Aerotide Mechanism of Action

Pharmacotherapeutic group: Adrenergics in combination with corticosteroids or other drugs, excl. anticholinergics. ATC code: R03AK.
Pharmacology: Pharmacodynamics: Mechanism of action: Because fluticasone/salmeterol contains both fluticasone and salmeterol, the mechanisms of action described in the following sections for the individual components apply to fluticasone/salmeterol. These drugs represent 2 classes of medications (a synthetic corticosteroid and a selective, long-acting beta-2 adrenergic receptor agonist) that have different effects on clinical, physiological, and inflammatory indices.
Fluticasone: Fluticasone is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone as a human glucocorticoid receptor agonist with an affinity 18 times more than dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in humans are consistent with these results. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to inhibit multiple cell types (eg, basophils, eosinophils, lymphocytes, macrophages, mast cells, neutrophils) and mediator production or secretion (eg, cytokines, eicosanoids, histamine, leukotrienes) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. Inflammation is also a component in the pathogenesis of COPD. In contrast with asthma, however, the predominant inflammatory cells in COPD include neutrophils, CD8+ T-lymphocytes, and macrophages. The effects of corticosteroids in the treatment of COPD are not well defined, and inhaled corticosteroids and fluticasone, when used apart from fluticasone/salmeterol, are not indicated for the treatment of COPD.
Salmeterol: Salmeterol is a long-acting beta-2 adrenergic agonist. In vitro studies and in vivo pharmacologic studies demonstrate that salmeterol is selective for beta-2 adrenoceptors compared with isoproterenol, which has approximately equal agonist activity on beta-1 andbeta-2 adrenoceptors. In vitro studies show salmeterol to be at least 50 times more selective for beta-2 adrenoceptors than albuterol. Although beta-2 adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle, and beta-1 adrenoceptors are the predominant receptors in the heart, there are also beta-2 adrenoceptors in the human heart, comprising 10% to 50% of the total beta adrenoceptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta-2 agonists may have cardiac effects.
The pharmacologic effects of beta-2 adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D2, from the human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating, factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyperresponsiveness.
Pharmacokinetics: Absorption: Fluticasone: The absolute bioavailability of fluticasone propionate for each of the available inhaler devices has been estimated from within and between study comparisons of inhaled and intravenous pharmacokinetic data. In healthy adult subjects the absolute bioavailability has been estimated for salmeterol-fluticasone propionate pressurized inhalation is 5.3%. In patients with asthma or COPD a lesser degree of systemic exposure to inhaled fluticasone propionate has been observed. Systemic absorption occurs mainly through the lungs and is initially rapid then prolonged. The remainder of the inhaled dose may be swallowed but contributes minimally to systemic exposure due to the low aqueous solubility and pre-systemic metabolism, resulting in oral availability of less than 1%. There is a linear increase in systemic exposure with increasing inhaled dose.
therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the drug in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picograms/mL or less) achieved after inhaled dosing.
Distribution: Fluticasone: A large volume of distribution of fluticasone propionate at steady-state is approximately 300 L and a terminal half-life of approximately 8 hours. Plasma protein binding is moderately high (91%).
Salmeterol: After regular dosing with salmeterol xinafoate, hydroxynaphthoic acid can be detected in the systemic circulation, reaching steady state concentrations of approximately 100 nanograms/mL. These concentrations are up to 1,000 fold lower than steady state levels observed in toxicity studies. No detrimental effects have been seen following long-term regular dosing (more than 12 months) in patients with airway obstruction.
Metabolism: Fluticasone: Fluticasone propionate is cleared from the systemic circulation, principally by metabolism to an inactive carboxylic acid metabolite, by the cytochrome P450enzyme CYP3A4. Care should be taken when co-administering known CYP3A4 inhibitors, as there is potential for increased systemic exposure to fluticasone propionate.
Salmeterol: An in vitro study showed that salmeterol is extensively metabolized to alpha-hydroxysalmeterol (aliphatic oxidation) by cytochrome P450 3A4 (CYP3A4). A repeat dose study with salmeterol and erythromycin in healthy volunteers showed no clinically significant changes in pharmacodynamic effects at 500 mg three times daily doses of erythromycin. However, a salmeterol-ketoconazole interaction study resulted in a significant increase in plasma salmeterol exposure (see Precautions and Interactions).
Excretion: Fluticasone: Fluticasone propionate is cleared very rapidly from the systemic circulation. The disposition of fluticasone propionate is characterised by high plasma clearance (1,150 mL/min). The renal clearance of fluticasone propionate is negligible (<0.2%) and less than 5% as the metabolite.
Toxicology: Preclinical safety Data: The only safety concerns for human use derived from animal studies of salmeterol xinafoate and fluticasone propionate given separately were effects associated with exaggerated pharmacological actions. In animal reproduction studies, glucocorticosteroids have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not seem to be relevant for man given recommended doses. Animal studies with salmeterol xinafoate have shown embryofoetal toxicity only at high exposure levels. Following co-administration, increased incidences of transposed umbilical artery and incomplete ossification of occipital bone were found in rats at doses associated with known glucocorticoid-induced abnormalities. The non-CFC propellant, HFA-134a, has been shown to have no toxic effect at very high vapour concentrations, far in excess of those likely to be experienced by patients, in a wide range of animal species exposed daily for periods of two years.