Detrimental effects of beta-blockers in COPD: a concern for nonselective beta-blockers. A comparison of oral metoprolol and propranolol in patients with chronic bronchitis. Bisoprolol in patients with heart failure and moderate to severe chronic obstructive pulmonary disease: a randomized controlled trial. The effects of oral propranolol and metoprolol on lung function and exercise performance in chronic airways obstruction. Effect of beta-adrenergic blockade on hyperventilation and exercise tolerance in emphysema. Labetalol, beta blockers, and acute deterioration of chronic airway obstruction. The effect of beta-blockers on ventilatory function in chronic bronchitis. Beta-adrenoceptor blockers and terbutaline in patients with chronic obstructive lung disease. Effects and interaction after oral administration. Comparison of effects of propranolol and metoprolol on airways obstruction in chronic bronchitis. Comparative effects of celiprolol, propranolol, oxprenolol, and atenolol on respiratory function in hypertensive patients with chronic obstructive lung disease. [Effects of a new cardioselective beta-adrenergic blocker (atenolol) on airway resistance in chronic obstructive disease (author's transl)]. Reversibility of bronchospasm in airway obstruction. Effects of muliple doses of metoprolol and propranolol on ventilatory function in patients with chronic obstructive lung disease. Ventilatory effects of long-term treatment with pindolol and metoprolol in hypertensive patients with chronic obstructive lung disease. A comparison of celiprolol and chlorthalidone in hypertensive patients with reversible bronchial obstruction. Effects of single oral doses of bisoprolol and atenolol on airway function in nonasthmatic chronic obstructive lung disease and angina pectoris. Comparison of atenolol and oxprenolol in patients with angina or hypertension and co-existent chronic airways obstruction. Comparative effects of bisoprolol and acebutolol in smokers with airway obstruction. Cardio-selective and non-selective beta-blockers in chronic obstructive pulmonary disease: effects on bronchodilator response and exercise. Effect of metoprolol on cardiac and pulmonary function in chronic obstructive pulmonary disease.
beta-Blockers are known to worsen FEV(1) and airway hyperresponsiveness (AHR) in patients with asthma. Both characteristics determine the outcome of COPD, a disease with frequent cardiac comorbidity requiring beta-blocker treatment.
                To determine the effects of beta-blockers on AHR (provocative concentration of methacholine causing a 20% fall in FEV(1) [PC(20)]), FEV(1), and response to formoterol in patients with COPD.
                A double-blind, placebo-controlled, randomized, cross-over study.
                An ambulatory, hospital outpatient clinic of pulmonary diseases.
                Patients with mild-to-moderate irreversible COPD and AHR.
                Fifteen patients received propranolol (80 mg), metoprolol (100 mg), celiprolol (200 mg), or placebo for 4 days, followed by a washout period >/= 3 days. On day 4 of treatment, FEV(1) and PC(20) were assessed. Immediately hereafter, formoterol (12 microg) was administered and FEV(1) was measured for up to 30 min.
                PC(20) was significantly lower (p < 0.01) with propranolol and metoprolol treatment (geometric means, 2.06 mg/mL and 2.02 mg/mL, respectively) than with placebo (3.16 mg/mL) or celiprolol (3.41 mg/mL). FEV(1) deteriorated only after propranolol treatment (2.08 +/- 0.31 L) [mean +/- SD] compared with placebo (2.24 +/- 0.37 L). The fast bronchodilating effect of formoterol was hampered by propranolol (mean increase in FEV(1) at 3 min, 6.7 +/- 8.9%) but was unaffected by the other beta-blockers (16.9 +/- 9.8%, 22 +/- 11.6%, and 16.9 +/- 9.0% for placebo, metoprolol, and celiprolol, respectively).
                Pulmonary effects did not occur by celiprolol. Only propranolol reduced FEV(1) and the bronchodilating effect of formoterol. Both metoprolol and propranolol increased AHR. Thus, different classes of beta-blockers have different pulmonary effects. The anticipated beneficial cardiovascular effects of a beta-blocker must be weighted against the putative detrimental pulmonary effects, ie, effect on FEV(1), AHR, and response to additional beta(2)-agonists. A double-blind study of oral metoprolol and propranolol in nine patients with chronic bronchitis (Medical Research Council definition) showed no appreciable deterioration in lung function or significant differences between the two drugs. Heart failure (HF) and chronic obstructive pulmonary disease (COPD) frequently coexist. No study has prospectively examined the effects of beta-blockade in those with both conditions.
                We randomized 27 patients with HF and coexistent moderate or severe COPD to receive bisoprolol or placebo, titrated to maximum tolerated dose over 4 months. The primary outcome was forced expiratory volume in 1 s (FEV(1)). The study is registered with ClinicalTrials.gov, number: NCT00702156. Patients were elderly and predominantly male. Cardiovascular comorbidity, smoking history, and pulmonary function were similar in each group (mean FEV(1) 1.37 vs. 1.26 L, P = 0.52). A reduction in FEV(1) occurred after 4 months following treatment with bisoprolol compared with placebo (-70 vs. +120 mL, P = 0.01). Reversibility following inhaled beta(2)-agonist and static lung volumes were not impaired by bisoprolol. All measures of health status exhibited a consistent non-significant improvement, including the Short Form 36 physical and mental component scores (2.6 vs. 0.5 and 0.8 vs. -0.3, respectively), Minnesota Living with Heart Failure Questionnaire (-2.5 vs. 3.5) and Chronic Respiratory Questionnaire (0.07 vs. -0.24). The mean number of COPD exacerbations was similar in the bisoprolol and placebo groups (0.50 and 0.31, respectively, P = 0.44).
                Initiation of bisoprolol in patients with HF and concomitant moderate or severe COPD resulted in a reduction in FEV(1). However, symptoms and quality of life were not impaired. Fifteen men with chronic airways obstruction received a test dose of propranol 20 mg orally. Six developed increased breathlessness. Nine who tolerated the test dose received metoprolol (100 mg) and propranolol (80 mg) on different days in a randomized double-blind fashion. Changes in resting and exercise heart rate, spirometry and exercise tolerance were measured 1 and 6 hours later. The drugs had similar effects on heart rate. Propranolol, but not metoprolol, caused significant reduction in forced expiratory volume in one second (FEV1) and peak expiratory flow rate. Neither drug produced significant changes in forced vital capacity (FVC) or exercise performances in the group as a whole, although the range of changes was wide. Despite considerable reduction in FEV1 and FVC in some individuals, most reported no increase in symptoms. Changes in exercise tolerance at 1 hour correlated significantly with changes in FVC but not with those in FEV1. It is proposed that changes in FEV1, though of pharmacological interest, may be less relevant clinically than changes in FVC. Ventilation, heart rate, and arterial blood gas tensions were measured at rest and during incremental exercise in 10 patients with emphysema after intravenous placebo or 7 mg metoprolol. Metoprolol reduced heart rate by 14% (P less than 0.001) and ventilation by 11% (P less than 0.01), but there was no significant difference in arterial O2 or CO2 tension (Pao2 and PaCO2, respectively). Metoprolol increased the time to exhaustion on a cycle ergometer (P less than 0.05) but did not improve the 12-min walking distance. A double-blind randomized crossover comparison of 4 wk treatment with atenolol (100 mg/day), metoprolol (100 mg/day), or matched placebo was performed in 12 patients with emphysema. Both beta-adrenoceptor antagonists reduced resting heart rate by 33% (P less than 0.001) and resting minute ventilation by 11% (P less than 0.025). There was no change in resting or exercise Pao2 or Paco2. During steady-state exercise on a cycle ergometer, atenolol and metoprolol reduced ventilation by 14 and 4%, respectively. This was accompanied by 11 and 5% reductions in O2 consumption (P less than 0.05) and 13 and 6% falls in CO2 production (P less than 0.05). There were no significant changes in tests of exercise tolerance, but forced expiratory volume in 1 s and forced vital capacity were reduced during beta 1-adrenergic blockade. beta 1-Blocking drugs reduce hyperventilation in emphysema by reducing pulmonary gas exchange without a change in arterial blood gas tensions. Increased airflow obstruction prevents this reduction being of therapeutic value. The effects on lung function of labetalol (a combined alpha and beta adrenergic receptor blocker) and three beta adrenergic receptor blockers (propranolol, atenolol, metoprolol) have been assessed in patients with chronic airflow obstruction using a double-blind trial. With the dosages used, all drugs produced an equivalent fall of blood pressure. Propranolol was the only drug that significantly increased airways obstruction (FEV1, specific airways resistance). Following salbutamol, labetalol was associated with a significantly greater improvement of airflow than either propranolol or metoprolol. On these acute studies, the order of preference for beta blocking drugs in management of hypertension in patients with obstructive airways disease, would be labetalol, (atenolol) or (metoprolol) and then propranolol. The effect of propranolol and atenolol on air-flow obstruction in patients with chronic bronchitis was evaluated by means of a double-blind, placebo-controlled cross-over trial. Fifteen patients with chronic bronchitis and mild air-flow obstruction, in whom there was no clinical suggestion of asthma, were studied. Two patients developed symptomatic increases in air-flow obstruction on propranolol and were withdrawn from the study. A symptomatically insignificant but statistically significant increase in air-flow obstruction was observed during treatment with both propranolol and atenolol. We studied the effects of a combined treatment with beta 2-stimulating and beta-blocking drugs in 35 patients suffering from chronic obstructive lung disease (COLD) and ischemic heart disease, and/or arterial hypertension. The drugs used were equipotent repeated oral doses of metoprolol (100 mg twice daily [bid]), propranolol (80 mg bid), and a matching placebo for beta-adrenoceptor blockade given in a double-blind and crossover fashion. The intake period of each beta-blocker was two days with consecutive two-day-washout period; 2.5 mg terbutaline and beta-stimulator placebo, respectively, were given throughout the whole trial three times daily (tid). Propranolol alone caused severe deterioration of lung function. After 18 patients had been studied, this drug had to be excluded from the trial. When compared with placebo, metoprolol provoked increasing obstruction, too, but to a significantly lesser degree than propranolol. These negative effects on FEV1 and FRC were completely equalized by terbutaline. Predictive factors for the tolerability of beta-blockers in patients with COLD could not be found. Therefore, careful observations in the initial phase of the treatment with beta-selective blockers are necessary. nan The aim of the study was to compare the pulmonary effects of four beta-blockers with different ancillary properties: propranolol (non-beta 1 selective without ISA), oxprenolol (non-beta 1 selective with ISA), atenolol (beta 1 selective), and celipropol (beta 1 selective with mild beta 2-agonist and alpha 2-antagonist activity) in hypertensive patients with chronic obstructive lung disease. Ten asthmatic patients, all males, aged 50-66 years were studied. Entry criteria were a) DBP greater than or equal to 95 mmHg and less than or equal to 115 mmHg; b) FEV1 less than 70% of the theoretical values; c) FEV1 increase of at least 20% after salbutamol inhalation (200 micrograms). After a 2-week washout period on placebo, each patient received propranolol (80 mg/day), oxprenolol (80 mg/day), atenolol (100 mg/day), and celiprolol (200 mg/day) for 1 week, according to a randomized, cross-over design. At the end of the washout and of each treatment period, airway function, assessed by FEV1, FVC, and FEV1%, was evaluated by spirometry both in the basal condition and after salbutamol inhalation. Unlike propranolol and oxprenolol, which significantly reduced FEV1 and inhibited the bronchodilator response to inhaled salbutamol, atenolol and celiprolol did not significantly affect respiratory function and did not antagonize salbutamol effects. Celiprolol more closely approached placebo in its respiratory effects than did atenolol, although the differences were not statistically significant. The effect of 4-(2-hydroxy-3-isopropylamino-propoxy)-phenyl acetamide (atenolol, ICI 66 082) (100 mg) on airway resistance (Rt), thoracic gas volume (IGV), pulse rate and blood pressure was tested as a double blind study in 20 patients with chronic obstructive airway disease in comparison to propranolol (80 mg) and placebo. The effect on pulse rate was equipotent, but when using propranolol the mean increase of Rt was larger and increased Rt-values (greater than or equal 1.5 cm H2O/l/sec) were observed more frequently than after atenolol application. These differences were significant for 1 h after application. The augmentation of IGV was significantly larger after propranolol than after atenolol. We conclude that atenolol, in comparison to propranolol, has a relative but no specific cardioselectivity. In a double-blind, randomized crossover study of 12 patients suffering from chronic bronchitis, the comparative influence of equipotent doses of pindolol (5 mg) and metoprolol (100 mg) on the bronchodilatory potential of inhaled fenoterol (0.4 mg), a beta 2-agonist, was investigated by means of body plethysmography. Neither beta-blocker caused bronchospasm or attenuated the bronchodilation due to fenoterol. The results are not pertinent to the potential risk of bronchospastic complications induced by beta 1-selective or nonselective drugs, but they rule out a therapy-oriented differentiation between pindolol and cardioselective agents as far as the potential response to the bronchodilating activity of inhaled sympathomimetics is concerned. The effect of metoprolol on pulmonary function was compared with that of propranolol and placebo in twelve patients with chronic obstructive lung disease. Propranolol caused a significant reduction in FEV1 compared with metoprolol and placebo. Metoprolol gave a slight reduction compared with placebo. FVC was not significantly influenced by metoprolol, but propranolol caused a significant depression compared both with metoprolol and placebo. The isoprenaline-mediated increase in FEV1 and FVC was not significantly altered after metoprolol compared with placebo. After propranolol the isoprenaline-mediated increases in FEV1 and FVC were 40 and 24% lower respectively than after metoprolol and placebo. Unwanted effects and pulmonary symptoms were at an acceptable level in all cases except in two patients who had to be given i.v. theophyllamine therapy during propranolol treatment. It is concluded that metoprolol exhibits a selective beta1-blocking action and thus may be given to patients with chronic obstructive lung disease provided that adequate beta2-stimulator treatment is given concomitantly. Effects of long-term treatment with pindolol (10 mg twice daily) and metoprolol (100 mg twice daily) on lung function and blood pressure were investigated in eight patients with chronic obstructive lung disease and hypertension. After a placebo period, both beta-adrenoceptor blockers were administered double-blind and cross-over for 4 weeks. By assessing parameters of expiratory flow an attempt was made to distinguish between large and small airways function. Diastolic blood pressure decreased significantly during both pindolol and metoprolol (P less than 0.01). Except for a decrease in forced expiratory volume in 1 s (FEV1) during metoprolol treatment, there was no other change in expiratory flow parameters after placebo or both beta-adrenoceptor blockers. Inhalation of terbutaline induced a small improvement in large airways function after placebo and metoprolol, but not after pindolol; there was no effect of terbutaline on parameters of small airways function. If a beta-adrenoceptor blocker is necessary in patients with chronic obstructive lung disease, a beta 1-adrenoceptor selective blocker is preferred in combination with bronchodilator agents. The objective of this study was to evaluate the effects of celiprolol, a new beta-blocking drug, on the clinical condition and pulmonary function of hypertensive patients with reversible bronchial obstruction. Celiprolol was compared with chlorthalidone, an antihypertensive drug without known effect on bronchial tone. The study consisted of a 4-week placebo run-in period and a 12-week titration period in which the dose of both drugs was increased at 4-week intervals if blood pressure was not reduced adequately. The doses of celiprolol were 200, 400, or 600 mg once daily; those for chlorthalidone 12.5, 25, or 37.5 mg once daily. Entry criteria were a diastolic blood pressure between 90 and 115 mg Hg, and FEV-1 between 40% and 80% of predicted value, increasing by 15% or more after salbutamol, and a need for occasional bronchodilator therapy. Prophylactic medication for asthma was given in constant dosage for a month before the study and throughout the study. Preliminary results on 66 patients demonstrate that neither drug had a clinically significant effect on FEV-1, FEF 25-75, or FVC. Clinical variables were not significantly changed by either drug: the average monthly asthma attacks fell from 18 to 13 with celiprolol and from 11 to 7 with chlorthalidone. FEF was reduced by more than 50% in two patients on celiprolol and three on chlorthalidone. Monthly asthma attacks increased by more than 100% in five patients on celiprolol and four on chlorthalidone. Thus, preliminary results are unable to demonstrate adverse effects from celiprolol in patients with asthma and hypertension. A randomized, placebo-controlled, double-blind crossover investigation in 12 patients with non-asthmatic chronic obstructive lung disease and co-existing stable angina pectoris was done to compare two beta 1-selective adrenoceptor blocking agents, atenolol 100 mg and bisoprolol 20 mg. Systolic and diastolic blood pressures (SBP, DBP), heart rate (HR) as well as airway resistance (AWR, and less frequently forced expiratory volume in 1 s (FEV1) and intrathoracic gas volume (ITGV) were measured in the sitting position before and at various times up to 24 h after drug intake. During the first 4 h both beta-blockers produced a significant reduction in HR in comparison to placebo (p less than 0.01). Atenolol 100 mg significantly increased AWR relative to placebo and bisoprolol (p less than 0.05). After 24 h, a significant reduction in HR (p less than 0.01) could only be demonstrated after bisoprolol, whereas atenolol alone led to a significant elevation in AWR relative to placebo and bisoprolol (p less than 0.05) at that time. It is concluded that bisoprolol appears to have a high degree of beta 1-selectivity, thus providing a wide split between beta 1- and beta 2-adrenoceptor blockade. Bisoprolol in its therapeutic dose range is expected to be relatively safe as regards bronchoconstriction in patients suffering both from hypertension and/or angina pectoris and chronic obstructive lung disease. 1 The effects of atenolol (50 mg and 100 mg) and oxprenolol (80 mg) on respiratory function were studied in ten patients with angina pectoris or hypertension complicated by chronic airways obstruction. 2 In patients with "fixed" airways obstruction, neither atenolol nor exprenolol significantly affected airways resistance. 3 In patients with "labile" airways obstruction, atenolol did not produce a significant increase in airways obstruction, whereas oxprenolol did. 4 Following isoprenaline challenge (1500 microgram by inhalation), atenolol permitted full bronchodilatation, whereas oxprenolol almost completely blocked the action of isoprenaline. 5 Partial agonist activity appears to be of less clinical importance than cardioselectivity. 1. The effects of single oral doses of 10 mg bisoprolol and 400 mg acebutolol on respiratory function were studied in nine smokers with airway obstruction in a double-blind, placebo-controlled experiment. 2. The effects of the drugs were assessed by measuring specific airway conductance (sGaw) for 3 h after their administration and by studying their interaction with the bronchodilator response to inhaled salbutamol. 3. sGaw did not change for 3 h after bisoprolol or acebutolol administration. The bronchodilator response to inhaled salbutamol was not affected by bisoprolol but significantly reduced by acebutolol (P less than 0.05 vs placebo). 4. Under these conditions, bisoprolol behaves like a selective beta 1-adrenoceptor antagonist but acebutolol exhibits less beta 1-adrenoceptor selectivity. Patients with chronic obstructive pulmonary disease (COPD) often have co-existing cardiovascular disease and may require beta-blocker treatment. There are limited data on the effects of beta-blockers on the response to inhaled beta2-agonists and exercise capacity in patients with COPD.
                To determine the effects of different doses of cardio-selective and non-selective beta-blockers on the acute bronchodilator response to beta-agonists in COPD, and to assess their effects on exercise capacity.
                A double-blind, randomized, three-way cross-over (metoprolol 95 mg, propranolol 80 mg, placebo) study with a final open-label high-dose arm (metoprolol 190 mg). After 1 week of each treatment, the bronchodilator response to salbutamol was measured after first inducing bronchoconstriction using methacholine. Exercise capacity was assessed using the incremental shuttle walk test.
                Eleven patients with moderate COPD were recruited. Treatments were well-tolerated although two did not participate in the high-dose metoprolol phase. The area under the salbutamol-response curve was lower after propranolol compared with placebo (P=0.0006). The area under the curve also tended to be lower after high-dose metoprolol (P=0.076). The per cent recovery of the methacholine-induced fall was also lower after high-dose metoprolol (P=0.0018). Low-dose metoprolol did not alter the bronchodilator response. Oxygen saturation at peak exercise was lower with all beta-blocker treatments (P=0.046).
                Non-selective beta-blockers and high doses of cardio-selective beta-blockers may inhibit the bronchodilator response to beta2-agonists in patients with COPD. Beta-blockers were also associated with lower oxygen saturation during exercise. The clinical significance of these adverse effects is uncertain in view of the benefits of beta-blocker treatment for cardiovascular disease. We evaluated the effects of oral metoprolol, 200 mg daily, on cardiac and pulmonary function in 6 patients with chronic reversible airways obstruction and no cardiac dysfunction. The patients were clinically stable. In all patients, baseline forced expiratory volume in 1 second (FEV1) was less than 60% predicted, and increased at least 15% after isoproterenol inhalation. Resting control first pass right and left ventricular radionuclide ejection fractions were normal or only slightly depressed. Compared to placebo, metoprolol did not significantly affect FEV1 or forced vital capacity. Metoprolol did not significantly alter left or right ventricular ejection fraction, measured by first pass radionuclide technique. On patient experienced increased dyspnea on metoprolol, which was not accompanied by changes in clinical exam, spirometry, or ejection fraction. We conclude that metoprolol may be safely administered to a subset of stable patients with chronic reactive airways disease.
Cardioselective beta-blockers, given to patients with COPD in the identified studies did not produce adverse respiratory effects. Given their demonstrated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardioselective beta-blockers should not be routinely withheld from patients with COPD.