- sponse to exercise compared with placebo, urating concentrations will produce a lower consistent with P2 antagonism: (mean maximal response, with salmeterol having a difference and 95% confidence interval lower efficacy than formoterol.' In other words, (CI) compared with placebo) salmeterol they are less efficient than a full agonist at 0-20 (0.02 to 0.38) mmol/l, formoterol 0-17 activating the receptor transduction mech- (0.00 to 0.34) mmol/l, propranolol 0 45 anism required to produce a maximal cellular to blunted (0.08 0.82) mmol/l. Propranolol response. Thus, as partial agonists the ex- on September 30, 2021 by guest. Protected copyright. the heart rate delta response to exercise, pression oftheir P2 agonist or antagonist activity consistent with P, blockade, whilst sal- may be modulated by the presence of a full 12 meterol and formoterol had no effect. Sal- agonist such as isoprenaline or adrenaline. It meterol and formoterol, like propranolol, could be predicted from first principles that, attenuated the hypokalaemic, tremor, and in the presence of a low concentration of a full heart rate delta responses to fenoterol agonist, salmeterol and formoterol would be compared with placebo, in keeping with P2 expected to behave as 12 agonists, occupying blockade: potassium, salmeterol 0-18 (0.0 additional receptors and therefore augmenting to 0.36) mmol/l, formoterol 0-17 (-0.03 the overall response. However, in the presence to 0.37) mmolll, propranolol 0-80 (0.54 to ofhigh concentrations ofa full agonist they may 1-06) mmolll; tremor, salmeterol -0-69 behave as 12 antagonists because, by occupying (-1.26 to -0.12) log units, formoterol receptors that would otherwise have been oc- Department of -0-71 (-1.53 to 0.11) log units, pro- cupied by the full agonist, they will reduce the Clinical pranolol -0 85 (-166 to -0.04) log units; Pharmacology, overall response.2 Ninewells Hospital and heart rate, salmeterol -6 (-13 to 1) beats/ By evaluating the 12 receptor mediated Medical School, min, formoterol -10 (-19 to -1) beats/ modulation of exercise-induced hyperkalaemia University of Dundee, propranolol -18 (-29 to -7) beats/ to raised levels of Dundee DD1 9SY, UK min, due endogenous adrenaline, A Grove min. we have previously shown that oral salbutamol B J Lipworth Conclusions - At rest with low endogenous exhibits P2 antagonist effects at extrapulmonary Reprint requests to: adrenergic tone salmeterol and formoterol 12 receptors in vivo.' We were therefore in- Dr B J Lipworth. showed equivalent P2 mediated agonist terested to investigate whether similar effects Received 30 January 1995 activity in terms of serum potassium and occurred with inhaled long acting 12 agonists Retumed to authors 20 July 1995 finger tremor responses. In the presence given that they, like salbutamol, are not full 12 Revised version received of raised endogenous adrenergic tone at receptor agonists. 14 August 1995 Accepted for publication peak exercise and in the presence of feno- The aim of the present study was to evaluate 4 September 1995 terol (an exogenous full P2 receptor agon- in vivo P2 agonist/antagonist activity of sal- /2 agonistlantagonist activity offormoterol and salmeterol 55 meterol and formoterol at extrapulmonary 02 MEASUREMENTS receptors at rest when there is low endogenous Heart rate was monitored and recorded using adrenergic tone, and during exercise when a 12-lead electrocardiograph with stress test endogenous adrenergic tone is high. adaptor (HP4700A, Hewlett Packard, Palo Thorax: first published as 10.1136/thx.51.1.54 on 1 January 1996. Downloaded from Furthermore, recent in vitro data have shown Alto, California, USA). Heart rate was cal- that salmeterol inhibits fenoterol and sal- culated from the mean of five consecutive R-R butamol induced relaxation in precontracted intervals. Postural finger tremor was measured guinea pig airways.4 Thus, 12 receptor mediated by a previously validated method9 with an responses were also evaluated in the presence accelerometer transducer (Entran Ltd, Ealing, offenoterol, an exogenous full P2 receptor agon- UK) attached to the distal phalanx of the ist.5-7 Propranolol was included as a positive middle finger. Each measurement consisted of control for the effects of 1,3 and 12 receptor four recordings, the results ofwhich were stored antagonism. on computer disc for subsequent spectral ana- lysis of total tremor power >2 Hz (units mg2/s) using computer assisted autocovariance. The mean of three consistent recordings was used Methods in subsequent analysis. Serum potassium was SUBJECTS analysed by flame photometry (IL943 analyser, Eight healthy volunteers (two women) with a Instrumentation Lab Ltd, Warrington, UK), mean (SE) age of 27 (1 9) years completed the samples being analysed in batches at the end study. Each volunteer had a normal physical of the study with each sample analysed in examination including 12-lead ECG, haem- duplicate. The normal reference range for our atological and biochemical screen prior to in- laboratory is 3 5-5 5 mmol/l, and the co- clusion in the study. None of the subjects was efficients ofvariability for analytical imprecision taking regular medication. The study was within and between assays are 041 % and approved by the local ethics committee, and 1 04%, respectively. subjects gave informed written consent. STATISTICAL ANALYSIS Finger tremor data were transformed using PROTOCOL logarithm to base 10 to achieve conformation A single blind randomised (Latin square) cross- to a normal distribution prior to analysis. Data over, placebo controlled design was used. Sub- were then analysed using the Statgraphics soft- jects attended the laboratory on four occasions ware package (STSC Software, Rockville, at least one week apart. USA). Effects at rest and in response to exercise An intravenous cannula was inserted into a and fenoterol were all analysed as delta re- http://thorax.bmj.com/ forearm vein to allow blood sampling. After 30 sponses - that is, the difference between the minutes of supine rest baseline measurements response before and after drug administration (to) of heart rate, postural finger tremor, and (tl-t0), before and after exercise (t2-tl), and serum potassium were made. Subjects then before and after fenoterol (t4-t3). Comparisons received inhaled salmeterol 300 jig (Serevent were made by multifactorial analysis ofvariance metered dose inhaler, 25 gg per actuation, Allen (MANOVA) using subjects, treatments, and and Hanburys, Uxbridge, Middlesex, UK), or time as within factors for the analysis. Where inhaled formoterol 72 gg (Foradil metered dose the overall MANOVA was significant, Dun- on September 30, 2021 by guest. Protected copyright. inhaler, 12 gig per actuation, Ciba-Geigy, Basel, can's multiple range testing was used to estab- Switzerland), or inhaled placebo or oral pro- lish where differences between treatments were pranolol, 80 mg, with double dummies as ap- significant. Differences from placebo, where propriate. One hour after administration of the significant, were calculated as means and 95% drugs measurements of potassium, heart rate, confidence intervals. A probability value of and tremor were repeated (t,) and subjects then p<005 (two tailed) was considered significant underwent a standardised three minute exercise for all tests. step test in order to produce a maximal heart rate response.8 Peak exercise
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