Pharmacology: Pharmacodynamics: Budesonide is a glucocorticosteroid which possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids.
The precise mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory effects (including T-cells, eosinophilic cells and mast cells) such as inhibition of the release of inflammatory mediators and inhibition of cytokine-mediated immune response, are probably important. The strength of budesonide, measured as affinity for glucocorticoid receptors, is approximately 15 times stronger than that of prednisolone. Glucocorticoids reduce airway inflammation and thus reduce airway hyper-responsiveness to a variety of stimuli, as well as to effectively prevent exercise-induced asthma.
Regular treatment with glucocorticoids improves lung function, reduces the number of acute exacerbations and reduces surrogate markers of airway inflammation including decreased eosinophils in sputum and decreased exhaled NO.
The most important aspect of inhaled glucocorticoids is that they exert their effects locally and have much reduced systemic exposure thus reducing side effects substantially. Following inhalation the proportion of drug absorbed and which together with the swallowed fraction could resulted in undesired systemic effects, e.g. suppression of the hypothalamic-pituitary-adrenal (HPA) axis, osteoporosis and insulin sensitivity depends on the individual compound properties and metabolic liability.
Pharmacokinetics: Absorption: In adults the systemic availability of budesonide following administration of Talgan Inhalation 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 min after start of nebulisation is approximately 4 nmol/L after a single dose of 2 mg. 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: Budesonide is mainly eliminated by metabolism. 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. Negligible metabolic inactivation has been observed in human lung and serum preparations.
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.
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.