Budecort Mechanism of Action

Pharmacotherapeutic group: Other anti-asthmatics, inhalants, glucocorticoids. ATC-code: R03B A02.
Pharmacology: Pharmacodynamics: Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect.
Turbuhaler: The precise mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory effects such as inhibited release of inflammatory mediators and inhibition of cytokine-mediated immune response are probably important. The activity of budesonide, measured as its affinity for glucocorticosteroid receptors is approx. 15 times higher than that of prednisolone.
Budesonide has anti-inflammatory effects shown as reduced bronchial obstruction during both the early and the late phase of an allergic reaction. In hyper-reactive patients budesonide reduces the histamine and metacholine reactivity in the airways.
Studies have shown that the earlier budesonide treatment is initiated after the onset of asthma, the better lung function can be expected.
Studies in healthy volunteers with Budesonide (BUDECORT TURBUHALER) have shown dose-related effects on plasma and urinary cortisol. At recommended doses, Budesonide (BUDECORT TURBUHALER), causes significantly less effect on the adrenal function than prednisone 10 mg, as shown by ACTH tests.
In children over the age of 3 years, no systemic effects have been detected with doses up to 400 micrograms per day. In the range 400-800 micrograms per day biochemical signs of a systemic effect may occur. With daily doses in excess of 800 micrograms such signs are common.
Asthma, like inhaled corticosteroids, can delay growth. However, studies in children and adolescents who were treated with budesonide for a long period (up to 11 years) show that the patients reach the expected adult height.
Inhalation therapy with budesonide is effective in preventing exercise-induced asthma.
Respules: Topical anti-inflammatory effect: The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions involving T-cells, eosinophils and mast cells, such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important. The intrinsic potency of budesonide, measured as the affinity to the glucocorticoid receptor, is about 15 times higher than that of prednisolone.
A clinical study in asthmatics comparing inhaled and oral budesonide at similar plasma concentrations demonstrated statistically significant evidence of efficacy with inhaled but not oral budesonide compared with placebo. Thus, the therapeutic effect of conventional doses of inhaled budesonide may be largely explained by its direct action on the respiratory tract.
Budesonide has shown anti-anaphylactic and anti-inflammatory effects in provocation studies in animals and patients, manifested as decreased bronchial obstruction in the immediate as well as the late allergic reaction.
Exacerbations of asthma: Inhaled budesonide has been shown to effectively treat and prevent exacerbations of asthma in both children and adults.
In a double-blinded, placebo-controlled, randomised study of moderate to severe acute asthma, the efficacy of nebulised budesonide (2.4 mg divided into 3 doses, at half hourly intervals) was compared to oral prednisolone (2 mg/kg, single dose), both added to nebulised salbutamol treatment. Eighty children, 2 years to 12 years of age admitted to emergency department were included. After one hour, oxygen saturation, respiratory rate and symptom scores (pulmonary index and respiratory distress) were significantly improved in the budesonide group compared to the prednisolone group. The proportion of patients ready for discharge at the end of 2 hours after the third dose of nebulisation was significantly higher in the budesonide group than in the prednisolone group (54% versus 18%, p<0.001).
The effect of nebulised budesonide 1 mg twice daily, when added to standard bronchodilator treatment and on top of systemic steroids was evaluated in double-blind randomised, placebo-controlled trial in 100 preschool children (7 months to 6 years of age) hospitalised for moderate to severe asthma exacerbation. All patients received 1 mg/kg/day of intravenous methylprednisolone for up to 5 days, and nebulized salbutamol and ipratropium bromide, for 2 days. Length of hospital stay was significantly shorter in the budesonide group than in placebo group (median: 44 versus 80 hours, respectively; p=0.01). Cumulative discharge rates were significantly higher in the budesonide group at 48, 60 and 72 hours (60% versus 24%, (p<0.001); 68% versus 32%, (p<0.001); and 76% versus 48% patients, (p=0.004), respectively).
The efficacy of nebulised budesonide (1.5 mg divided into 3 doses of 0.5 mg over 1 hour) added to a systemic corticosteroid (oral prednisolone 2 mg/kg) and bronchodilators was evaluated in a double-blind, randomised, placebo-controlled study comprising 945 children 2 years to 12 years of age with moderate to severe asthma exacerbation. In the subpopulation of patients with most severe exacerbation, hospitalisation rate was significantly lower in the budesonide group vs. placebo (35.5% vs. 53.4%; Odds Ratio=0.42; 95% CI=0.19, 0.94; p=0.03, i.e., reduction in odds by 58%).
The clinical efficacy and safety of nebulised budesonide in three doses (1 mg twice daily, 2 mg twice daily and 2 mg four times daily) compared with intravenous prednisolone 40 mg/day was evaluated in an open-label, randomised, controlled trial comprising 85 adult patients with severe acute asthma. All groups received nebulized terbutaline, oxygen and anti-infective treatment. At 24 hours post treatment both the budesonide 8 mg/day and prednisone groups showed significant improvements in clinical symptom score with no statistically significant difference between groups. At 72 hours of treatment, clinical symptom scores, FEV₁ and arterial blood gases improved for all four groups. There was no statistically significant difference between budesonide 4 mg/day, 8 mg/day and prednisolone groups (p>0.05). A statistically significant difference was noted compared to dose of 2 mg/day (p<0.05) favoring higher doses of budesonide or prednisolone treatment. At 10 days of treatment, clinical symptom scores, lung function and arterial blood gases improved for all four groups with no statistically significant difference. However, elevated blood glucose, and decreased plasma cortisol concentration compared to baseline was noted in the prednisolone group and not in any of the budesonide groups.
Exercise-induced asthma: Therapy with inhaled budesonide, administered either as once or twice daily has been effective when used for prevention of exercise-induced bronchoconstriction.
Budesonide has been shown to decrease airway reactivity to histamine and methacholine in hyperreactive patients.
Exacerbations of COPD: Several studies on nebulised budesonide, 4-8 mg/day has shown to effectively treat exacerbations of COPD.
The efficacy of budesonide was evaluated in an open label, randomised, comparative study in 78 hospitalised patients with acute exacerbations of COPD in two parallel groups receiving nebulised budesonide (n=37) 4 mg/day (2 mg twice daily) or intravenous infusion of prednisolone 120-180 mg/day (n=41) for 7-14 days. Patients treated with nebulized budesonide or prednisolone showed similar improvements in FEV₁, SpO₂ (saturation as measured by pulse oximetry) and symptoms (CAT score).
In a multi-center randomised controlled, single-blind study involving 471 patients with acute exacerbations of COPD, patients were treated with nebulised budesonide 6 mg/day (2 mg three times/day); or intravenously injected methylprednisolone (40 mg/day) for 10 days. Clinical efficacy of nebulised budesonide in comparison to systemic methylprednisolone as measured by FEV₁, PaCO₂ and symptoms (CAT score) was comparable, while PaO₂ improved more in the methylprednisolone group.
In a double-blind randomised placebo-controlled study involving 199 patients with acute exacerbations of COPD, patients were treated with nebulised budesonide 8 mg/day (2 mg four times a day (n=71) or 30 mg oral prednisolone every 12 hours (n=62) or placebo (n=66) for 3 days. Improvement in post bronchodilator FEV₁ compared to placebo was 0.10 L for budesonide and 0.16 L for prednisolone; the difference between the active treatments was not statistically significant. The proportion of patients showing clinical improvement in postbronchodilator FEV₁ of at least 0.15 L was greater in the nebulised budesonide group (34%) and the prednisolone group (48%) than in the placebo group (18%). The differences were statistically significant for both active treatments versus placebo (p <0.05) but not between the active treatments.
Clinical - croup: A number of studies in children with croup have compared Budesonide (BUDECORT RESPULES) Nebulizing Suspension with placebo. Examples of representative studies evaluating the use of Budesonide (BUDECORT RESPULES) Nebulizing Suspension for the treatment of children with croup are given as follows.
Efficacy in children with mild to moderate croup: A randomised, double-blind, placebo-controlled trial in 87 children (aged 7 months to 9 years), admitted to hospital with a clinical diagnosis of croup, was conducted to determine whether Budesonide (BUDECORT RESPULES) Nebulizing Suspension improves croup symptom scores or shortens the duration of stay in hospital. An initial dose of Budesonide (BUDECORT RESPULES) Nebulizing Suspension (2 mg) or placebo was given followed by either Budesonide (BUDECORT RESPULES) Nebulizing Suspension 1000 mcg or placebo every 12 hours. Budesonide (BUDECORT RESPULES) Nebulizing Suspension statistically significantly improved croup score at 12 and 24 hours and at 2 hours in patients with an initial croup symptom score above 3. There was also a 33% reduction in the length of stay.
Efficacy in children with moderate to severe croup: A randomised, double-blind, placebo-controlled study compared the efficacy of Budesonide (BUDECORT RESPULES) Nebulizing Suspension and placebo in the treatment OF croup in 83 infants and children (aged 6 months to 8 years) admitted to hospital for croup. Patients received either Budesonide (BUDECORT RESPULES) Nebulizing Suspension 2000 mcg or placebo every 12 h for a maximum of 36 h or until discharge from hospital. The total croup symptom score was assessed at 0, 2, 6, 12, 24, 36 and 48 hours after the initial dose. At 2 hours, both Budesonide (BUDECORT RESPULES) Nebulizing Suspension and placebo groups showed a similar improvement in croup symptom score, with no statistically significant difference between the groups. By 6 hours, the croup symptom score in the Budesonide (BUDECORT RESPULES) Nebulizing Suspension group was statistically significantly improved compared with the placebo group, and this improvement versus placebo was similarly evident at 12 and 24 hours.
Growth: Asthma as well as inhaled glucocorticosteroids may affect growth.
Effects of Budesonide (BUDECORT RESPULES) Nebulizing Suspension on growth have been studied in 519 children (age 8 months to 9 years) in three prospective randomised, open-label studies.
Overall, there was no significant difference in growth between children treated with Budesonide (BUDECORT RESPULES) Nebulizing Suspension and those treated with conventional asthma therapy. Two studies (n=239 and 72 respectively) showed a 7 mm and 8 mm greater growth after one year's treatment with Budesonide (BUDECORT RESPULES) Nebulizing Suspension compared to the control group, conventional asthma therapy including inhaled glucocorticosteroids (not statistically significant), while in one study (n=208) the growth during one year was 8 mm lower in the Budesonide (BUDECORT RESPULES) Nebulizing Suspension group than in the control group, conventional asthma therapy without inhaled glucocorticosteroids (statistically significant difference).
Pharmacokinetics: Turbuhaler: Absorption: Inhaled budesonide is rapidly absorbed. The peak plasma concentration is reached within 30 minutes after inhalation. In studies, the average deposition of budesonide in the lungs after inhalation via Turbuhaler has been shown to be 25-35% of the metered dose. The systemic bioavailability is approx. 38% of the metered dose.
Distribution and metabolism: Plasma protein binding is approx. 90%. The volume of distribution is approx. 3 L/kg. Budesonide undergoes extensive (approx. 90%) first pass metabolism in the liver to metabolites with low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide.
Elimination: Budesonide is eliminated through metabolism, catalysed primarily by the enzyme CYP3A4. The metabolites are excreted in the urine in unchanged or conjugated form. Only negligible amounts of unchanged budesonide are recovered in the urine. Budesonide has a high systemic clearance (approx. 1.2 L/min), and the plasma half-life after intravenous administration is on average 4 hours. The pharmacokinetics of budesonide is proportional to the dose at relevant dosages.
The pharmacokinetics of budesonide in children and in patients with impaired renal function is unknown. Exposure to budesonide may be increased in patients with hepatic disease.
Respules: Absorption: In adults the systemic availability of budesonide following administration of Budesonide (BUDECORT RESPULES) Nebulizing Suspension via a jet nebuliser is approximately 15% of the nominal dose and 40% to 70% of the dose delivered to the patients. A minor fraction of the systemically available drug comes from swallowed drug. The maximal plasma concentration, occurring about 10 to 30 minutes after start of nebulisation is approximately 4 nmol/L after a single dose of 2 mg.
Distribution: Budesonide has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85-90%.
Biotransformation: Budesonide undergoes an extensive degree (≈90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.
Elimination: The metabolites of budesonide are excreted as such or in conjugated form mainly via the kidneys. No unchanged budesonide has been detected in the urine. Budesonide has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of budesonide after intravenous dosing averages 2-3 hours.
Linearity: The kinetics of budesonide are dose-proportional at clinically relevant doses.
Children: In 4-6 year-old asthmatic children, the systemic availability of budesonide following administration of Budesonide (BUDECORT RESPULES) Nebulizing Suspension via a jet nebuliser (Pari LC Jet Plus with Pari Master compressor) is approximately 6% of the nominal dose and 26% of the dose delivered to the patients. The systemic availability in children is about half that in healthy adults. The maximal plasma concentration, occurring approximately 20 minutes after start of nebulisation is approximately 2.4 nmol/L in 4-6 years old asthmatic children after a 1 mg dose.
Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults.
The exposure (C_max and AUC) of budesonide following administration of a single 1 mg dose by nebulisation to 4-6-year-old children is comparable to that in healthy adults given the same delivered dose by the same nebuliser system.
Toxicology: Respules: Preclinical safety data: Results from acute, subacute and chronic toxicity studies show that the systemic effects of budesonide, eg, decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex, are less severe or similar to those observed after administration of other glucocorticosteroids.
Budesonide, evaluated in six different test systems, did not show any mutagenic or clastogenic effects.
An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be verified in two repeat studies, in which the incidence of gliomas did not differ between any of the groups with active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.
Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in one of two repeat studies with budesonide as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class-effect.
Available clinical experience shows that there are no indications that budesonide or other glucocorticosteroids induce brain gliomas or primary hepatocellular neoplasms in man.