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ae

Current Hypertension Reviews, 2019, 15, 22-31

REVIEW ARTICLE
ISSN: 1573-4021
eISSN: 1875-6506

Three Generations of β-blockers: History, Class Differences and Clinical

Applicability
BENTHAM
SCIENCE

Gabriel T. do Valea,*, Carla S. Cerona, Natália A. Gonzagaa, Janaina A. Simplicioa and Júlio C. Padovanb

a
Laboratório de Farmacologia, Escola de Enfermagem de Ribeirão Preto, USP, Ribeirão Preto, SP, Brazil; bThe Rocke-
feller University, Laboratory of Blood and Vascular Biology, New York, NY, USA

Abstract: Background: Beta-adrenergic receptors are expressed in cardiomyocytes and activated

by either noradrenaline released from sympathetic synapses or circulating catecholamines. Their
corresponding receptors have three subtypes, namely, β1, β2 and β3, which are members of the G
protein-coupled receptors (GPCRs) family. Activation of β1-adrenergic receptors causes various
physiological reactions including cardiac contraction and renin secretion from juxtaglomerular cells
of the kidney. Antagonists of β-adrenergic receptors, known as β-blockers, have been used effec-
tively for over four decades and have beneficial effects in the treatment of cardiovascular diseases.
ARTICLE HISTORY
There are three generations of β-blockers according to their pharmacological properties. First-
generation β-blockers are non-selective, blocking both β1- and β2-receptors; second-generation β-
Received: June 28, 2018 blockers are more cardioselective in that they are more selective for β1-receptors; and third-
Revised: September 11, 2018
Accepted: September 11, 2018
generation β-blockers are highly selective drugs for β1-receptors. The latter also display vasodilator
actions by blocking α1-adrenoreceptors and activating β3-adrenergic receptors. In addition, third-
DOI: generation β-blockers exhibit angiogenic, antioxidant, anti-proliferative, anti-hypertrophic and anti-
10.2174/1573402114666180918102735
apoptotic activities among other effects that are still under investigation.
Current Hypertension Reviews

Conclusion: The objective of this review is to describe the evolution observed during the develop-
ment of the three distinctive generations, thereby highlighting the advantages of third-generation β-
blockers over the other two drug classes.
Keywords: β-blockers, antagonists, β-adrenergic receptors, cardiovascular diseases, clinical applicability, G protein–coupled
receptors (GPCRs).

1. INTRODUCTION transmembrane domains, and Dixon et al. described that

those were G-protein-coupled receptors [5, 6]. In 1989,
Adrenergic receptors comprise a class of G protein-
Emorine et al. observed the existence of a third isoform of β-
coupled receptors targeted by catecholamines, in particular
adrenergic receptors (β3), which also belongs to the family of
noradrenaline and adrenaline. In 1906, Dale [1] was the first
G-protein-coupled receptors [7].
to introduce the concept of a receptor in association with the
sympathetic nervous system (SNS). In 1948, Alquist divided As antagonists to these receptors, β-blockers comprise an
adrenergic receptors into α (excitatory) and β (inhibitory) essential class of cardiovascular drugs designed to reduce
according to their functional effects of vasoconstriction and morbidity and mortality in patients with cardiovascular dis-
vasodilatation, respectively [2]. Two decades later, eases. These drugs decrease the number of deaths, strokes,
Richardson et al. showed that activation of β-receptors in the and heart attacks associated with hypertension. β-blockers
heart muscle mediated positive chronotropic and inotropic reduce sympathetic nervous system activity through block-
effects [3]. In the same year, Lands et al. subdivided β- ade of β-adrenergic receptor subtypes. The specificity of β-
adrenergic receptors into β1 (cardiac effects) and β2 (bron- blockers is directly related to the greater affinity the drug has
chodilator and vasodilator effects) [4]. Later on, Yarden et al. for β1- over β2-receptors at usual therapeutic levels. There
demonstrated that β-adrenergic receptors consisted of seven have been several β-blockers developed with distinct phar-
macological and hemodynamic properties, which may be
divided into three distinct generations according to differ-
*Address correspondence to this author at the Universidade de São Paulo, ences in those pharmacological properties. First-generation
Escola de Enfermagem de Ribeirão Preto/Laboratório de Farmacologia,
Avenida Bandeirantes 3900, CEP 14040-902, Ribeirão Preto, SP, Brazil;
β-blockers were non-selective, blocking both β1 and β2 -
Tel: +55-16-3315-0540, Fax: +55-16-3315-0518; receptors; second-generation β-blockers are more cardiose-
E-mail: gabriel-farma@hotmail.com lective in that they show higher affinity for β1-receptors; and

1875-6506/19 $58.00+.00 © 2019 Bentham Science Publishers

Three Generations of β-blockers Current Hypertension Reviews, 2019, Vol. 15, No. 1 23

third-generation β-blockers present varied selectivity for β1 - of guanylate cyclase (GC) and formation of cGMP [9, 11].
receptors. The latter also display vasodilator actions by
blocking α1-adrenoreceptors and activating β3-adrenergic In cardiomyocytes, there is the prevalence of β1-
receptors. adrenergic receptors with a molar ratio of 4:1 in comparison
to the β2 form. Cardiac expression of β3-adrenergic receptors
In this review, we discuss the development of the three is low under physiological conditions but it has been shown
distinct generations of β-blockers and highlight the advan- to increase in the cardiac muscle of some patients with heart
tages of the third-generation drugs over the previous two β- disease [12, 13]. Activation of β1-adrenergic receptors in
blocker classes. For the selection of articles, a MEDLINE- cardiomyocytes leads to changes in its conformation, which
based search was conducted using the following keywords: in turn promotes activation of Gs proteins by exchanging
“β-blockers”, “β-adrenergic receptor”, “β1-adrenergic recep- guanosine triphosphate (GTP) for the diphosphate form
tor antagonist”, “first generation”, “second generation”, (GDP) and dissociation of the G protein into an activated Gα
“third generation”, “evolution”, “extra β1-effect”, “cardio- subunit and the allosteric Gβγ complex [13, 14]. Activation
vascular diseases” and “selectivity”. The list of articles was of adenylyl cyclase (AC) leads to cAMP formation, followed
subsequently narrowed down to those containing abstracts by activation of protein kinase A (PKA), which in turn is
and to articles published in English. Information analysis responsible for the phosphorylation of L-type calcium chan-
started with the title, followed by the abstract and then the nels [9, 15] and sarcoplasmic reticulum calcium-release
complete report. channels [9, 16]. These responses increase the intracellular
calcium concentration thereby promoting contraction. In
2. β-ADRENERGIC SIGNALING addition, PKA can phosphorylate myofilaments, such as tro-
β-adrenergic receptors are activated by the catechola- ponin I, reducing its sensitivity to calcium [9, 17]. These
mines noradrenaline and adrenaline, and they are members responses are directly linked to cardiac chronotropic and
of the seven-transmembrane superfamily of receptors. There inotropic effects. Conversely, phosphorylation of phospho-
are three β-adrenergic receptors subtypes, namely β1, β2, and lamban-type calcium channels is responsible for reuptake of
β3. β-adrenergic receptors are implicated in several physio- cytosolic calcium by the sarcoplasmic reticulum, causing
logical functions, particularly in the cardiovascular and pul- relaxation of the cardiac muscle [13, 18]. Under conditions
monary systems. Table 1 summarizes the responses pro- of chronic activation of β-adrenergic receptors, three types of
duced by the stimulation of β-adrenergic receptors from dis- intracellular enzymes may be activated as a compensatory
tinctive tissues. Their influence on the cardiovascular system mechanism: i) receptor G protein-coupled kinases (GRK),
is exerted both directly through an increase of the cardiac which are responsible for the phosphorylation of β1-
contractions and indirectly by means of renin secretion by adrenergic receptors with subsequent desensitization; ii)
the juxtaglomerular cells of the kidney. phosphodiesterases (PDEs), which are capable of hydrolyz-
Activation of β-adrenergic receptors occurs primarily by ing cAMP; and iii) general phosphatases [19].
noradrenaline released by sympathetic nerve terminals, It is important to mention that renal juxtaglomerular cells
which form a network around the cardiomyocytes. A secon- are in contact with sympathetic nerve varicosities expressing
dary mode of activation is through circulating catechola- post-junctional β1-adrenergic receptors. Their activation in-
mines [8, 9]. Cardiomyocytes express all three isoforms of β- duces renin release, increasing the activity of the renin-
adrenergic receptors: β1, β2 and β3. While β1-adrenergic re- angiotensin system (RAS), which is involved in the patho-
ceptors are coupled to a stimulatory G protein (Gs), β2 - physiology of cardiovascular diseases [20].
receptors are coupled to both a stimulatory (Gs) and an in-
hibitory G-protein (Gi), with predominant activation of the 3. ANTAGONISTS OF β-ADRENERGIC RECEPTORS
stimulatory one (Gs) [9, 10]. Finally, β3-adrenergic receptors
are Gi-protein-coupled and additional intracellular signaling β-adrenergic antagonists, also called β-blockers, are
includes activation of nitric oxide synthases (NOS), activation molecules that compete with catecholamines for the binding

Table 1. Responses stimulated by β-adrenergic receptors in distinctive tissues.

Tissue/Receptor
β1 [21-23]
β2 [24-26]
β3 [27]

G Protein Activation
Gs
Gi and Gs
Gi

Adipocytes
-
-
Lipolysis and thermogenesis

Heart
Positive inotropism and chronotropism
Positive inotropism and chronotropism
Negative inotropism

Ileo and colon
-
-
Relaxation

Lung
-
Relaxation
Relaxation

Peripheral sympathetic nerves
Release of norepinephrine
Release of norepinephrine
-

Kidney justaglomerullar cells
Secretion of renin
-
-

Vascular
Relaxation
Relaxation
Relaxation

24 Current Hypertension Reviews, 2019, Vol. 15, No. 1 do Vale et al.

Table 2. First published article about each β-blocker.

β-Blocker
First Published Article

Propranolol
Black, et al. A new adrenergic betareceptor antagonist. Lancet. 1964.

Practolol
Dunlop D & Shanks RG. Selective blockade of adrenoceptive beta receptors in the heart. Br J Pharmacol Chemother. 1968.

Atenolol
Barrett AM, et al. A new type of cardioselective adrenoceptive blocking drug. Br J Pharmacol. 1973.

Metoprolol
Ablad B, Carlsson E, Ek L. Pharmacological studies of two new cardioselective adrenergic beta-receptor antagonists. Life Sci I. 1973.

Kennedy I & Levy GP. Combined alpha- and beta-adrenoceptor blocking drug AH 5158: further studies on alpha adrenoceptor block-
Labetalol

ade in anaesthtized animals. Br J Pharmacol. 1975.

Bartsch W, et al. Pharmakologie und klinische Pharmakologie des neuen vasodilatierenden B-Rezeptoren-Blockers BM 14.190. Thera-
Carvedilol

piewoche. 1982.

Van de Water A, et al. Pharmacological and hemodynamic profile of nebivolol, a chemically novel, potent, and selective beta 1-
Nebivolol

adrenergic antagonist. J Cardiovasc Pharmacol. 1988.

site on β-adrenergic receptors. James Black was the pioneer Black et al., started to look for a large number of compounds
in the development of this class of drugs. There are currently with better therapeutic effects and no aggressive toxicity
more than twenty antagonists commercially available for until found the propranolol [30]. This compound presents
clinical use. The action of β-blockers in the cardiovascular one chiral center, constituting a racemic mixture of R- and S-
system includes negative inotropic and bradycardic effects, enantiomers, which the R-stereoisomer (R- configuration at
which translate into a lower cardiac output. In addition, an- the hydroxyl) has no pharmacological effect while its S- iso-
tagonism of β1-receptors from the juxtaglomerular cells can form contains all the pharmacological properties of propra-
reduce the activity of the renin-angiotensin system, resulting nolol [31].
in decreased blood pressure [21-28]. Despite the common
In this sense, propranolol, the first β-blocker used in the
mechanism to all members of this class of drugs, there are
clinic, was developed by James Black in 1964, who demon-
several differences in their specific activities.
strated the antagonistic effect of this drug in reducing iso-
The most important pharmacodynamic difference among prenaline-induced increases in heart strength and heart rate
β-blockers is their selectivity for adrenergic receptors and [30]. Propranolol has a high lipophilicity and can cross the
their subtypes. There are also three generations of β- blood-brain barrier. When administered orally, it shows good
blockers. Representatives of the first generation are non- absorption but suffers first-pass metabolism, with only 25%
selective antagonists of receptors of type β1 and β2. Repre- of the drug reaching systemic circulation. It has a large dis-
sentatives of the second generation have selectivity for β1 tribution volume (about 4L/kg) and 90% binding to plasma
receptors compared to β2, also called cardioselectivity, but proteins. Propranolol clearance varies according to hepatic
this feature is dose-dependent. Representatives of the third blood flow and it is consequently dependent on hepatic
generation are known as vasodilators as a direct result of their physiology such as the presence of pathologies of the liver
effects on the cardiovascular system in addition to blocking and/or concomitant administration of other drugs that also
β1 receptors. For example, third-generation β-blockers both affect the hepatic biotransformation of this drug. In addition,
block α1-adrenoreceptors and activate β3-receptors with further propranolol also shows a comparatively short half-life (3-6
increase of NOS activity and NO generation. An understand- hours) [28]. The main cardiovascular effect of propranolol is
ing of the differences among the generations of β-blockers is reduction of the systolic and diastolic blood pressures asso-
critical to the correct utilization of these drugs [28]. ciated with decreased cardiac output and reduced activity of
the renin-angiotensin system [28].
4. FIRST GENERATION OF β-BLOCKERS
Based on its clinical applications, Hansson and Zweifer
Based on isoprenaline structure, in 1958 Powel and Slater observed that administrations of either four or two daily
introduced the first β-receptor antagonist named doses of propranolol (160-320 mg) were able to reduce
dichrloroisoprenaline, but successive researchers have dem- blood pressure in hypertensive patients to normal levels [32].
onstrated that this compound effectively antagonized myo- They also observed a decrease in diastolic blood pressure
cardial rate and tension, but also presented sympathomimetic with decreased plasma renin activity after four weeks of
activity [29]. At this time, Black and Stephenson (1962) tried treatment. However, the antihypertensive response was not
several compounds, with small structural changes (Fig. 1), observed after administration of a single dose of propranolol.
that could antagonize β effects, without agonistics actions. MacLeod et al. developed a study involving 63 hypertensive
Then, pronethalol was published as the first completely an- patients with mean systolic blood pressure of 173 ± 5 mmHg
tagonist of β-adrenergic receptors without any sympath- and diastolic blood pressure of 110 ± 3 mmHg at the start of
omimetic activity on the cardiovascular system [29]. On the the treatment. Patients were initially subjected to a regimen
other hand, pronethalol demonstrated a variety of side effects of four daily administrations of propranolol (40-320 mg) for
as lightheadedness and slight incoordination followed by twelve weeks and were then switched to a twelve-week pe-
nausea and vomiting that could be associated with non- riod wherein they were given the same total daily amount but
specific action of pronethalol on the central nervous system. through only two administrations. Both twelve-week treat-
Three Generations of β-blockers Current Hypertension Reviews, 2019, Vol. 15, No. 1 25

OH H
HO N (+) b1-adrenergic receptor
b3-adrenergic receptor
HO (+) b2-adrenergic receptor
Isoprenaline
S position
S position (+)
Effect
S position Effect Para position
Effect Para position OH SRRR - b1-blocker
OH Selectivity
Selectivity H H SSSR- b3- agonist
OH O N O N
H O O
OH OH
O N H
O N O
N H2N
H Practolol Atenolol F F
Propranolol Nebivolol

(-) (-)
(-) (-) S - b1-blocker
(-) S and R - a1-blocker

b2-adrenergic receptor b1-adrenergic receptor (-) O N

O
OH
H
OH H
H3CO HN O N
N Carvedilol
a1-adrenergic receptor (-) H Carazolol
(-) (-)

(-)
S position
Effect RR - b1- blocker O NH 2
Para position SR - a1- blocker
OH
Selectivity H OH
O N CH3

CH3 N
H3CO H
Metoprolol OH
Labetalol

H2NOC CH3

HO CHCH3 NHC CH3

O N
H OH
CH3
OH AH3474
Alprenolol

Fig. (1). Schematic summary of the chemical development of β-blockers. The development of each β-blocker was based in a primary com-
pound (green arrow). According to the evolution of each antagonist some fundamental characteristics can be observed as the radical groups in
para- position and R or S conformation of hydroxyl from chiral carbon (blue circle). Based on each chemical structures the β-antagonists pre-
sented its respective pharmacological actions (red arrow). (The color version of the figure is available in the electronic copy of the article).

ments with propranolol led to reduced diastolic and systolic showed an increase in peripheral vascular resistance, which
blood pressures, therefore indicating the antihypertensive may be associated with the antagonistic activity on β 2 recep-
effect of this drug [33]. tors in the peripheral vasculature [35].
Propranolol is also effective in infarcted patients, In addition to increased peripheral vascular resistance,
whether with congestive heart failure or not. Chadda et al. the non-selective β 1-adrenergic antagonism of propranolol
accompanied patients who had been treated with propranolol can cause serious adverse effects, which are associated with
(180-240 mg) or a placebo for 25 months and observed that β2-receptor antagonism, such as bronchospasm in patients
treatment with propranolol was able to reduce the mortality with asthma or chronic obstructive pulmonary disease.
rates of those patients with or without congestive heart fail- Moreover, propranolol may increase peripheral vascular re-
ure compared to patients treated with placebo. The reduction sistance due to β2 antagonism on peripheral vasculature [28].
in mortality was associated with decreasing cardiovascular
To address this adverse effect, Boskabady and Snashall
events, such as reduction of sudden death, myocardial infarc-
evaluated the respiratory function in symptomatic and as-
tion recurrence and decrease in the number of coronary
ymptomatic patients with asthma and healthy volunteers
events. The beneficial effect of propranolol in infarcted pa-
tients, with or without congestive heart failure, is associated after the administration of isolated isoprenaline (0.65–22
nmol) and isoprenaline preceded by propranolol (4–20 μg/kg
with its ability to decrease both contractile strength and heart
intravenously). They observed that healthy volunteers, with-
rate, resulting in an anti-ischemic effect [34].
out pulmonary pathologies, showed no significant changes in
The administration of propranolol in individuals with respiratory function after treatment with propranolol fol-
angina may also have beneficial effects. Pine et al. observed lowed by isoprenaline. In contrast, patients with sympto-
that increasing doses of β -blockers (40-320 mg) improved matic or asymptomatic asthma showed a significant reduc-
patient performance during physical evaluations as measured tion of respiratory function after administration of propra-
by increased oxygen volume (VO2) emitted during the test. nolol. This difference in responses between symptomatic and
Furthermore, decreased heart rates and systolic blood pres- healthy volunteers may be associated with the fact that asth-
sures were also observed during physical evaluation when matics have a bronchodilator protective effect related to cir-
compared to patients who had not been treated with the drug. culating adrenaline, which is lost following low doses of β 2-
Nevertheless, patients subjected to propranolol treatment receptors antagonists [36].
26 Current Hypertension Reviews, 2019, Vol. 15, No. 1 do Vale et al.

Another important aspect to consider is that adrenaline there was no β2-adrenergic receptor antagonism, that is, the
exerts an essential role in hypoglycemia recovery, leading to bronchodilating effect of isoprenaline was counteracted by
symptoms such as tremor and tachycardia, which may be the bronchoconstricting effect of histamine. These experi-
masked by β-blockers [37]. Finger tremor, for example, is ments helped to establish the idea of a selectivity for β1 -
associated with peripheral β-receptors activation [38], and adrenergic receptors by practolol [40].
propranolol was described to block such response during
Atenolol (4-(2'-hydroxy-3'-isopropylaminopropoxy)
hypoglycemia [39]. The increase in tremor during treatment
phenylacetamide), another β-blocker of second generation,
with β1-selective antagonist was similar to that for the pla-
was developed in 1973 by Barret et al. based on practolol
cebo administration, which suggests that tremor is only
characteristics. The drug has only one structural difference,
partly mediated by β2-receptors [39]. Thus, by masking the
the exchange of benzylacetamide for a phenylacetamide, but
effects of hypoglycemia, propranolol may represent a risk
for diabetics under insulin treatment and its use may be lim- still in para- position (Fig. 1) [41]. As practolol, atenolol
presents one chiral center constituting a racemic mixture of
ited for this class of patients.
R- and S-enantiomers, which the R-stereoisomer (R- con-
In summary, first-generation β-blockers can lower blood figuration at the hydroxyl) has no pharmacological effect
pressure through decreasing contractile strength of the heart while its S- isoform contains all β1-adrenergic receptor an-
and its rate, and consequently, it can reduce cardiac output. tagonist effects [31].
These mechanisms of action allow for their use in patients
suffering from hypertension, angina and post-myocardial In this sense, the same selectivity for β1-adrenoreceptors
over β2 analogs was observed for atenolol, which demon-
infarction. However, the use of propranolol is not indicated
strated similar antagonistic effect as practolol to antagonize
for diabetics or patients with specific lung pathologies, such
isoprenaline-induced increase in heart rate in vivo. In addi-
as asthma or chronic obstructive pulmonary disease.
tion, when its ability to antagonize the vasodilator effect of
5. SECOND GENERATION OF β-BLOCKERS isoprenaline was measured, atenolol was shown to be less
potent than propranolol. Studies in vitro showed that propra-
Based on the non-selective β-blockers structures, Dunlop nolol and atenolol both displayed comparable potencies as
and Shanks studied several compounds until practolol (4-(2- antagonists of the chronotropic effects induced by isoprena-
hydroxy-3 isopropylaminopropoxy) acetanilide) has been line, while atenolol was shown to be less potent than propra-
found in 1968 [40]. At this moment, the authors observed nolol in antagonizing isoprenaline-induced tracheal relaxa-
that some compounds as N-isopropylmethoxamine and di- tion. These findings demonstrate a cardioselectivity for
methyl isopropylmethoxamine blocked β-receptor in canine members of the second generation of β-blockers in compari-
peripheral blood vessels, suggesting that this response could son to those from the first generation [41].
be associated to compounds which presented a metal
attached to the alpha carbon. Different from these molecules, Regarding its pharmacokinetic properties, atenolol is a
practolol presents a benzylacetamide in para- position, char- hydrophilic drug with an absorption rate around 50%. It has
acterizing the first β-blocker that displayed selectivity for β1 - a half-life in the range of 5–8 hours and it is eliminated pri-
adrenergic receptors (Fig. 1) [40]. As propranolol, practolol marily by the kidneys without any biotransformation where
presents one chiral center, constituting a racemic mixture of one finds it in urine in its original form [28]. Nobre et al.
R- and S-enantiomers, which the R-stereoisomer (R- con- evaluated its antihypertensive effect at 90 mg/kg using the
figuration at the hydroxyl) has no pharmacological effect two-kidney-one-clip (2K1C) hypertension model, and they
while its S- isoform contains all β1-adrenergic receptor an- compared the effects of this β-blocker with other anti-
tagonist effects [31]. hypertensives, such as hydrochlorothiazide (at 20 mg/kg)
and losartan (at 10 mg/kg). After fifteen days of treatment, a
In this sense, Dunlop and Shanks showed that when prac- reduction in blood pressure was observed for all these drugs,
tolol was infused for 30 minutes (1-100 μg/kg/min) it was but atenolol also showed decreased heart rate [42]. A treat-
able to antagonize the effect of isoprenaline (0.2 μg/kg/min) ment of atenolol (25-100 mg) was also administered to pa-
and decrease heart rate, and at 0.5 mg/kg it counteracted the tients submitted to three weekly dialysis sessions, which
increase in contraction frequency and contraction strength of produces an increase in blood pressure by increased sympa-
the cardiac muscle caused by the agonist. Practolol was also thetic activation and activity of the renin-angiotensin system.
shown to antagonize the effects of propranolol (1-25 In this scenario, atenolol was administered after each dialysis
μg/kg/min) and pronethalol (4-100 μg/kg/min), both repre- session for a period of twelve months with evaluations con-
sentatives of first-generation β-blockers. However, practolol ducted every three months, and the drug was shown to lower
did not antagonize isoprenaline-induced hypotension, sug-
systolic and diastolic blood pressures. This indicated that the
gesting a cardioselectivity for β1-adrenergic receptors. To
antihypertensive effect of atenolol is related to its ability to
test this hypothesis, isoprenaline (0.1 mg/kg) was adminis-
reduce cardiac output and its activity on the renin
tered in conjunction with either propranolol (0.1-0.4 mg/kg)
angiotensin system [43].
or practolol (1-4 mg/kg), followed by the administration of
histamine, which causes bronchoconstriction. The animals In addition, atenolol also showed beneficial effects in
that received treatment with propranolol followed by hista- individuals with angina. Tardif et al. evaluated the effect of
mine died, demonstrating that propranolol antagonizes the this second-generation β-blocker at a dose of 50 mg for one
bronchodilator effect of isoprenaline, thereby favoring the month followed by treatment with the same dose of 100 mg
bronchoconstricting response of histamine. Conversely, ani- for three months. Both doses of atenolol were able to reduce
mals that received treatment with practolol survived because heart rate during physical evaluation and repose. Addition-
Three Generations of β-blockers Current Hypertension Reviews, 2019, Vol. 15, No. 1 27

ally, treatment with atenolol at both doses reduced the num- ity rate in patients treated with metoprolol when compared to
ber of weekly angina attacks and it was shown to increase those in the placebo group. Additionally, other parameters
the patient’s physical resistance during exercise assessment were observed including a lower risk of death associated
as well, based on the increasing length of the exercise and with cardiovascular events, a decreased risk of sudden death
time it took for the patient to develop an angina attack. The and a lower risk of death associated with worsening conges-
beneficial effects of atenolol are due to its ability to reduce tive heart failure. These responses are directly linked to the
both heart rate and contractile force, and consequently de- ability of metropolol in reducing the energy demands of the
crease the oxygen demands by the heart muscle [44]. heart muscle, which are accompanied by a decrease in ven-
tricular remodeling and reduction of ventricular dysfunction
Metoprolol, a third representative of second-generation
aggravations [49].
β-blockers was presented in 1973 by Ablad et al. [45]. This
β1-adrenergic receptor antagonist was developed based on These findings show that second-generation β-adrenergic
alprenolol structure (1-(2-allylphenoxy)-3-isopropylamino- antagonists have β1-receptor selectivity. As such, they are
propan-2-ol), a non-selective β-blocker not approached in involved in reducing cardiac contractile strength and rate,
this review. A series of meta- and para- analogues of leading to a decrease in cardiac output, and they are involved
alprenolol were studied and para- compounds demonstrated in lowering the activation of the rennin-angiotensin system
a higher affinity to β1-adrenergic receptor than β2 isoform. as well, which also cooperates to reduce blood pressure.
This finding led to the synthesis of a variety of para- Thus, representatives of second-generation β-blockers are a
substituted phenoxy-isopropylaminopropanols with featured useful pharmacological choice in the treatment of hyperten-
for metoprolol therapeutic effects (Fig. 1) [45]. Metoprolol is sion, angina and congestive heart failure, with less risk of
also composed by on chiral center constituting a racemic adverse effects associated with β2-receptor antagonism.
mixture of R- and S-enantiomers, which the R-stereoisomer
(R- configuration at the hydroxyl) has no pharmacological 6. THIRD GENERATION OF β-BLOCKERS
effect while its S- isoform contains all β1-adrenergic receptor
antagonist effects [31]. In 1972, Farmer et al., described for the first time the
characteristics of labetalol (5- {1-hydroxy-2- [(1-methyl-3-
In this sense, metoprolol also showed similar potency to phenylpropyl) amino] ethyl} salicylamide), a molecule that
propranolol in antagonizing increased frequency and cardiac is chemically related to AH3474 (5-(2-t-butylamino-1-
contractile force induced by isoprenaline (0.1 μg/kg). hydroxyethyl) salicylamide) which is a β-receptor antagonist
Metoprolol also showed a comparatively lower potency than with less potency than propranolol [50]. Labetalol has 2
propranolol in antagonizing the vasodilating and chiral centers which results in four stereoisomers with RR-
bronchodilating effects of isoprenaline. The cardioselectivity responsible for β1-blocking effect, while SR- is responsible
of metoprolol for β1-receptors was established after these for α1-blocking activity (Fig. 1) [31].
experiments [45]. The main pharmacokinetic properties of
metoprolol include lipophilicity, high absorption rate, In 1975, Kennedy and Levy demonstrated that labetalol,
extensive first-pass metabolism and an elimination half-life the first representative of the third-generation of β-blockers,
of 3 to 4 hours [28]. antagonized isoprenaline-induced increase in contractile
force and heart rate. Besides β-adrenergic antagonism, labe-
Ljung et al. studied the antihypertensive effects of me- talol showed α1-adrenergic antagonist effect. They also re-
toprolol in spontaneously hypertensive rats (SHR). The ani- ported that labetalol (1mg/kg) shifted the diastolic pressure
mals showed a blood pressure reduction after oral treatment curve for phenylephrine and noradrenaline, which are potent
with metoprolol (0.7 mmol/kg) for five months. The same α1-adrenergic agonists. Furthermore, it was observed that
effect was observed after administration of metoprolol intra- labetalol (3 mg/kg) reduced the hypertensive effect of
venously (15 μmol/kg) for four days and orally (0.7 noradrenaline in vivo [51]. Regarding the pharmacokinetic
mmol/kg) for thirteen days [46]. Sumbria et al. also observed characteristics, labetalol is a drug with high absorption,
an antihypertensive effect in hypertensive patients treated which undergoes an intensive first-pass metabolism and has
with metoprolol (25-200 mg). After six months of treatment, an elimination half-life in the range of 3 to 8 hours [28].
metoprolol decreased both systolic and diastolic blood pres-
sures to normal levels with no change in left ventricular Others third-generation β-blockers were developed a few
mass. These results showed an antihypertensive effect with- years later. Carvedilol (Carbazolyl-(4)-oxy)-3-(2-methoxy-
out anti-hypertrophic effect [47]. phenoxy ethyl)-amino)-propranol-(2)), a second representative
of third generation β-blockers has structural similarity to
Cocco and Chu showed that metoprolol (50-200 mg) also carazolol, an antagonist with cardiotoxicity in higher doses.
has a beneficial effect on patients with angina. Metoprolol A 2-methoxy-phenyl-ethyl residue at the aliphatic nitrogen is
treatment for twelve months reduced the number of attacks responsible for carvedilol vasodilating properties. Carvedilol
per week when compared to the placebo group. Moreover, also presents one chiral center constituting a racemic mixture
reduction of the heart rate and both systolic and diastolic in which the S- stereoisomer presents β1-adrenergic receptor
blood pressures at rest and during physical evaluation were antagonism, while R- and also S-stereoisomer blockade α1
also observed, and so was an increase in total exercise length receptor (Fig. 1) [31].
and in exercise duration prior to an angina attack [48].
In this sense, in 1982, Bartsch et al. showed that carve-
Merit also studied the use of metoprolol in patients with dilol was a potent β-adrenergic antagonist that also blocked
congestive heart failure. His findings showed a lower mortal- α1-adrenergic receptors [52]. Carvedilol is a lipophilic drug
28 Current Hypertension Reviews, 2019, Vol. 15, No. 1 do Vale et al.

Three Generations
1962 1968 1975

1st Generation 2nd Generation 3rd Generation

• Non-selective
N l ti β • β1 antagonism; • Variable β-antagonism;
antagonism;
• Strength and heart • Strength and heart rate;
• Strength and heart rate; rate;
• Cardiac output
• Cardiac output; • Cardiac output;
• RAS
• RAS; • RAS;
• Peripheral vascular
• Blood pressure; • Blood pressure; resitance
• Treatment: Hipertension, • Treatment: • Blood pressure
Angina, Heart attack Hipertension,
• Other effects
• Bronchoconstriction; Angina, Congestive
heart failure
• Risk for diabetics
Fig. (2). Summary of the evolution of β-blockers and their basic differences. The therapeutic effects and disadvantages of first-generation
β-blockers relative to the second and third generations are shown in bold. For second-generation β-blockers, therapeutic effects and advan-
tages over representatives of the first generation are shown in bold. Finally, the therapeutic effects and activity on β1-adrenergic receptor are
shown in bold for the third-generation β-blockers as an advantage over the two previous generations.

with a high absorption rate which undergoes extensive first- four months had their antioxidant enzyme activities in-
pass biotransformation and has an elimination half-life in the creased, such as superoxide dismutase, catalase and glu-
range of 7-10 hours [28]. tathione peroxidase [57]. This antioxidant effect showed by
third-generation β-blockers is not observed in treatments
Eggertsen et al. treated hypertensive patients with third- with representatives of the second generation [58].
generation antagonist at 25 mg and they observed a rapid
reduction of both systolic and diastolic blood pressures in Zepeda et al. described that the antihypertensive effect of
conjunction with a steep reduction in peripheral vascular carvedilol (12.5mg for twelve weeks) was accompanied by
resistance. The latter would turn out to be a peculiar charac- an improvement in endothelial function, which was inde-
teristic of third-generation β-blockers, and it is associated pendent of increased plasma NO levels but rather associated
with the representatives of this class to act as antagonists to with a reduction in oxidative stress, represented by decreased
α1-adrenergic receptors [53]. plasma levels of 8-isoprostane and erythrocyte malondialde-
hyde [59]. Le et al. also observed that carvedilol displayed
Sabellek et al. treated hypertensive individuals with ei-
antioxidant effects. In the latter study, the effect of carvedilol
ther two doses of carvedilol daily for twelve months or a
was compared to that of metoprolol in animals subjected to
single dose for six months and they noticed a reduction of
congestive heart failure. Carvedilol showed anti-
both systolic and diastolic blood pressures to normal levels.
hypertrophic, anti-fibrotic and pro-angiogenic effects. Both
More importantly, carvedilol reduced blood pressure within metoprolol and carvedilol reduced blood pressure, but me-
two hours of its administration. This response was main-
toprolol did not show the extra β -adrenergic effects dis-
tained for 24 hours, a characteristic not observed for β-
played by third-generation β -blockers [60]. Jonsson et al.
blockers of the first and second generations [54]. More re-
compared the effects of carvedilol and atenolol in patients
cently, Chen et al. studied the effects of carvedilol in hyper-
with acute myocardial infarction. Although both drugs re-
tensive rats. After eight weeks of treatment at 25 mg/kg, it
duced systolic and diastolic blood pressures as well as heart
was observed that carvedilol administration reduced blood rates to normal levels, carvedilol showed a stronger antioxi-
pressure independently of NOS activation. These researchers
dant action than atenolol, highlighting the clinical superiority
also showed that carvedilol treatment produced anti-fibrotic
of third-generation β-blockers [61].
and protective effects on the myocardial structure in these
animals [55]. Nebivolol is the latest third-generation β -blocker and it
was introduced in 1988 by Van de Waters et al. [62]. This is
Kaski et al. reported the beneficial effects of carvedilol
the only antagonist which differs completely from the mo-
(25 mg) in patients with angina. Treatment with carvedilol lecular structure of propranolol [31, 62]. Nebivolol (1-(6-
for one week reduced the rate of angina attacks, accompa-
fluorochroman-2-yl)-2-[2-(6-fluorochroman-2-yl)-2-
nied by an increase in physical resistance during exercise
hydroxyethylamino] ethanol), presents 4 chiral centers, while
evaluation. This beneficial effect of carvedilol is associated
the others β -blockers contain only 1 or 2. Surprisingly, dif-
with its ability to decrease the cardiac contractile force and
ferent from the majority of β-blockers, nebivolol presents β 1
rate with a consequent reduction of the demands of the heart
antagonistic effect in SRRR-enantiomer, while SSSR- acts as
muscle for oxygen [56]. Kowalski et al. also showed that a vasodilator (Fig. 1) [31].
angina patients treated with carvedilol at 25 and 50 mg for
Three Generations of β-blockers Current Hypertension Reviews, 2019, Vol. 15, No. 1 29

In low concentrations, nebivolol has been shown to an- atenolol for six months, after switched to nebivolol. Upon
tagonize the effects of increasing heart rate caused by iso- switch to the β-adrenergic antagonist, erectile function was
prenaline although comparatively higher doses of nebivolol observed to improve in twenty of these patients, with eleven
were needed to antagonize the relaxant effects of the tracheal individuals later reporting normalization of this function
smooth muscle, showing that nebivolol displayed a high se- [72]. When treated with metoprolol for twelve weeks,
lectivity for β1-adrenergic receptors. In addition, nebivolol Brixius et al. observed that hypertensive patients with a his-
was able to decrease blood pressure in hypertensive rats at tory of erectile dysfunction actually displayed decreased
lower doses to those of propranolol and atenolol, representa- erectile function, based on the International Dysfunction
tives of the first and second generation of β-blockers, respec- Index Scale Function. Conversely, patients treated with ne-
tively. The antihypertensive response was associated with bivolol did not present alterations of erectile function [73].
rapid lowering of peripheral vascular resistance, a peculiar
characteristic of third-generation β-blockers. Regarding its Based on these findings, nebivolol is recommended for
treatment of hypertension and heart attacks, with or without
pharmacokinetic properties, nebivolol is a well-absorbed
congestive heart failure. Furthermore, although other β-
drug and undergoes extensive first-pass biotransformation.
adrenergic antagonists are not usually considered first choice
Its elimination half-life is around twelve hours and occurs
in the treatment of hypertension [74, 75], nebivolol has been
mainly through feces (44%) and urine (37%) [63]. Based on
shown to have a similar efficacy to calcium channels block-
its pharmacological characteristics, several clinical trials
have evaluated its antihypertensive effect with doses ranging ers, antagonists of AT1 receptors and angiotensin converting
enzyme (ACE) inhibitors in reducing both systolic and dia-
from 5 to 40 mg per day. In these studies, reduction of both
stolic blood pressures in adults with mild to moderate hyper-
systolic and diastolic blood pressures was observed, consoli-
tension [76-78].
dating its antihypertensive effect [64-66].
In summary, third-generation β-blockers have beneficial
In 2014, Zang et al. showed beneficial effects of nebivo-
effects in patients with cardiovascular diseases when com-
lol in mice that were subjected to acute myocardial infarc-
tion. Treatment with nebivolol for four weeks reduced fi- pared to the representatives of previous two generations.
Nebivolol and carvedilol are able to reduce peripheral vascu-
brous tissue, decreased the diameter of the left ventricle at
lar resistance expediently and thereby lower cardiac work,
end-systole and diastole, improved ejection fraction and car-
which is accompanied by a decrease in oxygen demands by
diac shortening, and showed anti-apoptotic effect in cardio-
the heart muscle. In addition, representatives of the third
myocytes. These protective effects of nebivolol were all as-
generation of β-blockers exhibit angiogenic, anti-
sociated with β3-adrenergic receptors and they were accom-
panied by activation of NOS [67]. hypertrophic, antioxidant, antifibrotic and anti-apoptotic
effects, leading to lowering of the blood pressure, reduction
Ceron et al. compared the effects of nebivolol and me- of cardiac remodeling and decrease in endothelial and car-
toprolol in hypertensive rats. Both β-adrenergic antagonists diac dysfunction.
had antihypertensive effects but only nebivolol showed anti-
hypertrophic effects in the aortic tissue, accompanied by CONCLUSION
systemic and vascular antioxidant effect. In addition, treat- Since the development of propranolol, the selectivity of
ment with nebivolol reduced gelatinolytic activity and aortic β-blockers for β1-adrenergic receptor has been increasing
levels of the matrix metalloproteinase-2 (MMP-2) as well as with concomitant improvement of their therapeutic safety,
tissue hypertrophy. Neither of these effects was observed especially for diabetics and patients with pulmonary dys-
after treatment with metoprolol [68]. Rizzi et al. addressed functions. More recently, with the development of third-
the effects of nebivolol in the heart of hypertensive rats and generation β-blockers, antagonism of β1-adrenergic receptors
showed, much like in the previous study, that nebivolol dis- have been shown to be a part of the effects, which include
played antihypertensive, anti-hypertrophic and antioxidant reduction of peripheral vascular resistance due to α1 -
effects, whilst reducing gelatinolytic activity and cardiac adrenergic receptors, increase of eNOS activity, anti-
levels of MMP-2 [69]. hypertrophic and antioxidant properties. In this manner, the
Zepeda et al. demonstrated the beneficial effects of ne- use of nebivolol and carvedilol, as examples of third-
bivolol in hypertensive patients subjected to administrations generation β-blockers, has improved the survival rate of pa-
of 5 mg/day for twelve weeks in that it produced an im- tients suffering from hypertension, angina and congestive
provement in endothelial function, represented by an in- heart failure.
crease in dilation of the brachial artery associated with in-
creased plasma levels of NO [59]. This endothelial effect of CONSENT FOR PUBLICATION
nebivolol might be associated with increased tissue expres- Not applicable.
sion of endothelial NOS (eNOS), as observed by Zhou et al.
[70]. However, it was subsequently shown that this effect in CONFLICT OF INTEREST
particular was due to the activation of β3-adrenergic recep-
The authors declare no conflict of interest, financial or
tors [71].
otherwise.
The vasodilator effect of nebivolol, which is mediated by
an increase in NO levels, is also associated with beneficial ACKNOWLEDGEMENTS
effects in patients with erectile dysfunction. Doumas et al.
Declared none.
studied 29 hypertensive patients treated with metoprolol or
30 Current Hypertension Reviews, 2019, Vol. 15, No. 1 do Vale et al.

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