Fortra Mechanism of Action

Pharmacology: Pharmacodynamics: Budesonide + Formoterol fumarate dihydrate Pressurized Inhalation Suspension have different modes of action and show additive effects in terms of reduction of asthma and COPD exacerbations. The specific properties of Budesonide and Formoterol allow the combination to be used as maintenance treatment of asthma. The respective mechanisms of both drugs are discussed as follows.
Budesonide: Budesonide is a glucocorticosteroid which when inhaled has a dose-dependent anti-inflammatory action in the airways, resulting in reduced symptoms and fewer exacerbations. Inhaled Budesonide has less severe adverse effects than systemic corticosteroids. The exact mechanism responsible for the anti-inflammatory effect of glucocorticosteroids is unknown.
Formoterol: Formoterol is a selective β₂ adrenoceptor agonist which when inhaled results in rapid and long-acting relaxation of bronchial smooth muscle in patients with reversible airways obstruction. The bronchodilating effect is dose dependent, with an onset of effect within 1-3 minutes. The duration of effect is at least 12 hours after a single dose.
Pharmacokinetics: Absorption: Orally inhaled Budesonide is rapidly absorbed in the lungs and peak concentration is typically reached within 20 minutes. After oral administration of Budesonide peak plasma concentration was achieved in about 1 to 2 hours and the absolute systemic availability was 6%-13% due to extensive first pass metabolism. In contrast, most of the Budesonide delivered to the lungs was systemically absorbed. In healthy subjects, 34% of the metered dose was deposited in the lung with an absolute systemic availability of 39% of the metered dose.
Inhaled Formoterol is rapidly absorbed; peak plasma concentrations are typically reached at the first plasma sampling time, within 5-10 minutes after dosing. As with many drug products for oral inhalation, it is likely that the majority of the inhaled Formoterol delivered is swallowed and then absorbed from the gastrointestinal tract.
Distribution and Metabolism: Plasma protein binding is approximately 90% for Budesonide and 50% for Formoterol. Volume of distribution is about 3L/kg for Budesonide and 4L/kg for Formoterol. Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6-beta-hydroxy-Budesonide and 16-alfa-hydroxy-prednisolone, is less than 1% of that of Budesonide. Formoterol is inactivated via conjugation reactions (active O-demethylated and deformylated metabolites are formed, but they are seen mainly as inactivated conjugates).
Elimination: Budesonide is eliminated via metabolism mainly catalyzed by the enzyme CYP3A4. The metabolites of Budesonide are eliminated in urine as such or in conjugated form. Budesonide has a high systemic clearance (approximately 1.2 l/min). Only negligible amounts of unchanged budesonide have been detected in the urine. Budesonide has a high systemic clearance (approximately 1.2 l/min) and the plasma elimination half-life after i.v. dosing averages 4 hours.
The major part of dose of Formoterol is transformed by liver metabolism followed by renal elimination. After inhalation, 8% to 13% of the delivered dose of Formoterol is excreted unmetabolized in the urine. Formoterol has a high systemic clearance (approximately 1.4 l/min) and the terminal elimination half-life averages 17 hours.