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|Year : 1995 | Volume
| Issue : 1 | Page : 24-6
Salmeterol: a long acting bronchodilator.
D Bhadoria, P Bhadoria
Department of Medicine, University College of Medical Sciences (Delhi University).
Department of Medicine, University College of Medical Sciences (Delhi University).
Source of Support: None, Conflict of Interest: None
Keywords: Adrenergic beta-Agonists, chemistry,pharmacology,Albuterol, analogs &derivatives,chemistry,pharmacology,Asthma, drug therapy,Bronchodilator Agents, chemistry,pharmacology,Human, Molecular Structure,
|How to cite this article:|
Bhadoria D, Bhadoria P. Salmeterol: a long acting bronchodilator. J Postgrad Med 1995;41:24
Asthmatic symptoms are best treated with inhaled ?2- adrenoceptor agonists as they cause bronchodilatation by acting directly on bronchial smooth muscle. The major drawback of conventional ?2 stimulants is their short duration of action (3-6 hours) needing frequent administration. Therefore, they fail to abolish nocturnal symptoms of asthma. A drug that is effective through inhalation for at least 12 hours could overcome these problems by causing round the clock bronchodilatation. Salmeterol is such an advance over salbutamol and related ?2 agonists developed originally by Glaxo Group Research Ltd. UK.
Salmeterol is N- substituent of salbutamol. Its structure has been compared with salbutamol in [Figure:1].
It has two critical parts: saligenin-ethanolamine molecule and an aryl group; both linked by a long flexible carbon chain incorporating an oxygen function. The tail end of this side chain gets attached to a domain on the cell membrane (exosite or exoreceptor) near to ?2-receptor,. This anchoring mechanism enables the head region of the lipophilic molecule of salmeterol to activate the beta receptors repeatedly producing prolonged action. It is a potent and highly specific ?2-stimulant,. being more than 4000 fold weaker on cardiac ?2-receptors than isoprenaline. In vitro, it is about 5-10 times more potent, in molar terms, than salbutamol or isoprenaline in relaxing prostaglandin (PGF2 alpha), or electrically stimulated guinea-pig trachea, for at least 12 hours. These prolonged effects on airway smooth muscle have been confirmed in vivo, in animal models,, and in clinical studies,. However it is a slow acting drug. The onset of inhibition of contractile response (i.e. relaxation), with equipotent concentrations, in electrically stimulated guinea-pig trachea occurs at an average interval of 29 minutes for salmeterol, 1-2 minute for isoprenaline, 3.2 minute for salbutamol and 5.5 minute for clenbuterol (all short acting beta ?-2 stimulants),. In vitro, it is a potent inhibitor of mediators of inflammation (histamine, leukotrienes C4/D4 and PGD 2 release from antigen-challenged human lung, being 5-10 times more potent, in equipotent doses, than salbutamol. In bronchodilator doses, in vivo, it inhibits vascular permeability and protein extravasation into the airway lumen for upto 8 hours and, platelet activating factor or antigen stimulated infiltration of inflammatory cells into the lung for 24 hours. These actions seem to be mediated through beta ?2-adrenergic receptors.
Salmeterol, in 50 and 100 meg doses, is approximately equipotent to salbutamol 200 mcg, in terms of peak bronchodilator effects, which lasts almost three times as long as that of salbutamol (at least 12 hours),. It provides effective protection against bronchoconstriction induced by histamine, allergen, methacholine, hyperventilation, and exercise, for at least 12 hours. In fact, recent evidence suggest that even smaller doses of 50?g may cause bronchodilatation for as much as 24 hours in mild asthmatics. It completely suppresses both the early and late asthmatic responses to allergen challenge and allergen induced rise in non-specific bronchial hyper-responsiveness for 34 hours. These effects seem to be unrelated to bronchodilatation (functional antagonism). It means that salmeterol possesses clinically relevant anti-inflammatory actions as well, acting at multiple sites in inflammatory process through ? 2-receptors. The observation is further substantiated by the fact that salmeterol, after 4 weeks of treatment of asthmatics, improved not only the lung functions but also the macroscopic signs and the markers of inflammation. as verified by bronchoscopy, and bronchoalveolar lavage studies, respectively. Despite its anti-inflammatory action and bronchoprotection it remains unproven if salmeterol like corticosteroids or sodium chromoglycate could reduce the non-specific hyper-responsiveness of bronchial asthma in the long run.
Salmeterol is as sate as salbutamol. It is superior in twice daily doses, to salbutamol 200 meg or terbutaline 500 mcg given four times a day and dose titrated theophylline, in symptomatic management of asthma,. Clinically recommended doses vary from 12.5-100 ?g twice a day. However, in more severe cases using 100 ?g twice a day provides better control of asthmatic symptoms,,. In all grades of asthma, it improves morning and evening peak expiratory flow and, reduces diurnal variation, nocturnal awakenings, and the need of rescue doses of salbutamol for breakthrough Symptoms,. Thus it provides better control of asthma round the clock, and improves quality of life including sleep,,,.
It should be noted that salmeterol is intended only for regular treatment of mild to severe asthma. and has been used in trials, only in conjunction with inhaled corticosteroids and a short acting beta-agonist, theophylline etc,. In addition, despite its long duration of action, salmeterol has slower onset of action than salbutamol,,,.
Consequently, salmeterol has not been studied as symptomatic therapy in acute asthma. The incidence of side effects like palpitation, tremor. headache etc., are similar between salmeterol (50?g twice a day and salbutamol, (200?g four times a day). However there is a small increase in incidence of tremors if the dose of salmeterol is increased to 100?g twice a day,.
Continuous monotherapy with salmeterol for three months induces tachyphylaxis in mild asthmatics. This is in contrast to other studies that have failed to show any tachyphylaxis over a period from one to three months,,. Moreover, there has not been any loss of efficacy in studies conducted over one year. However, it must be noted that studies not showing any tachyphylaxis had a large number of patients receiving inhaled corticosteroids which are known to facilitate the effects of catecholamine, and have been shown to reverse the tachyphylaxis of high dose of salbutamol in normal individuals. Thus it is possible that tachyphylaxis to salmeterol in these studies was not apparent or delayed as a result of concomitant corticosteroid administration. Since more studies are needed to clarity this doubt it would be prudent to use corticosteroids in asthmatics who require regular ?2-stimulanis for the control of their symptoms not only to treat underlying airway inflammation, but also to reduce the risk, if any, of tachyphylaxis with salmeterol as well,.
Thus in short, salmeterol is a potent, highly specific and long-acting ?2-adrenoreceptor agonist. It has a definite place in management of all grades of asthma, more so in patients who have nocturnal symptoms. It must be noted that due to its slow onset of action and non-availability of data, it cannot be recommended for symptomatic management of acute asthma. Therefore rapidly and short acting ?2-agonists like salbutamol still remain drugs of choice in emergency situations.
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