corticosteroids in asthma: inhaled or oral?

Drugs 20: 81-86 (1980) 0012-6667/80/0700-0081/$01.50/0 © AD IS Press Australasia Pty Ltd. All rights reserved.

Corticosteroids in Asthma: Inhaled or Oral?

Peter W. Trembath Respiratory Unit, Austin Hospital, Heidelberg, Melbourne

The outlook for the patient severely affected by asthma was greatly improved with the introduction of corticosteroid therapy in 1948. Nevertheless, the dramatic benefits for the patient were not without cost, owing to the many unwanted and occasionally devastating side effects associated with the use of oral or parenteral corticosteroids. In response to the problem of side effects, efforts were made to syn-thesise corticosteroids which would be effective in asthmatic patients when administered by inhalation using metered aerosols. This was achieved with the introduction of beclomethasone dipropionate aerosol. Relatively low doses were administered directly by inhalation, so that therapeutic effects could be achieved in asthmatics while systemic side effects of significance were virtually eliminated, provided the maximum recommended dose was not exceeded. Consequently, many patients who required regular maintenance therapy with oral corticosteroids found that their asthma could be well controlled by the use of inhaled corticosteroids. At the same time, their oral corticosteroids could be withdrawn or continued at a substantially lower dosage, thereby reducing un-wanted side effects to a minimum.

In this article, the respective merits of inhaled vs oral administration of corticosteroids in asthma will be discussed. It should be appreciated that the choice of oral or inhaled corticosteroids is not appropriate in

patients with very severe asthma (which might war-rant admission to hospital), where the choice of ad-ministration of corticosteroids lies between the paren-teral and oral routes. Consequently, discussion will be confined to asthmatics with moderate disease severity, and the factors influencing the selection of the oral and/or aerosol routes of administration of corticosteroids.

I. Are There Suitable Treatment Alternatives to Corticosteroids in Asthma?

It is clearly important that adequate alternative treatment for asthma has been attempted before start-ing a patient on corticosteroid therapy. The main alternative forms of drug treatment for asthma at present include the ~2 sympathomimetic agents, theophylline and its derivatives, and sodium cromo-glycate.

1.1 ~2 Sympathomimetic Agents

The ~2 sympathomimetic agents include salbu-tamol, terbutaline and fenoterol. These drugs are best given as metered aerosols, with little to choose between the respective compounds. They generally


result in effective bronchodilatation for some hours after each dose, with only minimal effects on the heart.

Another advantage of oral corticosteroids over aerosol corticosteroids is found when oral treatment is required in patients who are unable to effectively use metered aerosols, although this problem may to some extent be overcome by the use of the dry powder formulation of beclomethasone (i.e. 'Rotacaps'). Some workers have found that certain patients have responded well to beclomethasone aero-sol therapy while they were inpatients and their medication was closely supervised, but the improve-ment could not be sustained after they left hospital.

1.2 Theophylline Derivatives

Oral theophylline derivatives are also of considera-ble benefit to many patients with asthma, and a poor response may possibly be due to an inadequate dose, or to intolerable side effects. It is important to ap-preciate that the dose requirements of theophylline vary markedly from person to person, and some of this variability is due to the presence of other diseases such as cor pulmonale, pulmonary oedema or hepatic cirrhosis. The dose requirements of theophylline tend to be greater in heavy smokers due to an increased rate of metabolism.

In patients who cannot tolerate therapeutically effective doses of theophylline when given alone, a change to a lower dose of theophylline in combination with a ~2 sympathomimetic aerosol may provide effective bronchodilatation, with a reduction in the likelihood of side effects developing from either medication.

I .3 Sodium Cromoglycate

Sodium cromoglycate is effective as a prophylactic agent in many patients, particularly the young and those with exercise-induced asthma. However, even in some patients with 'intrinsic' asthma, a favourable

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response to sodium cromoglycate may be seen, although regular treatment for at least 4 weeks may be necessary before such a response is apparent. Sodium cromoglycate is of no value in the treatment of acute severe asthmatic attacks.

I .4 When Should Corticosteroids be Considered?

In a patient who is not acutely ill, there will be time to adjust the above medication to achieve op-timal bronchodilatation with minimum side effects. However, if the patient is failing to respond ade-quately to the above treatment, e.g. is unable to carry out usual daily duties, losing time from work or school, or suffering from significant sleep distur-bance, then it is necessary to consider the use of corti-costeroids in addition to the above treatment. In some patients, the introduction of corticosteroids should not be delayed until other treatment has been op-timised - admission to hospital and more intensive therapy needs to be considered if the patient is acutely ill.

2. Use of Beclomethasone Aerosol

2.1 Advice to the Patient

It is most important that the patient be given a clear understanding of the reasons for prescribing beclomethasone aerosol, and where appropriate, the purpose in using beclomethasone should be con-trasted with the use of sympathomimetic aerosol bronchodilators. The patient also needs clear instruc-tions on the method of use of the metered aerosol in-haler.

When an aerosol bronchodilator such as sal-butamol or terbutaline is prescribed concurrently, the patient should be advised to use the bronchodilator about I 5 minutes before using the beclomethasone aerosol, in order to obtain the maximum benefit from the latter. The patient should also be carefully advised on what steps to take if he develops an acute attack of asthma, or if he fails to improve symptomatically to


the prescribed treatment regimen. In such situations, it may be necessary to prescribe a short course of high dose oral corticosteroids, with a relatively rapid reduction in dosage according to the clinical response. It may be valuable to give the patient written instruc-tions and a supply of oral corticosteroid tablets to use in such a situation, particularly if the patient has pre-viously suffered from acute severe exacerbations of asthma.

2.2 Advantages of Beclomethasone Aerosol

Beclomethasone aerosol is of particular advantage in asthmatics who might otherwise need a low main-tenance dose of oral corticosteroids, particularly in the relatively stable patient. Alternatively, the use of beclomethasone aerosol may reduce the maintenance dose of oral corticosteroids, so that unwanted side effects can be minimised. Where the choice between oral and inhaled corticosteroids is appropriate for the individual patient, the particular advantage of the in-haled corticosteroids is that systemic side effects can generally be avoided.

2.3 Dosage Regimen

Beclomethasone is a potent corticosteroid. The dose delivered per puff is approximately 50J.1g, and only about 10% of this dose is likely to be inhaled into the lower respiratory tract. Nevertheless, a dose of 400J.1g per day is sufficient to be therapeutically effective in long term treatment of many patients. Some authorities have found additional benefit by in-creasing the daily dose of beclomethasone up to 1600J.1g per day, and have claimed that this treatment is preferable to using oral corticosteroids at the biologically equivalent dose. [The manufacturers sug-gest a daily dose of 200 to 400J.1g, and recommend that the daily dose should not exceed 1000J.1g (20 puffs).]

A very small quantity of the delivered dose of beclomethasone will be absorbed systemically, but even a delivered dose of 400J.1g per day may result in

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suppression of adrenal function, when assessed by an ACfH stimulation test. However, such a dose is unlikely to produce clinically detectable systemic side effects. The risk of systemic side effects developing is dose-dependent. Consequently, if very large doses of beclomethasone are used, systemic side effects may develop, and there may be little advantage over using the lowest effective maintenance dose of oral cortico-steroids, particularly if the latter can be successfully taken on alternate days (see section 3.5).

2.4 Disadvantages of Beclomethasone Aerosol

Beclomethasone aerosol is of virtually no value in treating an acute attack of asthma. It is most impor-tant that the patient be warned that despite the similar appearance of the aerosol inhalers, beclomethasone is not an appropriate alternative to the ~2 sympatho-mimetic aerosols.

The development of oral candidal infection can sometimes be troublesome, and is more common when higher doses of beclomethasone are used. The risk of this occurring may be reduced by rinsing the mouth with water immediately after using the aero-sol, or by specific antifungal treatment, although in some cases beclomethasone therapy may have to be discontinued. Some patients also complain of hoarse-ness of the voice, which does not appear to be related to laryngeal candidal infection.

3. Use of Oral Corticosteroids

Many of the large range of synthetic cortico-steroids available for oral use are particularly potent when compared with cortisone. This can be a disad-vantage in the treatment of asthma because of the limited flexibility in choosing the minimal effective corticosteroid dose. Prednisolone is a common choice of oral corticosteroid, and is available as I mg, 5mg and 25mg tablets. Prednisolone should be prescribed in preference to the closely related compound pred-nisone. Although the latter is metabolised to phar-

Corticosteroids in Asthma: Inhaled or Oral? 84

macologically active prednisolone in the liver, this Oral corticosteroids obviously also have an impor-metabolism is subject to considerable interpatient tant place in the management of episodes of acute variation, and the overall bioavailability of prednisone severe asthma. As stated previously, beclomethasone is less reliable. aerosol is not a satisfactory alternative in such a situa-

3.1 Indications for Oral Corticosteroids

The treatment of asthma with corticosteroids is in-dicated when the expected therapeutic benefit out-weighs its risks; for this, the anticipated duration of treatment also needs to be considered. For long term treatment, the risk/benefit assessment for oral corti-costeroids will differ from the assessment for beclomethasone aerosol. Obviously in the latter case, the criteria for its use would be less stringent.

3.2 Advantages of Oral Corticosteroids

In many patients, the degree of disability caused by their asthma is of sufficient severity to warrant the use of oral corticosteroids, perhaps concurrently with beclomethasone aerosol. In less severely affected patients, the clinician may judge that the patient would be satisfactorily controlled with beclometha-sone aerosol rather than oral corticosteroids. How-ever, even in this situation it is worth considering starting the patient on a short course of oral cortico-steroids, e.g. prednisolone 20 to 40mg daily for 2 or 4 weeks, before introducing beclomethasone aerosol (overlapping treatment during the last week). Treat-ment with a short course of oral corticosteroids before starting beclomethasone aerosol may result in a faster improvement in lung function, including re-sponsiveness to aerosol bronchodilators.

Another advantage of oral corticosteroids over aerosol corticosteroids is found when oral treatment is required in patients who are unable to effectively use metered aerosols. Some workers have found that certain patients responded well to beclomethasone aerosol therapy while they were inpatients and their medication was closely supervised, but the improve-ment could not be sustained after they left hospital.

tion.

3.3 Disadvantages of Oral Corticosteroids

The principal side effects of oral corticosteroids are obviously their systemic side effects, and the side effects related to the reduction or cessation of such therapy. The systemic side effects of corticosteroids are well known, and include fluid retention, hyper-tension, hyperglycaemia, psychosis, dyspepsia, adren-al cortical suppression, and reduced responsiveness to stress such as infections. Many of these side effects are potentially serious and indicate the need for par-ticular care in the selection and supervision of patients to be placed on such treatment. Patients receiving oral corticosteroids need to be appropriately advised of the nature and potential hazards of their treatment, and the measures to be taken if their symptoms deterio-rate, if they develop an intercurrent infection, or if they require surgery.

3.4 Reduction of Oral Corticosteroid Dosage

If the patient has received a short 2 to 4 week course of corticosteroids and has responded satisfac-torily, the dose of oral corticosteroids may generally be reduced fairly quickly, either stopping completely or reducing the dose to the anticipated maintenance level over a few days. Adrenal function may not return to normal for some days (or weeks), although this is not usually a practical problem following a short course of oral corticosteroids. However, a sud-den increase in symptom severity indicates the need to resume corticosteroid therapy at least temporarily.

On the other hand, where it is planned to reduce the dose of oral corticosteroids in patients who have been receiving such treatment for an extended period, the rate of dosage reduction needs to be considerably


Table I. Summary of the use of corticosteroids in asthma

1. Consider using oral corticosteroids: a) In treatment of acute severe asthma attacks, in some

cases preceded by parenteral corticosteroids b) In patients with moderately severe asthma which is

showing little response to aerosol bronchodilators. The oral corticosteroid dose may be reduced and beclomethasone introduced following clinical improve-ment

c) In patients requiring low dose corticosteroid therapy, who are unable to effectively use a metered aerosol in-haler. Control in these patients may be possible using an alternate-day oral corticosteroid dosage regimen

2. Consider using beclomethasone aerosol: a) In patients who are not adequately responding to ap-

propriate doses of alternative therapy such as ~2 sym-pathomimetic aerosols, theophylline, sodium cromo-glycate, etc.

b) As a replacement for oral corticosteroids when the maintenance dose is low. Oral corticosteroid dosage reduction should be gradual, and immediately increased if symptoms worsen significantly. Increasing the dose of beclomethasone aerosol in such circumstances is not an effective alternative

c) In patients requiring moderate oral corticosteroid main-tenance doses. Concurrent administration of beclomethasone aerosol should enable a reduction of oral corticosteroid dosage, and reduce the risk of ad-verse effects from corticosteroid therapy

slower. The duration of treatment with oral cortico-steroids therefore needs to be considered when decid-ing the rate of corticosteroid reduction, irrespective of whether the objective is to discontinue corticosteroid therapy completely or to change over to beclometha-sone aerosol. In general, the rate of reduction also tends to be less as the daily oral corticosteroid dose is reduced. For example, in a patient taking 25mg of prednisolone per day it may be possible to reduce this dose at a rate of 5mg per day every I to 2 weeks until the dose reaches 15mg per day, thereafter by 2.5mg per day every I to 2 weeks until the dose is IOmg per day, with subsequent dose reductions of I to 2mg per day every 2 to 4 weeks.

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These rates would need to be modified depending on the individual's response, and adequate and con-tinued supervision during this period is essential. The 'steroid withdrawal syndrome' may occur during the reduction of oral corticosteroid dosage, and is charac-terised by fever, malaise, arthralgia, abdominal pain, nausea, vomiting and changes in affect. These symp-toms may be sufficient to necessitate briefly resuming a higher corticosteroid dosage.

3.5 Alternate Day Oral Corticosteroid Therapy

This has been recommended in an effort to reduce the incidence or severity of side effects of oral cortico-steroids. Patients requiring more than 15 to 20mg of prednisolone daily are unlikely to be adequately con-trolled with alternate day oral corticosteroid therapy because of worsening symptoms - particularly on the corticosteroid-free day. Some workers have found a similar degree of suppression of the hypothalamic-pituitary-adrenal axis with alternate day oral cortico-steroids and beclomethasone aerosol, although the latter was given in high doses. The relative merits of alternate day lOW-dose oral corticosteroids and beclomethasone aerosol still require clarification. However, there are some suggestions that the latter may offer greater therapeutic advantages.

4. Oral Corticosteroids and Beclomethasone Aerosol in Combination

It has been previously stated (section 2.2) that beclomethasone may be of value in patients requiring maintenance oral corticosteroids, by reducing the daily oral corticosteroid dosage and minimising the risks of side effects. Although such combination therapy is valuable, the manipulation of the different dosage forms may appear complicated.

For example, one suggested method is to (I) deter-mine the minimum oral corticosteroid dose require-ment initially and maintain this for a few weeks to ensure stability of control; then (2) introduce


beclomethasone aerosol and increase the dose up to the maximum; then (3) reduce the prednisolone dose gradually (completely if possible); and finally (4) reduce the beclomethasone aerosol dose so that the patient is maintained on the minimum effective doses of oral and aerosol corticosteroids.

5. Conclusion

The management of the moderately affected asthmatic has been significantly enhanced by the in-troduction of beclomethasone dipropionate aerosol. The number of patients requiring long term mainte-nance with oral corticosteroids has been substantially reduced. In some patients, the combined use of oral and inhaled corticosteroids has resulted in lower maintenance doses of oral corticosteroids, and conse-quently diminished risks of developing adverse dose-related side effects. However, it is important to ap-preciate that the need for oral or parenteral cortico-steroids in the severely affected patient still remains, and should be provided without delay.

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Further Reading References

BacaI, E. and Patterson, R.: Long-term effects of beclomethasone dipropionate on prednisone dosage in the corticosteroid-depen-dent asthmatic. Journal of Allergy and Clinical Immunology 62: 72-75 (\978).

Collins, J.V.; Clark, TJ.H.; Brown, D. et aI.: The use of cortico-steroids in the treatment of acute asthma. Quarterly Journal of Medicine 34: 259-273 (\ 975).

Editorial: Are steroid inhalers safer than tablets? Lancet I: 589-590 (\ 979).

Lahdensuo, A.; Alanko, K.; Poppius, H. et aI.: A comparative study of the efficacy of inhaled beclomethasone and systemic prednisolone in bronchial asthma. Scandinavian Journal of Respiratory Diseases 55: 309-319 (\ 974).

Toogood, J.H.; Lefcoe, N.M.; Haines, D.S.M. et aI.: Minimum dose requirements of steroid-dependent asthmatic patients for aerosol beclomethasone and oral prednisone. Journal of Allergy and Clinical Immunology 61: 355-364 (\ 978).

Wyatt, R.; Waschek, J.; Weinberger, M. et aI.: Effects of inhaled beclomethasone dipropionate and alternate-day prednisone on pituitary-adrenal function in children with chronic asthma. New England Journal of Medicine 299: \387- \392 (\ 978).

Author's address: Dr Peter W. Trembath. Respiratory Unit, Austin Hospital, Heidelberg, Victoria 3084 (Australia).

corticosteroids in asthma: inhaled or oral?

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