Clinical implications of drug-induced desensitization of the beta receptor after continuous oral use of terbutaline

Abstract

Normal (n = 6) and asthmatic (n = 8) subjects received oral therapy with 5 mg of terbutaline three times a day for 2 wk, followed by 1 wk of placebo administration. The asthmatics were deprived of all bronchodilator therapy for at least 10 days prior to the investigation. At day 0, 7, 14, and 21 of this scheme, directly before (0900 hr) and 3 hr after oral administration of 5 mg of terbutaline, blood was sampled for (1) in vitro stimulation experiments of leukocytes, (2) determining the beta-adrenoceptor binding capacity of lymphocytes, (3) determination of plasma cyclic AMP levels, and (4) measurement of terbutaline serum concentrations. In addition to these variables, spirometry and finger tremor measurements were performed. Compared with baseline values, it appeared that most of these variables (plasma cyclic AMP, serum terbutaline, spirometry, and finger tremor) showed elevated levels at 0900 hr after 7 and 14 days of therapy with terbutaline. Three hours after an oral dose of 5 mg of terbutaline on days 7 and 14 of therapy with terbutaline, these variables were not significantly different from the 3-hr level of day 0, with the exception of terbutaline serum concentration, which was significantly higher on days 7 and 14 (p < 0.04). Furthermore, the in vitro stimulation and binding experiments showed a reduced beta-adrenergic response and a decrease in the number of beta-adrenergic receptors. Also a reduced response for the in vivo measurements was registered. This suggests that desensitization occurred. Since the basal lung function of the asthmatic subjects remained clinically improved during the oral terbutaline therapy (2.1 ± 0.4 and 1.9 ± 0.4, FEV 1 in liters, mean ± SEM) as compared with the values before therapy (1.6 ± 0.3), the beta-adrenergic therapy still remained beneficial. Therefore desensitization should be interpreted as cellular protection against over stimulation to prevent cellular exhaustion via the beta-adrenergic receptor. Since our study suggests a basal beta-adrenergic subsensitivity in asthmatics, as seen from the lower basal cyclic AMP levels of the mixed leukocytes, there could be some risk from reinforcement of the beta-adrenergic subsensitivity by beta-2-adrenergic agents. This process may lead to a domination of constrictive mechanisms in the asthmatics. For this reason, maximal beta-adrenergic monotherapy should be avoided. From this point of view it would be advisable to consider as a better alternative combination therapy of beta-adrenergic drugs with theophylline and/or anticholinergic drugs in lower dosages than would be used in monotherapy. Such a combination therapy should be utilized when prophylactic drugs like cromoglycate or corticosteroids administered systemically or by inhaler have only little effect.