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• GJF
  • Joint Wound Care Formulary
  • . . . Introduction
  • 1. Gastro-Intestinal System
  • 2. Cardiovascular System
  • 3. Respiratory System
    • Administration of drugs to the lungs
    • 3.1 Bronchodilators
    • 3.2 Corticosteroids
    • 3.3 Cromoglicate, related therapy and leukotriene receptor antagonists
    • 3.4 Antihistamines, and the treatment of allergic emergencies
    • 3.5 Respiratory stimulants and pulmonary surfactants
    • 3.6 Oxygen
    • 3.7 Mucolytics
    • 3.9 Cough preparations
  • 4. Central Nervous System
  • 5. Infections
  • 6. Endocrine System
  • 7. Obstetrics, Gynaecology and Urinary Tract Disorders
  • 8. Malignant Disease and Immunosuppresion
  • 9. Nutrition and Blood
  • 10. Musculoskeletal and Joint Disease
  • 11. Eye
  • 12. Ear, Nose and Oropharynx
  • 13. Skin
  • 14. Immunological products and vaccines
  • 15. Anaesthesia
  • Appendix 1. Drugs for emergency use in General Practice
  • Appendix 2. Palliative Care
  • Appendix 3. Oral Nutritional Supplements (ONS)
  • Appendix 4. Gluten-free and cow's milk protein-free products
  • Medicines No Longer included in the GJF
  • Medicines not recommended for use in NHS Grampian
• eGJF
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3.1 Bronchodilators

In this section:

• Short-acting bronchodilators
• Long-acting beta2-agonist bronchodilators
• Long-acting antimuscarinic bronchodilator
• Oral theophylline derivatives
• Prescribing points

Links to guidance:

• British Guideline on the Management of Asthma
• Chronic obstructive pulmonary disease: Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update)

Short-acting bronchodilators

Salbutamol (metered dose and dry powder inhalation devices (100micrograms/inhalation), nebuliser solution (2.5mg or 5mg in 2.5mL), tablets, m/r tablets, syrup, injection).

Terbutaline (dry powder inhalation devices (500micrograms/inhalation), tablets, m/r tablets, nebuliser solution (5mg in 2mL), syrup, injection (500micrograms/mL)).

Are the recommended short-acting beta2-agonists. There is virtually no difference in efficacy between them they should only be prescribed on a "when required" basis for relief of symptoms. 
Inhalation is the preferred method of administration because it provides more rapid relief and causes fewer side-effects.
Oral preparations are available, administered twice daily, for patients who cannot manage the inhaled route, however they are less effective than when given by inhalation and have no proven value in chronic stable disease. 
Patients with asthma using short-acting beta2-agonist bronchodilators more than once per day or more than three times per week, should have their asthma control re-assessed (SIGN/BTS).
Nebulisation (preferably oxygen driven) of nebuliser solution of salbutamol or terbutaline is used for the treatment of acute asthma both in hospital and general practice. The dose given by nebuliser is substantially higher than that given by inhaler.
Potentially serious hypokalaemia may be caused by large doses of beta2-agonists. Particular caution is required in severe asthma as this effect may be potentiated by concomitant treatment with theophylline and its derivatives, corticosteroids, diuretics, and by hypoxia.

Ipratropium metered dose inhaler (20micrograms/inhalation), nebuliser solution (250 and 500micrograms) is a short-acting antimuscarinic bronchodilator. It may provide some bronchodilation in patients with acute exacerbations of chronic obstructive pulmonary disease. It can also provide short-term relief in chronic asthma.

Nebulised iptratropium may be of benefit in life-threatening asthma and acute asthma. It is available combined with salbutamol as UDVs; proprietary name Combivent®. It is more cost-effective to use ipratropium and salbutamol nebules separately than using Combivent® nebules. This may be more convenient for selected patients, in whom the benefit of the combination has been demonstrated. There is no evidence of efficacy of regular nebulised therapy in the management of stable COPD and appropriate use of inhaled corticosteroid/long-acting beta2-agonist and long-acting antimuscarinic is strongly recommended (see section 3.2). However, the advent of longer acting inhaled bronchodilators with demonstrated effectiveness in terms of quality of life and exacerbation frequency (primarily tiotropium) has largely superseded the use of nebulised short-acting bronchodilators in stable COPD. There is no evidence that nebulised short-acting bronchodilators have any prognostic benefit, nor any significant benefit in terms of exacerbation frequency. Consequently while they may still be used for symptomatic relief of breathlessness by some patients (who have often been using them for many years) in general the place of short acting nebulised drugs in stable COPD is increasingly marginal. Symptoms of breathlessness in stable COPD should be managed by a combination of pharmacological (long-acting bronchodilators and inhaled short-acting bronchodilators) and non pharmacological approaches (patient education and pulmonary rehabilitation) which have a much stronger evidence base.

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Long-acting beta2-agonist bronchodilators

Salmeterol metered dose (25micrograms/inhalation) and dry powder inhalers (50 micrograms/inhalation). 

Formoterol metered dose (12micrograms/inhalation) and dry powder inhaler (6 micrograms and 12 micrograms/inhalation).

Indacaterol inhalation powder (150micrograms and 300micrograms  hard capsules, for use with Onbrez Breezhaler® ). Note: indacaterol is licensed for use in COPD only. 

Long-acting beta2-agonists (LABA) are administered twice daily. Formoterol has a more rapid onset of action than salmeterol. Long-acting beta2-agonists are indicated as first-line add-on therapy at Step 3 in the BTS/SIGN guidelines (see BNF). In asthma they should only be prescribed when patients are already receiving inhaled corticosteroid therapy and not replace it and should be stopped if there is no benefit. LABA monotherapy is associated with adverse outcomes in stable asthma and should not be used. They are not suitable for the relief of an acute asthma attack - a short-acting beta2-agonist, e.g. salbutamol or terbutaline, will have a faster onset of action and will produce more rapid relief of symptoms.

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Long-acting antimuscarinic bronchodilator

Tiotropium as tiotropium bromide monohydrate, inhalation powder (18mg hard capsule for use with HandiHaler® device), Spiriva® is a recommended therapy in stable COPD - used once daily as a maintenance bronchodilator. It is not suitable for the relief of acute bronchospasm. 

Tiotropium solution for inhalation (2.5micrograms/inhalation) Spiriva® Respimat® is restricted to use for COPD patients who have poor manual dexterity and therefore have difficulty using the HandiHaler® device. 

Aclidinium as aclidinium bromide, inhalation powder (400 micrograms/metered inhalation, Eklira Genuair® )  is another recommended therapy in stable COPD - used twice daily as a maintenance bronchodilator.
Each delivered dose is equivalent to 322micrograms and the recommended dose is one inhalation of 322micrograms aclidinium twice daily. 

• Tiotropium and aclidinium are only licensed for COPD. 
• Tiotropium and aclidinium are not suitable for the relief of acute bronchospasm and must not be given in combination with ipratropium.
• Patients with severe COPD who receive home nebulised ipratropium or Combivent® should not be prescribed tiotropium/aclidinium in addition. In general such patients should be converted to tiotropium/aclidinium rather than regular nebulised therapy as there is considerably more evidence to support the long-term efficacy of this approach.

Oral theophylline derivatives

Uniphyllin Continus® (tablets).
Phyllocontin® (m/r aminophylline tablets).
Slo-Phyllin® (capsules) - may be useful because dose range covers all age groups.

Theophylline is a bronchodilator used for reversible airways obstruction (NICE). It may have an additive effect when used with small doses of beta2-adrenoreceptor agonists; this combination may increase the risk of side effects including hypokalaemia.

Modified-release preparations of theophylline and aminophylline are used to supplement inhaled corticosteroids and long-acting beta2-agonist in asthma (Steps 3 and 4 of the BTS/SIGN guidelines, see BNF) and stable chronic obstructive pulmonary disease. It is not effective in acute exacerbation of COPD. It is affected by various diseases and by drugs taken concurrently, in particular clarithromycin, ciprofloxacin and erythromycin increase the half life (see BNF for all drug interactions). These drug interactions can have clinically significant effect(s) because theophylline has a narrow margin between therapeutic and toxic plasma concentrations.
Due to the risk of toxicity local practice is generally to use low dose theophylline. Doses higher than 200mg twice daily Uniphylline MR or equivalent should be used under specialist supervision.
Rarely it may be appropriate to administer a larger morning or evening dose in some patients, in order to achieve optimum therapeutic effect when symptoms are most severe, e.g. at the time of the "morning dip" in lung function (SPC).
In patients whose night time or day time symptoms persist despite other therapy and who are not currently receiving theophylline, then the total daily requirement may be added to their treatment regimen as either a single evening or morning dose (SPC).

SPECIAL INDICATIONS

Aminophylline injection (25mg/mL) is given by very slow infusion to patients whose condition is very severe when first seen or who deteriorate or fail to improve rapidly when treated with steroids and/or beta2-agonists. Plasma levels should be monitored because of the narrow margin between the therapeutic and toxic dose. It should be given with caution and with dose modification in patients already receiving oral theophylline or aminophylline because of the risk of serious side-effects, e.g. convulsions and arrhythmias can occur and cardiac monitoring is advised. 

PRESCRIBING POINTS FOR BRONCHODILATORS

• Patients require instruction on the use of all inhalers, especially pMDIs. Inadequate technique may be mistaken for drug failure. It is therefore important to review inhaler technique regularly and especially prior to addition of medication.
• The recommended first-line treatment for patients with COPD is inhaled short acting bronchodilators.  A long-acting beta2-agonist or a long-acting antimuscarinic antagonist should be prescribed in people with COPD and FEV1 >50% predicted who continue to experience problems despite the use of short-acting drugs (NICE).
• Tiotropium is only licensed for COPD.
• Tiotropium is not suitable for the relief of acute bronchospasm and must not be given in combination with ipratropium.
• Patients with severe COPD who receive home nebulised ipratropium or Combivent® should not be prescribed tiotropium in addition. In general such patients should be converted to tiotropium rather than regular nebulised therapy as there is considerably more evidence to support the long-term efficacy of this approach.
• Theophylline has a narrow range between therapeutic and toxic effects; therapy should be monitored.
• Different brands of modified-release theophylline have different bioavailability; prescribers should specify the brand to be dispensed.
• Theophylline and aminophylline interact with many drugs; see BNF for details.
• Smoking cessation may increase theophylline levels, this is independent of any nicotine replacement therapies that may be prescribed.
• The dose delivered by nebuliser is many times higher than that delivered by metered dose inhaler. Patients should be warned that it is dangerous to exceed the stated dose and that if they fail to respond to the usual dose of their nebuliser solution, they should call for help.

PAEDIATRIC NOTES - BRONCHODILATORS

See Guidelines for hospital management of acute asthma in children in Grampian.

Salbutamol and terbutaline are the short-acting beta2-agonists of choice. The route of choice is by inhalation (see notes on administration of drugs to the lungs). For nebulisation, salbutamol is the product of choice, with terbutaline only used if the patient does not respond to salbutamol.
Ipratropium nebuliser solution may be used in infants, where beta2-agonists have been shown to be ineffective. Ipratropium and salbutamol may also be used in combination.
Salmeterol may be added to existing inhaled steroid therapy (400 micrograms/day of beclometasone or equivalent) before putting patients on high dose steroids. Not recommended in children under 4 years.
Theophylline is available in modified-release capsules containing 60mg and 125mg (Slo-Phyllin®), the contents of which can be sprinkled over food.

Adrenaline/epinephrine is used for the relief of acute croup when dexamethasone is ineffective. 1mL of 1 in 1,000 adrenaline is diluted with saline and administered by nebulisation. The effect wears off rapidly.

GERIATRIC NOTES - BRONCHODILATORS

Theophyllines. There is a tendency for theophylline clearance to decrease with age, leading to higher serum levels. A reduction of the adult dosage may be required. Elderly patients are also much more susceptible to the adverse effects of theophyllines.
Beta2-agonists. Elderly patients are at increased risk of side-effects from the beta2-agonists. It is advisable to start treatment with the minimum dose.