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Improving asthma treatment- choosing the right medication vital to meet this national disease priority

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Improving the treatment of asthma, an inflammatory condition of the airways, is a chronic disease priority in Australia, where the national asthma rates remain higher than international rates.1 2.2 million Australians, including 1 in 9 adults and 1 in 6 children, are affected by the condition.1 Asthma may cause considerable disruptions to daily life,2 and is associated with greater ill health, psychological distress and behavioural problems.3 The disease may also be fatal and in 2004, 311 asthma-related deaths occurred in Australia.1 However, morbidity and mortality associated with the condition can be reduced with proper management. Pharmacotherapy is a key component of optimal management; however, choosing the right medicines, those which not only control symptoms but also reduce atrophy of the airways associated with chronic asthma, can be challenging.1

Goals of asthma pharmacotherapy

The goals of asthma pharmacotherapy are to achieve symptom control and optimise lung function while using the lowest possible dose of medicine(s) and minimising treatment-related adverse events. Ideally patients will experience few symptoms, have little need for asthma relief medications and maintain normal lung function and unimpaired daily living.1 Goals are similar for adult and child patients; however, minimising side-effects is of particular importance in paediatric patients.4

There is a delicate balance between safety and efficacy considerations, as higher doses not only increase efficacy but typically also increase the risk of side effects.5 The best combination of drugs to achieve these goals varies primarily depending on the patient’s age and the severity of their asthma.1

 

Asthma pharmacotherapies in Australia

Pharmacotherapies for asthma can be categorised as symptom relievers, prophylactics and symptom controllers.


Reliever medications: Bronchodilators
Bronchodilators, also known as ‘relievers’ because they relieve the symptoms of acute asthma, are required by all asthmatic patients except those using eformoterol (a symptom controller, e.g. Foradile, Oxis) for maintenance therapy. These patients typically use Symbicort (a fixed dose combination containing eformoterol and budesonide), which is appropriate for symptom control and acute relief.1

Inhaled short acting β2 agonists are the most common bronchodilators, and are recommended for use in all patients who do not use eformoterol. They should only be used for symptom relief; regular therapy provides no clinical benefit. Patients who experience only intermittent attacks which are adequately relieved by bronchodilators do not require additional therapy. Symptomatic dosing should relieve symptoms for at least 3–4 hours. Shorter periods of relief indicate worsening asthma and need for additional treatments.1 Patients who experience persistent (> 3 times per week) attacks also require additional therapy with prophylactic anti-inflammatories or symptom controllers.1


Prophylactic: Anti-inflammatory agents
Anti-inflammatory agents work by preventing future inflammatory responses to allergens which cause asthma. They should be prescribed to all patients who have acute symptoms requiring bronchodilator therapy > 3 times per week, as well as those who experience night time symptoms at least once per week.1 Bear in mind that asthma symptoms do not always correlate with severity; a patient who is receiving effective treatment may exhibit few symptoms because their asthma is well controlled.6 Those with impaired lung function or who have experienced asthma exacerbation in the previous 2 years should also be prescribed anti-inflammatory therapy.1 



Inhaled corticosteroids
Inhaled corticosteroids (ICS) are the first line prophylactic treatment for asthma. Formulations available in Australia include beclomethasone dipropionate-HFA (Qvar), budesonide (Pulmicort), fluticasone propionate (Flixotide) and ciclesonide (Alvesco).1 ICS should be started at a low dose with upward or downward titration to find the lowest dose which effectively controls symptoms. Early ICS treatment is recommended for both adults and children with persistent symptoms as it can prevent irreversible lung function impairments which are associated with ongoing acute episodes of asthma.1

However, only 14% of Australian asthmatics report using these drugs daily for asthma control. The majority of those who do use ICS are using the highest available dose.3 Concerns by prescribing doctors regarding systemic side-effects in the long-term use of ICS may contribute to the low rates of use.7 However, evidence suggests ICS are safe for use by both adults and children, and adverse events can be minimised with optimal ICS selection.8 

Asthma image

For more information about how glucocorticosteroids work, formulations available and their correct use in respiratory indications, see Respiratory Indications for Glucocorticosteroids.

 

Properties of the ideal ICS
The ideal ICS is absorbed rapidly at the target site with minimal systemic absorption. In asthma treatment, high pulmonary deposition and retention are key features of the ideal ICS.8 Small particle size is also important because the smallest airways may be smaller than the particle size of the formulation. This makes airway deposition impossible and increases the probability that the particles will be deposited in the mouth and throat.5 However, ensuring high pulmonary deposition alone does not guarantee reduced systemic circulation, as much of the drug eventually enters systemic circulation following deposition in the lungs. Onsite activation to an active metabolite, high onsite protein binding (once bound to protein the drug is pharmacologically inactive), high receptor potency, low oral bioavailability and extensive metabolism and rapid elimination are also important factors for reducing systemic absorption.5,8

Ciclesonide is a prodrug ICS which is activated in the lungs, and has been formulated to reduce gastro-intestinal absorption and enhance first-pass metabolism by the liver.4 It has a favourable profile in terms of the ideal asthma ICS characteristics. For example, 52% of the dose is deposited in the lungs (compared to 12% and 18% respectively for fluticasone and budesonide). While 38% of the dose remains in the oropharyngeal cavity, ciclesonide’s onsite activation to its active metabolite occurs primarily in inflammatory cells, and so limits conversion to the active metabolite at non-target sites. Ciclesonide is also retained in the lungs for extended periods because the concentration of active metabolite increases as ciclesonide concentrations decrease with metabolism.8


ICS therapy for adult patients
ICS therapy should be instituted in all adults who experience persistent (> 3 times per week) asthma attacks. In adults, the efficacy of ICS is superior to other anti-inflammatory agents including leukotriene receptor agonists (montelukast, e.g. Singulair), cromones (sodium cromoglycate, e.g. Intal Forte CFC-free, and nedocromil sodium, e.g. Tilade CFC-free) and theophylline (Austyn, Nuelin). However, in cases where ICS are contraindicated, one of the fore-mentioned medicines must be instituted for prophylaxis.1

Combinations of ICS and other anti-inflammatory agents is also an option. ICS/leukotriene receptor agonist combinations are associated with small improvements in symptoms and lung function and a reduction in acute episodes. When combined with theophylline, lung function also improves; however, side effects are more common than with ICS monotherapy. There is no evidence that anticholinergics used in combination with ICS offer clinical benefit over ICS monotherapy.1

A short course (1–2 weeks) of high dose ICS may also be used to treat chronic severe exacerbations of asthma in adults. Oral corticosteroids (prednisolone, e.g. Panafcortelone, Predsolone, 20–30 mg per day) are a further option, but should be used only as a last resort to treat asthma exacerbations.3



ICS therapy for paediatric patients
In children, anti-inflammatory agents are unnecessary for those with infrequent asthma episodes.1 ICS are recommended as first-line treatment in moderate-severe cases,1 requiring use of asthma relievers more than once a week.4 However, in mild cases other anti-inflammatory agents are equally viable.  Practitioners must choose between low dose ICS, montelukast or inhaled cromone.1 ICS are the most effective option in persistent asthma and monotherapy appears to be as effective as combined therapy. Adding montelukast to ICS at best leads to modest improvements in lung function and overall asthma control typically deteriorates as the ICS is tapered down.4

The benefits of ICS include reduced morbidity, mortality and asthma exacerbations and improvement of symptoms, airway hyper-responsiveness and lung function. For school age children this may improve attendance and enable participation in sport and other activities which untreated or poorly treated asthma previously prevented. While they are not always prescribed due to safety concerns, evidence suggests low to medium doses have no effect on the hypothalamic-pituitary-adrenal axis, bone or growth in school age children and are associated with low rates of other adverse events.4

 

Symptom controllers: Long acting β2 agonists
Symptom controllers in the form of long acting β2 agonists (LABA) which achieve prolonged bronchodilation, may also be used as preventive therapy in adult patients with moderate persistent asthma which fails to respond to anti-inflammatory therapy alone. They are not indicated as monotherapy.1 RCTs of LABAs used as monotherapy reported life-threatening asthma exacerbations, including the need for intubation and asthma-related death in some patients. However, there is no evidence to associate combination ICS and LABA therapy with life-threatening asthma exacerbations.6

LABA therapy in combination with ICS improves symptom control and reduces the need for ICS therapy. Two options are available: Eformoterol with rapid (1–3 minutes) onset or salmeterol with slower (15–20 minute) onset.1

There is limited evidence regarding the safety and efficacy of these drugs in children; however, eformoterol may be prescribed to children ≥ 5 years and salmeterol to children ≥ 4 years.1 Available evidence suggests that the addition of LABA to and ICS regime does not reduce asthma exacerbations in children although it may have a favourable effect on lung function and reduce growth impairment compared to a higher dose of ICS.4


Fixed dose combination medicines
Eformoterol combined with budesonide (Symbicort is a fixed dose combination) may be used as maintenance, or maintenance and relief therapy. When used for asthma relief, additional doses are taken symptomatically.1 The eformoterol/budesonide combination may be used as treatment for severe exacerbations. Double the normal daily dose is recommended. Typically eight doses administered in two sittings is sufficient; however, some patients may require 12 doses.3 Practitioners must be cognisant that this increases the daily ICS dose.1

Salmeterol may be used in combination with fluticasone (including from the fixed-dose inhaler Seretide); however, this combination is only appropriate for maintenance therapy. As with ICS monotherapy, downward titration to establish the lowest possible therapeutic dose, and if possible to eliminate LABA from the regimen, is an important therapy goal.1


Fixed dose combinations delivered from a single inhaler are equally effective as the use of two medications delivered individually and there is no difference in adherence between the two. However, downward lowest-dose finding titration may require cessation of the fixed dose combination, in favour of two separate inhalers, as typically the dose of only one drug is reduced.1


Other options
Immunoglobulin E (IgE) may also be administered to patients with poorly controlled asthma, in combination with other medicines. Omalizumab (Xolair), a recombinant humanised monoclonal antibody against IgE prevents the inflammatory response at a higher point in the asthma cascade compared to other anti-inflammatories, by blocking the release of inflammatory mediators.1 While evidence suggests its use is associated with a small reduction in the required dose of ICS,6 the therapy is relatively expensive,1 and its efficacy has not been directly compared with more cost effective additive therapies like ICS/LABAs.6

 

Inhaler device and technique influence efficacy of treatment

The optimal combination of pharmacotherapy may change over time and regular review and comprehensive education are mandatory for optimising treatment efficacy.3 Review should ensure that the correct medications are combined with the best inhaler device for the patient, and that the inhaler device is used correctly.1,4 Inhaler device4 and technique1 influence the proportion of the dose which reaches the lungs and can have a remarkable influence on the efficacy of treatment.4

Some suggest the correct drug administration method is as important as selecting the medicine itself.2 The right device, one which can be used effectively, also increases the likelihood the patient will adhere to the treatment. This is a key determinant of treatment success, however only 20–73% of patient adhere to their inhaled medications properly.2 Medication changes or dose increases should not be instituted until proper adherence and correct use of the inhaler has been established.1 Correct use should not be assumed; many patients are unable to used their inhaler device correctly.2

There is little difference in the effectiveness of different inhaler devices when used correctly; however, it is important to bear in mind that the inhaler technique is influenced by the device used. There are numerous different devices available for administering asthma medications, and there is little advice to guide practitioners trying to select the correct device for their patient. Whatever device is selected, education and training in device use can increase the likelihood it will be used successfully. However, if the patient remains unable to use the device correctly after education and training, a new device should be trialled.2

 

More effective treatment depends on choosing the correct pharmacotherapies

Asthma treatment in Australia remains sub-optimal, and greater attention to selecting the correct combination of pharmacotherapies, and the correct devices for administration of these, is required to improve treatment and reduce the burden of asthma. ICS are recommended as first-line prophylactic treatment in all patients with moderate-severe asthma; however, they are only used by 14% of the asthmatic population, despite being safe for adults and children.

Novel formulations such as the prodrug ciclesonide, which increase pulmonary and reduce systemic absorption have a favourable safety and efficacy profile. While ciclesonide and other ICS may not achieve adequate control of moderate-severe asthma when used as monotherapy, in the majority of cases they should be combined with other anti-inflammatories or long acting bronchodilators, rather than discarded from the regimen. Increasing the proportion of patients using ICS appears to be an important step for improving the efficacy of asthma treatment, and reducing morbidity and mortality associated with the disease in Australia.


References

  1. National Asthma Council Australia. Asthma Management Handbook. 2006. [cited 2 May 2012]. Available from: [URL Link]
  2. Lavorini F, Levy M, Dekhuijzen PNR, et al. Inhaler choice and inhalation technique- key factors for asthma control. Prim Care Respir J. 2009; 18(4): 241-2. [Citation | Full Text]
  3. Rudolphy S. Asthma Management in General Practice: A chronic disease priority. Aust Fam Phys. 2008; 37(9): 710-14. [Abstract | Full Text
  4. van Aalderan WMC, Sprikkelman AB. Inhaled corticosteroids in childhood asthma: the story continues. Eu J Pediat. 2011; 170: 709-18. [Abstract | Full Text]
  5. Derendorf H, Nave R, Drollman A, et al. Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma. Eu Respir J. 2006; 28: 1042-50. [Abstract | Full Text
  6. O’Byrne P. Global guidelines for asthma management- Summary of the current status and future challenges. Pol Arch Med Wewn. 2010; 120 (12): 511-517. [Abstract | Full Text
  7. Barnes PJ. Inhaled glucocorticoids for Asthma. NEMJ. 1995; 332; 13: 868-75. [Full Text]
  8. Cerasoli F. Developing the ideal inhaled corticosteroid. Chest. 2006; 130: 54S-60S. [Abstract | Full Text]

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Dates

Posted On: 24 June, 2012
Modified On: 16 September, 2014

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