Pulmicort Mechanism of Action

Pharmacotherapeutic group: Inhalation drugs for obstructive airway diseases. ATC code: R03BA02.
Pharmacology: Clinical - Bronchial asthma: 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 0.8mg have been found to suppress plasma cortisol levels and urinary cortisol secretion. A single inhalation of 3.2mg budesonide was found to suppress plasma cortisol levels to a degree similar to 10mg 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 1mg 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 hyper-responsiveness 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 1.6mg budesonide produced mild bronchodilation. This effect is maximal at 6 hours after inhalation with a duration of 12 hours.
Clinical - Croup: A number if studies in children with croup have compared Pulmicort Respules with placebo. Examples of representative studies evaluating the use of Pulmicort Respules 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 Pulmicort Respules improves croup symptom scores or shortens the duration of stay in hospital. An initial dose of Pulmicort Respules (2mg) or placebo was given followed by either Pulmicort Respules 1mg or placebo every 12 hours. Pulmicort Respules 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 Pulmicort Respules 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 Pulmicort Respules 2mg or placebo ever 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 initial dose. At 2 hours, both the Pulmicort Respules 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 Pulmicort Respules group was statistically significantly improved compared with the placebo group, and this improvement versus placebo was similarly evident at 12 and 24 hours.
Clinical - Exacerbation of chronic obstructive pulmonary disease (COPD): Several studies on nebulised budesonide, 4-8mg/day have 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 nebulised budesonide or prednisolone showed similar improvements in FEV1, SpO2 (saturation as measured by pulse oximetry) and symptoms (COPD Assessment Test (CAT)).
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) 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 post-bronchodilator 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.
Pharmacokinetics: Approximately 10% of the discharged dose of PULMICORT aerosol is deposited in the lungs.
The volume of distribution of budesonide in adult man is approximately 300L and in children is 3.1 to 4.8 L/kg indicating a high tissue affinity. Plasma protein binding is 88.3 ± 1.5% in humans.
In adults the plasma half-life following inhalation via aerosol was 2.0 ± 0.2 hours and in children 1.5 hour with peak plasma levels occurring immediately after administration.
Negligible biotransformation was observed in human lung and serum preparations.
PULMICORT is 90% inactivated on first pass through the liver, via metabolism to more polar metabolites with a more than 100-fold lower glucocorticosteroid systemic activity than the parent compound.
In human volunteers who inhaled tritiated budesonide, 31.8 ± 7.5% of the discharged dose was recovered in urine and 15.1 ± 4.3% in faeces (0-96h). Plasma clearance of unchanged budesonide was calculated to be 84 L/h in adults and 1.5 to 2 L/h/kg in children.