Pulmicort Mechanism of Action

Pharmacotherapeutic group: Turbuhaler: Inhalation drugs for obstructive airway diseases. ATC code: Turbuhaler: R03BA02.
Pharmacology: Pharmacodynamics: Turbuhaler: Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect.
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. Budesonide has been shown to decrease airway reactivity to histamine and methacholine in hyper-reactive patients.
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 Pulmicort Turbuhaler have shown dose-related effects on plasma and urinary cortisol. At recommended doses, Pulmicort 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. An initial small but generally transient reduction in growth (approximately 1 cm) has been observed, which usually occurs within the first year of treatment. Long-term studies in a clinical practice environment suggest that children and adolescents treated with inhaled budesonide on average achieve their adult target height. However, in a long-term double-blind study, in which the budesonide dose was generally not titrated to the lowest effective dose, children and adolescents treated with inhaled budesonide became on average 1.2 cm shorter as adults than those randomised to placebo. See Precautions about titration to the lowest effective dose and about monitoring the growth in children.
Inhalation therapy with budesonide is effective in preventing exercise-induced asthma.
Respules: 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 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 1.6 mg budesonide produced mild bronchodilation. This effect is maximal at 6 hours after inhalation with a duration of 12 hours.
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: 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 300 L 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 (0-96 h). Plasma clearance of unchanged budesonide was calculated to be 84 L/h in adults and 1.5 to 2 L/h/kg in children.
Toxicology: Preclinical safety data: Turbuhaler: In toxicity studies budesonide caused only the expected glucocorticoid effects.
Budesonide has not exhibited any genotoxic effects.
In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant in humans at the recommended doses.