Salmeterol

Salmeterol is a selective long-acting (12 hour) β₂ adrenoceptor agonist with a long side chain which binds to the exo-site of the receptor.

These pharmacological properties of salmeterol offer more effective protection against histamine-induced bronchoconstriction and produce a longer duration of bronchodilation, lasting for at least 12 hours, than recommended doses of conventional short-acting β₂ agonists. In man salmeterol inhibits the early and late phase response to inhaled allergen; the latter persisting for over 30 hours after a single dose when the bronchodilator effect is no longer evident. Single dosing with salmeterol attenuates bronchial hyper-responsiveness. These properties indicate that salmeterol has additional non-bronchodilator activity, but the full clinical significance is not yet clear. The mechanism is different from the anti-inflammatory effect of corticosteroids which should not be stopped or reduced when salmeterol is prescribed.

Salmeterol has been studied in the treatment of conditions associated with COPD, and has been shown to improve symptoms, pulmonary function and quality of life.

Salmeterol acts locally in the lung and previous studies have suggested that plasma levels are not necessarily an indication of therapeutic effects. In addition there are only limited data available on the pharmacokinetics of salmeterol because of the technical difficulty of assaying the active substance in plasma due to the low plasma concentrations at therapeutic doses (approximately 200 picogram/ml or less) achieved after inhaled dosing.

The only findings in animal studies with relevance for clinical use were the effects associated with exaggerated pharmacological activity.

In reproduction and developmental toxicity studies with salmeterol xinafoate, there were no effects in rats. In rabbits, typical β2 agonist embryo fetal toxicity (cleft palate, premature opening of eyelids, sternebral fusion and reduced ossification rate of the frontal cranial bones) occurred at high exposure levels (approximately 20 times the maximum recommended daily dosage for humans, based on the comparison of areas under the curve.

Salmeterol xinafoate was negative in a range of standard genotoxicity studies.

The non-CFC propellant, norflurane (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 up to two years including no effects on the reproductive performance or embryofetal development.