Beta-Adrenoceptor Agonists

Synonyms: selective beta₂- adrenoceptor agonists, selective beta₂- stimulants

The selective beta₂-agonists are the mainstay of asthma treatment. They cause bronchodilation by mimicking the action of norepinephrine in sympathetic nerve endings.

• Salbutamol
• Terbutaline
• Bambuterol Hydrochloride
• Fenoterol Hydrobromide

• The selective beta₂-agonists such as salbutamol or terbutaline are the safest and most effective short-acting beta₂-agonists for asthma and are to be preferred to less selective agonists such as orciprenaline. They should be initiated at Step One of the British Guidelines for the short-term relief of asthma.¹ They should be prescribed on an as required basis, unless patients show benefit from regular use.²
• They can also be used before exercise in patients with exercise-induced asthma, but in such cases the dose of any preventive medication should also be reviewed.
• Selective beta₂-agonists are best taken via the inhaled route. Mild to moderate asthma responds rapidly. The duration of action is 3 to 5 hours. Patients should clearly be told what role beta₂-agonists play in the management of asthma, and be given a written management plan to ensure they know what to do if their asthma worsens.
• The British Guidelines recommend moving to Step 2 (the addition of preventive regular inhaled steroid) in the following circumstances:
  • Using inhaled beta2 agonists three times a week or more
  • Symptomatic three times a week or more; or waking one night a week
  • In adults and children aged 5-12, an exacerbation of asthma requiring oral corticosteroids in the last two years
• In an acute attack without life-threatening features, beta₂-agonists can be administered from a pressurised metered dose inhaler (pMDI) via a large volume spacer or by wet nebulisation driven by oxygen if available.
• Inhaled beta₂-agonists offer marginal benefit in children under 2, and there is no impact on hospital admissions.
• In pregnancy, treatment of an acute attack should be as for non-pregnant patients, including repeated doses of beta₂-agonists. Studies found no adverse effect of beta₂-agonists on perinatal mortality, congenital abnormalities, prematurity, mean birth weight, apgar scores or labour/ delivery complications.

Beta₂-agonists may be taken orally, but this should be reserved as second-line management for patients who cannot manage the inhaled route, as inhaled medication is more effective and has fewer side effects. In children, an inhaler with a spacer device should be tried before the inhaled route is abandoned in favour of oral medication.

Although salbutamol or terbutaline can be given by injection, the British Guidelines suggest that frequent doses given via a pMDI, or by wet nebulisation driven by oxygen is to be preferred. However, intravenous (IV) or intramuscular (IM) injection is an option for those patients in whom inhaled therapy cannot be used reliably. The Guidelines state that the subcutaneous route has been excluded in the meta-analyses reviewed.

In severe or life-threatening asthma, an early bolus of intravenous salbutamol has been shown to increase lung function in patients who have been given near-maximal doses of nebulised salbutamol. In severe refractory asthma, continuous infusion may be tried.

• Salmeterol
• Formoterol

These drugs were introduced in 1988 and were a significant advance in the management of asthma. They have a duration of action of about twelve hours. Salmeterol and formoterol are useful in the preventive management of chronic asthma and especially helpful in controlling nocturnal asthma. For adults and children over the age of five, they should be introduced at Stage Three of the British Guidelines - i.e. after an adequate trial of inhaled corticosteroids. Studies suggest that there is no benefit in initiating a combination of inhaled steroids and long-acting beta₂-agonist at this stage.

Salmeterol has a slower onset of action than salbutamol and should not be used in acute asthma attacks. Formoterol has a speed of onset similar to salbutamol and is licensed for short-term relief of acute asthma, as well as the prevention of exercise-induced asthma.

Long-acting beta₂-agonists have not been without their problems. When first introduced, salmeterol was used without corticosteroids, and this resulted in rare reports of life-threatening attacks (the SMART trial).³ High doses of formoterol (e.g.24 mcg twice daily) used without inhaled corticosteroids have been associated with an increase in severe attacks of asthma.⁴ In view of this, the MRHA have issued advice to prescribers to ensure safe use in the management of chronic asthma.⁵

Cautions

See individual monographs and standard product characteristics:^6,7

• Hyperthyroidism
• Cardiovascular disease
• Arrhythmias
• Susceptibility to QT-interval prolongation
• Hypertension
• Diabetes - monitor blood glucose, as there is a risk of ketoacidosis, particularly when the intravenous route is used.
• Pregnancy - high doses should be administered by inhalation, reserving the intravenous route for treatment failures. High doses can have an effect on the myometrium and cause cardiac problems.

Side-effects (rare with inhaled route)

• Fine tremor (particularly in the hands)
• Headache
• Cramps
• Palpitations
• Tachycardia and arrhythmias
• Disturbances of sleep
• Paradoxical bronchospasm, urticaria, and angioedema (rare)

Inhaler devices include pressurised metered-dose inhalers, breath-actuated inhalers and dry powder inhalers.
The British Guidelines recommend that:¹

• inhalers should only be prescribed after patients have received training in their use and have demonstrated satisfactory technique.
• children and adults with mild and moderate exacerbations of asthma should be treated by pMDI + spacer with doses titrated according to clinical response.
• in children aged 5-12, pMDI + spacer is as effective as any other hand held inhaler.
• in adults, pMDI ± spacer is as effective as any other hand held inhaler, but patients may prefer some types of dry powder inhalers (DPI).

Chlorofluorocarbon (CFC) propellants

CFC propellants have been replaced by hydrofluoroalkane (HFA) to protect the ozone layer. Patients should be reassured about the efficacy of the new inhalers. The aerosol may taste different, but as far as beta₂-agonists are concerned, there is a 1:1 equivalent dosage. The same cannot be said for steroid inhalers.

Metered dose inhalers

These should be shaken and then fired shortly after the start of a slow full inspiration. At full inflation the breath should be held for 10 seconds. Arthritic patients may be helped by a breath actuated or dry powder system.

Breath actuated inhalers

Breath actuated inhalers respond to a low inspiratory flow rate, but still require a propellant. Short and long acting beta agonists are now available in inhalers with hydrofluoroalkanes.

Spacer devices

These remove the need for coordination of breathing and actuation. Inhale as soon as possible after each single actuation. Empty the chamber by single large breaths or tidal breathing. Evaporation of propellant from the larger particles produces a small sized aerosol that penetrates further out into the lungs. Electrostatic charge can reduce drug delivery, so chambers should be washed in detergent and left to air dry (rather than wiped dry) once a month and changed every 6-12 months.

Dry powder inhalers

Dry powder inhalers release the fine powder on inspiration so problems of coordination are avoided, and there are no environmental worries. They make some patients cough. Multiple dose units with a dose counter are easy to use.

Nebuliser solutions

Nebuliser solutions of salbutamol and terbutaline are used in acute asthma. Patients with a severe attack of asthma should also have oxygen during nebulisation. The dose by nebuliser is substantially higher than by inhaler. Nebulisers can be driven by compressed gas (jet nebuliser), flow rates of 6 l/min are needed, or an ultrasonically vibrating crystal (ultrasonic nebuliser). In many situations equivalent effects can be obtained with metered dose inhalers and a spacer, but patients often have confidence in their nebuliser. Nebulisers are the preferred option in children aged 0-5 who are unable to use a pMDI and spacer effectively.¹

Subcutaneous injections

The British Guideline could find no evidence to support the use of this route in the management of asthma.

The less specific sympathomimetic agonists adrenaline, isoprenaline, orciprenaline and ephedrine are no longer routinely used for asthma as they can cause tachycardia, anxiety, restlessness, insomnia and tremor. Adrenaline (epinephrine) 1 in 1000 injection is used in anaphylactic reactions and by nebulisation in severe croup.