Relative potencies and time course of changes in adenosine 5'-monophosphate airway responsiveness with inhaled furosemide and bumetanide in asthma.
A randomized, double-blind, placebo-controlled study was conducted to compare the effects of two chemically unrelated "loop" diuretics, furosemide (40 mg) and bumetanide (2 mg) on the bronchoconstrictor response to inhaled adenosine 5'-monophosphate (AMP) in 12 subjects with asthma. In eight additional volunteers with asthma, we also carried out a separate randomized, double-blind study to examine in more detail the time course of change in bronchial reactivity to inhaled AMP after administration of nebulized furosemide and bumetanide. Inhaled loop diuretics significantly increased the provocative concentration of AMP causing a 20% fall in forced expiratory volume in 1 second (FEV1) from the value of 21.2 mg/ml (range, 2.5 to 96.9 mg/ml) after placebo administration to 83.4 mg/ml (range, 11.3 to 345.0 mg/ml) (p < 0.01) and 33.8 mg/ml (range, 4.7 to 120.9 mg/ml) (p < 0.05) after administration of furosemide and bumetanide, respectively. After placebo administration, the provocative concentration of AMP causing a 20% fall in FEV1 (PC20 AMP) at 10, 30, and 120 minutes did not differ significantly; their geometric mean (range) values were 57.8 mg/ml (10.9 to 341.0 mg/ml), 55.0 mg/ml (13.2 to 304.1 mg/ml), and 52.8 mg/ml (14.4 to 252.2 mg/ml), respectively. When compared with placebo, inhaled furosemide significantly reduced the airway responsiveness to AMP at all time points; the PC20 AMP values at 10, 30, and 120 minutes were 154.6 mg/ml (29.4 to 658.7 mg/ml) (p < 0.01), 142.6 mg/ml (25.5 to 639.9 mg/ml) (p < 0.01), and 103.9 mg/ml (12.5 to 605.5 mg/ml) (p < 0.05), respectively. The PC20 values for AMP after pretreatment with bumetanide were significantly increased up to 110.2 mg/ml (25.9 to 639.0 mg/ml) (p < 0.01) and to 92.0 mg/ml (21.6 to 531.7 mg/ml) (p < 0.05) at 10 and 30 minutes, respectively. At 120 minutes, inhaled bumetanide failed to affect AMP airway responsiveness; the PC20 AMP was not significantly different from that of placebo, with a value of 71.5 mg/ml (22.6 to 318.0 mg/ml). We conclude that comparable equidiuretic doses of furosemide and bumetanide are effective in attenuating the airway response to AMP, with furosemide being approximately 2.5 times more potent than bumetanide (p < 0.01). The time course of change in bronchial reactivity to AMP is similar for both drugs with a peak effect at 10 minutes. It is possible that the mechanism(s) underlying the protective effects of inhaled loop diuretics in asthma may be distinct from those responsible for their diuretic properties.
Polosa
R
R
Istituto Malattie Apparato Respiratorio, University of Catania, Italy.
Rajakulasingam
K
K
Prosperini
G
G
Church
M K
MK
Holgate
S T
ST
D000249:Adenosine Monophosphate / Q000494:pharmacology*; D000280:Administration, Inhalation; D000328:Adult; D001249:Asthma / Q000503:physiopathology*; D001980:Bronchi / Q000187:drug effects*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction / Q000187:drug effects*; D002034:Bumetanide / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D005665:Furosemide / Q000494:pharmacology*; D006801:Humans; D008297:Male; D013997:Time Factors
D002034:Bumetanide; D000249:Adenosine Monophosphate; D005665:Furosemide