almeterol: Salmeterol is a selective LABA. In vitro studies show salmeterol to be at least50 times more selective for beta2-adrenoceptors than albuterol. Although beta2-adrenoceptors arethe predominant adrenergic receptors in bronchial smooth muscle and beta1-adrenoceptors arethe predominant receptors in the heart, there are also beta2-adrenoceptors in the human heartcomprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptorshas not been established, but their presence raises the possibility that even selectivebeta2-agonists may have cardiac effects.
The pharmacologic effects of beta2-adrenoceptor agonist drugs, including salmeterol, are at leastin part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes theconversion of adenosine triphosphate (ATP) to cyclic-3′,5′-adenosine monophosphate (cyclicAMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibitionof 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 cellmediators, such as histamine, leukotrienes, and prostaglandin D2, from human lung. Salmeterolinhibits histamine-induced plasma protein extravasation and inhibits platelet-activatingfactor-induced eosinophil accumulation in the lungs of guinea pigs when administered by theinhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuateallergen-induced bronchial hyperresponsiveness.
12.2 Pharmacodynamics
Hypothalamic Pituitary Adrenal Axis Effects (HPA)There are no HPA data from controlled trials of the AirDuo Digihaler in healthy subjects orsubjects with asthma.
Cardiovascular Effects and Effects on Potassium and GlucoseAirDuo Digihaler in Healthy SubjectsThere were no clinical trials conducted with AirDuo Digihaler that assessed cardiovascular (CV)effects in healthy subjects.
Other Fluticasone Propionate and Salmeterol Dry Powder Inhaler (DPI) Products in HealthySubjectsSince systemic pharmacodynamic effects of salmeterol are not normally seen at the maximumapproved salmeterol dosage, higher doses were used to produce measurable effects. Four trialswere conducted with healthy adult subjects to assess CV effects:1. Single-dose crossover trial using 2 inhalations of fluticasone propionate and salmeterolDPI (500/50 mcg) (two times the maximum approved salmeterol dosagefor that DPI perdosing interval), fluticasone propionate DPI 500 mcg and salmeterol DPI 50 mcg givenconcurrently, or fluticasone propionate DPI 500 mcg given alone,
2. Cumulative dose trial using 50 to 400 mcg of salmeterol DPI (1 time to 8 times themaximum approved salmeterol dosage per dosing interval for that DPI, respectively)
given alone, or fluticasone propionate and salmeterol DPI (500/50 mcg),3. Repeat-dose trial for 11 days using 2 inhalations twice daily of fluticasone and
salmeterol DPI (250/50 mcg) (two times the maximum approved salmeterol dosage for that DPI per dosing interval), fluticasone propionate DPI 250 mcg, or salmeterol DPI
50 mcg, and
4. Single-dose trial using 5 inhalations of fluticasone propionate and salmeterol DPI(100/50 mcg) (five times the maximum approved salmeterol dosage for that DPI per
dosing interval), fluticasone propionate DPI 100 mcg alone, or placebo.
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