Basic & Clinical Pharmacology & Toxicology, 2015, 117, 5–14

Doi: 10.1111/bcpt.12396

MiniReview

Third-Generation Beta-Adrenoceptor Antagonists in the Treatment of Hypertension and Heart Failure Filip Y. Fisker1, Daniela Grimm1 and Markus Wehland2 1

Department of Biomedicine, Pharmacology, Aarhus University, Aarhus, Denmark and 2Clinic for Plastic, Aesthetic and Hand Surgery, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany (Received 22 December 2014; Accepted 26 February 2015) Abstract: Hypertensive treatment with beta-adrenoceptor antagonists (BAAs) has been successfully applied for four decades. These drugs have a beneficial effect on the health of the patients by both decreasing number of deaths and improving morbidity. Nevertheless, the BAAs differ in pharmacological properties. They have different lipophilicity, different adrenoceptor selectivity and/or varying additional abilities in cardiac tissue and periphery vasculature hereby exceeding their known receptor-blocking effects. Nebivolol shows nitric oxide-mediated vasodilating properties that improve arterial rigidity. Carvedilol has anti-oxidative and antiproliferative effects, which exert a beneficial effect on patients with chronic congestive heart failure (CHF). These findings suggest that the true potential of the third-generation BAAs and their value in the treatment of CHF, hypertension and following cardiovascular events has yet to be acknowledged. This MiniReview provides an overview of the third-generation BAAs and their effects on the vasculature of hypertensive patients and patients with CHF. Additionally, BAAs that potentially can be used in different patient groups are discussed.

Hypertension Hypertension is a physical condition where the systolic and/or the diastolic arterial blood pressure (BP) is elevated in such a manner that an increased risk of cardiovascular complications can be found [1]. In fact, as of 2010, hypertension is the leading risk factor for disease burden worldwide [2]. A correlation between increasing BP and risk of cardiovascular events has been shown, which apparently is already in effect at such low BP values as 115/75 mmHg [3,4] It is therefore almost impossible to declare a distinct borderline BP between a normal BP and an increased BP. According to the guidelines of the European Society of Cardiology, hypertension is defined by systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg for office measurements, while cut-offs of 130/80 mmHg are specified for 24-hr BP measurements [1]. The BP is given by the cardiac output (CO) and the total peripheral resistance (TPR). Usually, hypertension is characterized by a normal CO and an increased TPR. The latter can be the effect of structural changes in the vasculature like hypertrophy or remodelling of media musculature in the smaller arteries and arterioles. An increased activity in the sympathetic nervous system (SNS) or the renin–angiotensin–aldosterone system (RAAS) can also add to the vasoconstriction by increasing TPR [5]. An increased sensitivity towards natural Author for correspondence: Daniela Grimm, MD, Department of Biomedicine, Pharmacology, Aarhus University, Wilhelm Meyers All
e 4, DK-8000 Aarhus C, Denmark (fax +45 8612 8804, e-mail [email protected]).

catecholamines in the bloodstream is also a possible, but not proved, explanation of hypertension. If left untreated, hypertension will result in hypertrophy of the left ventricle. This is mainly caused by increased pressure load, and possibly additional factors with a direct/indirect trophic effect such as volume load and growth factors like catecholamines and angiotensin II. On the vascular level, untreated hypertension can lead to various complications. The exposure to elevated pressure induces an increased proliferation of the vessel wall, resulting in a reduced luminal volume and an increased media/lumen ratio. Further hypertensioninduced lesions can lead to remodelling of the vessel wall and ultimately to the development of atherosclerosis. In addition, hypertension can also cause endothelial dysfunction, the impaired reaction to vasoconstrictive or vasorelaxant stimuli. If a vessel wall is already weakened, aneurysms can occur, which, upon rupture, can pose a life-threatening danger for the patient. The mentioned physiological parameters and structural changes cause hypertension, which is a predisposing factor of cardiovascular events. This demands a treatment of hypertension – and the focus of this review will be the pharmacology of beta-adrenoceptor antagonists (BAAs). Beta-adrenoceptors Beta-adrenoceptors (b-AR) are a class of G protein-coupled receptors that mediate cardiovascular function induced by activation of the SNS upon binding of their ligands, the

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catecholamines (fig. 1). They can be found in many tissues of the human body, including the lungs, the kidney, the brain and, most importantly for this MiniReview, the heart. In cardiac tissue, the predominant AR is b1 that plays a major role in the regulation of heart function. b-AR activation by naturally occurring catecholamines and/or administered b-adrenoceptor agonists leads to stimulation of cardiac function, including increases in heart rate (HR; positive chronotropism), force of contraction (positive inotropism), acceleration of relaxation (positive lusitropism) and automaticity [6]. Furthermore, systemic and metabolic effects of b-AR activation by its agonist adrenaline, for instance, include increased activation of hormone-sensitive lipase, inactivation of glycogen synthesis and activation of phosphorylase kinase, which result in increased lipolysis and increased degradation of glycogen reserves. Specifically for the heart, adrenaline binds to b1-AR, which stimulates creation of cAMP through a GS protein and increased adenylyl cyclase activity. In the sinus node, cAMP activates a cyclic nucleotide-regulated sodium channel, which exerts an effect that creates action potentials at a faster rate than normally by opening voltage-regulated T- and L-type calcium channels, and an increased HR [7,8]. The high amount of calcium in the sarcoplasmic reticulum (SR) after the opening of the channels is quickly released during the action potential, which results in an increased inotropism [9]. Under exposure to high levels of catecholamines, a downregulation of b1-AR and b2-AR is observed in the heart. This is caused by phosphorylation of the b-AR by either protein kinase A or b-AR kinase. This is of significance in the case of congestive heart failure (CHF), where high levels of compensatory catecholamines are present [9].

Methods The background data for this MiniReview were found in textbooks, clinical trials, articles and reviews on the subject matter. Different databases and search engines were used: PubMed, Clinicaltrials.gov, Google and Scopus. Various search strategies were employed, including searches with keywords such as ‘carvedilol and hypertension’, advanced searches with more specificity and searches via MeSH words. Truncations, wildcards and similar search techniques were employed to ensure a complete coverage of search terms.

Beta-adrenoceptor antagonists Overview of the three generations of BAA. Propranolol was the first BAA to be introduced in 1964, and since then a variety of other BAA have arrived on the market. BAAs can be classified into three generations. The oldest and first generation of BAA is characterized by its unselective antagonism towards both b1-AR and b2-AR with an aim of reducing DBP and SBP [10]. Therefore, when applied with the aim of countering hypertension by lowering the work of the heart, they are likely to antagonize b2-AR as well. This interaction can cause serious b2-AR-related side effects such as bronchospasms, which is a potentially lethal condition for patients with asthma or chronic obstructive pulmonary disease (COPD). Another side effect of the first generation of BAA can be an unwanted increase in vascular resistance due to antagonism of b2-ARs in the peripheral vasculature. Examples of second-generation BAAs are metoprolol and bisoprolol. They are characterized by their extraordinarily high affinity for b1-AR compared to b2-AR, which is why they are called b1-selective or cardioselective. Although this specificity in affinity is dose dependent, the selectivity can be diminished if a larger dose of the drug is administered [11]. The third and newest generation of BAA includes compounds such as carvedilol and nebivolol, which may differ in cardioselectivity but have extra cardiovascular abilities – in most of the cases, they exert an additional vasodilative effect (table 1) [11]. All three generations can be classified by their hydro-/lipophilicity as well. The more lipophilic the drug is the better it is absorbed by the gastrointestinal tract. To a considerable extent, metabolism will already happen in the gut wall in addition to the liver as the main site. Lipophilic drugs are usually eliminated quickly, with half-lives as short as 1–5 hr. The time of impact is also affected by the lipophilicity of the drug. Table 1. Characteristics of the pharmacological properties of the third-generation BAAs.

Fig. 1. Agonist (A) reacts with b-AR, which results in activation of the G protein Gs. After activation, the a-subunit of Gs interacts with adenylyl cyclase (AC) to increase formation of cAMP. Agonist-occupied b-ARs are phosphorylated by G protein receptor kinases (GRK). In the endosome, agonist–receptor complexes can then either become dephosphorylated, recycled and brought back to the surface of the cell or undergo degradation in the lysosomes of the cell. Modified from Ref. [6].

Drug Labetalol Carvedilol Nebivolol

b1/b2selectivity + 0 +++

Lipophilicity

Oral bioavailability (%)

Plasma half-life (hr)

Low Moderate High

~33 ~30 12–96

3–4 7–10 11–40

According to Post et al. [6].

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Furthermore, the lipophilic drugs tend to have more central adverse effects as they cross the blood–brain barrier more easily [12]. BAA modes of action in hypertension treatment. The mechanism underlying the essential hypertension is complex and has not yet been completely defined, but it is evident that the activation of the SNS plays an important role in its pathogenesis. Blockade of b-AR interferes with the sympathetic regulation of the heart. The HR and contractility are only marginally affected by the BAA administration at rest, but it suppresses prominently the increase in HR and cardiac contractility induced by stress and/or physical exercise [11,12]. The mechanism of antihypertensive effects of BAAs is likewise unknown, even though a number of explanations have been proposed to play an essential role. They include the following effects [11]:

• • • • • • • •

Reduction of cardiac output Central nervous system effects Renin–angiotensin–aldosterone system inhibition Reduction of plasma volume Peripheral vascular resistance reduction Improvements of vascular compliance Baroreceptor resetting Reduction of pressor response to exercise and stressrelated catecholamines All these effects are possible propositions of a solution in the pursuit of finding the best treatment for the state of hypertension and its sequelae. Third-generation BAAs and their specialties The development of third-generation BAAs was an important advancement because the previous generations have a range of side effects, which may affect some patients severely. This problem was partly solved by the introduction of b1-selective BAAs. Studies show that vasodilating BAAs, as they are associated with less adverse effects and less extent of cardiac dysfunctions developed, have beneficial effects compared with the conventional BAAs [13]. This can assist in enhancing the quality-of-life variables for the given patients. Possible advantages of third-generation BAAs can be improving insulin resistance, decreasing LDL levels and increasing HDL in the blood, attenuating asthma attacks, alleviating coronary vasospasms, controlling peripheral circulatory disturbances and preventing erectile dysfunction and better patient compliance. The vasodilation is a product of several underlying mechanisms, including release of nitric oxide (NO), anti-oxidative effects and blockade of calcium influx [13]. Vasodilation on both the arterial and the venous side results in less peripheral vascular resistance (PVR). This reduces the myocardial demand for oxygen and the work of the heart. Without knowing the precise mechanism, it has been shown that the vasodilative BAAs can reverse pathogenic arterial remodelling [11].

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This remodelling increases the media-to-lumen ratio, resulting in an elevated PVR, reduced vasodilative abilities of the coronary arteries, and a higher risk of cardiovascular complications [11]. Labetalol. Labetalol is a non-selective BAA, which is lipophilic. It has a slight sympathomimetic ability and a-AR antagonistic effects as well, which might be involved in mediating its vasodilatory actions. However, the mechanism of the vasodilative effects is still not fully understood; therefore, more research is needed [13]. What is well known and beneficial about labetalol is its hemodynamic profile, as it reduces PVR, but only slightly modifies HR, CO and restitution of vascular remodelling [13]. Nebivolol. Nebivolol is a BAA with a high affinity for the b1-AR. It is very lipophilic but has no sympathomimetic or a1-AR antagonistic activity [14]. There are two stereoisomers of nebivolol: D- and L-nebivolol. They differ in both hemodynamic profile and selectivity. For instance, the Denantiomer binds to the b1-AR with an about 175-fold higher affinity than the L-enantiomer, which leaves the b1-antagonistic effect almost entirely to the D-enantiomer [14]. On the other hand, the L-enantiomer induces an endothelium-derived NO release, which reduces the vasoconstriction and removes reactive oxygen species (ROS) during oxidative stress [15,16]. It also results in an endothelium-dependent peripheral vasodilation, which is one of the promising effects of nebivolol. The NO release induced by nebivolol was also shown by Zepeda et al. [17] in addition to a significant antihypertensive effect. The reduction in BP was also attributed to the rise in NO concentration in this study. On the molecular level, it has been suggested that nebivolol acts via the endothelial b3-AR, which both induces the endothelial NO synthase and inhibits the NADPH oxidase, increasing the bioavailability of NO [18]. Maffei et al. [19,20] were able to directly observe the endothelial NO release induced by nebivolol in doses inside the therapeutic range. They also found that the main nebivolol metabolites retained the ability to induce NO production. Carvedilol. Carvedilol is a non-selective BAA that antagonizes b1-AR, b2-AR and a1-AR. It has a very lipophilic profile, facilitating a fast and extensive absorption. It does not exert any sympathomimetic activity either [21,22]. Comparable to other BAA, it reduces SBP and DBP as well as HR during exercise/stress and at rest. It inhibits left ventricular remodelling and improves its function in hypertensive patients. The main vasodilative action of carvedilol is contributed to its a1-AR-antagonistic effect, but it is also suggested that it induces the release of endogenous NO [21]. Carvedilol also inhibits oxygen radical-induced lipid peroxidation (fig. 2) and protects against ROS-mediated cell damage, which points towards carvedilol having a scavenging ability of free radicals and anti-oxidative properties [23].

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Fig. 2. Underlying mechanisms for both nebivolol and carvedilol concerning vasodilator actions in peripheral vasculature and reduction of ROS. ROS, reactive oxygen species; sGC, soluble guanylyl cyclase; AC, adenylyl cyclase; L-type VGCC, L-type voltage-gated Ca2+ channel. Modified from Ref. [13].

Reactive oxygen species can also cause DNA damage – carvedilol reduces this damage significantly [24]. General oxidative stress in both poly- and mononuclear cells as well as C-reactive protein (CRP) levels in hypertensive patients is also lowered as an effect of carvedilol [25]. As reviewed by Wehland et al. [11], carvedilol has an extensive amount of other effects such as inhibition of basal mitogenesis, inhibition of DNA synthesis of cultured vascular smooth muscle cells and anti-apoptotic abilities among other effects. Many of these effects could be useful additional effects, but more research is needed to determine their true value. Current clinical trials of carvedilol and nebivolol Research with both carvedilol and nebivolol continues. An overview of the recent trials is presented in tables 2 and 3. Of note, most of the trials are either aimed at the investigation of the BP-lowering effects of third-generation BAAs in comparison with earlier BAAs or other antihypertensive drugs or at testing the safety and tolerability of third-generation BAAs. So far, only very few data on their long-term effects exist. According to new clinical trials studying the effect of carvedilol and nebivolol, it is clear that they both have a BPlowering effect on SBP and DBP. This is the case in both monotherapy and in combination with other antihypertensive agents. The BP-lowering effect is mostly attributed to the BAA-induced effect but also to the possible vasodilative effects of the two drugs. BAAs in congestive heart failure Congestive heart failure is a relatively common condition. People from most age groups are susceptible to it, but the prevalence is highest among the elderly. BAAs are a treatment option in CHF and have proved to be a major pharmacological advance in the treatment of CHF (fig. 3). Even though many physicians have yet to embrace the BAAs as a valid treatment [26], many clinical trials and pertinent studies are rallying

information about BAA in CHF, so that they can become a standard in the treatment of CHF in the future [6,27,28]. As described by Lopez-Sendon et al. [12], all patients with mild, moderate and severe CHF should be treated with BAA unless there is a contraindication. Nevertheless, it seems that BAAs are underused in the treatment of CHF. The beneficial role of BAA in CHF treatment is supported by many smallscale studies as well as large-scale, long-term placebo-controlled trials, including over 15.000 patients [29–31]. In these studies, the BAAs reduced sudden cardiac death, total mortality, cardiovascular mortality and death due to progression of CHF. These findings have proved to be present in all age, gender, functional class and suppressed left ventricular ejection fraction groups. Outstanding examples were the trials with carvedilol, COPERNICUS and CAPRICORN, both of which found that carvedilol has a significant beneficial effect on the patients with CHF [32–34]. Furthermore, the CARMEN [35] trial showed that early combination therapy with carvedilol and ACE inhibition can reverse a remodelling of the left ventricle in patients with heart failure, and it was suggested to include beta-blockade into the therapeutic regimen without delay. Similar findings were reported by the ANZ HeFT study, where beneficial effects on LV size and function were reported, while no effects on exercise performance or worsening of HF were observed [36]. Moreover, carvedilol reduced the risk of cardiovascular complications related to deaths and/or hospitalizations of patients with CHF, who also received diuretics, digoxin and ACE inhibitors [37]. To compare the use of first- and second-generation BAAs with third-generation BAAs like carvedilol, the COMET trial comes of use: the results of this study suggest that carvedilol is superior to metoprolol in extending life in CHF patients [38]. A protocol of clinical guidance for the use of BAAs in CHF could be listed as follows [12]: Patients who should have BAA treatment: All patients with chronic, stable heart failure without contraindications such as symptomatic hypotension, bradycardia or asthma. The prospects of the treatment: Primarily prophylactic against death and new hospitalisations for cardiovascular reasons. Time of treatment onset: When there is no sign of fluid retention, diuretics can be used first. In stable patients, in the hospital or in outpatient clinics. Dosage: Begin with a low dose and increase it slowly. Aim for target dose for the specific patient or, if not tolerated, the highest tolerated dose. Monitoring: Monitor for signs of CHF symptoms, fluid retentison, hypotension and bradycardia. Instruct patients to measure their weight daily and increase diuretic dose accordingly. Clinical use of BAA in different patient groups Elderly. One of the major health burdens in the Western society is the development of hypertension mainly because of lifestyle. The elderly patients belong to a group that develops hypertension

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Randomized, prospective, parallel-group, active controlled, open-label, single-blind study 160 (80 pts. for each arm) patients with new diagnosis of heart failure 24-month duration 10 mg/day nebivolol versus 50 mg/day carvedilol

Double-blind, randomized, placebo-controlled, parallel-group, multi-centre study 338 patients (87 pts. at 20, 78 pts. at 40, 88 pts. at 80 mg/day controlled-release carvedilol, 85 pts. placebo) 6-week duration

Prospective, placebo-controlled, crossover, double-blind, randomized, single-centre clinical trial. 20 patients (25 mg/day carvedilol, 5 mg/day nebivolol 1-month duration with each drug

Controlled-release carvedilol in the treatment of essential hypertension [59]

Comparison of antihypertensive efficacy of carvedilol and nebivolol in mild-to-moderate primary hypertension: a randomized trial [60]

Design

Comparative long-term effects of nebivolol and carvedilol in hypertensive heart failure patients [58]

Title

Overview of the recent phase II/phase III studies using carvedilol.

20 mg carvedilol: 6.75/ 4.4 (149.5/98.3) 40 mg carvedilol: 10.06/ 7.9 (151.4/98.9) 80 mg carvedilol: 12.48/ 9.6 (150.7/99.2) Placebo: 0.63/+0.38 (149.9/99.5)

Carvedilol: 7.2/ 5.8 (141/92.4) Nebivolol: 7/ 6.8 (141/92.4) Placebo: 2.9/2 (141/92.4)

Both nebivolol and carvedilol significantly reduced both SBP and DBP in men and women (few test subjects!)

Nebivolol: 8.4/ 12 (125/92) Carvedilol: 11/ 6 (121/89)

DBP (baseline) (mmHg)

Carvedilol controlled-release (CR) reduced both DBP and SDP after 6 weeks of treatment with statistic significance. HR and PP were reduced as well

Both carvedilol and nebivolol reduced BP and HR in hypertensive patients and their ability of physical exercise (walking test) improved

Results

Table 2.

Carvedilol and nebivolol both reduced BP effectively compared to placebo, but no difference between the two was obtained

Carvedilol CR is a very effective antihypertensive agent with clear dose-related peak blood pressure reduction

Carvedilol and nebivolol appear to have a similar effect in the treatment of hypertensive patients with CHF

Conclusion

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Efficacy and safety of nebivolol (added to lisinopril or losartan) in hypertensive patients [65]

Study of the efficacy and safety of nebivolol in younger patients (18–54 years) [64]

A study on the efficacy and safety of nebivolol monotherapy in Hispanic hypertensive patients [62] The effect of nebivolol in hypertensive patients with coronary artery disease [63]

Nebivolol in patients with systolic stage 2 hypertension (NEB-MD-20) [61]

Title

Randomized, double-blind, placebo-controlled multi-centre trial 432 patients (290 pts. nebivolol 20 mg/day, 142 pts. placebo) 6-week duration Prospective, randomized, double-blind, placebo-controlled, dose-titration study 277 patients (141 pts. nebivolol 5, 10, 20, 40 mg/day, 136 pts. placebo) Randomized, double-blind control trial 39 patients (21 pts. nebivolol 5, 10, 20, 40 mg/day, 18 pts. carvedilol 12.5, 25, 50 mg/day each after 4 weeks of metoprolol run-in phase) 18-week duration terminated early due to difficulties with enrolment Randomized, double-blind, placebo-controlled study 641 patients (427 pts. nebivolol 5, 10, 20 mg/day, 214 pts. placebo) 8-week duration Double-blind, placebo-controlled trial 491 patients (258 pts. nebivolol 5, 10, 20, 40 mg/day, 233 pts. placebo as add-on to lisinopril or losartan treatment) 12-week duration

Design

Overview of the recent ongoing phase II/phase III studies using nebivolol.

Nebivolol added to other antihypertensive treatment like lisinopril (ACE inhibitor) and losartan (AngIIR inhibitor) reduced both SBP and DBP after 12 weeks of treatment

Nebivolol: 10.1/ 7.8 (163.1/98.2) Placebo: 7.3/ 3.5 (162.4/96.8)

Nebivolol: 13.7/ 11.8 (not reported) Placebo: 5.5/ 5.5 (not reported)

Nebivolol: 5.5/ 3.1 (135.1/81.1) Carvedilol: 0.4/1.1 (136.9/78.2)

Nebivolol reduced both SBP and DBP after 18 weeks, but only slightly

Nebivolol reduced both seated SBP and DBP after 8 weeks of treatment

Nebivolol has a BP-lowering effect when compared to placebo

Nebivolol: 14.1/ 11.1 (not reported) Placebo: 9.3/ 7.3 (not reported)

Nebivolol reduced both seated SBP and DBP after 8 weeks of nebivolol treatment

Nebivolol added to other antihypertensive agents has a BPlowering effect when compared to placebo

Nebivolol has a BP-lowering effect when compared to placebo

Nebivolol has a BP-lowering effect when compared to carvedilol. Although the difference was nonsignificant, only few subjects were enrolled and tested

Nebivolol has a BP-lowering effect when compared to placebo

Conclusion

Nebivolol: 18.2/ 12.3 (166.7/100.9) Placebo: 12.3/ 5.7 (166.9/100.6)

DBP (baseline) (mmHg)

Nebivolol reduced both SBP and DBP after 6 weeks of nebivolol monotherapy

Results

Table 3.

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do not have an effect on uterine contraction [12]. In Denmark, labetalol is the BAA of choice in pregnancy [41].

Fig. 3. Effects of the third-generation BAA in CHF: carvedilol and nebivolol are both anti-oxidative and antiproliferative agents, which may contribute to their anti-atherosclerotic action. In addition, carvedilol has an anti-apoptotic effect on endothelial cells. Both drugs can treat arrhythmias, reduce the effect of the sympathetic nervous system by making the actions of the natural catecholamines less effective and exert positive effects on the energy metabolism. Modified according to Ref.[11].

naturally due to an increase in arterial stiffness and a decline in renal function and other factors. This demands a well-considered treatment for hypertension, tailored for the elderly, if possible. In the early stage of the treatment, it is important to remember that elderly most often have other medical conditions and a compromised drug metabolism, which makes them susceptible to orthostatic hypotension for instance. There are several different options of drugs, such as diuretics and ACE inhibitors, and BAAs are usually not among the first choice for first-line therapy [39]. Studies comparing BAAs with diuretics have shown that diuretics are superior to BAAs on all outcome [39]. Although this does not mean that BAAs do not have any uses at all. There are various conditions in which BAAs are used frequently such as CHF, coronary artery disease (CAD), postmyocardial infarction, senile tremor, supraventricular and ventricular arrhythmias [39]. The SENIORS trial, however, which compared the effect of nebivolol with placebo in elderly patients with heart failure receiving optimal standard therapy, only showed small beneficial effects of additional BAA on all-cause mortality or hospital admission for heart failure. It has been speculated that this might be due to the inclusion of patients with an LVEF higher than 0.35 or a drug-specific effect [40]. Pregnancy. There is no evidence of teratogenic effects of BAA used during pregnancy. BAAs are indicated in patients with hypertension, including pregnant women. The BAA treatment can be continued during delivery, although selective agents such as a first-generation BAA or nebivolol are preferred, because they

Diabetes. Studies have tested antihypertensive drugs in patients with diabetes. Hypertension is a common feature of both type I and II diabetes, which makes these patients a potential treatmentdemanding group. The choice of antihypertensive drugs should be based on tolerability and efficacy in the specific patient. Because BP is harder to control in patients with diabetes, a combination of drugs is often used. Special conditions and comorbidities of the patient should be taken into account [1]. If the patient does not have any other risk factors or conditions, a combination of diuretics and ACE inhibitors is usually indicated. The BAAs become the drugs of choice, mainly in combination therapy when the patient suffers from conditions like CHF and coronary heart disease (CHD), even though they might have insulin-sensitivity-impairing effects [1]. A selective BAA should be the drug of choice in a patient depending on insulin. Overall, the beneficial effects overrule the side effects in the patients with diabetes in most cases. A network metaanalysis including 22 trials showed that the association of BAAs with incident diabetes was higher than those from angiotensin receptor blockers, ACE inhibitors and calcium channel blockers and lower than that from diuretics [42]. It should be noted, however, that an association as indicated by certain odds ratios does not necessarily indicate a direct causality, as further confounding factors cannot be ruled out. Adverse effects In general, BAAs are well tolerated, but in cases with large doses, severe adverse effects can occur. Due to the aforementioned effects of BAAs, an overdose or hypersensitivity can cause extreme bradycardia, hypotension and AV block. This can be managed by close monitoring of the patient to find the optimal dose. BAAs can cause an insufficient tissue blood flow by blocking b2-AR. This can lead to cold extremities and Raynaud’s phenomenon and worsen other vascular diseases. These cardiovascular side effects are serious, but the effect of the treatment is often valued over the possible side effects. It should be noted that these side effects are not as severe with BAAs that have vasodilative effects, such as nebivolol [12]. In the lungs, the BAAs can lead to bronchospasms, making asthma and COPD contraindications to consider in the treatment with BAAs. The BAAs should also be used with care in the treatment of patients with type I diabetes as they can mask some of the symptoms of hypoglycaemia such as tremor or tachycardia. Depending on the lipophilicity of the individual drug, central adverse effects can occur. The more lipophilic the drug is the easier it can traverse the blood–brain barrier. Once it enters the CNS, it can cause central side effects such as fatigue, headache, nightmare, sleep disturbance, depression and even insomnia. Another side effect that has a great impact on

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some people’s quality of life is sexual dysfunction, manifested in erectile dysfunction and loss of libido [11,12,43]. The Role of BAAs in the Current Guidelines for Hypertension Management Until recently, BAAs were commonly considered to be among the five drug classes (BAAs, diuretics, calcium channel blockers, angiotensin converting enzyme blockers and angiotensin receptor blockers) equally suitable for first-line hypertension therapy. Over the last few years, however, this has changed. At the moment, the only major hypertension societies still recommending BAAs as a first-line drug are the European Society of Cardiology (ESC)/European Society of Hypertension (ESH) and the Canadian Hypertension Education Program (CHEP) [1,44]. All other major guidelines such as the JNC 8 guidelines as well as those from the British National Institute for Health and Clinical Excellence (NICE), the American Society of Hypertension (ASH) and the International Society for Hypertension in Blacks (ISHIB) among others have relegated BAAs to second- or third-line positions [45–48]. Earlier studies such as the Swedish Trial in Old Patients (STOP) Hypertension-1 trial, the Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) study or the Medical Research Council (MRC) trial suggested improvements in mortality, stroke and heart failure under BAA treatment [49–52]. More recent studies and meta-analyses, however, have revised this. It has been shown that BAAs are inferior to calcium channel blockers, RAAS inhibitors or diuretics due to a smaller impact on the reduction of end-points such as cardiovascular events, mortality, coronary heart disease or stroke [53–55]. The Losartan Intervention For Endpoint reduction in hypertension study (LIFE) in particular, which demonstrated an increased rate of the primary combined end-point of death, myocardial infarction or stroke under atenolol compared to losartan therapy, led to the new JNC8 assessment [56]. This observation was confirmed by a meta-analysis including data on BAA trials from 1985 up to 2005 [57]. It was shown that BAAs exhibit a 16% higher relative risk of stroke than other antihypertensive drugs in patients with primary hypertension. It should be noted, however, that these studies and metaanalyses mostly used first- or second-generation BAAs and that comparable data on third-generation BAAs do not yet exist. It therefore remains to be elucidated whether their additional actions such as vasodilation can ameliorate their disadvantages compared to other drugs and put them back on the map of hypertension therapy.

Conclusions b-ARs are found in many tissues of the human body. BAAs like carvedilol and nebivolol interact with these b-ARs and, as a result, have an effect on multiple organs, including blood vessels and heart tissue, which is of great importance in the treatment of hypertension and its possible sequelae. Focusing on nebivolol, this drug is lipophilic and has a great selectivity

for b1-AR and thereby it reduces arterial pressure in hypertensive patients and preserves left ventricular function in patients with CHF. Another beneficial feature of nebivolol is the safety of use for patients with asthma or patients with COPD. In addition to its BP-lowering abilities, nebivolol also induces endothelium-dependent vasodilation mediated by NO. Carvedilol is a lipophilic, non-selective BAA that reduces BP in hypertensive patients and reduces HR during both exercise and rest. It betters left ventricular function in hypertensive patients as well. Carvedilol also has vasodilative properties. These effects are mainly contributed to a1-AR-antagonizing effects. This drug also has a wide variety of other effects, which might be useful in the treatment of hypertensive patients. Both drugs can be very beneficial in the treatment of CHF. Currently, clinical trials focusing on the effects of carvedilol and nebivolol in hypertensive patients are ongoing and will show promising results. These drugs should be administered in relation to given standards on different groups of patients and their adverse effects; although relatively few and rare, they should be noted as well. Factoring in the pharmacological profiles of these third-generation BAAs, the positive effects and additional benefits are hard to overlook. These BAAs could be taken into account when considering new drugs of choice in the treatment and prevention of hypertension. Outlook BAAs constitute an antihypertensive treatment regimen in thriving development; especially third-generation BAAs have a great potential because of their additional effects, such as vasodilation and their mild side effect profile. Nevertheless, more large-scale clinical trials on third-generation BAAs are needed to further substantiate their role in the treatment of hypertensive patients in the future. References 1 Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, B€ohm M et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013;34:2159–219. 2 Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2224–60. 3 Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13. 4 Rapsomaniki E, Timmis A, George J, Pujades-Rodriguez M, Shah AD, Denaxas S et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and agespecific associations in 1
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