Adrenergic receptors of airway smooth muscle are primarily of the beta-2 subtype.30 Beta-2 receptor activation by beta-2 agonists like albuterol causes bronchodilation by increasing adenylyl cyclase activity and inhibiting the cholinergic pathway. Therefore, nonselective beta blockers like propranolol can cause bronchoconstriction in susceptible individuals.31 As a result, the safety of beta blocker therapy in patients with COPD has been a common and longstanding concern. Traditional dogma has stated that beta blockers are contraindicated in COPD because of their bronchoconstrictive properties and “competition” with beta-2 agonists.32 Therefore many physicians have avoided prescribing beta blockers in patients with COPD.33,34
However, selective beta-1 blockers like atenolol and metoprolol, which have a 20-fold greater affinity for beta-1 receptors than beta-2 receptors, are less likely to induce bronchoconstriction. A meta-analysis concluded that, in patients with COPD, single-dose or long-term treatment with selective beta blockers did not have a significant effect on forced expiratory volume in 1 second (FEV1), beta-agonist response, inhaler use, or respiratory symptoms.35 Even in patients with COPD who had reactive airway disease, the use of selective beta blockers was only associated with a small decrease in FEV1 and a similar small increase in beta-agonist response with the first dose, both of which normalized with continued treatment.36 Cardioselective beta-1 blockers such as metoprolol, bisoprolol, or nebivolol may be beneficial in COPD. Atenolol does not reduce cardiovascular events in patients with hypertension. Nonselective beta blockers such as propranolol may induce bronchospasm and should not be used in patients with COPD. Beta blockers with intrinsic sympathomimetic activity cause less reduction in pulmonary function tests than propranolol but have not been compared to cardioselective agents.
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There is good evidence that the use of beta blockers reduces mortality in post-myocardial infarction patients with COPD or those undergoing major vascular surgery.37 There is also some evidence that the use of beta blockers in patients with COPD may actually reduce the risk of exacerbations and improve survival.38 However, a recent time-dependent analysis from Sweden suggests that beta blockers decrease survival in oxygen-dependent COPD.39 Similarly, in a randomized, double-blind, crossover trial, cardioselective beta blockers worsened airway obstruction in COPD patients.40 Formgren reported that the cardioselectivity of certain beta blockers can be lost at higher doses.41
Among the cardioselective beta blockers, bisoprolol may have the least effect on pulmonary function in patients with COPD.42,43 These studies show that treatment with atenolol produced a statistically significant increase in airway resistance when compared to bisoprolol and placebo. However, neither atenolol nor bisoprolol produced any significant changes in the more commonly used parameters of pulmonary function such as peak expiratory flow rate (PEFR), FEV1, and forced vital capacity (FVC).
Nebivolol is also an effective alternative in COPD patients.44–46 Nebivolol is a third-generation beta-adrenergic receptor antagonist with high beta-1 selective adrenergic receptor antagonism and vasodilating properties that induces a substantial decrease of arterial pressure in hypertensive subjects while preserving their left ventricular function. Respiratory effects of nebivolol have been widely investigated in animal models, in healthy volunteers, and in clinical trials carried out on patients suffering from bronchial asthma and COPD.44–46 In contrast to older compounds, nebivolol, which modulates the endogenous production of nitric oxide and affects oxidative cascade, proved clinically well tolerated in terms of respiratory outcomes in this type of subject. Moreover, due to the substantial dissociation between its cardiac and pulmonary activity, nebivolol confirmed a very good safety profile when regularly administered to hypertensive subjects with obstructive respiratory comorbidities.44–46
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Therefore, despite some conflicting data, selective beta-1 blockers appear to be relatively safe to use as an antihypertensive in stable COPD patients with irreversible or partially reversible airway obstruction and may in fact have some other additional benefits. However, if time permits, it would be safer to start a beta blocker at a small dose and carefully monitor for side effects as the dose is increased. During such initiation, patients with COPD should be carefully monitored for new symptoms (eg, dyspnea, exercise intolerance, cough) or changes in medication-use patterns (eg, increased need for a beta-agonist inhaler) that should then prompt reevaluation about the use of the drug. In a similar vein, the safety of starting beta blocker therapy in a patient during an exacerbation of COPD is not known, and so these agents should not be used during an exacerbation if hypertension is the only indication.
It needs to be emphasized that atenolol, despite its relatively safe profile in COPD patients, has very limited effectiveness in the treatment of hypertension, including a small or even negative influence on central blood pressure, arterial stiffness (pulse pressure), vascular resistance/remodeling, and prevention of target organ damage, and therefore should be avoided.46,47