Prior treatment with diuretic augments the hypokalemic and electrocardiographic effects of inhaled albuterol.
OBJECTIVE
High doses of inhaled albuterol produce substantial improvements in bronchodilatation but are associated with dose-related systemic side effects including hypokalemia and hypomagnesemia. Concomitant diuretic therapy also produces these metabolic sequelae and may therefore precipitate cardiac arrhythmias in patients taking this combination of drugs. The purpose of this study was to investigate the electrocardiographic (ECG) effects of high-dose inhaled albuterol, and to evaluate whether potentiation occurs with bendrofluazide.


METHODS
Ten normal subjects (mean age [+/- SEM]: 29 +/- 2 years, four women, six men) received seven days of treatment with either bendrofluazide 5 mg or identical placebo in a single-blind, randomized, cross-over design, with a 10-day washout period. After each treatment period, responses (potassium, magnesium, ECG) to cumulative doubling doses of inhaled albuterol (100 micrograms to 2,000 micrograms) were measured.


RESULTS
Baseline potassium levels (mean and 95% confidence intervals) were lower after pretreatment with bendrofluazide compared with placebo (3.07 mmol/L [2.89 to 3.25 mmol/L] versus 3.78 mmol/L [3.62 to 3.93 mmol/L]; p less than 0.001). The combination of bendrofluazide and albuterol produced a lower absolute level of potassium than did placebo and albuterol: (2.72 mmol/L [2.50 to 2.95 mmol/L] versus 3.18 mmol/L [3.09 to 3.27 mmol/L]; p less than 0.001). Mean (+/- SEM) potassium fell to a lower level with bendrofluazide and albuterol in women than in men (2.45 +/- 0.04 mmol/L versus 2.90 +/- 0.13 mmol/L; p less than 0.005). Albuterol alone produced a small but significant fall in magnesium (0.842 mmol/L [0.815 to 0.869 mmol/L] to 0.789 mmol/L [0.757 to 0.820 mmol/L]; p less than 0.001), but no further change after bendrofluazide. Pretreatment with bendrofluazide increased the frequency (p less than 0.001) and amplitude (p less than 0.05) of U waves due to albuterol. Albuterol also attenuated T-wave amplitude (p less than 0.001) and prolonged the Q-Tc interval (p less than 0.001), with no additive effect from bendrofluazide. ST-segment depression (p less than 0.001) occurred in five subjects who inhaled albuterol.


CONCLUSIONS
These findings show that treatment with bendrofluazide augments the hypokalemic and ECG effects of high-dose inhaled albuterol. The arrhythmogenic potential of this interaction may be important in patients with acute exacerbations of chronic airflow obstruction, who have concomitant hypoxemia and ischemic heart disease.
Lipworth
B J
BJ
Department of Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom.
McDevitt
D G
DG
Struthers
A D
AD
D000280:Administration, Inhalation; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage / Q000009:adverse effects*; D001539:Bendroflumethiazide / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004232:Diuretics / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004357:Drug Synergism; D004562:Electrocardiography; D004573:Electrolytes / Q000097:blood; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007008:Hypokalemia / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male
D004232:Diuretics; D004573:Electrolytes; D001539:Bendroflumethiazide; D003404:Creatinine; D000420:Albuterol