ß2 selective adrenoceptor agonists (ß2 stimulants) have been used for 30 years for the relief of symptoms in patients with all grades of asthma. They can also be used before activities likely to precipitate airway narrowing and are sometimes taken as regular treatment by patients with chronic asthma. The first ß2 stimulants to be introduced were shorter-acting drugs such as salbutamol and terbutaline. The longer-acting ß2 stimulants, salmeterol and eformoterol, were developed more recently and their role in treating asthma is not yet fully defined. In this article we review the current place of ß2 stimulants in asthma management.

General guidelines
Guidelines produced by the British Thoracic Society and other expert groups1 , and soon to be updated, recommend a stepwise approach to the treatment of asthma. A shorter-acting ß2 stimulant is recommended for occasional use 'as required', in the minimum dose needed to control symptoms, either alone in patients with mild asthma (step one), or with regular prophylactic medication (low-dose inhaled corticosteroid, sodium cromoglycate or nedocromil sodium) in those with more frequent symptoms (step two). Treatment should be by inhalation, which enhances the drug's therapeutic selectivity by increasing its local concentration in the airways and reducing the likelihood of adverse systemic effects. If, despite compliance with these treatments, asthma remains inadequately controlled, treatment with high-dose inhaled corticosteroid, delivered by a large volume holding chamber (spacer), should be started (step three).1

Introduction of a longer-acting inhaled ß2 stimulant has been reserved until step four, when it has been one option (an oral long-acting ß2 stimulant is another) for patients who continue to have symptoms despite high-dose inhaled corticosteroid. Recent randomised, controlled studies lasting up to 6 months have, however, suggested that the addition of salmeterol might be an effective alternative to increasing the dose of corticosteroid in those who remain symptomatic on a conventional dose.2,3

Use in acute asthma

Treatment of mild or moderate symptoms
Most teenagers and adults carry one of the shorter-acting ß2 stimulant inhalers - either a metered dose inhaler (MDI) or a dry powder device - to relieve symptoms 'as needed'. For infants and toddlers, the ß2 stimulant needs to be inhaled from a MDI using a face mask and valved spacer. Children over 5 years can usually use a dry powder device or breath-actuated MDI, but few children under 10 years can manage a standard MDI with ease. The dose needed by children may be similar to that used by adults. Flexibility of dosing should be encouraged within an agreed, written, self-management plan. However, frequent use of a ß2 stimulant by any patient should prompt a review of inhaler technique, compliance and of the need for a step up in preventive treatment.

Treating severe attacks
A patient with a severe asthma attack will need higher doses of ß2 stimulant, which are usually given by nebuliser. Giving ß2 stimulants by nebulisation is easier than intravenous administration and less likely to cause unwanted effects.4 In adults or older children with severe acute asthma, first-line emergency treatment should be with salbutamol 5 mg or terbutaline 10 mg by nebuliser, together with oxygen in high concentration and systemic corticosteroid.1 Lower doses (2.5 mg salbutamol or 5 mg terbutaline) should be used for infants and pre-school children.1 In a child with a moderately severe attack, administration via MDI + large-volume spacer (up to 10 puffs of salbutamol or terbutaline) is an effective alternative to nebulised therapy5 and many prefer this approach for emergency treatment. In very young infants, administration via MDI + spacer avoids the transient bronchoconstriction and hypoxaemia which is sometimes seen with nebulised ß2 stimulants (possibly in response to the acidity or osmolality of the nebuliser solution).6 Although ß2 stimulants seem generally less effective before the age of one year (and ineffective in acute viral bronchiolitis in infants under 6 months old), some placebo-controlled studies have shown benefit.7

The longer-acting ß2 stimulants do not have a place in the immediate management of acute symptoms.

Preventing symptoms
ß2 stimulants have anti-bronchoconstrictor activity and will prevent or ameliorate bronchoconstriction if taken prior to an activity or stimulus that is likely to bring it on. Many patients can prevent exercise-induced bronchoconstriction if they inhale a shorter-acting ß2 stimulant 5-10 minutes before exercise starts. The longer-acting ß2 stimulants are designed for regular twice-daily administration and not for use prior to specific activities such as exercise.

Ameliorating chronic asthma

Short-acting ß2 stimulants
Patients with mild or moderate chronic asthma should take shorter-acting ß2 stimulants only as needed to relieve symptoms. Regular (fixed-interval) use gives no additional benefit and may possibly cause harm.

The concerns about harm have come partly from several short-term studies which show a small increase in bronchial responsiveness to constrictor stimuli when the bronchodilating effect of the ß2 stimulant wears off.8 In addition, in a randomised, double-blind crossover study in 64 patients with moderate chronic asthma, asthma control (peak expiratory flow rate, daytime and night-time symptoms, use of supplemental relief bronchodilator) was worse during 6 months of regular treatment with fenoterol (400 micrograms 4 times daily) than with placebo.9 These findings added to concerns generated by earlier epidemiological data, which had shown a temporal association between the rise in asthma deaths and increased use of isoprenaline, during the 1960s, and of fenoterol in New Zealand in the 1970s.10 Later, a very large cohort study in North America showed that excessive use of inhaled ß2 stimulants generally was associated with increased risk of death from asthma.11 Whether these associations were causal is still debated.12

Several placebo-controlled trials have found no evidence of deterioration in lung function or control of asthma symptoms with regular compared to 'as needed' inhaled salbutamol.13-15 However, regular treatment gives no clear advantages, either on conventional clinical outcomes or quality-of-life scores16, and it usually leads to more of the drug being taken. In other studies, regular treatment with salbutamol or terbutaline gave less satisfactory control than did nedocromil17, inhaled corticosteroids18 or long-acting inhaled ß2 stimulants.13,14

Some patients with severe chronic asthma continue to take shorter-acting ß2 stimulants on a regular basis, by inhaler or nebuliser, sometimes against medical advice. Whether some of these patients have developed tolerance to ß2 stimulants and are taking high doses to try to overcome their reduced efficacy is unclear. More information in needed on the relative benefit and risk of the shorter-acting ß2 stimulants in this situation.

Longer-acting inhaled ß2 stimulants
Salmeterol and eformoterol are given regularly twice daily by inhalation and should not be used 'as needed' to relieve episodes of bronchoconstriction. A single dose of either drug gives bronchodilatation lasting for up to 12 hours. Eformoterol has an onset of action similar to salbutamol, with peak bronchodilatation after about 30 minutes19, salmeterol takes 1-2 hours to achieve maximum bronchodilatation.20

Clinical studies
In two double-blind comparisons in a total of 556 patients with mild or moderate chronic asthma, bronchodilatation with salmeterol (42 micrograms twice daily) was sustained over 24 hours, and morning and evening peak flow rates increased significantly more than with regular salbutamol (180 micrograms 4 times daily) or placebo, with no loss of efficacy over 12 weeks.13,14 Daytime and night-time symptoms were fewer and less severe with salmeterol and the need for relief bronchodilator less than with these comparators. With salmeterol, nights disturbed by asthma symptoms fell by 52%, compared to 21% with placebo.13 In other placebo-controlled studies, salmeterol improved quality of life16 and, in patients with nocturnal asthma, the quality of sleep.21 Inhaled salmeterol gave better symptom control with fewer unwanted effects than did individually titrated doses of oral theophylline.22

Most studies have not demonstrated a reduction in exacerbations of asthma during treatment with salmeterol. In one large post-marketing surveillance study of 25 180 patients23, patient withdrawals due to asthma exacerbations were significantly fewer in those given salmeterol than in those given regular salbutamol (2.9% vs. 3.8%).

Two randomised, double-blind studies2,3, each lasting 6 months and together involving a total of 1167 patients who were inadequately controlled by a conventional dose of inhaled beclomethasone dipropionate, have compared the effect of adding salmeterol with that of increasing the dose of beclomethasone (to 500 micrograms twice daily in the first study2 and to 1000 micrograms twice daily in the second3). In both studies, patients randomised to salmeterol 50 micrograms twice daily showed a bigger increase in peak flow rates and experienced greater relief of symptoms than those who increased the dose of inhaled corticosteroid, with no difference between groups in the number of exacerbations.2,3 The second of these studies also found that salmeterol 100 micrograms twice daily was no more effective than 50 micrograms twice daily, but unwanted effects (tremor) were more likely to be troublesome with the higher dose.3

Long-term studies with eformoterol are fewer but, in those that have been published, the benefits, compared to regular salbutamol, appear similar to those found with salmeterol.24 Eformoterol in a dose of 12 micrograms twice daily seems as effective, in most patients, as treatment with the higher dose of 24 micrograms twice daily.25 There are no published studies comparing eformoterol with inhaled corticosteroid.

In adolescents and children, the short-term effects of long-acting inhaled ß2 stimulants appear similar to those seen in adults, but published data on their long-term use, or their use in very young children, are few. In the UK, salmeterol is licensed for use in children aged 4 years and over; eformoterol is not licensed for patients under 18 years.

Oral ß2 stimulants
There are very few published studies of the long-term efficacy and safety of regular treatment with oral ß2 stimulants in adults. The ability of inhaled salbutamol to protect against exercise-induced bronchoconstriction is reduced after regular treatment with oral salbutamol26, as it is with regular inhaled short-acting27 or long-acting ß2 stimulants.28
Bambuterol, a terbutaline prodrug, was designed to reduce the systemic adverse effects associated with oral ß2 stimulants. The long half-life of bambuterol (20 hours) allows once-daily dosing. Taken at bedtime, bambuterol 20 mg improved nocturnal asthma symptoms and reduced the overnight dip in peak flow rate more effectively than did placebo in 28 patients who had remained symptomatic despite treatment with inhaled or oral corticosteroid.29 As with other ß2 stimulants, bambuterol may cause tremor, headache and dizziness.

How safe are ß2 stimulants?
All ß2 stimulants, whether short- or long-acting, can cause tremor, palpitations, headache, muscle cramp and hypokalaemia. These effects are more likely to occur with high doses and if ß2 stimulants are taken together with other drugs that predispose to the same adverse effects, such as theophylline. Their incidence is generally low with salmeterol or eformoterol when given in the manufacturers' recommended doses of 50 micrograms and 12 micrograms twice daily respectively, and is similar to that seen with salbutamol 200 micrograms 4 times daily, but the effects last longer. Systemic effects may be marked if these doses are exceeded. Single doses of ß2 stimulants given orally cause more adverse effects with less benefit than when given by inhalation.

Though unpleasant, the unwanted effects of ß2 stimulants are not often serious, but nebulised therapy may occasionally precipitate angina.30 Cardiac dysrhythmias, though rare, are potentially a risk especially in a patient with myocardial disease, hypoxaemia or hypokalaemia.

Uncommonly, paradoxical bronchoconstriction occurs after inhalation of a ß2 stimulant. The effect, which is possibly due to propellants or dispersants in the aerosol rather than the drug itself, appears more common with salmeterol MDI (incidence about 1%31) than with other ß2 stimulants, presumably because of the slower onset of its bronchodilator action. It is occasionally severe and is another reason why long-acting ß2 stimulants should not be used during acute attacks of asthma.

Most patients do not develop severe unwanted effects with ß2 stimulants. Whether treatment could very occasionally cause or render a patient more vulnerable to a life-threatening event, and by what mechanism as a result of a dysrhythmia or through the development of tolerance - is uncertain. Tolerance is the likely reason for the rebound bronchconstriction seen in several studies after the bronchodilating effect of short-acting ß2 stimulant wears off18; tolerance could also lead to some loss of protection against bronchoconstrictor stimuli when long-acting ß2 stimulants are given regularly.32 Very many patients take ß2 stimulants; whether - if only in a small minority - these developments could lead to clinically important vulnerability to asthma attacks, needs more study.

Conclusion
Inhaled short-acting ß2 stimulants such as salbutamol and terbutaline have a major role in the treatment of symptoms and attacks of asthma, whether mild or severe, although their efficacy is less predictable in acute wheezing episodes in infants. They should be used on an 'as required' basis, in the lowest dose needed to control the symptoms or to protect against a known provoking stimulus such as exercise. Regular fixed-interval use of short-acting ß2 stimulants confers no benefit to patients with asthma of moderate severity; whether it helps patients with more severe asthma requires further study.

The longer-acting ß2 stimulants, salmeterol and eformoterol, should not be used for the acute relief of symptoms. They now have an established role, given in regular twice-daily dosage, as adjunctive treatment in patients with chronic asthma who remain inadequately controlled despite being fully compliant with an optimal (high) dose of inhaled corticosteroid. Some evidence suggests that salmeterol is effective when introduced earlier instead of increasing a conventional dose of inhaled corticosteroid. If this is done, patients should continue to be monitored and the dose of corticosteroid increased in those in whom salmeterol fails to produce a response.

Excessive reliance on 'as needed' short-acting ß2 stimulants should be taken to indicate failed management and should prompt a review of treatment. It will usually mean the patient needs to be moved up a step in the treatment schedule.

Reprinted with permission from Drug and Therapeutics Bulletin 1997;35:1-4.

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