Elsevier

Canadian Journal of Cardiology

Volume 28, Issue 3, May–June 2012, Pages 334-340
Canadian Journal of Cardiology

Review
The Evolving Role of β-Adrenergic Receptor Blockers in Managing Hypertension

https://doi.org/10.1016/j.cjca.2012.04.001Get rights and content

Abstract

β-Adrenergic blocking agents (or β-blockers) have been widely used for the treatment of hypertension for the past 50 years, and continue to be recommended as a mainstay of therapy in many national guidelines. They have also been used in a variety of cardiovascular conditions commonly complicating hypertension, including angina pectoris, myocardial infarction (MI), acute and chronic heart failure, as well as conditions like essential tremor and migraine. Moreover, they have played a primary role in controlling blood pressure in patients with these specific comorbidities and in reducing cardiovascular risk with regard to the composite outcome of death, stroke, and MI among patients younger than 60 years of age. However, in patients 60 years of age or older, β-blockers were not associated with significantly lower rates of MI, heart failure or death, and demonstrated higher rates of stroke compared with other first-line therapies. Consequently, the Canadian Hypertension Education Program recommends the use of β-blockers as first-line therapy in hypertensive patients younger than 60 years of age but not for those age 60 and older, with the exception of patients with concomitant β-blocker-requiring cardiac diseases. Several reports suggest that the lack of consistent outcome data may relate to the use of traditional β-blockers such as atenolol and their ability only to reduce cardiac output, without beneficial effect on peripheral vascular resistance. The present report will describe the clinically relevant mechanisms of action of β-blockers, their pharmacological differences, their metabolic effects, and their usefulness in patients with hypertension.

Résumé

Les inhibiteurs de récepteurs β-adrénergiques (β-bloquants) ont été largement utilisés pour le traitement de l'hypertension artérielle au cours des 50 dernières années, et ils continuent d'être recommandés comme une thérapie principale dans de nombreuses directives nationales. Ils sont aussi utilisés dans le traitement de nombreuses pathologies cardiovasculaires notamment l'angine, l'infarctus du myocarde et l'insuffisance cardiaque. Conséquemment, ils continuent de jouer un rôle de premier plan dans le contrôle de la pression artérielle particulièrement chez les patients atteints de problèmes cardiovasculaires concomitants. Globalement, ils ont démontré une diminution du risque cardiovasculaire combiné (mortalité, AVC, infarctus du myocarde) chez les patients de moins de 60 ans. Cependant, chez ceux âgés de plus de 60 ans, les β-bloquants n'ont pas permis de réduire l'incidence combinée de mortalité, d'infarctus du myocarde et d'insuffisance cardiaque. Ils ont de plus été associés à une augmentation de la survenue des AVC, lorsque comparés aux autres classes d'agents antihypertenseurs. Le Programme Éducatif Canadien sur l'Hypertension recommande de privilégier aux patients de moins de 60 ans l'usage des β-bloquants comme traitement de première intention, à moins que ceux-ci présentent une maladie cardiovasculaire concomitante. Plusieurs auteurs suggèrent que les données probantes en défaveur de cette classe d'agents pourraient être reliées à l'utilisation de β-bloquants plus traditionnels comme l'aténolol et ce, en raison de leurs effets principalement en lien avec la réduction du débit cardiaque, sans effet significatif sur la résistance vasculaire périphérique. Cet article vise donc à décrire le mécanisme d'action des β-bloquants, leurs caractéristiques pharmacologiques, leurs effets métaboliques ainsi que leur utilité clinique chez les patients atteints d'hypertension artérielle.

Section snippets

Drug Development

During the last 50 years, new techniques involving molecular pharmacology and radioligands have allowed more precise definition of the nature and role of the different subtypes of adrenoreceptors.14 Using pharmacologic, biochemical, and molecular biological techniques, 3 subtypes of β-adrenergic receptors have now been well characterized.15 The β1 receptor is mainly found in the heart, where it represents 75%-80% of the β-adrenoreceptor mass. The β2 receptor predominates in a number of sites

Mechanisms of Action

Pharmacological agents that block β-adrenergic receptors act quite differently depending on the receptor subtypes they target.15 In general, nonselective agents like propranolol nonselectively block both β1 and β2 receptors. By blocking β1 receptors, they reduce heart rate, nodal conduction velocity, and contractility. On the other hand, by blocking β2 receptors, they tend to promote vascular smooth muscle contraction and thus to increase peripheral resistance.17 Second-generation agents such

Pharmacological Characteristics

The differences in pharmacological effects introduce the concept that β-blockers represent a very heterogeneous class of antihypertensive agents.11 Indeed, β-blockers differ with respect to their β1 receptor selectivity, intrinsic sympathomimetic activity (ISA), membrane-stabilizing activity, lipophilicity, vasodilatory mechanisms and pharmacokinetic characteristics. In clinical practice, β-blockers are selected according to these characteristics. As shown in Table 2, different generations of

Clinical Efficacy of β-Blockers in Hypertension

Many studies have demonstrated the antihypertensive efficacy of the β-blockers as a class of drugs.35 In addition, other studies have demonstrated their efficacy in preventing cardiovascular events. In 2006, Khan and McAllister published a meta-analysis based on 21 trials involving more than 145,000 patients36 in response to the analysis from Lindholm et al.12 As compared with placebo, β-blockers used as first-line monotherapy reduced major cardiovascular outcomes (composite end point of death,

Drug Combinations With β-Blockers in Hypertension

As a large proportion of hypertensive patients will frequently require more than 1 medication to obtain BP control,1, 40 physicians should know which antihypertensive agent to combine with β-blockers. In terms of synergistic effects, dihydropyridine calcium channel blockers (DHP-CCB) represent a good selection to combine with β-blockers. On the one hand, the potent vasodilatory effect of DHP-CCB produces reflex tachycardia that can be counteracted by β-blockers. On the other hand, combining

Metabolic Effects of β-Blockers

Since the widespread use of β-blockers in hypertension, the metabolic tolerability profile of these agents has always been of concern. Indeed, abnormalities in glucose and insulin levels as well as in lipid and carbohydrate metabolism have been reported in several publications dealing with the effects of traditional β-blockers in pooled datasets.19, 27 With regard to lipid profile, Kasiske et al. published a meta-analysis of 474 studies regrouping more than 65,000 patients performed between

Side Effect Profile of β-Blockers

Despite compelling evidence for benefits in favour of β-blocker treatment in hypertension and a number of associated conditions, there is an ongoing reluctance for many clinicians to use these agents.18 This may be due to concerns about tolerability, and mainly to central nervous system side effects like depression, fatigue, nightmares, and sexual dysfunction. One should be cautious when using these agents in patients with asthma or chronic obstructive pulmonary disease because of the risk of

MI

Conventional β-blockers have clearly demonstrated their efficacy to reduce mortality after MI. A meta-analysis of 17 studies showed that there is a definite relationship between efficacy to reduce the incidence of MI and the reduction of heart rate at rest.28 This may explain why β-blockers with ISA have not shown efficacy in preventing new events.26

Angina pectoris

CHEP recommends conventional β-blockers as the treatment of choice in hypertension associated with angina pectoris.1 In fact, the reduction of

Are All β-Blockers Equally Effective in Hypertension?

Most authors consider the antihypertensive effect of the different β-blocking agents to be equal when administered at equipotent doses.56 Characteristics of cardioselectivity, duration of action, lipophilicity, and ISA may affect efficacy and tolerability. In the clinical setting, clinicians should choose a specific agent to optimize the tolerability profile (cardioselective agent vs asthma or Raynaud's phenomenon; less lipophilic agent vs central effects such as fatigue, insomnia; agent with

Conclusion

For many years, β-blockers have been used for the treatment of hypertension, for which they are clearly effective. Meta-analyses have also shown that they are effective in reducing cardiovascular events, especially in patients younger than 60 years of age. However, the mechanism of action of conventional β-blockers depends largely on reducing heart rate and cardiac output, which may not be optimal because there is little effect on peripheral vascular resistance, the primary abnormality in

Disclosures

No grants from the pharmaceutical industry or external sponsors have been received for this work. No conflicts of interest, financial or otherwise, are declared by the authors.

Acknowledgements

The authors thank Dr Sheldon W. Tobe for his help in reviewing the manuscript.

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