Giona Easyhaler Mechanism of Action

Pharmacotherapeutic group: Glucocorticoids. ATC code: R03BA02.
PHARMACOLOGY: Pharmacodynamics: Budesonide is a glucocorticosteroid which possesses a high local anti-inflammatory action.
Topical anti-inflammatory effect: The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions, such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important.
Onset of effect: After a single dose of orally inhaled budesonide, delivered via dry powder inhaler, improvement of the lung function is achieved within a few hours. After therapeutic use of orally inhaled budesonide delivered via dry powder inhaler, improvement in lung function has been shown to occur within 2 days of initiation of treatment, although maximum benefit may not be achieved for up to 4 weeks.
Airway reactivity: Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyper-reactive patients.
Exercise-induced asthma: Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma.
HPA axis function: A study in healthy volunteers with Giona Easyhaler has shown dose-related effects on plasma and urinary cortisol. At recommended doses, budesonide causes less effect on the adrenal function than prednisolone 10mg, as shown by ACTH tests.
Paediatric population: Limited data from long term studies suggest that most children and adolescents treated with inhaled budesonide ultimately achieve their adult target height. However, an initial small but transient reduction in growth (approximately 1 cm) has been observed. This generally occurs within the first year of treatment (see Precautions).
Slit lamp examinations were performed in 157 children (5-16 years old), treated with an average daily dose of 504 μg for 3-6 years. Findings were compared with 111 age-matched asthmatic children. Inhaled budesonide was not associated with an increased occurrence of posterior subcapsular cataract.
Pharmacokinetics: The activity of Giona Easyhaler is due to the parent active substance, budesonide, which is provided as a mixture of two epimers (22R and 22S). In glucocorticoid receptor affinity studies, the 22R form is twice as active as the 22S epimer. These two forms of budesonide do not interconvert. The terminal half-life is the same for both epimers (2-3 hours). In asthmatic patients, approximately 15-25% of the inhaled budesonide dose from Easyhaler reaches the lungs. The largest fraction of the inhaled dose is retained in the oropharynx and swallowed if not rinsed out.
Absorption: After oral administration of budesonide, peak plasma concentration is achieved in about 1-2 hours and the absolute systemic availability is 6-13%. In plasma, 85-95% of budesonide is bound to proteins. In contrast, peak plasma concentration is reached approximately 30 minutes after inhalation. Most of budesonide delivered to the lungs is systemically absorbed.
Distribution: Budesonide has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85-90%.
Biotransformation and Elimination: Budesonide is mainly eliminated by metabolism. Budesonide is rapidly and extensively metabolised in liver via cytochrome P4503A4 to two major metabolites. The in vitro glucocorticoid activity of these metabolites is less than 1% of that of the parent compound. Negligible metabolic inactivation has been observed in human lung and serum preparations.
Budesonide is excreted in urine and faeces in the form of conjugated and non-conjugated metabolites.
Linearity: The kinetics of budesonide are dose-proportional at clinically relevant doses.
Paediatric population: 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.
Special patient populations: The exposure to budesonide may be increased in patients with liver disease.
Toxicology: Preclinical safety data: Non-clinical data with budesonide reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, or carcinogenic potential.
In animal studies on reproductive toxicity, glucocorticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal results do not seem to be relevant for humans given recommended doses.