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Inhaled budesonide is now well established in the management of adult and childhood asthma, and when nebulised, shows considerable promise in recurrent wheezing and in severe asthma in infants. Studies conducted since the drug was previously reviewed in the Journal in 1984 have confirmed the comparable efficacy of equal doses of budesonide and beclomethasone dipropionate, the ability of budesonide to reduce oral maintenance corticosteroid requirements, and demonstrated its potential as first-line treatment of mild to moderate asthma.
Recent studies have established the usefulness and good tolerability of intranasal budesonide in the treatment of seasonal allergic and perennial rhinitis where the drug is more effective than disodium cromoglycate and at least as effective as beclomethasone dipropionate.
After up to 10 years of treatment with inhaled budesonide there is no evidence that the drug damages the tracheobronchial lining or the nasal mucosa.
Inhaled corticosteroids continue to play an important role in the treatment of asthma with an increasing focus on their role as first-line therapy, and widespread clinical experience has shown budesonide is an effective and well tolerated member of this class which should be considered where inhaled or intranasal administration of a corticosteroid is indicated.
Budesonide has a high ratio of topical to systemic activity compared with reference corticosteroids such as beclomethasone dipropionate. In healthy volunteers, high doses of budesonide cause less depression of plasma cortisol urinary free cortisol excretion than equal dosages of beclomethasone dipropionate. The dosage of inhaled budesonide required to suppress fasting plasma cortisol levels in adults varies considerably between individuals. The adrenal suppressive effect of high dosages of inhaled corticosteroids may be reduced by mouth rinsing and use of a large volume spacer device which reduces oropharyngeal deposition and the amount swallowed.
Several studies suggest that inhaled budesonide may affect biochemical markers of bone turnover less than similar dosages of beclomethaspme dipropionate, and indicate that short term inhalation of budesonide has a less adverse effect on bone metabolism than dosages of oral prednisolone expected to exert a similar antiasthmatic effect. Long term studies are needed to determine if short term changes observed result in substantial loss of bone mass.
Treatment with inhaled budesonide reduces T cell-mediated inflammation in bronchial wall, epithelial eosinophils and lymphocytes in lamina propria, released eosinophilic cationic protein in bronchoalveolar lavage fluid, and plasma leakage into tracheobronchial airways. Reduced numbers of inflammatory cells were present in lung biopsies from patients with asthma treated long term with inhaled budesonide. Regular inhalation of budesonide is associated with improved airway responsiveness and concomitant clinical improvement. Protection against bronchial hyperresponsiveness after corticosteroid withdrawal is dependent on the duration, and possibly the total dosage of corticosteroid treatment. Bronchial antigen challenge in asthmatic patients results in both an immediate and a delayed type of asthmatic reaction. The latter is prevented by acute inhalation of a corticosteroid but the immediate reaction was historically thought to be unaffected by these drugs. However, the immediate reaction is now known to be attenuated according to the dosage and duration of inhaled corticosteroid. Similarly, exercise-induced asthma can be prevented by 3 or 4 weeks’ treatment with inhaled budesonide, whereas a single dose is ineffective.
The immediate reaction to nasal challenge is also inhibited only after 1 week of pretreatment with usual dosages of intranasal budesonide or beclomethasone dipropionate.
Following inhalation or intranasal administration of budesonide, peak plasma concentrations were reached within 15 to 45 minutes. Systemic bioavailability was 73%, which increased to about 100% after instillation of an alcohol (ethanol) solution directly onto nasal mucosa, compared with 10.7% after oral administration, where there was evidence of extensive first-pass metabolism. Volume of distribution of budesonide is about 300L. The concentration of budesonide in lung tissue 1.5 to 4 hours after inhalation of a single 1600μg dose was 15.5 nmol/h compared with 0.63 nmol/L in plasma at the same time.
The major metabolic pathway, 16α, 17α-acetal cleavage, is unique to budesonide among the topical corticosteroids and may increase the overall rate of inactivation. The relatively short elimination half-life following inhalation (about 2 hours) and high plasma clearance (83.7 L/h) highlight the rapid elimination of budesonide.
Studies published since the previous review of budesonide in the Journal confirm the generally similar efficacy of equal dosages of budesonide and beclomethasone administered by inhalation to adult patients with chronic asthma. These studies also confirm that individualised dosages of budesonide can be substituted for systemic corticosteroids in at least 40 to 50% of patients, often along with an improvement in pulmonary function or symptomatic control, particularly in those patients treated with prednisolone 5 to 7.5mg daily for less than 5 years. Long term treatment of newly diagnosed asthma patients with either inhaled budesonide 1200μg daily or terbutaline 750μg daily showed the inhaled corticosteroid to be more effective in increasing peak expiratory flow rate (PEFR) and in reducing symptoms, bronchial hyperreactivity and supplemental β2-adrenoceptor agonist use.
Inhaled budesonide 200 and 400μg daily were better tolerated and tended to be more effective than individually titrated dosages of slow release theophylline on the basis of changes in PEFR and supplemental β2-agonist requirements. These results and the finding that budesonide 400 and 800μg daily improved control of asthma when substituted for oral β2-agonists and/or theophylline, indicate that budesonide may be an effective first-line treatment for patients with mild asthma. The optimum frequency of administration of inhaled budesonide in patients whose asthma was either stable or unstable remains the subject of debate, but in clinical practice it is usually administered twice daily. Initial studies comparing a recently introduced inspiratory flow-driven dry powder inhaler with a pressurised inhaler plus a large volume cone spacer suggest that the new delivery system is at least as effective as traditional systems, causes less cough immediately after inhalation and is preferred by patients.
In the treatment of persistent wheezing in children aged less than 3.5 years, budesonide was effective when inhaled via a large volume spacer fitted with a facemask, but optimum dosage has to be determined individually. Studies in older children reported inhaled budesonide 200 to 400μg daily to be of similar efficacy to oral prednisolone 10mg, and an equal dose of beclome-thasone dipropionate when administered using the same delivery system, and more effective than disodium cromoglycate 8mg daily. Nebulised budesonide from a suspension containing a high concentration of the drug was consistently effective in improving control of childhood severe asthma in anecdotal reports and nonblinded trials, but results of double-blind trials have not always demonstrated superiority over placebo. Further studies are needed to determine optimum dosage via this delivery method and to assess the effect on growth and adrenal function.
Intranasal budesonide 400μg daily used to treat seasonal allergic rhinitis was as at least as effective as the same dose of beclomethasone dipropionate, more effective than disodium cromoglycate in relieving nasal symptoms and more effective than oral terfenadine or a single intramuscular injection of methylprednisolone in relieving nasal symptoms. Patients with perennial rhinitis have also been successfully treated with intranasal budesonide, which was more effective than alternative treatments, as have those with recurrent nasal polyposis.
Generally budesonide is well tolerated at usual therapeutic dosages, with local effects such as hoarseness (dysphonia), sore throat and local irritation causing cough being reported most commonly. At dosages of 800μg daily inhaled budesonide does not depress plasma cortisol levels, but individual sensitivity to the adrenocortical suppressive effect of inhaled corticosteroids varies. Initial data indicate no adverse effect on growth and weight gain among children treated for 1 year with inhaled budesonide 200 to 400μg daily, but the effects of higher dosages are not known. Biopsy specimens from lung mucosa and upper respiratory tract tissues of patients treated with inhaled budesonide for up to 10 years showed reduced numbers of inflammatory cells and no evidence of atrophy after 7 to 15 months. Intranasal budesonide 400μg daily is well tolerated with infrequent local adverse effects and rare reports of contact allergy.
Dosage and Administration
The inhaled dose of budesonide for the treatment of asthma in adults should be individualised. The recommended initial dose is 400 to 1600 μg/day divided into 2 or 4 administrations. Usually 200 to 800 μg/day is suitable for maintenance but the lowest dose that leaves the patient symptom free should be used. In children with asthma the recommended dose is 200 to 400 μg/day, divided into 2 or 4 administrations.
In treatment of rhinitis the dosage is 400 μg/day, which can be instilled into each nostril morning and evening or once daily in the morning. Once a good response has been achieved, this dosage can be halved.
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