Dose-effect relationship of the beta-agonists fenoterol and salbutmol in patients with asthma

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Date: June 1994
From: Chest(Vol. 105, Issue 6)
Publisher: Elsevier B.V.
Document Type: Article
Length: 3,432 words

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Question: What is the relative per microgram potency and side effect profile of the [beta]-agonists salbutamol and fenoterol? Method: The relative bronchodilator ([delta] [FEV.sub.1] V25, V50) potency and side effect profile ([delta] tremor, heart rate, breathlessness, BP) of nebulized salbutamol and fenoterol were evaluated by means of a randomized, double-blind, crossover, cumulative (50 to 2,500 [mu]g) dose-response study. Both [beta]-agonists were administered to 12 patients with stable asthma over age 18 years with baseline [FEV.sub.1] between 35 to 70 percent predicted. Results: (1) Salbutamol and fenoterol both provided significant bronchodilatation compared with baseline. (2) There was no dose-effect difference between the two [beta]-agonists with respect to bronchodilator response. (3) Overall there was no significant difference between the side effect profiles of the two [beta]-agonists, although at the highest dose of fenoterol, there was marginally greater tremor when measured by accelerometry. (4) There was no difference in the vital signs or subjective patient evaluation of tremor, palpitations, or breathlessness as estimated by a visual analogue scale. (5) No significant adverse reactions occurred. Summary and conclusion: Equivalent bronchodilatation and similar side effect profiles were measured in a group of patients with stable asthma after treatment with nebulized salbutamol or fenoterol in the dose range 50 to 1,250 [mu]g (cumulative, 2,500 [mu]g). This indicates that both [beta]-agonists have similar per microgram potency and side effect profiles. Observed clinical differences in response or side effects associated with fenoterol metered-dose inhaler administration may be a result of its higher dose per puff metered-dose inhaler formulation.

(Chest 1994; 105:1738-42)

MDI=metered-dose inhaler; V25 and 50=maximum flow rate at 25 percent and 50 percent respectively, of vital capacity; VAS=visual analogue scale

Key words: adverse effects, asthma; beta agonists, bioequivalence; nebulization

With the rising asthma death rate in most industrialized countries during the 1980s,[1] considerable attention has been focused on possible causes. One hypothesis suggests that these patients die of cardiac complications due to excessive catecholamine administration. In particular, the [beta]-agonist fenoterol[2] that showed significant correlation with asthma deaths in a New Zealand case control study[3] and with asthma deaths and near deaths in a recent Saskatchewan study.[4] Unlike the lower dose formulation of salbutamol metered-dose inhaler (MDI) (100 [mu]g per puff) fenoterol was, until recently, provided in a high-dose MDI formulation of 200 [mu]g per puff, raising the possibility that this might have facilitated [beta]-agonist overdose by patient self-administration during severe attacks of asthma.

Although fenoterol has been widely available (except in the United States) for many years, the bioequivalence and relative side effect profile of fenoterol vs salbutamol has not been clearly established.[5,6] A cumulative dose-response study comparing nebulized solutions of fenoterol and salbutamol over a range of clinically relevant doses was, therefore, undertaken in patients with stable asthma.

Methods

Study Design

A randomized double-blind crossover cumulative response study was performed to establish the therapeutic ratio and side effect profiles between placebo and six dose levels of fenoterol and salbutamol respirator solution (50 to 2,500 [mu]g cumulative at interval of about 1 h over approximately 6 h)...

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Gale Document Number: GALE|A15537446