This document summarizes the use of beta-blockers (b-blockers) for treating hypertension. It discusses that b-blockers are appropriate for hypertension treatment, especially for patients with heart disease or arrhythmias. It also notes that b-blockers are heterogeneous in their properties and effects. The document provides details on the various types of b-blockers, their mechanisms of action, effectiveness, appropriate combinations with other drugs, and other clinical applications beyond hypertension.

1. ASH SPECIAL ISSUE PAPER
REVIEW PAPER
b-Adrenergic Blockers
William H. Frishman, MD;1 Elijah Saunders, MD2
From the Department of Medicine, New York Medical College ⁄ Westchester Medical Center, Valhalla, NY;1 and the Department of Medicine,
University of Maryland Medical Center, Baltimore, MD2
Key Points and Practical Recommendations pathomimetic activity, membrane-stabilizing activity, b1
• b-Blockers are appropriate treatment for patients with selectivity, a1-adrenergic–blocking effect, tissue solubil-
hypertension and those who have concomitant ische- ity, routes of systemic elimination, potencies and dura-
mic heart disease, heart failure, obstructive cardiomy- tion of action, and specific effects may be important in
opathy, or certain arrhythmias. the selection of a drug for clinical use.
• b-Blockers can be used in combination with other anti- • b-Blocker usage to reduce perioperative ischemia and
hypertensive drugs to achieve maximal blood pressure cardiovascular complications may not benefit as many
control. Labetalol can be used in hypertensive emer- patients as was once hoped and may actually cause
gencies and urgencies. harm in some individuals. Currently the best evidence
• b-Blockers may be useful in patients having hyperki- supports b-blocker use in two patient groups: patients
netic circulation (palpitations, tachycardia, hypertension, undergoing vascular surgery with known ischemic heart
and anxiety), migraine headache, and essential tremor. disease or multiple risk factors for it and for patients
• b-Blockers are highly heterogeneous with respect to already receiving b-blockers for known cardiovascular
various pharmacologic effects: degree of intrinsic sym- conditions. J Clin Hypertens (Greenwich). ****;**:**–**.
HISTORY OF USE CLINICAL EXPERIENCES
b-Blockers have been given many names in the literature
(b-adrenergic–blocking agents, b-adrenergic antago- Chronic BP–Lowering Effects
nists, b-antagonists, b-adrenergic receptor antagonists). In usually prescribed dosages, b-blockers have similar
We have used the term b-blockers throughout our man- antihypertensive efficacy3; however, the findings of
uscript to avoid any confusion. recent meta-analyses have demonstrated that b-block-
The antihypertensive effect of b-blockers was first ers may have less-protective effects on cardiovascular
documented by Pritchard almost half a century ago.1,2 and cerebrovascular end points than other antihyper-
Propranolol was the first b-blocker approved as an tensive drugs, especially in the elderly.6–13 There are
oral antihypertensive agent. Propranolol was also used also data to suggest that some b-blockers may have
as an adjunct therapy to phentolamine, an a-adrener- lesser effects on central aortic pressure than other
gic blocker, in the treatment of pheochromocytoma.3,4 antihypertensive drug classes.14 However, b-blockers
Ultimately, labetalol, a combined a ⁄ b-blocker, in its remain appropriate treatments for hypertensive
intravenous form, was demonstrated to be of clinical patients with concomitant ischemic heart disease,
use in the treatment of hypertensive emergencies and angina pectoris, post–myocardial infarction, left ven-
in an oral form for hypertensive urgencies.3,5 tricular dysfunction with heart failure, obstructive car-
To date, 14 b-blockers have received Food and Drug diomyopathy, arrhythmias, aortic dissection, and
Administration (FDA) approval for oral use in patients hyperkinetic circulations (tachycardia, palpitations,
with systemic hypertension (Table I). Sustained-release hypertension, anxiety).15,16
formulations of metoprolol, propranolol, and carvedi- True dose equivalence among the various b-blockers
lol have allowed these short-acting b-blockers to be has not been established, in part because few head-to-
used once daily in hypertension. head studies have been performed with individual
b-blockers. b-Blockers, alone and in combination with
MECHANISM OF ACTION other antihypertensives, will reduce BP in patients with
There is no consensus as to the exact mechanism(s) by combined systolic and diastolic hypertension and
which b-blockers lower blood pressure (BP), and it is in most patients with isolated systolic hypertension.
likely that multiple modes of action are involved Uncommonly there is a paradoxical elevation of sys-
(Table II).3 tolic pressure during b-blockade in persons with severe
aortic arteriosclerosis, presumably due to the increased
Address for correspondence: William H. Frishman, MD, Department of stroke volume caused by rate slowing in the setting of
Medicine, New York Medical College, Munger Pavilion, Room 263, increased impedance.4 Escalating doses of b-blockers
Valhalla, NY 10595
E-mail: william_frishman@nymc.edu
and combined a ⁄ b-blockers can induce salt and water
retention, requiring adjunctive diuretic therapy.4
DOI: 10.1111/j.1751-7176.2011.00515.x
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2. b-Adrenergic Blockers | Frishman and Saunders
and postoperative hypertension.5 It can also be used in
TABLE I. Pharmacodynamic Effects of b-
oral form to treat patients with hypertensive urgencies.5
Adrenergic–Blocking Drugs Used in Hypertension
b1-Blockade Relative B1 Intrinsic Combinations With Other Drugs
Potency Ratio Selectivity Sympathomimetic The antihypertensive effect of a b-blocker is enhanced
Drug (Propranolol=1.0) Activity by the simultaneous administration of a diuretic.3 The
Acebutolol 0.3 + + combination of a b-blocker with hydrochlorothiazide
Atenolol 1.0 ++ 0 doses as low as 6.25 mg have been approved along
Betaxolol 1.0 ++ 0 with an atenolol ⁄ chlorthalidone combination. b-Block-
Bisoprolola 10.0 ++ 0 ers are also useful add-on therapy in the setting of
Carteolol 10.0 0 + vasodilator-related tachycardia, as may occur with
Carvedilolb 10.0 0 0 hydralazine, minoxidil and dihydropyridine calcium
Labetalolc 0.3 0 +? entry blockers.4
Metoprolol 1.0 ++ 0
Nadolol 1.0 0 0 Patient Subgroup Responses
Nebivolold 10.0 ++ 0 There are few predictors of response to a b-blocker,
Penbutolol 1.0 0 + but b-blockers are useful in hyperkinetic forms of
Pindolol 6.0 0 ++
hypertension as in individuals with a high cardiac
Propranolol 1.0 0 0
awareness profile or somatic manifestations of anxiety,
Sotalol 0.3 0 0
such as tremor, sweating, and tachycardia.4 Although,
Timolol 0.6 0 0
there is a limited relationship between plasma renin
+ = modest effect; ++ = strong effect; 0 = no effect. aBisoprolol is activity and response to a b-blocker, certain patient
also approved as a first-line antihypertensive therapy in combination
with a very low-dose diuretic. bCarvedilol has peripheral vasodilating
subsets demonstrate lower response rates to b-blocker
activity and additional a1-adrenergic–blocking activity. cLabetalol monotherapy, including low-renin, salt-sensitive
has additional a1-adrenergic–blocking activity and direct vasodilatory individuals, such as many blacks with hypertension.4
activity (b2-agonism); it is available for use in intravenous form for
hypertensive emergencies. dNebivolol can augment vascular nitric Racial differences in the BP response to traditional
oxide release. Adapted with permission from Frishman.42 b-blockers are diminished when the drug is combined
with a thiazide diuretic or a vasodilating b-blocker,
such as labetalol, carvedilol, or nebivolol.4 For exam-
ple, nebivolol may have an antihypertensive effect in
TABLE II. Proposed Mechanisms to Explain the African Americans as monotherapy that differs from
Antihypertensive Actions of b-Blockers traditional b-blockers.17 The elderly and diabetic
1. Reduction in heart rate and cardiac output populations respond in a fairly heterogeneous fashion
2. Central nervous system inhibitor effect to b-blocker monotherapy. Certain b-blockers can be
3. Inhibition of renin release used with caution in pregnancy-related hypertension.18
4. Reduction in venous return and plasma volume
5. Reduction in peripheral vascular resistance (intrinsic HETEROGENEITY AMONG b-BLOCKERS
sympathomimetic activity drugs, a ⁄ b-blockers, b-Blockers as a group have similar therapeutic effects,
potentiation of nitric oxide) despite their structural differences.3 Their varied aro-
6. Improvement in vascular compliance matic ring structures confer many pharmacokinetic
7. Resetting of baroreceptor levels differences, including completeness of gastrointestinal
8. Effects on prejunctional b-receptors: reduction in
absorption, degree of first-pass hepatic metabolism,
norepinephrine release
lipid solubility, protein binding, volume of distribu-
9. Attenuation of pressor response to catecholamines
tion, penetration into the central nervous system,
with exercise and stress
concentration in the myocardium, rate of hepatic
Modified from Frishman.43 biotransformation, pharmacologic activity of metabo-
lites, and renal clearance.3 The relevance of these
Abrupt discontinuation of a b-blocker, particularly variations depends on the clinical conditions present
when administered in high doses, may be followed by in the individual being treated. In contrast to other
adrenergically mediated withdrawal symptoms and the classes of antihypertensive drugs, important differ-
appearance of angina pectoris in patients with coro- ences in intrinsic chemical properties of b-blockers
nary artery disease.4 Therefore, when necessary, a (Table I) translate into significant clinical differences
step-wise reduction in dose is advised in all high-risk in effects.3
patients.4
Solubility, Elimination, and Duration of Effects
Hypertensive Urgencies and Emergencies The b-blockers can be divided into two broad catego-
The combined a ⁄ b-blocker labetalol is the only ries by their solubilities, metabolism, and elimination
b-blocker indicated for parenteral management of hyper- routes.19 Lipid-soluble agents are eliminated primarily
tensive emergencies and for treatment of intraoperative by hepatic metabolism and tend to have relatively
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3. b-Adrenergic Blockers | Frishman and Saunders
short plasma half-lives with wider variations in Combined a ⁄ b-Adrenergic–Blocking Activity
plasma concentrations. Water-soluble agents that are Carvedilol and labetalol are b-blockers with antagonis-
eliminated unchanged by the kidney tend to have tic properties at both a- and b-adrenergic receptors,
longer half-lives and more stable plasma concentra- with direct vasodilator activity.3,21 Like other b-block-
tions.3 Propranolol and metoprolol are both lipid-solu- ers, they are useful in the treatment of hypertension
ble, are almost completely absorbed by the small and angina pectoris. However, unlike most b-blocking
intestine, and are largely metabolized by the liver. drugs, the additional a-adrenergic–blocking actions of
They tend to have highly variable bioavailability and carvedilol and labetalol lead to a reduction in periph-
relatively short plasma half-lives. A lack of correlation eral vascular resistance that acts to maintain higher
between the duration of clinical pharmacologic effect levels of cardiac output.
and plasma half-life may explain why these drugs can
be effective even when administered once or twice Nitric Oxide–Releasing Activity
daily.3 Differences do emerge when the duration of Nebivolol is a b1-selective blocker that has additional
effect of individual b-blockers is compared.3 Several b- vasodilator actions apparently related to an enhance-
blockers do not provide full 24-hour coverage and ment of nitric oxide activity.22 Whether this additional
thus fail to be effective in blunting early morning rises property in a b-blocker confers greater benefits has not
in BP. Dose titration is effective in some patients, par- yet been determined.
ticularly in those with heart rate–driven forms of
hypertension.4 OTHER APPLICATIONS
The therapeutic efficacy and safety of b-blockers have
Extended-Release Preparations been well established after over 40 years of clinical
Extended-release formulations of carvedilol, metopro- experience in human beings. The clinical utility of
lol, and propranolol are available that allow once- b-blockers has been documented in patients with
daily dosing of these drugs. angina pectoris, cardiac arrhythmias, and congestive
cardiomyopathy and for reducing the risk of mortality
b1-Selectivity and possibly nonfatal reinfarction in survivors of acute
When used in low doses, b1-selective–blocking agents myocardial infarction.3,23 Of course, not all of the
such as acebutolol, betaxolol, bisoprolol, esmolol, agents in the class of b-blockers have shown benefit in
atenolol, metoprolol, and nebivolol inhibit cardiac each of the clinical applications listed above. Most
b1-receptors but have less influence on bronchial and antihypertensive drugs, including b-blockers, can
vascular smooth muscles (Table I). In higher doses (eg, reduce left ventricular mass and wall thickness,
>50 mg ⁄ d of metoprolol), however, b1-selective–block- although b-blockers have been found to be less effec-
ing agents also block b2-receptors.3 Accordingly, tive in this regard than diuretics, angiotensin-convert-
b1-selective agents may be marginally safer than nonse- ing enzyme inhibitors, calcium antagonist, and
lective agents in patients with reactive airway disease, angiotensin receptor blockers.4,24 b-Blockers may be
but b1-blockers may still aggravate bronchospasm in useful as primary protection against cardiovascular
certain patients. A second theoretical advantage is that morbidity and mortality in certain hypertensive
unlike nonselective b-blockers, b1-selective blockers in patients. The drugs have also been found to be of
low doses may not block the b2-receptors that mediate use for a host of other cardiovascular and noncardiac
dilatation of arterioles.3 disorders.3,19,25
b-Blockers will reduce perioperative ischemia, and
ISA or Partial Agonist Activity studies published in the 1990s suggested that their
Certain b-blockers are partial agonists at b1-adrenergic routine administration before surgery provided
receptor sites, b2-adrenergic receptor sites, or both.20 protection against perioperative cardiovascular
This combined action manifests itself as a neu- complications.26–28 Based on these early studies, sev-
tral effect on heart rate when the sympathetic ner- eral national organizations endorsed the perioperative
vous system is not activated (supine rest) and as a use of b-blockers as a best practice in certain
blunted increase in heart rate when the sympathetic patients.29–31 However, more recent evidence has been
system is activated during the stress of exercise accumulating to suggest that routine use of b-blockers
(Table I). may not benefit as many patients as was once hoped
It is still debated whether the presence of partial and may actually cause harm in some individuals.32,33
agonist activity in a b-blocker constitutes an overall The benefit of b-blockers may be only present in high-
advantage or disadvantage in cardiac therapy.20 risk cardiac patients undergoing high-risk surgery.
Currently the best evidence supports their use in
Membrane-Stabilizing Activity two patient groups: patients undergoing vascular
At concentrations well above therapeutic levels, certain surgery who have known ischemic heart disease or
b-blockers have a quinidine-like or local anesthetic multiple risk factors for it and patients who are
membrane-stabilizing activity (potentially antiarrhyth- already receiving b-blockers for cardiovascular
mic) on the cardiac action potential (Table I). conditions.26–28,30,31
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4. b-Adrenergic Blockers | Frishman and Saunders
ADVERSE EFFECTS AND CONTROVERSIES
CONTRAINDICATIONS The Seventh Report of the Joint National Committee
Most b-blockers, at least in the usual antihypertensive on Prevention, Detection, Evaluation and Treatment
dose range, should not be used in patients with of High Blood Pressure (JNC-7) has recommended b-
asthma, reactive airway disease, acute decompensated blockers as potential first-line treatment for hyperten-
congestive heart failure with systolic dysfunction, heart sion. These recommendations were based on the
block (greater than first degree), and sick sinus syn- reduction of morbidity and mortality in large clinical
drome.3 b-blockers have been documented to increase trials, but most of the benefit related to secondary car-
the risk of new-onset diabetes34 and this risk increases diovascular protection (in established disease) rather
with duration of therapy.35 These drugs should be than primary prevention of events.39 The most recent
used with caution in insulin-dependent diabetes, European guidelines40 state that large-scale meta-anal-
because they may worsen glucose intolerance, mask yses of available trial data confirm that diuretics, b-
the symptoms of hypoglycemia, prolong recovery from blockers, angiotensin-converting enzyme inhibitors,
hypoglycemia, or increase the magnitude of the hyper- angiotensin receptor blockers, and calcium channel
tensive response to hypoglycemia. There is probably a blockers do not differ significantly in their ability to
shorter recovery period from hypoglycemia with b1- lower BP and to exert cardiovascular protection both
selective adrenergic blockers. b-Blockers should not be in elderly and younger patients. The apparent lack of
discontinued abruptly in patients with known ischemic b-blocker benefit in primary prevention, especially
heart disease. If a patient has serious contraindications reducing strokes in the elderly, has been attributed to
to b-blockers, unacceptable side effects or persistent atenolol and is probably not generalizable to all b-
angina, calcium antagonists should be administered. blockers. In this regard, almost all clinical trials have
Long-acting dihydropyridine and nondihydropyridine employed atenolol, once daily, which is a significant
agents are generally as effective as b-blockers in reliev- problem in study design because the half-life of the
ing angina. b-Blockers may increase levels of plasma drug is only 6 to 9 hours. In contrast to ischemic heart
triglycerides and reduce those of high-density lipo- disease and heart failure where heart rate reduction by
protein cholesterol.3 b-Blockers with intrinsic sympat- b-blockade diminishes the risk, heart rate in hyperten-
homimetic activity (ISA) and ⁄ or a-blocking vasodilator sion reduction with b-blockers may increase cardiovas-
activity have little or no adverse effect on plasma cular mortality and other outcomes.41
lipids.3
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