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Canadian Journal of Cardiology

Contemporary Use of β-Blockers: Clinical Relevance of Subclassification

Open AccessPublished:December 06, 2013DOI:https://doi.org/10.1016/j.cjca.2013.12.001

      Abstract

      β-Adrenergic receptor blockers or β-blockers represent one of the oldest classes of cardiovascular agents and have been considered a cornerstone therapy for hypertension and heart disease for the past 5 decades. They are advocated as a first-line treatment for uncomplicated essential hypertension in patients younger than 60 years of age as recommended by the Canadian Hypertension Education Program. However, despite the well-established antihypertensive and cardiovascular benefits of β-blockers, a number of studies argue that they might not have the same clinical advantages of other classes of agents in terms of morbidity/mortality outcomes. This review will focus on the heterogeneity of the pharmacologic characteristics of β-blockers, and we will discuss the metabolic and hemodynamic differences within the β-blocker class and try to assess the potential implications of these differences for optimal selection in hypertension.

      Résumé

      Les bloqueurs des récepteurs β-adrénergiques ou β-bloqueurs représentent l’une des plus anciennes classes d’agents cardiovasculaires et ont été considérés comme étant la pierre angulaire du traitement de l’hypertension et de la cardiopathie au cours des 5 dernières décennies. Ils sont recommandés par le Programme éducatif canadien sur l’hypertension comme traitement de première intention de l’hypertension essentielle non compliquée chez les patients de moins de 60 ans. Cependant, en dépit des avantages bien établis des β-bloqueurs contre l’hypertension et les maladies cardiovasculaires, de nombreuses études soutiennent qu’ils pourraient ne pas avoir les mêmes avantages cliniques que les autres classes d’agents en matière de résultats sur la morbidité et la mortalité. Cette revue mettra l’accent sur l’hétérogénéité des caractéristiques pharmacologiques des β-bloqueurs. De plus, nous discuterons des différences métaboliques et hémodynamiques au sein de la classe des β-bloqueurs, et essaierons d’évaluer les implications potentielles de ces différences pour réaliser une sélection optimale lors d’hypertension.
      β-blockers represent one of the oldest classes of cardiovascular agents and have been considered a cornerstone therapy in heart disease such as heart failure
      • McKelvie R.S.
      • Moe G.W.
      • Ezekowitz J.A.
      • et al.
      The 2012 Canadian Cardiovascular Society heart failure management guidelines update: focus on acute and chronic heart failure.
      and acute myocardial infarction (MI).
      • O'Gara P.T.
      • Kushner F.G.
      • Ascheim D.D.
      • et al.
      2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
      They are indicated for uncomplicated essential hypertension in patients younger than 60 years of age.
      • Hackam D.G.
      • Quinn R.R.
      • Ravani P.
      • et al.
      The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.
      Despite the well established antihypertensive benefits of β-blockers, some argue that they might not have the same clinical advantages of other classes of agents in terms of morbidity/mortality outcomes in patients with hypertension.
      • Lindholm L.H.
      • Carlberg B.
      • Samuelsson O.
      Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis.
      • Messerli F.H.
      • Grossman E.
      • Goldbourt U.
      Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review.
      β-blockers represent a heterogeneous group of agents possessing several pharmacological properties that differentiate them and this might have a significant effect on clinical end points. In addition, these properties might influence their tolerability and adherence profile that frequently limit their use in clinical practice.
      • Phillips S.M.
      • Marton R.L.
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      Barriers to diagnosing and managing heart failure in primary care.
      • Everly M.J.
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      Beta-blocker underuse in secondary prevention of myocardial infarction.
      • Komajda M.
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      • et al.
      The EuroHeart Failure Survey programme–a survey on the quality of care among patients with heart failure in Europe. Part 2: treatment.
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      Misperceptions about beta-blockers and diuretics: a national survey of primary care physicians.
      For the clinician and for the patient, adherence is quite important because adherence is a key element in chronic disorders such as hypertension and coronary artery disease (CAD).
      • Volpe M.
      • Chin D.
      • Paneni F.
      The challenge of polypharmacy in cardiovascular medicine.
      The role of β-blockers in hypertension has been challenged by recent meta-analyses that found that stroke reduction might not be optimal when compared with other classes of antihypertensive agents.
      • Lindholm L.H.
      • Carlberg B.
      • Samuelsson O.
      Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis.
      • Messerli F.H.
      • Grossman E.
      • Goldbourt U.
      Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review.
      • Bradley H.A.
      • Wiysonge C.S.
      • Volmink J.A.
      • Mayosi B.M.
      • Opie L.H.
      How strong is the evidence for use of beta-blockers as first-line therapy for hypertension? Systematic review and meta-analysis.
      In this article, the efficacy of β-blockers will be discussed, with a focus on the different pharmacologic characteristics. In addition, as discussed in a previous article,
      • Poirier L.
      • Lacourciere Y.
      The evolving role of β-adrenergic receptor blockers in managing hypertension.
      the authors will discuss the potential clinical implications of these differences important for the clinician prescribing them.

      Mechanism of Action

      β-blockers reduce sympathetic nervous system activity through blockade of adrenergic receptor subtypes, particularly β1, β2, and β3. β1 receptors are primarily in the heart and some of the beneficial effects of blockade include bradycardia and improved diastolic coronary filling time, reduced oxygen requirements, and a reduction of renin, all beneficial in heart failure and myocardial ischemia. β2 receptors are mostly located in smooth muscle of blood vessels and the bronchial tree and stimulation leads to dilation. β3 receptors are located in adipocytes and the heart, and blockade by nonselective agents might contribute to their weight-increase and metabolic effects.
      • Arner P.
      The beta 3-adrenergic receptor–a cause and cure of obesity?.
      β-blocker specificity refers to the drugs' greater affinity for β1 receptors over β2 at usual drug levels, and therefore specificity for cardiac effects, and nonspecific agents that also block β2 receptors reduce antihypertensive activity.
      • Webb A.J.
      • Fischer U.
      • Rothwell P.M.
      Effects of β-blocker selectivity on blood pressure variability and stroke: a systematic review.
      Since the work of Raymond Ahlquist
      • Ahlquist R.P.
      A study of the adrenergic receptors.
      and James Black,
      • Walker M.J.
      The major impacts of James Black's drug discoveries on medicine and pharmacology.
      many different β-blockers with distinct pharmacologic and hemodynamic properties were developed (Table 1). A total of 12 orally administered β-blockers are currently available in Canada. The second-generation β-blockers (atenolol, bisoprolol, etc) were developed with a higher affinity for the β1 receptor and are called cardioselective β-blockers. Blood pressure (BP) reduction for these more traditional first- and second-generation β-blockers might be achieved through a reduction in cardiac output, through heart rate and contractility reduction, but no beneficial effect or even an increase in peripheral vascular resistance.
      • De Caterina A.R.
      • Leone A.M.
      The role of beta-blockers as first-line therapy in hypertension.
      The third generation β-blockers (carvedilol, labetalol, nebivolol) have vasodilating properties mediated by α-adrenoreceptor blockade and/or through nitric oxide (NO) release.
      • Vanhoutte P.M.
      • Gao Y.
      Beta blockers, nitric oxide, and cardiovascular disease.
      They reduce BP by decreasing peripheral vascular resistance while maintaining or increasing cardiac output.
      • Vanhoutte P.M.
      • Gao Y.
      Beta blockers, nitric oxide, and cardiovascular disease.
      Finally, β-blockers also differ in other pharmacologic characteristics such as lipophilicity and intrinsic sympathetic activity (ISA).
      Table 1Pharmacological properties of the different β-blockers
      Adapted from Manrique et al.,
      • Manrique C.
      • Giles T.D.
      • Ferdinand K.C.
      • Sowers J.R.
      Realities of newer Beta-blockers for the management of hypertension.
      Frishman and Saunders,
      • Frishman W.H.
      • Saunders E.
      Beta-Adrenergic blockers.
      and Mason et al.
      • Mason R.P.
      • Giles T.D.
      • Sowers J.R.
      Evolving mechanisms of action of beta blockers: focus on nebivolol.
      Drugβ1-Blockade potency ratioβ1/β2 selectivityISALipophilicityHalf-life (hours)Other
      Nadolol1.000Low12-24
      Pindolol6.00++High3-4
      Propranolol1.000High3-4
      Sotalol0.300Low12Antiarrythmic effects
      Timolol0.600High4-5
      Acebutolol0.3++Moderate3-4
      Atenolol1.0+0Low6-9
      Bisoprolol10.0++0Moderate9-12
      Metoprolol1.0++0High3-4
      Labetolol0.3+0Low3-4α1-Blocking effect, direct β-vasodilation
      Carvedilol10.000Moderate7-10α1-Blocking effect
      Nebivolol10.0+++0Moderate8-27Endothelium-dependent, NO-mediated vasodilation
      0, absent; +, low; ++, moderate; +++, strong; ISA, intrinsic sympathetic activity; NO, nitric oxide.

      Efficacy of β-Blockers as a Monolithic Class

      Hypertension

      There is a misconception that this class of agents might not lower BP equivalently to other classes of antihypertensive agents. A meta-analysis published by the Blood Pressure Treatment Trialists' Collaboration
      • Neal B.
      • MacMahon S.
      • Chapman N.
      Blood Pressure Lowering Treatment Trialists' Collaboration
      Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration.
      involving 37,872 patients and comparing different classes of antihypertensive agents (angiotensin-converting enzyme inhibitors, calcium channel blockers, β-blockers and/or diuretics) has shown that differences in outcomes were minimal on a 2- to 8-year follow-up duration for the same BP-lowering. Some have also questioned the efficacy of β-blockers in terms of hard end points, especially on stroke prevention, when compared with other classes of antihypertensive agents (see Khan et al., in this issue of the Canadian Journal of Cardiology
      • Kuyper L.M.
      • Khan N.A.
      Atenolol vs nonatenolol β-blockers for the treatment of hypertension: a meta-analysis.
      ). Khan and McAlister published a meta-analysis in 2006 on 145,811 patients from 21 hypertension trials.
      • Khan N.
      • McAlister F.A.
      Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis.
      Their results showed that, in placebo-controlled trials and active comparator studies, β-blockers reduced major cardiovascular outcomes in younger patients but not in older patients, with the excess risk being particularly marked for stroke. It has been shown that the nonvasodilating β-blockers, such as atenolol, lower BP by reducing cardiac output while systemic vascular resistance remains unchanged or actually increases, simulating the effect of aging.
      • Kamp O.
      • Sieswerda G.T.
      • Visser C.A.
      Comparison of effects on systolic and diastolic left ventricular function of nebivolol versus atenolol in patients with uncomplicated essential hypertension.
      In elderly individuals, low cardiac output and increased peripheral resistance due to noncompliant arteries typically characterize their hemodynamic profile.
      • De Caterina A.R.
      • Leone A.M.
      Why beta-blockers should not be used as first choice in uncomplicated hypertension.
      In younger patients, particularly linked to obesity and the metabolic syndrome, greater sympathetic activity leads to an increase in cardiac output and heart rate and increased peripheral vascular resistance, in part due to endothelial dysfunction. In this setting, a β-blocker with vasodilating properties might lead to a correction of these pathological changes.
      • Kamp O.
      • Sieswerda G.T.
      • Visser C.A.
      Comparison of effects on systolic and diastolic left ventricular function of nebivolol versus atenolol in patients with uncomplicated essential hypertension.
      Consequently, in light of these data, the Canadian Hypertension Education Program still recommends that β-blockers be used as the initial therapy for hypertension in uncomplicated patients younger than 60 years of age.
      • Hackam D.G.
      • Quinn R.R.
      • Ravani P.
      • et al.
      The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension.

      Angina and MI

      β-blockers remain the standard of care for patients with CAD, particularly for those having experienced an acute MI.
      • Bangalore S.
      • Steg G.
      • Deedwania P.
      • et al.
      β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease.
      Benefits of β-blockers on cardiovascular outcomes seem to be in direct relation to β1-receptor blockade and not on the selectivity because atenolol and metoprolol have shown similar results on mortality in patients who have had an MI.
      • Manrique C.
      • Giles T.D.
      • Ferdinand K.C.
      • Sowers J.R.
      Realities of newer Beta-blockers for the management of hypertension.
      Indeed, β-blockers decrease the work of the heart by reducing heart rate, contractility, and systolic BP. For example, a chart review study of more than 69,000 patients treated with β-blockers after an MI has demonstrated that β-blockers were associated with a 40% improvement in survival and that β-blocker subtype had little influence on mortality
      • Gottlieb S.S.
      • McCarter R.J.
      Comparative effects of three beta blockers (atenolol, metoprolol, and propranolol) on survival after acute myocardial infarction.
      ; the different subtypes of β-blockers all demonstrated significant reductions in mortality.
      Beta-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction. I. Mortality results.
      • Dargie H.J.
      Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial.
      However, β-blockers with ISA have been associated with reduced clinical benefits in patients who have had a recent MI.
      • Freemantle N.
      • Cleland J.
      • Young P.
      • Mason J.
      • Harrison J.
      Beta blockade after myocardial infarction: systematic review and meta regression analysis.
      The role of β-blockers in patients with coronary risk factors or a remote MI or stroke was assessed in a recent meta-analysis, regrouping 44,708 patients from the Reduction of Atherothrombosis for Continued Health (REACH) Registry, demonstrated that β-blockers were not associated with a lower risk of the composite cardiovascular event after a 44-month median follow-up.
      • Bangalore S.
      • Steg G.
      • Deedwania P.
      • et al.
      β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease.
      However, in patients with an MI within 1 year of enrollment to the study, the use of β-blockers was associated with an improvement of the secondary outcome (cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for atherothrombotic events).
      • Bangalore S.
      • Steg G.
      • Deedwania P.
      • et al.
      β-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease.

      Heart failure

      Patients with heart failure in whom there is no contraindication should receive a β-blocker on a background of angiotensin-converting enzyme-inhibition. These agents act by decreasing sympathetic nervous system activation and thereby improve morbidity and mortality outcomes. In this regard, results from major studies involving bisoprolol,
      The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.
      carvedilol,
      • Packer M.
      • Bristow M.R.
      • Cohn J.N.
      • et al.
      The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group.
      and metoprolol
      MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF).
      have demonstrated significant morbidity and mortality benefits, with a mortality reduction of approximately 35% across trials.
      • Pedersen M.E.
      • Cockcroft J.R.
      The latest generation of beta-blockers: new pharmacologic properties.
      In Canada, only these 3 β-blockers possess the indication in heart failure. In heart failure, the degree of ISA impairs efficacy with bisoprolol, carvedilol and metoprolol having no ISA. When carvedilol was compared with metoprolol in patients with chonic heart failure in the Carvedilol Or Metoprolol European Trial (COMET), carvedilol was found to be superior.
      • Poole-Wilson P.A.
      • Swedberg K.
      • Cleland J.G.
      • et al.
      Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial.
      Similarly, carvedilol was found to reduce hospitalization for heart failure or death in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study.
      • Ruwald M.H.
      • Ruwald A.C.
      • Jons C.
      • et al.
      Effect of metoprolol versus carvedilol on outcomes in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy).
      Interestingly, in the Beta-blocker Evaluation of Survival Trial (BEST) trial, bucindolol, a nonselective β-blocker with weak α-blocking properties, also reduced hospitalization for heart failure.
      • White M.
      • Desai R.V.
      • Guichard J.L.
      • et al.
      Bucindolol, systolic blood pressure, and outcomes in systolic heart failure: a prespecified post hoc analysis of BEST.
      However, all-cause mortality was significantly reduced by 23%, but only in patients who had a systolic BP > 120 mm Hg.
      • White M.
      • Desai R.V.
      • Guichard J.L.
      • et al.
      Bucindolol, systolic blood pressure, and outcomes in systolic heart failure: a prespecified post hoc analysis of BEST.
      The Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) in 2128 patients aged 70 years and older with heart failure independent of left ventricular ejection fraction at entry demonstrated that nebivolol significantly reduced the composite outcome of all-cause mortality and cardiovascular hospital admission by 14% but not the risk of all-cause mortality compared with placebo.
      • Flather M.D.
      Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS).
      However, in a subgroup of patients with low left ventricular ejection fraction (< 35%) and a median age of 75 years, mortality was reduced by 38%, showing similar results as those reported with other agents. Cruickshank suggests that the ISA on the β2 and the β3 receptors is responsible for the reduction of effect on heart failure with nebivolol.
      • Cruickshank J.M.
      Are we misunderstanding beta-blockers.
      However, this is not supported by the work of Brixius et al., showing that nebivolol seems devoid of ISA in human myocardium.
      • Brixius K.
      • Bundkirchen A.
      • Bölck B.
      • Mehlhorn U.
      • Schwinger R.H.
      Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium.

      Pharmacological Differences and Their Clinical Implications

      Cardioselectivity

      By definition, β1/β2-selectivity, or cardioselectivity, represents the pharmacological characteristic of an agent that will preferentially block β1 receptors, predominantly present in the heart and renal juxtaglomerular apparatus, and consequently have less influence on vascular smooth muscle and bronchial β2 receptors. This feature possessed by many β-blockers is of interest in clinical practice but the extent of selectivity is not absolute and ranges widely among the agents.
      • Weber M.A.
      The role of the new beta-blockers in treating cardiovascular disease.
      Bisoprolol and nebivolol have the highest β1 selectivity profile compared with other β-blocking agents commonly used.
      • Manrique C.
      • Giles T.D.
      • Ferdinand K.C.
      • Sowers J.R.
      Realities of newer Beta-blockers for the management of hypertension.
      Of note, this clinical feature is influenced by the magnitude of the dose and even cardioselective agents can exert some inhibition of β2-receptors, at higher dosage (equivalent to > 50 mg/d metoprolol).
      • Frishman W.H.
      • Saunders E.
      Beta-Adrenergic blockers.
      In terms of BP reduction, it seems that cardioselectivity might influence the extent of the antihypertensive effect. In fact, nonselective agents, by their blocking effect on β-2 vasodilatory receptors, might be less effective than cardioselective agents, those agents demonstrating less systolic BP variability compared with nonselective agents.
      • Webb A.J.
      • Fischer U.
      • Rothwell P.M.
      Effects of β-blocker selectivity on blood pressure variability and stroke: a systematic review.
      Bisoprolol 10 to 20 mg once daily has indeed been shown to lower BP more effectively than atenolol 50 to 100 mg once daily, a moderately cardioselective β-blocker.
      • Neutel J.M.
      • Smith D.H.
      • Ram C.V.
      • et al.
      Application of ambulatory blood pressure monitoring in differentiating between antihypertensive agents.
      The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
      • Dahlöf B.
      • Sever P.S.
      • Poulter N.R.
      • et al.
      Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.
      examined 19,257 hypertensive patients with at least 3 other risk factors and treated with either an amlodipine-based treatment or an atenolol-based treatment. Results favoured the amlodipine-based treatment over atenolol for BP-lowering, metabolic effects, and hard outcomes. A substudy of the ASCOT trial, the Conduit Artery Function Evaluation (CAFE) trial,
      • Williams B.
      • Lacy P.S.
      • Thom S.M.
      • et al.
      Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study.
      investigated the effects of both study treatments on brachial and central aortic pressures, finding that the amlodipine-based therapy decreased central systolic pressure significantly more than the atenolol-based treatment, possibly contributing to more strokes in the atenolol-based treatment group. A recent Cochrane review concluded that, based on the literature comparing β-blockers, especially atenolol, with placebo and other classes of agents, the evidence does not support their use as first-line drugs in the treatment of hypertension.
      • Wiysonge C.S.
      • Bradley H.A.
      • Volmink J.
      • et al.
      Beta-blockers for hypertension (Review).
      Cardioselectivity was not found to reduce aortic pulse pressure in a recent study comparing bisoprolol with atenolol.
      • Park S.
      • Rhee M.Y.
      • Lee S.Y.
      • et al.
      A prospective, randomized, open-label, active-controlled, clinical trial to assess central haemodynamic effects of bisoprolol and atenolol in hypertensive patients.
      Bronchial reactivity in asthma appears to be less enhanced with more cardioselective β-blockers and is a concern with nonselective agents.
      • Hollenberg N.K.
      The role of beta-blockers as a cornerstone of cardiovascular therapy.
      A meta-analysis demonstrated less adverse respiratory effects in patients with “mild-to-moderate reactive airway disease”,
      • Salpeter S.
      • Ormiston T.
      • Salpeter E.
      Cardioselective beta-blockers for chronic obstructive pulmonary disease.
      but reactive airways disease still remains a limitation for the use of these agents in clinical practice.

      Vasodilation

      In addition to their β1 receptor-blocking activity, third generation β-blockers also exert their clinical effects through vasodilatory properties. In Canada, labetalol and nebivolol are indicated for the treatment of hypertension and carvedilol is indicated for the treatment of heart failure. On a mechanistic point of view, carvedilol and labetalol are vasodilatory through α1-adrenoreceptor antagonism. Carvedilol has also been associated with an increase in plasma levels of NO that occurs through stimulation of NO synthase.
      • Afonso R.A.
      • Patarrao R.S.
      • Macedo M.P.
      • Carmo M.M.
      Carvedilol action is dependent on endogenous production of nitric oxide.
      Nebivolol has vasodilatory properties through increased NO bioavailability, which seems mainly responsible for its clinical effect.
      • Vanhoutte P.M.
      • Gao Y.
      Beta blockers, nitric oxide, and cardiovascular disease.
      Others have also suggested activation of β3 adrenoreceptors as a possible mechanism explaining the effect of nebivolol on stimulation of endothelial NO synthase.
      • Pasini A.F.
      • Garbin U.
      • Stranieri C.
      • et al.
      Nebivolol treatment reduces serum levels of asymmetric dimethylarginine and improves endothelial dysfunction in essential hypertensive patients.
      These agents, acting mainly through the reduction of peripheral vascular resistance, have little or no effect on cardiac output.
      • Kamp O.
      • Sieswerda G.T.
      • Visser C.A.
      Comparison of effects on systolic and diastolic left ventricular function of nebivolol versus atenolol in patients with uncomplicated essential hypertension.
      Vasodilatory β-blockers provide additional benefits such as reduced ventricular preload and afterload, improved renal blood flow, enhanced sodium secretion, and favourable effects on myocardial cells.
      • Bakris G.
      An in-depth analysis of vasodilation in the management of hypertension: focus on adrenergic blockade.
      In contrast to traditional β-blockers that do not reduce peripheral vascular resistance, vasodilatory agents might provide beneficial effects on endothelial dysfunction, vascular remodelling, and progression of target organ damage.
      • Bakris G.
      An in-depth analysis of vasodilation in the management of hypertension: focus on adrenergic blockade.
      Atenolol as an example, did not demonstrate improvements in small artery structure and endothelial function despite equal BP-lowering with calcium channel blockers or angiotensin blockers, which did demonstrate improvements.
      • Schiffrin E.
      Remodeling of resistance arteries in essential hypertension and effects of antihypertensive treatment.
      Some of the rationale for lack of atenolol's effect included lack of effect on oxidative stress and peripheral vasoconstriction.
      • Schiffrin E.
      Remodeling of resistance arteries in essential hypertension and effects of antihypertensive treatment.
      Two studies comparing nebivolol and atenolol have shown that nebivolol has a more pronounced effect on reducing aortic pulse pressure and wave reflection and increasing pulse pressure amplification.
      • Mahmud A.
      • Feely J.
      Beta-blockers reduce aortic stiffness in hypertension but nebivolol, not atenolol, reduces wave reflection.
      • Dhakam Z.
      • Yasmin
      • McEniery C.M.
      • et al.
      A comparison of atenolol and nebivolol in isolated systolic hypertension.
      These effects might be due to the associated vasodilation. Because stroke risk is associated with higher central aortic pressure,
      • Hashimoto J.
      • Ito S.
      Aortic stiffness determines diastolic blood flow reversal in the descending thoracic aorta: potential implication for retrograde embolic stroke in hypertension.
      vasodilatory β-blockers might be more beneficial than atenolol on stroke protection. Whether this will actually translate into additional benefits in terms of morbidity/mortality end points requires further investigation.
      In the major clinical trials, β-blockers have been associated with metabolic disturbances.
      • Messerli F.H.
      • Bangalore S.
      • Yao S.S.
      • Steinberg J.S.
      Cardioprotection with beta-blockers: myths, facts and Pascal's wager.
      As a class, they have been associated with decreases in insulin sensitivity and an increased incidence of new onset diabetes.
      • Messerli F.H.
      • Bangalore S.
      • Yao S.S.
      • Steinberg J.S.
      Cardioprotection with beta-blockers: myths, facts and Pascal's wager.
      Weight gain, attenuation of the β receptor-mediated release of insulin from pancreatic β-cells, and decreased blood flow in skeletal muscle tissue microcirculation are possible mechanisms leading to decreased glucose uptake and increased insulin resistance.
      • De Caterina A.R.
      • Leone A.M.
      Why beta-blockers should not be used as first choice in uncomplicated hypertension.
      These data have come from studies involving traditional selective or nonselective β-blockers, such as atenolol, metoprolol, and propranolol.
      • Bangalore S.
      • Parkar S.
      • Grossman E.
      • Messerli F.H.
      A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus.
      A meta-analysis of 12 studies reporting data on 94,492 patients has shown a 22% increased risk of new-onset diabetes in patients treated with these 3 agents compared with other classes of antihypertensive agents, with the exception of the diuretic agents.
      • Bangalore S.
      • Parkar S.
      • Grossman E.
      • Messerli F.H.
      A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus.
      Recent data emerging from the use of vasodilatory β-blockers suggest that these agents might share neutral or even beneficial effects on metabolic parameters compared with more traditional β-blockers. With regard to lipid abnormalities, agents possessing vasodilatory properties such as carvedilol and nebivolol seem to have a neutral or beneficial effect on lipoprotein lipase activity and levels of triglycerides and high-density lipoprotein cholesterol, in contrast to more conventional older β-blockers.
      • De Caterina A.R.
      • Leone A.M.
      The role of beta-blockers as first-line therapy in hypertension.
      With respect to glycemic effects, results from a study comparing atenolol with nebivolol in patients with impaired glucose tolerance demonstrated that, compared with baseline, atenolol induced a significant reduction in insulin sensitivity and in glucose disappearance rate as measured using a euglycemic hyperinsulinemic clamp and nebivolol showed a neutral effect on these parameters.
      • Poirier L.
      • Cléroux J.
      • Nadeau A.
      • Lacourcière Y.
      Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients.
      Similarly, the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) study,
      • Fonseca V.
      • Bakris G.L.
      • Bell D.S.
      • et al.
      Differential effect of beta-blocker therapy on insulin resistance as a function of insulin sensitizer use: results from GEMINI.
      which compared metoprolol with carvedilol in 1235 patients with diabetes and hypertension, showed that both treatments provided equivalent BP reduction but significantly more patients in the metoprolol group had to discontinue the study because of poor glycemic control. Carvedilol, compared with metoprolol, improved endothelial function and oxidative stress in patients with type 2 diabetes mellitus.
      • Bank A.J.
      • Kelly A.S.
      • Thelen A.M.
      • Kaiser D.R.
      • Gonzalez-Campoy J.M.
      Effects of carvedilol versus metoprolol on endothelial function and oxidative stress in patients with type 2 diabetes mellitus.
      Finally, some have suggested that vasodilatory β-blockers might be better tolerated than nonvasodilatory agents. Studies assessing quality of life suggested that agents such as nebivolol might be as well tolerated as the angiotensin receptor blocker, losartan.
      • Vanbortel L.
      • Bulpitt C.
      • Fici F.
      Quality of life and antihypertensive effect with nebivolol and losartan.
      Among side effects negatively influencing patient compliance, sexual dysfunction has been reported in up to 20% of patients receiving β-blockers.
      • Manrique C.
      • Giles T.D.
      • Ferdinand K.C.
      • Sowers J.R.
      Realities of newer Beta-blockers for the management of hypertension.
      Nebivolol has been associated with a significant improvement in erectile function compared with traditional β-blockers such as atenolol
      • Grassi G.
      • Trevano F.Q.
      • Facchini A.
      • et al.
      Efficacy and tolerability profile of nebivolol vs atenolol in mild-to-moderate essential hypertension: results of a double-blind randomized multicentre trial.
      and metoprolol.
      • Brixius K.
      • Middeke M.
      • Lichtenthal A.
      • Jahn E.
      • Schwinger R.H.
      Nitric oxide, erectile dysfunction and beta-blocker treatment (MR NOED study): benefit of nebivolol versus metoprolol in hypertensive men.
      It seems that the NO-mediated vasodilatory effects of nebivolol might contribute to sustained erectile function.
      • Grassi G.
      • Trevano F.Q.
      • Facchini A.
      • et al.
      Efficacy and tolerability profile of nebivolol vs atenolol in mild-to-moderate essential hypertension: results of a double-blind randomized multicentre trial.
      • Brixius K.
      • Middeke M.
      • Lichtenthal A.
      • Jahn E.
      • Schwinger R.H.
      Nitric oxide, erectile dysfunction and beta-blocker treatment (MR NOED study): benefit of nebivolol versus metoprolol in hypertensive men.

      ISA

      The β-blockers, acebutolol, labetalol, and pindolol, exhibit ISA due to partial agonism at 1 or more β-adrenergic receptors. Therefore, this property allows them to permit stimulation of β-adrenoreceptors and blockade of sympathetic nervous system signalling transmission.
      • Weber M.A.
      The role of the new beta-blockers in treating cardiovascular disease.
      ISA has been shown to attenuate the decrease in heart rate and cardiac output and the increase in peripheral vascular resistance, respectively produced by the blockade of the β1 and β2 receptors.
      • Prichard B.N.
      Pharmacologic aspects of intrinsic sympathomimetic activity in beta-blocking drugs.
      Consequently, possessing this property might lessen antihypertensive efficacy. Hence, ISA does not seem to provide any advantage in patients with CAD or hypertension because this pharmacologic property has not been associated with any additional benefits in terms of outcomes. In this regard, a metaregression analysis has shown that there was a near significant trend toward a decreased benefit of agents with ISA in patients after an MI.
      • Frishman W.H.
      • Saunders E.
      Beta-Adrenergic blockers.
      • Freemantle N.
      • Cleland J.
      • Young P.
      • Mason J.
      • Harrison J.
      Beta blockade after myocardial infarction: systematic review and meta regression analysis.
      However, the Acebutolol et Prévention Secondaire de l'Infarctus (APSI) trial has shown that acebutolol still decreases mortality at 5 years in patients who had an MI.
      • Cucherat M.
      • Boissel J.P.
      • Leizorovicz A.
      Persistent reduction of mortality for five years after one year of acebutolol treatment initiated during acute myocardial infarction. The APSI Investigators. Acebutolol et Prévention Secondaire de l'Infarctus.

      Lipophilicity/hydrophilicity

      Lipophilic agents, such as propranolol, metoprolol, and nebivolol
      • Gray C.L.
      • Ndefo U.A.
      Nebivolol: a new antihypertensive agent.
      have the ability to cross the blood-brain barrier. Lipophilic agents are primarily eliminated by hepatic metabolism and they tend to have shorter half-lives and wider variations in plasma concentrations.
      • Frishman W.H.
      • Saunders E.
      Beta-Adrenergic blockers.
      Because of their hepatic elimination, they are also generally more prone to clinically significant drug interactions. On the contrary, more hydrophilic agents such as atenolol, sotalol, and nadolol are excreted by the kidneys and therefore need to have their dosage adjusted according to renal function.
      • Sica D.A.
      • Black H.R.
      Pharmacologic considerations in the positioning of beta-blockers in antihypertensive therapy.
      Sotalol in particular should be used with caution in patients with low glomerular filtration rate (< 20 mL/min) because of the increased risk of torsade de pointes.
      • Deneer V.H.
      • van Hemel N.M.
      Is antiarrhythmic treatment in the elderly different? A review of the specific changes.
      Because of central nervous system penetration, lipophilic agents are frequently used for the treatment of migraine and essential tremor.
      • Frishman W.H.
      • Saunders E.
      Beta-Adrenergic blockers.
      With regard to cardiovascular protection, it has been suggested that lipophilic β-blockers might have a different effect on hard end points such as mortality, than hydrophilic agents. Indeed, it has been shown that vagal tone, which has been associated with mortality, might improve after penetration of central nervous system by lipophilic agents.
      • Townend J.N.
      • Littler W.A.
      Cardiac vagal activity: a target for intervention in heart disease.
      However, a study in 70,000 patients with MI has not been able to demonstrate that lipophilicity was an important characteristic in preventing mortality.
      • Gottlieb S.S.
      • McCarter R.J.
      Comparative effects of three beta blockers (atenolol, metoprolol, and propranolol) on survival after acute myocardial infarction.
      Lipophilic agents have commonly been identified as molecules with a poor tolerability profile. Some have postulated that the use of these agents might result in a greater incidence of central nervous system effects such as lethargy, confusion, and depression.
      • Sica D.A.
      • Black H.R.
      Pharmacologic considerations in the positioning of beta-blockers in antihypertensive therapy.
      A meta-analysis reporting results on more than 35,000 patients from 15 different trials has shown that β-blocker use was not associated with a significant risk of depressive symptoms but was associated with a small but significant risk of erectile dysfunction and fatigue.
      • Ko D.T.
      • Hebert P.R.
      • Coffey C.S.
      • Sedrakyan A.
      • Curtis J.P.
      • Krumholz H.M.
      Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction.
      Regarding the risk of fatigue, the authors reported that it was significantly more frequent with early-generation β-blockers (propranolol, timolol) compared with later-developed agents. The degree of lipophilicity was not related to the incidence of side effects.

      Who Should Receive β-Blockers in Cardiovascular Medicine?

      It remains quite clear that β-blocking agents with their ability to block the β1-adrenergic receptor are the drugs of choice in patients with acute or chronic cardiac ischemia. They are also part of the treatment for patients with heart failure in addition with a renin-angiotensin-aldosterone system inhibition-based treatment. For the treatment of hypertension, the Canadian Hypertension Education Program still recommends their use as a first-line option treatment in patients younger than 60 years of age. However, when addressing the question of the β-blockers place in therapy, the answer lies not in global generalizations but in assessing individual patient needs and specific β-blocking agent characteristics. Poor tolerability often explains the reluctance of some clinicians to recommend β-blockers to their patients. The new third-generation β-blockers with a favourable tolerability profile might represent an alternative in patients presenting side effects and necessitating the use of this cardiovascular class of agents. Further studies are required to demonstrate the efficacy of these agents and their role in the clinician's armamentarium.

      Funding Sources

      Publication of this article was supported by an unrestricted educational grant from Forest Laboratories, Inc. The sponsor had no input into the content or composition of any of the papers, and the authors did not receive any financial support from the sponsor for their efforts or time in writing the paper. Funds from the sponsor were used exclusively for covering publication costs.

      Disclosures

      L.P. is member of Forest Canada consulting board. S.W.T. has no conflicts of interest to disclose.

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