Pharmacology: Mechanism of Action: Fluticasone acts as a human glucocorticoid receptor agonist with an affinity for the receptor that is 18 times greater than that of dexamethasone, almost twice that of beclomethasone-17-monopropionate, and over three times that of budesonide. The anti-inflammatory actions of Fluticasone may contribute to its efficacy in asthma; however, its precise mechanisms are unknown. Corticosteroids have been shown to inhibit mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils. Corticosteroids also inhibit production or secretion of cell mediators such as histamine, leukotrienes, cytokines, and eicosanoids.
Salmeterol is a long acting beta-adrenergic agonist. It acts by stimulating beta2-adrenergic receptors in the lungs to relax bronchial smooth muscle, thereby relieving bronchospasm. This action is believed to result from increased production of cyclic adenosine 3,5-monophosphate (cyclic 3,5-AMP; cAMP) and ensuing reduction in intracellular calcium concentration caused by activation of the enzyme adenylate cyclase that catalyzes the conversion of adenosine triphosphate (ATP) to cAMP. Increased cAMP concentrations, in addition to relaxing bronchial smooth muscle, inhibit release of mediators of immediate hypersensitivity from cells, especially from mast cells.
Pharmacodynamics: Both Salmeterol and Fluticasone propionate have high lipocity and long duration of effect at their sites of action in the lung. The bronchodilator effect of Salmeterol lasts for about 12 hours as a result of high affinity binding to receptors within the β2-adrenoreceptor like wise Fluticasone has affinity for the glucocorticoid receptor and the half-life of the steroid receptor complex is >10 hrs.
Salmeterol and Fluticasone target different aspects of the disease process and varied evidence suggests that they produce complex mechanisms to produce relief of airway function.
Salmeterol protects against histamine, methacholine, cold air and sulphur dioxide-induced constriction and exercise induced asthma. There is no evidence of tolerance to the bronchodilator effects of Salmeterol. Salmeterol may also have anti-inflammatory properties
and can attenuate hyper responsiveness in patients with asthma.
Fluticasone propionate inhibits eosinophil activity resulting from the subsequent release of inflammatory mediators. It also appears to reduce bronchial hyper responsiveness in patients with asthma.
Given in fixed combination, the systemic dynamic effects of both Salmeterol and Fluticasone are essentially unchanged compared with their effects when given independently. No evidence of any untoward interactions between Salmeterol and Fluticasone was observed.
Pharmacokinetics: Pharmacokinetics of the fixed combination has not yet been established.
When Salmeterol is inhaled, plasma concentration of the drug cannot be detected even at 30 minutes after administration of the therapeutic doses. Nevertheless, in studies of single and multiple dose Salmeterol, there was no evidence that concomitant administration of Fluticasone propionate caused any alteration in the systemic availability of the drug versus monotherapy.
Similarly the systemic availability of Fluticasone propionate following inhalation is low, and studies comparing Fluticasone propionate monotherapy with each formulation strength of fixed combination Salmeterol and Fluticasone propionate indicated no increase in the systemic availability of the latter when Salmeterol was given concomitantly.
Both Salmeterol and Fluticasone propionate are metabolized by the cytochrome P450 enzyme CYP3A4, extensively so in the case of Fluticasone propionate, but only partly so in the case of Salmeterol.
Absorption: Fluticasone Oral bioavailability is less than 1%, due to incomplete absorption and presystemic metabolism in the intestine and liver. Systemic bioavailability via the DISKUS device averages 18%.
Salmeterol Systemic levels are low or undetectable after inhalation, due to small doses.
Distribution: Volume of distribution (VolD): Fluticasone: 4.2 L per kg (L/kg).
Protein binding: Fluticasone Very high (91%).
Salmeterol Very high (96%).
Biotransformation: Fluticasone: Total clearance is high; average 1093 mL per minute. The primary metabolite is the 17 β-carboxylic acid derivative of Fluticasone (via cytochrome P450 3A4).
Salmeterol: Metabolized by hydroxylation.
Half-life: Elimination: Fluticasone: 7.8 hours.
Salmeterol: 5.5 hours.
Time to peak concentration: Fluticasone: 1 to 2 hours following administration.
Salmeterol: 5 minutes following administration.
Peak plasma concentration: Fluticasone: Ranged from undetectable to 266 pg per mL after a 500 mcg twice daily dose. Mean concentration: 110 pg per mL.
Salmeterol: Mean concentrations: 167 pg per mL over 20 minutes following a chronic dosing schedule.
Elimination: Fluticasone: Renal: Less than 5%.
Fecal: Remainder of dose.
Salmeterol: Renal: 25%.