ASH SPECIAL ISSUE PAPER REVIEW PAPER b-Adrenergic Blockers William H. Frishman, MD;1 Elijah Saunders, MD2From 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, MD2Key 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 EXPERIENCESb-Blockers have been given many names in the literature(b-adrenergic–blocking agents, b-adrenergic antago- Chronic BP–Lowering Effectsnists, b-antagonists, b-adrenergic receptor antagonists). In usually prescribed dosages, b-blockers have similarWe have used the term b-blockers throughout our man- antihypertensive efﬁcacy3; however, the ﬁndings ofuscript 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 cardiovasculardocumented 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 areoral antihypertensive agent. Propranolol was also used also data to suggest that some b-blockers may haveas an adjunct therapy to phentolamine, an a-adrener- lesser effects on central aortic pressure than othergic blocker, in the treatment of pheochromocytoma.3,4 antihypertensive drug classes.14 However, b-blockersUltimately, labetalol, a combined a ⁄ b-blocker, in its remain appropriate treatments for hypertensiveintravenous 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, andAdministration (FDA) approval for oral use in patients hyperkinetic circulations (tachycardia, palpitations,with systemic hypertension (Table I). Sustained-release hypertension, anxiety).15,16formulations of metoprolol, propranolol, and carvedi- True dose equivalence among the various b-blockerslol 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 withMECHANISM OF ACTION other antihypertensives, will reduce BP in patients withThere is no consensus as to the exact mechanism(s) by combined systolic and diastolic hypertension andwhich 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 increasedAddress for correspondence: William H. Frishman, MD, Department of stroke volume caused by rate slowing in the setting ofMedicine, New York Medical College, Munger Pavilion, Room 263, increased impedance.4 Escalating doses of b-blockersValhalla, NY 10595E-mail: email@example.com and combined a ⁄ b-blockers can induce salt and water retention, requiring adjunctive diuretic therapy.4DOI: 10.1111/j.1751-7176.2011.00515.xOfﬁcial Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension 1
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 theseAbrupt discontinuation of a b-blocker, particularly variations depends on the clinical conditions presentwhen administered in high doses, may be followed by in the individual being treated. In contrast to otheradrenergically 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-blockersnary artery disease.4 Therefore, when necessary, a (Table I) translate into signiﬁcant clinical differencesstep-wise reduction in dose is advised in all high-risk in effects.3patients.4 Solubility, Elimination, and Duration of EffectsHypertensive 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 eliminationb-blocker indicated for parenteral management of hyper- routes.19 Lipid-soluble agents are eliminated primarilytensive emergencies and for treatment of intraoperative by hepatic metabolism and tend to have relatively2 The Journal of Clinical Hypertension Ofﬁcial Journal of the American Society of Hypertension, Inc.
b-Adrenergic Blockers | Frishman and Saundersshort plasma half-lives with wider variations in Combined a ⁄ b-Adrenergic–Blocking Activityplasma 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 hypertensionble, are almost completely absorbed by the small and angina pectoris. However, unlike most b-blockingintestine, and are largely metabolized by the liver. drugs, the additional a-adrenergic–blocking actions ofThey 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 higherbetween the duration of clinical pharmacologic effect levels of cardiac output.and plasma half-life may explain why these drugs canbe effective even when administered once or twice Nitric Oxide–Releasing Activitydaily.3 Differences do emerge when the duration of Nebivolol is a b1-selective blocker that has additionaleffect 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 additionalthus fail to be effective in blunting early morning rises property in a b-blocker confers greater beneﬁts has notin BP. Dose titration is effective in some patients, par- yet been determined.ticularly in those with heart rate–driven forms ofhypertension.4 OTHER APPLICATIONS The therapeutic efﬁcacy and safety of b-blockers haveExtended-Release Preparations been well established after over 40 years of clinicalExtended-release formulations of carvedilol, metopro- experience in human beings. The clinical utility oflol, and propranolol are available that allow once- b-blockers has been documented in patients withdaily dosing of these drugs. angina pectoris, cardiac arrhythmias, and congestive cardiomyopathy and for reducing the risk of mortalityb1-Selectivity and possibly nonfatal reinfarction in survivors of acuteWhen used in low doses, b1-selective–blocking agents myocardial infarction.3,23 Of course, not all of thesuch as acebutolol, betaxolol, bisoprolol, esmolol, agents in the class of b-blockers have shown beneﬁt inatenolol, metoprolol, and nebivolol inhibit cardiac each of the clinical applications listed above. Mostb1-receptors but have less inﬂuence on bronchial and antihypertensive drugs, including b-blockers, canvascular 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, andlective agents in patients with reactive airway disease, angiotensin receptor blockers.4,24 b-Blockers may bebut b1-blockers may still aggravate bronchospasm in useful as primary protection against cardiovascularcertain patients. A second theoretical advantage is that morbidity and mortality in certain hypertensiveunlike nonselective b-blockers, b1-selective blockers in patients. The drugs have also been found to be oflow doses may not block the b2-receptors that mediate use for a host of other cardiovascular and noncardiacdilatation of arterioles.3 disorders.3,19,25 b-Blockers will reduce perioperative ischemia, andISA or Partial Agonist Activity studies published in the 1990s suggested that theirCertain b-blockers are partial agonists at b1-adrenergic routine administration before surgery providedreceptor sites, b2-adrenergic receptor sites, or both.20 protection against perioperative cardiovascularThis 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 perioperativevous system is not activated (supine rest) and as a use of b-blockers as a best practice in certainblunted increase in heart rate when the sympathetic patients.29–31 However, more recent evidence has beensystem 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.32,33agonist 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 inMembrane-Stabilizing Activity two patient groups: patients undergoing vascularAt concentrations well above therapeutic levels, certain surgery who have known ischemic heart disease orb-blockers have a quinidine-like or local anesthetic multiple risk factors for it and patients who aremembrane-stabilizing activity (potentially antiarrhyth- already receiving b-blockers for cardiovascularmic) on the cardiac action potential (Table I). conditions.26–28,30,31Ofﬁcial Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension 3
b-Adrenergic Blockers | Frishman and SaundersADVERSE EFFECTS AND CONTROVERSIESCONTRAINDICATIONS The Seventh Report of the Joint National CommitteeMost b-blockers, at least in the usual antihypertensive on Prevention, Detection, Evaluation and Treatmentdose 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 theblock (greater than ﬁrst degree), and sick sinus syn- reduction of morbidity and mortality in large clinicaldrome.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) ratherwith duration of therapy.35 These drugs should be than primary prevention of events.39 The most recentused 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 channeltensive response to hypoglycemia. There is probably a blockers do not differ signiﬁcantly in their ability toshorter recovery period from hypoglycemia with b1- lower BP and to exert cardiovascular protection bothselective adrenergic blockers. b-Blockers should not be in elderly and younger patients. The apparent lack ofdiscontinued abruptly in patients with known ischemic b-blocker beneﬁt in primary prevention, especiallyheart disease. If a patient has serious contraindications reducing strokes in the elderly, has been attributed toto 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 haveLong-acting dihydropyridine and nondihydropyridine employed atenolol, once daily, which is a signiﬁcantagents are generally as effective as b-blockers in reliev- problem in study design because the half-life of theing angina. b-Blockers may increase levels of plasma drug is only 6 to 9 hours. In contrast to ischemic hearttriglycerides and reduce those of high-density lipo- disease and heart failure where heart rate reduction byprotein 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.41lipids.3 The Glycemic Effects in Diabetes Mellitus: Carvedi- Referenceslol-Metoprolol Comparison in Hypertensives (GEM- 1. Prichard BNC. Hypotensive action of pronethalol. Br Med J. 1964;INI), a study comparing the effects of carvedilol vs 1:1227–1228. 2. Prichard BNC, Gillam PMS. Use of propranolol (Inderal) in themetoprolol tartrate on glycemic and metabolic control treatment of hypertension. Br Med J. 1964;2:725–727.in participants with hypertension and diabetes already 3. Frishman WH. Alpha-and beta-adrenergic blocking drugs. In: Frish-receiving renin-angiotensin system blockade, demon- man WH, Sica DA, eds. Cardiovascular Pharmacotherapeutics, 3rd ed. Minneapolis, MN: Cardiotext Inc.; 2011:57–86.strated that carvedilol improved insulin sensitivity and 4. Frishman WH, Sica DA. b-Adrenergic blockers. In: Izzo JL Jr, Sicaglycemic control and reduced progression to microal- D, Black HR, eds. Hypertension Primer, 4th ed.: The Essentials of High Blood Pressure. Philadelphia, PA: Wolters Kluwer ⁄ Lippin-buminuria with equivalent BP lowering.36 Based on cott Williams & Wilkins; 2008:446–450.this study, it appears that the pharmacologic differ- 5. Mansoor GA, Frishman WH. Comprehensive management of hyper-ences among the b-blockers can affect the clinical util- tensive emergencies and urgencies. Heart Dis. 2002;4:358–371. 6. Messerli F, Grossman E, Goldbourt U. Are beta blockers efﬁcaciousity of these agents in hypertensive patients with as ﬁrst-line therapy for hypertension in the elderly? A systematicdiabetes. Of note, weight gain was less with carvedilol review. JAMA. 1998;279:1903–1907.than with metoprolol in GEMINI.37 7. Kaplan NM. Beta blockers in hypertension. Adding insult to injury (editorial comment). J Am Coll Cardiol. 2008;52:1490–1491. 8. MRC Working Party. Medical research council trial of treatment ofDRUG-DRUG INTERACTIONS hypertension in older adults: principal results. Br Med J. 1992; 304:405–412.There are special considerations when b-blockers are 9. Lever AF, Brennan PJ. MRC trial of treatment in elderly hyperten-combined with other drugs.38 Combinations of dil- sives. Clin Exp Hypertens. 1993;15:941–952.tiazem or verapamil with b-blockers may have addi- 10. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perin-tional depressant effects on the sinoatrial and dopril as required versus atenolol adding bendroﬂumethiazide asatrioventricular nodes and may also promote negative required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Bloodinotropy. Addition of H2-blocking agents to the com- Pressure Lowering Arm (ASCOT-BPLA), a multicentre randomised controlled trial. Lancet. 2005;366:895–906.bination of verapamil and b-blockers can also lead to 11. Aronow WS, Fleg JL, Pepine CJ, et al. ACCF ⁄ AHA 2010 Expertmyocardial depression. Combinations of b-blockers Consensus Document on Hypertension in the Elderly. A report of the American College of Cardiology Foundation Task Force onand reserpine may cause marked bradycardia and Expert Consensus Documents, in collaboration with the Americansyncope. Combination with phenylpropanolamine, Academy of Neurology, Association of Black Cardiologists, Ameri-pseudoephedrine, ephedrine, and epinephrine can can Geriatrics Society, American Society of Hypertension, American Society of Nephrology, American Society for Preventive Cardiology,cause elevations in BP due to unopposed a receptor– and the European Society of Hypertension. J Am Coll Cardiol.induced vasoconstriction. 2011;57:2037–2114.4 The Journal of Clinical Hypertension Ofﬁcial Journal of the American Society of Hypertension, Inc.
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