Salmeterol in the treatment of chronic asthma

American Family Physician,  August, 1997  by Gilbert E. D'Alonzo,  Kenneth A. Tolep

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According to the National Center for Health Statistics, nearly 12 million persons with asthma live in the United States. This inflammatory disease of the airways seems to be triggered by a variety of allergic and noxious substances that elicit bronchial hyperresponsiveness. This in turn causes wheezing and shortness of breath, as well as other symptoms. There is a close relationship between the intensity and extent of airway inflammation, bronchial hyperreactivity and the clinical manifestations of asthma. Therefore, anti-inflammatory medication is considered important, usually as first-line therapy.[1,2] Many physicians, however, use bronchodilators as primary treatment in patients with mild asthma and infrequent symptoms, adding anti-inflammatory medications as needed. With proper therapy, the asthmatic patient can maintain a normal activity level during exercise and sleep, achieve and maintain normal to near-normal pulmonary function, prevent chronic asthma symptoms and acute exacerbations, and limit visits to emergency departments and hospitals. Proper asthma management can be achieved through the creation of a partnership with asthma patients and by helping them understand and control their disease through physician-guided self-management.

Long-acting [Beta.sub.2]-Agonist Pharmacology

A new generation of beta2-agonist therapies, currently evolving, began with salmeterol (Serevent). Salmeterol has a long carbon side-chain[3,4] (Figure 1), which gives the molecule an extended duration of action -- at least 12 hours -- compared with albuterol (Proventil, Ventolin) or isoproterenol (Isuprel).[4,5]

While albuterol has a very rapid onset of effect, typically five to no more than 15 minutes, salmeterol has a delayed onset of action, nearly 20 minutes; therefore, this drug should not be used as acute therapy or in an emergency setting for the relief of bronchospasm.

[Beta.sub.2] agonists stimulate beta-adrenergic receptors, which are found on nearly every cell type in the lung, including airway epithelium, some mucosal glands, alveolar wall cells, vascular endothelium and the smooth muscle of the bronchi and pulmonary vessels. These receptors are also found on a variety of inflammatory cell membranes. The best understood function of stimulated [beta.sub.2] receptors in the lung is bronchial smooth muscle relaxation.

[BETA.sub.2] RECEPTORS AS ANTI-INFLAMMATORY AGENTS

Because [beta.sub.2] receptors are found on many other cells, some evidence indicates that their stimulation may favorably affect mediator release from immune effector cells, increase water content and secretions from mucous cells, enhance ciliary sweep rate on respiratory epithelial cells and even inhibit the movement of certain cells with pro-inflammatory capabilities through the vascular endothelial junctions. Therefore, when a [beta.sub.2] agonist is used, it is possible that more than bronchodilatation occurs.

It is obvious that salmeterol can be a potent bronchodilator but, since inflammation is so important in the pathophysiology of asthma, it is also necessary to consider the drug's potential anti-inflammatory actions. Salmeterol blocks the early and late asthmatic reactions to Whaled allergen and also subsequent airway hyperreactivity,[6,8] and in vitro studies have revealed that salmeterol can inhibit mast cell activation and degranulation,[9,10] and prevent increased vascular permeability in response to inflammatory mediators.[11]

SIDE EFFECTS

The side effects of salmeterol, which are similar to those of other [beta.sub.2] agonists, include tachycardia, palpitations, tremor, headache and hypokalemia.[12]

Over the past two years, a controversy has arisen over the potential role of [beta.sub.2]-agonist therapy in increasing the risk for asthma instability and death.[13-15 However, no rise in asthma mortality has occurred since salmeterol's introduction in the United Kingdom.[16] Furthermore, in large clinical trials extending from three months to one year, the incidence of asthma exacerbation and the use of rescue albuterol therapy decreased with the regular use of salmeterol.[4,5,17-19] Therefore, excess morbidity and mortality and increased asthma instability have not been identified with the regular use of salmeterol.

Salmeterol should not be used for "rescue" bronchodilatation during an acute asthmatic attack because of its delayed onset of action. Albuterol or another short-acting agent should be the drug of choice in an acute bronchospastic exacerbation.

Salmeterol: Clinical Studies

Oral sustained-release bronchodilators, in the forms of albuterol and theophylline, are being used as second-line therapy for control of asthma. Generally, patients with moderate and severe chronic asthma require multiple therapies for the prevention of asthma attacks.

Two controlled trials in more than 500 patients with mild-to-moderate asthma compared salmeterol (in a dosage of 42 [mu]g by inhalation twice daily) with albuterol (in a dosage of 100 [mu]g by inhalation four times daily) and placebo, over a 12-week study period.[3,4,19] Salmeterol was more effective in increasing morning and evening peak expiratory flow rates, improving overall asthma-symptom scores and decreasing the necessity for rescue used of albuterol. Patients also preferred salmeterol over albuterol. In patients regularly using salmeterol over three months' time, asthma deterioration was not evidenced. In the nearly one third of patients who were using inhaled corticosteroids on a regular basis, the addition of salmeterol further improved asthma control.