Tachyphylaxis to Systemic But Not to Airway Responses during Prolonged Therapy with High Dose Inhaled Salbutamol in Asthmatics

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Abstract
High doses of inhaled salbutamol produce substantial improvements in airway response in patients with asthma, and are associated with dose-dependent systemic beta-adrenoceptor responses. The purpose of the present study was to investigate whether tachyphylaxis occurs during prolonged treatment with high dose inhaled salbutamol. Twelve asthmatic patients (FEV1, 81 .+-. 4% predicted), requiring only occasional inhaled beta-agonists as their sole therapy, were given a 14-day treatment with high dose inhaled salbutamol (HDS), 4,000 .mu.g daily, low dose inhaled salbutamol (LDS), 800 .mu.g daily, or placebo (Pl) by metered-dose inhaler in a double-blind, randomized crossover design. During the 14-day run-in and during washout periods, inhaled beta-agonists were withheld and ipratropium bromide was substituted for rescue purposes. At the end of each 14-day treatment, a dose-response curve (DRC) was performed, and airway (FEV1, FEF25-75) chronotropic (HR), tremor, and metabolic (K, Glu) responses were measured at each step (from 100 to 4,000, .mu.g). Treatment had no significant effect on baseline values. There were dose-dependent increases in FEV1 and FEF25-75 (p < 0.001), and pretreatment with HDS did not displace the DRC to the right. DRC for HR (p < 0.001), K (p < 0.001), and Glu (P < 0.005) were attenuated after treatment with HDS compared with Pl. There were also differences between HDS and LDS for HR (p < 0.001) and Glu (p < 0.05) responses. Frequency and severity of subjective adverse effects were also reduced after HDS: tremor (p < 0.001), palpitations (p < 0.001). These results show that improved bronchodilatation is maintained during prolonged treatment (14 days) with high dose inhaled salbutamol, and that tachyphylaxis occurs to the systemic adverse effects.