Safety and tolerability of β-blockers: importance of cardioselectivity

[madman]

ABSTRACT

Cardioselective b-blockade is generally well tolerated in practice and contraindications to this therapy are uncommon. b-blockers are a diverse therapeutic class, and their individual tolerability profiles are influenced strongly by their pharmacodynamic effects across different adrenergic receptors. Bisoprolol,probably the b-blocker with the highest selectivity for blockade of b1- vs. b2-adrenoceptors, does not block b2-adrenoceptors to an appreciable extent at doses in therapeutic use. Side-effects often attributed to b-blockers, such as erectile dysfunction and adverse metabolic effects are uncommon with bisoprolol and other b-blockers used at doses which only block b1-adrenoceptors. Cautious use of a cardioselective b-blocker is not contraindicated in people with chronic obstructive pulmonary disease or asthma and the outcomes benefits of b-blockers in patients with coronary heart disease or heart failure are also apparent in patients with concurrent COPD. Starting with a low dose and titrating upwards carefully is important for optimising the tolerability of a b-blocker. Most people with hypertension will receive combination antihypertensive therapy in practice, and the low-dose combination therapy approach provides a useful strategy for optimising the efficacy and tolerability of a regimen that includes a b-blocker, compared with up-titrating an existing monotherapy.




Introduction

b-blockers are recognised as evidence-based care for the control of hypertension, especially in patients with comorbid coronary heart disease (CHD) and heart failure (HF)1. These are lifelong conditions, and it is important that patients take their medicines continuously. In addition, for people with CHD and HF, evidence-based therapies should be used whenever possible at the dosages evaluated in cardiovascular outcomes trials. Tolerability and safety are key determinants of the likelihood of a patient adhering well to a cardiovascular therapeutic regimen2. This review considers the tolerability and safety of b-blockers, with special reference to b-adrenoceptor selectivity and strategies to optimise tolerability and adherence to therapy.




Principal side-effects of b-blockers

*Importance of b-adrenoceptor selectivity


*Contraindications and precautions


*Most common side effects of b-blockers




Use of b-blockers in special populations

*Patients with airways disease
-Chronic obstructive airways disease
-Asthma


*Patients with dyslipidemia


*Patients with (or at risk of) diabetes


*Patients with chronic kidney disease (CKD)


*Patients with intermittent claudication (IC)




Other adverse events of special interest

*Effects on erectile dysfunction (ED)


*Psychiatric side-effects




Conclusions

b-blockers are a diverse therapeutic class, and their individual tolerability profiles are influenced strongly by their pharmacodynamic effects across different adrenergic receptors.Cardioselective b-blockade is well tolerated in practice, although these agents should be used with caution in people with COPD 12. The reported incidence of erectile dysfunction with b-blockers may reflect a nocebo effect to a large extent, as described above. A systematic review found that 28 of 33 side-effects commonly attributed to b-blockers were not more common during treatment with a b-blocker vs. placebo in double-blind, randomised clinical trials in populations with HF. Starting with a low dose and titrating upwards carefully is important for optimising the tolerability of a b-blocker12. Most people with hypertension will receive combination antihypertensive therapy in practice, and the low-dose combination therapy approach provides a useful strategy for optimising the efficacy and tolerability of a regimen that includes a b-blocker, compared with up-titrating an existing monotherapy1,20.

 

[madman]

Table 1. Overview of physiological implications of altered emodelin through different b-adrenoceptors during treatment with cardioselective or non-cardioselective b-blockers.

 

[madman]

Table 2. Contraindications to the use of a cardioselective b-blocker and noncardioselective agents with or without additional vasodilator properties.

 

[madman]

Figure 1. Side-effects of bisoprolol from a pooled analysis of placebo-controlled clinical trials. Shaded areas and associated labels show the standard body system classification for side-effects used in clinical trials (a side-effects in the central and autonomic nervous systems have been shown together here).Data for bisoprolol 5–40 mg (shown in the original source) have been omitted here as the maximum labelled dose of bisoprolol is 20 mg/day. URI: upper respiratory infection. Drawn from data presented in the US Prescribing Information for bisoprolol.

 

[madman]

Effects on erectile dysfunction (ED)

ED is common among patients with cardiovascular diseases and is frequently cited as a major side-effect of b-blockers 60.Cardioselective b-blockade with bisoprolol, metoprolol, acebutolol, atenolol or nebivolol was not associated with erectile dysfunction in studies conducted in populations with hypertension or HF 61–65, although a decrease in the International Index of Erectile Function-5 score with metoprolol has been reported 66. ED has been reported in patients taking propranolol in some but not all studies 67,68. The additional b3-adrenoceptor mediated generation of nitric oxide by nebivolol may ameliorate erectile dysfunction 61,64,66

A nocebo effect may be at play with regard to ED and b-blocker therapy, as physicians routinely warn patients of this possible side-effect. This was investigated in a study where 114 metoprolol-treated patients with hypertension were divided into three groups and given the following information: (a) they were receiving metoprolol and it might cause ED; (b) they were receiving metoprolol with no information on possible ED; (c) no information on metoprolol or ED 69. The subsequent incidence of ED in each group was 32%, 13%, and 8%, respectively, and placebo was as effective as the phosphodiesterase (PDE)-5 inhibitor, tadalafil, in reversing it. A 3-period crossover study in 96 men with newly diagnosed coronary artery disease but no history of ED involved treatment with atenolol throughout, but patients were informed before each successive treatment period: (a) of the drug name but not its side-effects; (b) of the drug name and its potential side-effects, including ED; and (c) of neither 70. Again, the subsequent incidence of ED was higher where patients were informed of the possibility of ED (31%),compared with being given the drug name only (16%) or no information (3%); again, a PDE-5 inhibitor (sildenafil) and placebo were similarly effective.