Continuing Evolution of the Role of Β-Blockers in the Treatment of Hypertension
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REVIEW Continuing evolution of the role of β-blockers in the treatment of hypertension The β-blockers have evolved into one of the most prescribed classes of drugs for the treatment of cardiovascular disease in general, and hypertension in particular. However, the class is one of the more heterogenous groups in pharmacological agents. The evolution of the β-blockers has included increased selectivity for the β1 receptor (cardioselective) and, more recently, development of β-blockers with vasodilating properties. As a result of this evolution, the current vasodilating β-blockers, i.e., nebivolol and carvedilol, have a better hemodynamic profi le and are devoid of many of the troublesome side effects, for example, fatigue, sexual dysfunction and increased insulin resistance and disturbances in glucose metabolism, found in the traditional β-blockers. Nebivolol produces vasodilation by a mechanism that includes increased bioavailability of nitric oxide that may bring other benefi ts. With these improvements in design, the future for the use of β-blockers appears bright. KEYWORDS: β-blockers, carvedilol, hypertension, nebivolol, nitric oxide Thomas D Giles Tulane University School of The classifi cation of α- and β-adrenoceptors by insulin resistance and hasten the appearance of Medicine, 109 Holly Drive, Ahlquist and colleagues in 1948 provided the hyperglycemia (diabetes mellitus). Additionally, Metairie, New Orleans, foundation for the development of drugs that the use of β-blockers in African–American LA 70005, USA could modulate the sympathetic nervous system hypertensive patients may be limited owing to Tel:. +1 504 834 8668 (SNS) [1] . The fi rst β-blocker, pronethalol, devel- the fact that traditional β-blockers are less effec- Fax: +1 504 836 0822 oped by Sir James Black, was limited clinically tive in lowering blood pressure (BP) in hyper- [email protected] due to safety concerns. However, the subsequent tensive African–American patients compared development of its successor, propranolol, earned with hypertensive Caucasian patients [9,10]. Black the Nobel Prize for Medicine in 1988, The newer (‘third-generation’) β-blocking and revolutionized the process of the laboratory drugs are characterized by the ability to pro- development of cardiovascular drugs [2]. The duce vasodilation, and include carvedilol, development of the β-blocking class of drugs labetalol and nebivolol. Carvedilol and labeta- provided clinicians with new tools to treat lol achieve vasodilation by interfering with the many cardiovascular disorders that now include: α1 adrenoceptor, whereas nebivolol utilizes a hypertension, heart failure, angina pectoris, cer- mechanism that is endothelial dependent and tain arrhythmias, post-myocardial infarction results in increased bioavailability of nitric ventricular dysfunction and high-risk patients, oxide (NO) (vide infra). including those with diabetes mellitus [3–5]. The fi rst widely used β-blocker, propranolol, Recent studies of traditional had equal blocking properties at both the β1 β-blockers and β2 adrenoceptor subtypes. Since blocking Despite their less-than-desirable side effect β2 receptors produced unwanted side effects profi le, the traditional β-blockers have been (e.g., vasoconstriction and bronchoconstriction), considered as ‘fi rst-line’ therapy in the man- new (second-generation) drugs were developed agement of hypertension by every report of the that were more selective for the β1 receptor, for US Joint National Committee on Prevention, example, metoprolol and atenolol. These drugs Detection, Evaluation and Treatment of were called cardioselective. However, at higher Hypertension (JNC), including the JNC 7 doses, blockade occurred at both receptors [6]. report [3]. However, a meta-ana lysis of 13 ran- The traditional β-blocking drugs are associ- domized clinical trials of β-blockers in the ated with many side effects, including fatigue, management of hyper tension, published in sexual dysfunction (erectile dysfunction), cold 2005 [11], concluded that atenolol was not as hands and weight gain [7], and have limited effi - effective as other antihypertensive drugs in the cacy in obese patients [8]. Moreover, these tradi- treatment of hypertension and that, in com- tional β-blockers have a propensity to increase parison with other antihypertensive drugs, the 10.2217/14750708.5.6.773 © 2008 Future Medicine Ltd Therapy (2008) 5(6), 773–778 ISSN 1475-0708 773 REVIEW Giles effects of β-blockers were associated with an treatment arm [16] . The trial was terminated increased incidence of stroke. It was suggested prematurely owing to excess mortality in the that atenolol should not be used in the treat- patients randomized to the β-blocker arm. ment of primary hypertension, and should not Explanations for this disappointing result are be used as a comparator in future randomized not entirely clear. However, a clue is available controlled trials of antihypertensive drugs. This from a substudy of ASCOT, the Conduit Artery suggestion was taken in the preparation of the Function Evaluation (CAFÉ) trial. In this trial, a UK’s National Institute for Health and Clinical noninvasive technique was used to compare the Excellence (NICE) guidelines for the treatment effects of atenolol-based therapy and amlodipine- of hypertension [12] . However, the suggestion based therapy on central (aortic) and peripheral was extended to all β-blockers, even though blood pressure [17] . Importantly, whereas the the data upon which it was based virtually all two treatment arms had similar blood-pressure- originated from studies of atenolol. lowering effects when measured in the brachial One randomized clinical trial that uti- artery, the β-blocker treatment was signifi cantly lized atenolol as the comparator drug was the less effective than the calcium channel blocker Losartan Intervention for Endpoint Reduction treatment in reducing central pressure. This dif- (LIFE) Study [13] . In this study of hypertensive ference in effectiveness of blood pressure lower- patients with left ventricular hypertrophy, the ing is particularly important, since both cardiac atenolol arm was approximately 25% more likely and stroke events are directly affected by the cen- than the angiotensin receptor blocker, losartan, tral blood pressure. These data may provide an arm to be associated with stroke events [13] . explanation for the apparent failure of traditional Nevertheless, atenolol was more effective in β-blockers to reduce major clinical events to the preventing ischemic events and more effective same extent as other antihypertensive therapies, than losartan in African–American subjects. for example, the LIFE trial. However, the atenolol-based therapy was at least equivalent to angiotensin-converting enzyme Third-generation β-blockers (ACE) inhibitor-based therapy in improving The third-generation β-blockers are character- cardiovascular and metabolic outcomes in the ized by the ability to produce arterial dilation UK Prospective Diabetes Study (UKPDS) when and reduce peripheral vascular resistance, in examining the importance of achieving tight addition to blocking the β-receptor. Traditional blood pressure control in patients with Type 2 β-blocking drugs targeted two primary adren- diabetes mellitus [14] . ergic receptors of norepinephrine. β1 recep- Atenolol, more than any other traditional tors predominate in healthy cardiac muscle, β-blocker, appears to be associated with signifi - while β2 receptors predominate in the bronchi. cantly higher rates of all-cause mortality, cardio- Traditional β-blockers, such as propranolol, are vascular mortality and stroke [11] . It should be nonselective and block both β1 and β2 recep- noted that in most clinical trials, atenolol was tors [6]. Second-generation β-blockers, such as dosed once daily, often at a dose of 50 mg. It acebutolol, atenolol, bisoprolol and metoprolol, has been demonstrated in many subjects that offer more selective β1 or β2 blockade [6]. atenolol is not a once-a-day drug, and thus the Third-generation, vasodilating β-blockers, patient is subjected to intermittent periods of i.e., bucindolol, labetolol, carvedilol and nebiv- withdrawal – defi nitely an untoward event. In olol, vary in their selectivity [18]. Carvedilol is the International Verapamil–Trandolapril Study nonselective with inhibition of the α1 receptor. (INVEST), where atenolol was dosed twice Labetolol is nonselective with a higher affi nity for daily, the β-blocker fared as well as the other the α1 receptor than for β1 and β2 receptors. treatment regimens tested [15] . Carvedilol is a nonselective β-blocker and Atenolol therapy was also evaluated in the provides α1-receptor blockade. The α1 recep- Anglo Scandinavian Cardiac Outcomes Trial tors mediate endothelial function and vaso- (ASCOT) [16] . In this study, conducted in a constriction in peripheral vessels, regulate blood large cohort of relatively high-risk middle- fl ow to the kidneys, and have been linked to aged hypertensive patients, a comparison of conditions such as myocardial hypertrophy and atenolol (usually paired with a thiazide) with benign hyperplasia of the periurethral prostate. the calcium channel blocker amlodipine (usu- Nebivolol, recently approved for use in the ally paired with perindopril) revealed that major treatment of hypertension in the USA, has cardiac and stroke outcomes clearly favored been shown to have higher β1 selectivity than the calcium channel blocker/ACE inhibitor other β-blockers, and endothelium-dependent 774 Therapy (2008) 5(6) future