Airway and Metabolic Responsiveness to Intravenous Salbutamol in Asthma: Effect of Regular Inhaled Salbutamol

Abstract

1. Airway, metabolic and cyclic nucleotide responses to intravenous salbutamol were measured in five patients with mild asthma who had taken no medication in the week before the study. The studies were repeated after the patient had taken regular inhaled salbutamol for 4 weeks, in doses increasing to 2000 micrograms daily in week 4. 2. The pretreatment airway, metabolic and cyclic nucleotide responses to salbutamol were similar to those previously reported in normal subjects. These patients therefore did not show evidence of partial beta-adrenoceptor blockade. 3. After 4 weeks' salbutamol therapy the airway response to intravenous salbutamol was unchanged. 4. The glucose, pyruvate and adenosine 3':5'-cyclic monophosphate (cyclic AMP) responses to intravenous salbutamol were depressed after regular salbutamol administration. The dose-response curve for non-esterified fatty acids and insulin, though displaced downwards, did not indicate an impaired response to salbutamol since the shape was unchanged. There was no significant change in the lactate, glycerol and total ketone response. 5. This study confirms that tissues differ in the ease with which they develop resistance to beta-adrenoceptor agonists. Asthmatic airways appear to be relatively protected from developing assistance when compared with other tissues in asthmatic patients and when compared with the airways of normal subjects.

Does tachyphylaxis occur to the non‐pulmonary effects of salmeterol?

“…Tachyphylaxis has been observed previously to the hyperglycaemic response observed after other P2-adrenoceptor agonists [5,6,16] so the results in the present study with salmeterol are consistent with these findings.…”

“…In both healthy subjects and asthmatics, tachyphylaxis can occur to metabolic, cardiovascular and tremorogenic effects of ,32-adrenoceptor agonists [4][5][6][7] whilst the effects on the lung are variable [8,9]. However, tachyphylaxis has not been shown to occur to the pulmonary effects of salmeterol after regular treatment in asthmatic subjects [10].…”

Potentiation of the adverse effects of intravenous terbutaline by oral theophylline.

“…Some of these patients may already have a low serum potassium as a result of treatment with corticosteroids or because they are receiving diuretics and digoxin for co-existent heart failure. Hypokalaemia has been associated with cardiac arrhythmias (Cole et al, 1981;Holland et al, 1981;Thomas, 1983 We (Smith & Kendall, 1985), and others (Holgate et al, 1980;Harvey et al, 1981) have previously shown that tolerance occurs to some of the unwanted responses to ,-adrenoceptor stimulants after long-term use, although the hypokalaemic response persists to some degree (Smith & Kendall, 1985). It is possible that the effects of such tolerance are offset by the combination of theophylline with the 32-adrenoceptor stimulant.…”

Regular nebulised terbutaline in chronic obstructive airways disease: dose‐response studies fail to detect tolerance.

“…However concerns remain over side effects (Harvey et al, 1981) and the possible development of tolerance. The question of tolerance to P2-adrenoceptor agonists has been extensively studied with clear evidence of tolerance as regards heart rate (Barnes and Pride, 1983), metabolic responses (Harvey & Tattersfield, 1982;Jenne etal., 1977), tremor (Prior & Cochrane, 1982) and bronchodilator effects in normal subjects (Larsson et al, 1977), but the majority of studies have failed to detect evidence of bronchodilator tolerance in asthma (Larsson et al, 1977;Nelson et al, 1983;Tattersfield, 1985).…”