Pharmacotherapeutic Group: Other Drugs for Obstructive Airway Diseases, inhalants, glucocorticoids. ATC Code: R03BA02.
Pharmacology: Pharmacodynamics: PULMICORT is a corticosteroid for inhalation use in the treatment and prophylaxis of asthma.
Studies in animals and humans have shown an advantageous ratio between topical anti-inflammatory activity and systemic glucocorticoid effect over a wide dose range. This is explained by the extensive first pass hepatic degradation of budesonide after systemic absorption, approximately 85-90%, in combination with the low potency of formed metabolites.
Budesonide is approximately twice as potent as beclomethasone dipropionate as shown in the skin blanching test for anti-inflammatory activity of topical steroids in humans. Budesonide has, however, less systemic effect than beclomethasone dipropionate, as measured by depression of morning plasma cortisol and effect on differential WBC count. The improved ratio of topical anti-inflammatory activity to systemic effect of budesonide is due to high glucocorticoid receptor affinity combined with a high first pass metabolism and a short half-life.
Doses of 0.8 mg have been found to suppress plasma cortisol levels and urinary cortisol secretion. A single inhalation of 3.2 mg budesonide was found to suppress plasma cortisol levels to a degree similar to 10 mg oral prednisolone.
Budesonide has been shown to counteract the mainly "IgE" but not the mainly "IgG" mediated lung anaphylaxis in guinea pigs. Pre-treatment for one to four weeks with inhaled budesonide 1 mg daily in asthmatic patients inhibited the immediate bronchial reaction to allergen challenge in a time-related manner; the late reaction is inhibited after one week of inhaled treatment.
Inhaled budesonide pre-treatment for 2 to 4 weeks has also been shown to reduce non-specific bronchial hyperresponsiveness in asthmatic patients to both direct (histamine, methacholine) and indirect (exercise) provocative stimuli in a time-related manner.
Budesonide did not potentiate β-receptor-mediated bronchodilation, and did not affect theophylline-induced relaxation of respiratory airway smooth muscle in guinea pigs. In man, single oral inhalations of up to 1.6 mg budesonide produced mild bronchodilation. This effect is maximal at 6 hours after inhalation with a duration of 12 hours.
Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect.
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 mastcells, 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, administered once or twice daily, has been shown to effectively prevent exacerbations of asthma in both children and adults.
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.
Growth: Asthma as well as inhaled glucocorticosteroids may affect growth.
Effects of Pulmicort Nebuliser 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 Pulmicort Nebuliser 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 Pulmicort Nebuliser 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 Pulmicort Nebuliser Suspension group than in the control group, conventional asthma therapy without inhaled glucocorticosteroids (statistically significant difference).
Pharmacokinetics: Absorption: In adults the systemic availability of budesonide following administration of Pulmicort Respule 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 min 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 iv dosing averages 2-3 hours.
Linearity: The kinetics of budesonide are dose-proportional at clinically relevant doses.
Children: In 4-6 years old asthmatic children, the systemic availability of budesonide following administration of Pulmicort Respule 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 min 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 (Cmax 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 nebulizer system.
Toxicology: 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.