Long-acting Inhaled β2-Agonists in Asthma Therapy

doi:10.1378/chest.113.4.1095

Chest

Volume 113, Issue 4, April 1998, Pages 1095-1108

https://doi.org/10.1378/chest.113.4.1095 Get rights and content

Objective

To review the pharmacology of the long-acting inhaled β₂-agonists, salmeterol and formoterol, summarize results of their clinical trials, evaluate their safety records, and discuss their roles in the treatment of asthma.

Data sources

Preclinical and clinical studies involving salmeterol or formoterol were identified by a MEDLINE search, weekly computerized literature updates, and manual searches. Studies of satisfactory quality were chosen for review.

Data synthesis

Salmeterol and formoterol are potent and selective β₂-adrenoceptor agonists with durations of action > 12 h. Their major differences are that formoterol has a rapid onset of action and is a partial agonist of high intrinsic efficacy, whereas salmeterol has a delayed onset and is a partial agonist of low intrinsic efficacy. Twice daily use of either drug results in improved lung function, reduced symptoms, and a better quality of life. These agents protect against exercise-induced asthma for 12 h and eliminate nighttime awakening in most patients. Limited tolerance develops, especially to their bronchoprotective effects, but their improvement of lung function is sustained.

Conclusions

Regular use of salmeterol or formoterol provides subjective and objective amelioration of asthma in patients experiencing excessive symptoms or physiologic impairment despite the regular administration of low doses of inhaled corticosteroids (equivalent to approximately 500 μg/d of beclomethasone). Intermittent use of either long-acting β₂-agonist can provide prolonged protection against exercise-induced asthma or nighttime symptoms. Patients should be instructed to continue taking inhaled steroids when long-acting β₂-agonists are administered on a regular schedule and to not take long-acting β₂-agonists between regularly scheduled doses. Used properly, they are effective and safe adjunctive agents in the treatment of asthma.

Section snippets

PHARMACOLOGY

Formoterol was synthesized as part of a series of phenylethanolamines being systematically optimized for β₂-adrenoceptor selectivity and potency. It was serendipitously found to have an extended duration of action when delivered by inhalation.⁷^,12, 13, 14 Salmeterol was the product of a strategy to utilize the head group of albuterol, taking advantage of its effective bronchodilation with minimal side effects, and to prolong its duration of action by extension of the lipophilic tail.⁷^,15, 16, 17

Sustained Improvement in Lung Function

The effects of long-acting β₂-agonists on lung function have been extensively evaluated in multiple large trials.39, 40, 41, 42^,⁴⁷^,⁴⁹^,⁵⁴^,⁵⁶^,⁵⁸^,⁶²^,⁶³^,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 These show that regularly used salmeterol or formoterol produces greater reduction of diurnal variation in peak expiratory flow rates and improvement in “baseline” lung function (ie, function prior to a scheduled dose of medication, which can reflect persistent bronchodilation from a previous dose)

INDICATIONS FOR USE

A stepped care approach to asthma therapy has been advocated by national and international consensus conferences.164, 165, 166, 167, 168, 169 Due to the variable course of asthma, patients are advised to readily step up to a higher treatment level when symptoms or physiologic measurements worsen, and cautiously step down to a lower treatment level after a period of clinical stability. Long-acting β₂-agonists are highly effective therapeutic agents for asthmatics who experience excessive

CAUTIONS

Risks from the improper use of long-acting β₂-agonists make patient education mandatory; these agents should not be used by patients unable to understand their limitations. First, the clinical anti-inflammatory effects of long-acting β₂-agonists are modest, if any, and they should be taken on a regular schedule only with the simultaneous administration of an inhaled or oral corticosteroid.⁹^,¹⁰^,¹⁷¹ Lung function actually deteriorated in children receiving salmeterol as maintenance monotherapy

SAFETY

Based on studies of short-acting β₂-agonists of intermediate efficacy, such as albuterol, most authorities agree that deleterious effects from the regular use of β₂-agonists are small, if any.175, 176, 177, 178 Experience with long-acting β₂-agonists supports this conclusion. There was no excess of asthma deaths over those expected in a double-blind trial involving >25,000 patients taking regular salmeterol or albuterol¹⁷⁹^,¹⁸⁰ or in >15,000 patients in a prescription-event monitoring study.¹⁸¹

CONCLUSIONS

Formoterol and salmeterol are highly selective inhaled β₂-agonists with durations of action far in excess of previously available agents. They differ in intrinsic efficacy, and in salmeterol's delayed onset and longer duration of action. The lower intrinsic efficacy of salmeterol offers theoretical advantages of reduced side effects and desensitization that remain to be convincingly demonstrated in clinical trials. Both agents provide symptomatic and objective amelioration of asthma for

ACKNOWLEDGMENTS

The authors thank Drs. Gary Anderson, Gilbert D'Alonzo, Giovanni Della Cioppa, Leland Fan, Malcolm Johnson, Joseph Rodarte, and the referees for their critical review and helpful comments.

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Further studies are needed with particular focus on: (1) the effects of systemic administration of terbutaline or bambuterol ; (2) the effects of short-term supratherapeutic inhalation, and (3) the determination of a urinary threshold for terbutaline, salmeterol and formoterol.
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Chest

ReviewsLong-acting Inhaled β2-Agonists in Asthma Therapy

Objective

Data sources

Data synthesis

Conclusions

Section snippets

PHARMACOLOGY

Sustained Improvement in Lung Function

INDICATIONS FOR USE

CAUTIONS

SAFETY

CONCLUSIONS

ACKNOWLEDGMENTS

Clin Chest Med

J Allergy Clin Immunol

Chest

Life Sci

Gen Pharmacol

Life Sci

Life Sci

J Biol Chem

Chest

Chest

J Biol Chem

J Biol Chem

Chest

Respir Med

Chest

Chest

Chest

Chest

J Allergy Clin Immunol

Am J Med

Lancet

Lancet

Chest

Sympathomimetic bronchodilators

Adrenergic agents

Salmeterol: an inhaled beta2-agonist with prolonged duration of action

Lung

Long-acting beta2-adrenoceptor agonists: a new perspective in the treatment of asthma

Eur Respir J

Long-acting inhaled beta agonists

J Asthma

Salmeterol for the treatment of asthma [editorial]

Ann Allergy Asthma Immunol

Safety and appropriate use of salmeterol in the treatment of asthma

J Allergy Clin Immunol

Why are long-acting beta-adrenoceptor agonists long-acting?

Eur Respir J

The 1990 Lilly prize lecture: a way of looking at agonism and antagonism; lessons from salbutamol, salmeterol and other beta-adrenoceptor agonists

Br J Clin Pharmacol

Salbutamol, salmeterol—a chemist's perspective

Actual Chim Thér

Long acting inhaled beta-adrenoceptor agonists: the comparative pharmacology of formoterol and salmeterol

Agents Actions Suppl

Relaxation kinetics of formoterol and salmeterol in the guinea pig trachea in vitro

Lung

Extent of salmeterol mediated reassertion of relaxation in guinea-pig trachea pretreated with the aliphatic side chain structural analogues

Br J Pharmacol

Comparison of duration of agonist action at beta(1)- and beta(2)-adrenoceptors in C6 glioma cells—evidence that the long duration of action of salmeterol is specific to the beta(2)-adrenoceptor

Mol Pharmacol

Stable activation and desensitization of β2-adrenergic receptor stimulation of adenylyl cyclase by salmeterol: evidence for quasi-irreversible binding to an exosite

Mol Pharmacol

Salmeterol-induced desensitization, internalization and phosphorylation of the human β2-adrenoceptor

Br J Pharmacol

Formoterol on airway smooth muscle and human lung mast cells: a comparison with salbutamol and salmeterol

Eur J Pharmacol

Formoterol, fenoterol, and salbutamol as partial agonists for relaxation of maximally contracted guinea-pig tracheae: comparison of relaxation with receptor binding

Lung

Functional and binding characteristics of long-acting β2-agonists in lung and heart

Am J Respir Crit Care Med

Relaxant effects and durations of action of formoterol and salmeterol on the isolated human bronchus

Eur Respir J

β-Adrenoceptor subtypes and the opening of plasmalemmal K+-channels in bovine trachealis muscle: studies of mechanical activity and ion fluxes

Br J Pharmacol

The interaction between salmeterol and β2-adrenoceptor agonists with higher efficacy of guinea-pig trachea and human bronchus in vitro.

Br J Pharmacol

Salmeterol, formoterol, and salbutamol in the isolated guinea pig trachea: differences in maximum relaxant effect and potency but not in functional antagonism

Reviews
Long-acting Inhaled β₂-Agonists in Asthma Therapy

Salmeterol: an inhaled beta₂-agonist with prolonged duration of action

Long-acting beta₂-adrenoceptor agonists: a new perspective in the treatment of asthma

Stable activation and desensitization of β₂-adrenergic receptor stimulation of adenylyl cyclase by salmeterol: evidence for quasi-irreversible binding to an exosite

Salmeterol-induced desensitization, internalization and phosphorylation of the human β₂-adrenoceptor

Functional and binding characteristics of long-acting β₂-agonists in lung and heart

β-Adrenoceptor subtypes and the opening of plasmalemmal K⁺-channels in bovine trachealis muscle: studies of mechanical activity and ion fluxes

The interaction between salmeterol and β₂-adrenoceptor agonists with higher efficacy of guinea-pig trachea and human bronchus in vitro.

Estimation of the efficacy and affinity of the β₂-adrenoreceptor agonist salmeterol in guinea pig trachea

Highly potent beta₂ sympathomimetic convert to less potent partial agonists as relaxants of guinea pig trachea maximally contracted by carbachol: comparison of relaxation with receptor binding and adenylate cyclase stimulation