7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Major side effects of beta blockers : Philip J Podrid, MD, FACC : Samuel L vy, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 15, 2023. INTRODUCTION Most of the major adverse effects of beta blocking drugs result from beta-adrenoreceptor blockade. Many signs and symptoms can therefore be induced because the beta receptors affect multiple metabolic and physiologic functions. Other reactions apparently unrelated to beta blockade can occur, but they are uncommon. The major side effects associated with the use of beta blockers will be reviewed here. Beta blocker intoxication (overdose) and the clinical use of these drugs for the treatment of arrhythmias, hypertension, myocardial infarction, and heart failure are discussed separately. (See "Beta blocker poisoning" and "Acute myocardial infarction: Role of beta blocker therapy" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker' and "Choice of drug therapy in primary (essential) hypertension".) ADVERSE CARDIAC EFFECTS Major cardiac effects caused by beta blockade include the precipitation or worsening of congestive heart failure, and significant negative chronotropy. Heart failure Beta blockers are an important component of long-term therapy for patients with chronic heart failure and reduced left ventricular systolic function, as these drugs reduce the detrimental effects of excess chronic catecholamine stimulation and downregulation of the beta receptor due to excessive sympathetic stimulation. With beta blockade, the beta receptors become upregulated and are therefore more responsive to sympathetic stimulation, an https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 1/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate important concern in patient with reduced left ventricular function and chronic heart failure. However, beta blockers may exacerbate symptoms in patients with acute decompensated heart failure or in those with preexisting myocardial dysfunction and borderline compensation, since the maintenance of cardiac output in such patients depends in part upon sympathetic drive. Hence, beta blockers should not be administered as new therapy until after heart failure is compensated. However, patients already receiving beta blockers can be continued on this therapy if there is decompensated heart failure. (See "Pharmacologic therapy of heart failure with reduced ejection fraction: Mechanisms of action", section on 'Beta blockers'.) Increased peripheral vascular resistance (and hence increase in afterload) induced by nonselective beta blockers, also may contribute to the decline in myocardial function in this setting. On the other hand, drugs with intrinsic sympathetic activity (ISA), such as pindolol or acebutolol, may be less likely to impair myocardial function [1]. Despite these concerns, only a minority of patients with stable heart failure deteriorate after the initiation of beta blocker therapy. As an example, worsening of heart failure was observed in only 6 percent of patients with chronic heart failure who were being treated with carvedilol [2]. Furthermore, long-term therapy with beta blockers is often beneficial in such patients, improving survival in patients with systolic heart failure and improving diastolic function in patients with diastolic heart failure. (See "Treatment and prognosis of heart failure with preserved ejection fraction" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) Another concern about beta blockers in patients with HF is the occurrence of other symptoms, including dizziness due to hypotension and bradycardia. One study that reviewed data from HF trials reported between 1966 and 2002 found that, although beta blockers were associated with these side effects, the absolute increase in symptoms was small and did not necessitate withdrawal of drug therapy [3]. Negative chronotropic effects Slowing of the resting heart rate and the development of sinus bradycardia is a normal response to treatment with a beta blocker. This effect is less prominent with drugs with ISA. Nevertheless, all beta blockers are relatively contraindicated in patients with symptomatic bradycardia that may be associated with sinus node dysfunction, especially if there is a further reduction in rate, unless an artificial pacemaker is present. Beta blockers also depress conduction through the atrioventricular (AV) node, potentially causing heart block. Use of a beta blocking drug can therefore lead to a serious bradyarrhythmia in patients with an underlying complete or partial AV conduction defect (ie, second- or third-degree AV block), especially if the patient is also receiving another agent that https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 2/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate impairs AV nodal conduction such as digoxin or a calcium channel blocker (ie, verapamil or diltiazem). Compounds with ISA may cause less impairment of AV conduction [4]. Beta blocker withdrawal Acute withdrawal of a beta blocker can lead to substantial morbidity and even mortality [5]. The most important concern with beta blocker withdrawal is the exacerbation of ischemic symptoms, including the precipitation of an acute myocardial infarction, in patients with known coronary artery disease. In some cases there may be the precipitation of serious ventricular tachyarrhythmia, including sudden cardiac death [6-8]. This can occur even in patients who have no previous history of coronary symptoms [8]. These withdrawal symptoms are due to increased sympathetic activity, which is a probable reflection of adrenergic receptor upregulation during the period of sympathetic blockade [9]. Upregulation of beta receptors results in an increase in beta receptor responsiveness to circulating catecholamines. The degree to which this will occur depends upon the relationship between the rate at which beta blockade wears off and the rate at which the receptors downregulate (the latter has a half-life of 24 to 36 hours) [10]. Thus, a hyperadrenergic state is most likely with short-acting drugs (such as propranolol), since receptor upregulation will persist after the antihypertensive effect has disappeared [5,10]. Gradual tapering of the propranolol dose will diminish the risk of withdrawal [7]. In comparison, withdrawal syndromes are relatively unusual with longer-acting agents (such as atenolol or nadolol) [5,10]. Although data about the timing of beta blocker withdrawal are not available, we use the following approach in patients who must stop taking a beta blocker: For beta blockers with shorter half-lives which require administration two or more times per day (eg, propranolol, short acting metoprolol, carvedilol), we have patients take their usual dose once daily for one week, then every other day for one week, then stop the medication. For beta blockers with longer half-lives that are administered once daily (eg, atenolol, long acting metoprolol, nadolol), we have patient take one-half their usual dose once daily for one week, then one-half their usual dose every other day for a week, then stop the medication. However, beta blocker withdrawal can be accomplished in less time if necessary, usually by taking one-half the usual dose every other day for a week. ADVERSE NONCARDIAC EFFECTS DUE TO BETA BLOCKADE The lungs, peripheral blood vessels, glucose metabolism, and central nervous system are all affected by beta blockade although the clinical magnitude of the last three effects seems less https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 3/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate pronounced than originally thought. Increased airways resistance Beta blockade with nonselective agents prevents bronchodilation due to bronchial beta-2 receptors [11]. This can lead to increased airways resistance in patients with bronchospastic disease, a problem that is less likely to occur with compounds with ISA or beta-1 selectivity [12-14]. Beta-1 selectivity is not absolute, however, and may diminish at higher doses. It has also been suggested that combined beta and alpha blockade with labetalol or carvedilol may be better tolerated than nonselective agents in patients with chronic lung disease [15]. All beta blockers should be avoided in patients with severe or decompensated bronchospastic disease; nonselective beta blockers should generally be avoided in susceptible patients with mild to moderate bronchospastic disease, while the selective beta blockers or possibly combined alpha and beta blockers appear to be safe and should be used with caution. Therapeutic doses of beta-1 selective beta blockers are generally well tolerated, although some patients who are using inhaled beta agonists may require an increase inhaler requirement [16]. This issue of beta blocker therapy in patients with chronic obstructive disease is discussed more fully elsewhere. (See "Management of the patient with COPD and cardiovascular disease", section on 'Treatment of CVD in patients with COPD'.) Exacerbation of peripheral artery disease Initial studies with nonselective beta blockers (eg, propranolol) in patients with severe peripheral artery disease described a variety of complications including worsening claudication, cold extremities, absent pulses, and, in some cases, cyanosis and impending gangrene [17]. Raynaud's phenomenon can also be a manifestation of nonselective beta blockade [18,19]. It was thought that both the reduction in cardiac output and blockade of beta-2-receptor-mediated vasodilation of vessels within skeletal muscle contribute to the vascular insufficiency [20]. Beta blockers with beta-1 selectivity or ISA do not affect the peripheral vessels to the same degree as the nonselective drugs. A meta-analysis of published studies in patients with mild to moderate peripheral artery disease found no exacerbation of symptoms with beta blockers [21]. Thus, the concern may be overstated, particularly in patients with mild to moderate disease treated with a beta-1 selective agent [22]. Although selective agents can also be used in patients with severe disease, they should be used cautiously [23]. (See "Management of claudication due to peripheral artery disease".) Facilitation of hypoglycemia Epinephrine, acting via the beta-adrenergic receptors, has important effects on glucose metabolism. It increases glucose production by stimulating both glycogenolysis and gluconeogenesis from amino acids, glycerol, and pyruvate. It also increases https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 4/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate the delivery of these gluconeogenic substrates from the peripheral tissue, inhibits glucose utilization by several tissues, and, via the alpha-2-receptors, inhibits insulin secretion. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".) All of these actions help to protect against the development of hypoglycemia. In addition, epinephrine induces early warning symptoms of neuroglycopenia, such as sweating and anxiety. Studies published in the 1960s showed that nonselective beta blockers can retard recovery from insulin-induced hypoglycemia [24] and that the reactions are more likely to be severe [25,26]. The latter effect is presumably due to diminished or absent early warning signs [27,28]. However, later studies showed that the effects on glucose metabolism may be less prominent with beta-1 selective drugs and those with ISA [29,30] and that an increased risk of serious hypoglycemia among patients with diabetes mellitus was hard to demonstrate [30]. Furthermore, carvedilol appears to promote glucose utilization and lower insulin levels in patients with type 2 diabetes [31]. Hyperkalemia Catecholamines have potentially important clinical effects on potassium balance, primarily by influencing the distribution of potassium between the extracellular fluid and the cells. In particular, stimulation of the beta-2-receptors by epinephrine promotes the movement of extracellular potassium into the cells, thereby lowering the plasma potassium concentration. (See "Causes of hypokalemia in adults", section on 'Elevated beta-adrenergic activity'.) These effects on potassium balance can be reversed by beta-adrenergic blockers, which will tend to impair potassium entry into the cells, thereby raising the plasma potassium concentration after a potassium load. This is most likely to occur with the nonselective beta blockers (such as propranolol or labetalol); in contrast, the beta-1 selective agents such as atenolol or metoprolol have little effect, since the beta-2 receptors remain intact [32,33]. In most cases, the administration of beta blockers is associated with only a minor elevation in the plasma potassium concentration of less than 0.5 meq/L, as the potassium that cannot enter the cells is excreted in the urine. True hyperkalemia is rare unless associated with a superimposed problem such as a marked potassium load, marked exercise (which is associated with the release of potassium from the cells into the extracellular fluid), hypoaldosteronism, heart failure exacerbation (with the potential for renal insufficiency due to a decreased cardiac output and reduced renal perfusion), or end-stage kidney disease [34-36]. Hyperkalemia has also been reported in renal transplant recipients treated with labetalol [37]. (See "Causes and evaluation of hyperkalemia in adults", section on 'Beta blockers'.) https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 5/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Depression, fatigue, sexual dysfunction Depression, fatigue, and sexual dysfunction are commonly cited side effects of beta blockers, and may be one reason why use of beta blockers is lower than desired for some approved indications [38]. However, these associations are primarily based upon case series and randomized trials with methodologic flaws. The best available data on this issue come from a systematic review of randomized trials, which found no increased risk of depression with beta blocker therapy, and only small increases in fatigue and sexual dysfunction [39]. The review included 15 randomized, placebo-controlled trials involving more than 35,000 patients who were followed for a minimum of six months. Both patient reported symptoms and withdrawal of therapy were investigated. The following findings were reported: There was a small significant increase in risk of fatigue (18 per 1000 patients, 95% CI 5-30). This is equivalent to one additional report of fatigue for every 57 patients treated per year. There was a small significant increase in risk of sexual dysfunction (5 per 1000 patients, 95% CI 2-8). This is equivalent to one additional report of sexual dysfunction for every 199 patients treated per year. There was no significant annual increase in risk of reported depressive symptoms. It has been hypothesized that lipophilic drugs (eg, propranolol, metoprolol) ( table 1) are associated with a higher incidence of central nervous system effects such as fatigue and depression because of their ability to penetrate the central nervous system. However, lipid solubility of the beta blockers did not affect the risk of adverse effects in this review. In trials testing early generation beta blockers (propranolol, timolol), the risk of fatigue, but not depression or sexual dysfunction, was higher (relative risk 1.78, 95% CI 1.08-2.93) when compared with later generation beta blockers. However, the number of trials was small and the confidence intervals were wide. One small study of 96 patients treated with atenolol suggested that erectile dysfunction was possibly related to knowledge about this as a side effect and the anxiety provoked rather than as a direct consequence of the drug [40]. In addition, among those who developed erectile dysfunction, sildenafil and placebo were equally effective as therapy. Thus, although beta blockers appear to cause small increases in the risk of fatigue and sexual dysfunction, the risk is much lower than previously thought, and beta blockers should not be withheld based upon concerns about developing these adverse effects. https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 6/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Lipid metabolism Beta blockers interfere with lipid metabolism and are associated with alteration of serum triglyceride and HDL-cholesterol concentrations. The effect varies based on the receptor selectivity and pharmacologic profile of each individual agent. This is discussed in greater detail separately. (See "Antihypertensive drugs and lipids", section on 'Beta blockers'.) Weight gain A systematic review of eight randomized trials of beta blockers versus placebo in hypertensive patients revealed a median increase in body weight in the beta blocker group of 1.2 kg (range -0.4 to 3.5 kg) [41,42]. Most of this weight gain occurred within the first few months. ADVERSE EFFECTS UNRELATED TO BETA BLOCKADE The major side effects unrelated to beta blockade are drug interactions and severe toxicity. The latter condition is most commonly associated with suicide attempts and accidental overdosing. Drug interactions The combined use of beta blockers and other agents can result in a number of adverse interactions ( table 2). Drugs that depress myocardial function or pacemaker activity, including calcium channel blockers and some antiarrhythmic agents which have negative inotropic effects (ie, disopyramide, propafenone, flecainide), are of particular concern when used in combination therapy with a beta blocker. These combinations are common in patients with ischemic heart disease and arrhythmias, who often have underlying abnormalities of myocardial function as well as depressed sinus and AV node activity. Additional information can also be found using the Lexicomp drug interactions tool. Antinuclear antibodies Beta blockers have also been associated with the development of antinuclear antibodies [43]. A cross-sectional study of 1500 hypertensive patients found a prevalence of antinuclear antibodies of more than 10 percent in those receiving atenolol, labetalol, and acebutolol [44]. However, rheumatic symptoms (generally persistent arthralgias and myalgias) are infrequent. ANA titers and symptoms resolve after the cessation of therapy. OVERDOSE Attempted suicide or accidental overdose with beta blockers can result in bradycardia, hypotension, low cardiac output, cardiac failure, and cardiogenic shock [45,46]. Bronchospasm and respiratory depression may also occur due perhaps to severe circulatory impairment or a central drug effect. The myocardium in severe intoxications may become relatively refractory to pharmacologic and electrical stimulation, resulting in asystolic death. Changes in mental status, convulsions, and coma have also been described. https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 7/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Sotalol intoxication differs from that seen with other beta blockers as this agent also has class III antiarrhythmic effects and can prolong time for membrane repolarization and refractoriness. This results in prolongation of the QT interval and may contribute to ventricular tachyarrhythmias, typically a type of polymorphic VT known as torsades de pointes. Intoxicated patients should be managed with intensive supportive care in facilities equipped for continuous cardiac monitoring and ventilatory support. (See "Beta blocker poisoning" and "Clinical uses of sotalol", section on 'Major side effects'.) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topic (see "Patient education: Side effects from medicines (The Basics)") Basics topic (see "Patient education: Side effects from medicines (The Basics)") SUMMARY AND RECOMMENDATIONS Major cardiac effects caused by beta blockade include the precipitation or worsening of congestive heart failure, and significant negative chronotropy. Adverse cardiac effects Heart failure Beta blockers may exacerbate heart failure (HF) in patients with decompensated HF. Beta blockers may also precipitate HF in those with preexisting myocardial dysfunction and borderline compensation since the maintenance of cardiac output in such patients depends in part upon sympathetic drive. Increased peripheral https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 8/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate vascular resistance, induced by nonselective beta blockers, also may contribute to the decline in myocardial function in this setting. (See 'Heart failure' above.) Negative chronotropic effects Beta blockers are relatively contraindicated in patients with symptomatic bradycardia that may be associated with a sinus node dysfunction, especially if there is a further reduction in rate. Beta blockers also depress conduction through the AV node, potentially leading to a serious bradyarrhythmia in patients with an underlying complete or partial AV conduction defect (ie, second or third degree AV block). This is especially true if the patient is also receiving another agent that impairs AV nodal conduction such as digoxin or a calcium channel blocker (ie, verapamil or diltiazem). (See 'Negative chronotropic effects' above.) Beta blocker withdrawal Acute withdrawal of a beta blocker can lead to increased sympathetic activity (most likely with short-acting drugs). This hyperadrenergic state may lead to accelerated angina, myocardial infarction, or even sudden death. Although no data are available, we use the following approach in patients who must stop taking a beta blocker (see 'Beta blocker withdrawal' above): For beta blockers with shorter half-lives which require twice daily administration (eg, propranolol, short acting metoprolol, carvedilol), we have patients take their usual dose once daily for one week, then every other day for one week, then stop the medication. For beta blockers with longer half-lives that are administered once daily (eg, atenolol, long acting metoprolol, nadolol), we have patient take one-half their usual dose once daily for one week, then one-half their usual dose every other day for a week, then stop the medication. However, beta blocker withdrawal can be accomplished in less time if necessary, usually by taking one-half the usual dose every other day for a week. Adverse noncardiac effects While beta blockers have many noncardiac effects, their effects on the lungs, energy levels, and sexual function are the most common and may be significant. Increased airway resistance Beta blockade with nonselective agents prevents bronchodilation due to bronchial beta-2 receptors, leading to increased airway resistance in patients with bronchospastic disease. While therapeutic doses of beta-1 selective beta blockers are generally well tolerated and can be safely used in most patients, the risks and benefits should be considered prior to initiating treatment in https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 9/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate patients with severe or decompensated bronchospastic airway disease. (See 'Increased airways resistance' above.) Depression, fatigue, and sexual dysfunction are commonly cited side effects of beta blockers. However, a systematic review of randomized trials found no increased risk of depression with beta blocker therapy, and only small increases in fatigue and sexual dysfunction. As such, while the occasional patient may need to discontinue a beta blocker because of one of these side effects, beta blockers should not be initially withheld based upon concerns about developing these adverse effects. (See 'Depression, fatigue, sexual dysfunction' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Taylor SH, Silke B, Lee PS. Intravenous beta-blockade in coronary heart disease: is cardioselectivity or intrinsic sympathomimetic activity hemodynamically useful? N Engl J Med 1982; 306:631. 2. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996; 334:1349. 3. Ko DT, Hebert PR, Coffey CS, et al. Adverse effects of beta-blocker therapy for patients with heart failure: a quantitative overview of randomized trials. Arch Intern Med 2004; 164:1389. 4. Frishman WH. Drug therapy. Pindolol: a new beta-adrenoceptor antagonist with partial agonist activity. N Engl J Med 1983; 308:940. 5. Houston MC. Abrupt cessation of treatment in hypertension: consideration of clinical features, mechanisms, prevention and management of the discontinuation syndrome. Am Heart J 1981; 102:415. 6. Miller RR, Olson HG, Amsterdam EA, Mason DT. Propranolol-withdrawal rebound phenomenon. Exacerbation of coronary events after abrupt cessation of antianginal therapy. N Engl J Med 1975; 293:416. 7. Rangno RE, Nattel S, Lutterodt A. Prevention of propranolol withdrawal mechanism by prolonged small dose propranolol schedule. Am J Cardiol 1982; 49:828. 8. Psaty BM, Koepsell TD, Wagner EH, et al. The relative risk of incident coronary heart disease associated with recently stopping the use of beta-blockers. JAMA 1990; 263:1653. https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 10/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate 9. Lefkowitz RJ, Caron MG, Stiles GL. Mechanisms of membrane-receptor regulation. Biochemical, physiological, and clinical insights derived from studies of the adrenergic receptors. N Engl J Med 1984; 310:1570. 10. Krukemyer JJ, Boudoulas H, Binkley PF, Lima JJ. Comparison of hypersensitivity to adrenergic stimulation after abrupt withdrawal of propranolol and nadolol: influence of half-life differences. Am Heart J 1990; 120:572. 11. Dunlop D, Shanks RG. Selective blockade of adrenoceptive beta receptors in the heart. Br J Pharmacol Chemother 1968; 32:201. 12. Beumer, HM, Hardonk, HJ . Effects of beta-adrenergic blocking drugs on ventilatory function in asthmatics. Eur J Clin Pharmacol 1972; 5:77. 13. Singh BN, Whitlock RM, Comber RH, et al. Effects of cardioselective beta adrenoceptor blockade on specific airways resistance in normal subjects and in patients with bronchial asthma. Clin Pharmacol Ther 1976; 19:493. 14. Skinner C, Gaddie J, Palmer KN. Comparison of effects of metoprolol and propranolol on asthmatic airway obstruction. Br Med J 1976; 1:504. 15. Sirak TE, Jelic S, Le Jemtel TH. Therapeutic update: non-selective beta- and alpha-adrenergic blockade in patients with coexistent chronic obstructive pulmonary disease and chronic heart failure. J Am Coll Cardiol 2004; 44:497. 16. Khosla S, Kunjummen B, Khaleel R, et al. Safety of therapeutic beta-blockade in patients with coexisting bronchospastic airway disease and coronary artery disease. Am J Ther 2003; 10:48. 17. Frohlich ED, Tarazi RC, Dustan HP. Peripheral arterial insufficiency. A complication of beta- adrenergic blocking therapy. JAMA 1969; 208:2471. 18. Simpson FO. Beta-adrenergic receptor blocking drugs in hypertension. Drugs 1974; 7:85. 19. Zacharias FJ, Cowen KJ, Prestt J, et al. Propranolol in hypertension: a study of long-term therapy, 1964-1970. Am Heart J 1972; 83:755. 20. Lundvall J, J rhult J. Beta adrenergic dilator component of the sympathetic vascular response in skeletal muscle. Influence on the micro-circulation and on transcapillary exchange. Acta Physiol Scand 1976; 96:180. 21. Radack K, Deck C. Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials. Arch Intern Med 1991; 151:1769. 22. Thadani U, Whitsett TL. Beta-adrenergic blockers and intermittent claudication. Time for reappraisal. Arch Intern Med 1991; 151:1705. https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 11/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate 23. Heintzen MP, Strauer BE. Peripheral vascular effects of beta-blockers. Eur Heart J 1994; 15 Suppl C:2. 24. Antonis A, Clark ML, Hodge RL, et al. Receptor mechanisms in the hyperglycaemic response to adrenaline in man. Lancet 1967; 1:1135. 25. Abramson EA, Arky RA, Woeber KA. Effects of propranolol on the hormonal and metabolic responses to insulin-induced hypoglycaemia. Lancet 1966; 2:1386. 26. Reveno WS, Rosenbaum H. Propranolol and hypoglycaemia. Lancet 1968; 1:920. 27. Lloyd-Mostyn RH, Oram S. Modification by propranolol of cardiovascular effects of induced hypoglycaemia. Lancet 1975; 1:1213. 28. Hirsch IB, Boyle PJ, Craft S, Cryer PE. Higher glycemic thresholds for symptoms during beta- adrenergic blockade in IDDM. Diabetes 1991; 40:1177. 29. Deacon SP, Barnett D. Comparison of atenolol and propranolol during insulin-induced hypoglycaemia. Br Med J 1976; 2:272. 30. Shorr RI, Ray WA, Daugherty JR, Griffin MR. Antihypertensives and the risk of serious hypoglycemia in older persons using insulin or sulfonylureas. JAMA 1997; 278:40. 31. Giugliano D, Acampora R, Marfella R, et al. Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial. Ann Intern Med 1997; 126:955. 32. Reid JL, Whyte KF, Struthers AD. Epinephrine-induced hypokalemia: the role of beta adrenoceptors. Am J Cardiol 1986; 57:23F. 33. Castellino P, Bia MJ, DeFronzo RA. Adrenergic modulation of potassium metabolism in uremia. Kidney Int 1990; 37:793. 34. Lim M, Linton RA, Wolff CB, Band DM. Propranolol, exercise, and arterial plasma potassium. Lancet 1981; 2:591. 35. Arthur S, Greenberg A. Hyperkalemia associated with intravenous labetalol therapy for acute hypertension in renal transplant recipients. Clin Nephrol 1990; 33:269. 36. Nowicki M, Miszczak-Kuban J. Nonselective Beta-adrenergic blockade augments fasting hyperkalemia in hemodialysis patients. Nephron 2002; 91:222. 37. McCauley J, Murray J, Jordan M, et al. Labetalol-induced hyperkalemia in renal transplant recipients. Am J Nephrol 2002; 22:347. 38. Gheorghiade M, Eichhorn EJ. Practical aspects of using beta-adrenergic blockade in systolic heart failure. Am J Med 2001; 110 Suppl 7A:68S. 39. Ko DT, Hebert PR, Coffey CS, et al. Beta-blocker therapy and symptoms of depression, https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 12/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate fatigue, and sexual dysfunction. JAMA 2002; 288:351. 40. Silvestri A, Galetta P, Cerquetani E, et al. Report of erectile dysfunction after therapy with beta-blockers is related to patient knowledge of side effects and is reversed by placebo. Eur Heart J 2003; 24:1928. 41. Sharma AM, Pischon T, Hardt S, et al. Hypothesis: Beta-adrenergic receptor blockers and weight gain: A systematic analysis. Hypertension 2001; 37:250. 42. Leslie WS, Hankey CR, Lean ME. Weight gain as an adverse effect of some commonly prescribed drugs: a systematic review. QJM 2007; 100:395. 43. Stephen SA. Unwanted effects of propranolol. Am J Cardiol 1966; 18:463. 44. Booth RJ, Wilson JD, Bullock JY. Beta-adrenergic-receptor blockers and antinuclear antibodies in hypertension. Clin Pharmacol Ther 1982; 31:555. 45. Self-poisoning with beta-blockers. Br Med J 1978; 1:1010. 46. Frishman W, Jacob H, Eisenberg E, Ribner H. Clinical pharmacology of the new beta- adrenergic blocking drugs. Part 8. Self-poisoning with beta-adrenoceptor blocking agents: recognition and management. Am Heart J 1979; 98:798. Topic 967 Version 30.0 https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 13/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate GRAPHICS Beta blocker properties Alpha Beta-1 Half l Drug ISA MSA Lipophilicity Usual dose* blockade selectivity hour Acebutolol No Yes Yes Yes Low 100 to 400 mg 3 to 4 twice per day Atenolol No Yes No No Low 50 to 200 mg once daily 6 to 9 Betaxolol No Yes No Yes Low 10 to 20 mg once daily 14 to 22 Bisoprolol No Yes No No Moderate 2.5 to 20 mg once daily 9 to 12 Carteolol No No Yes No Low 2.5 to 5 mg once daily 6 Carvedilol Yes No No Yes High 3.125 to 25 mg twice per day 7 to 10 Esmolol No Yes No No Low IV only 250 to 500 9 minut micrograms/kg over one minute then 25 to 50 micrograms/kg per minute as IV infusion; titrate incrementally up to maximum of 300 microgram/kg per minute https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 14/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Labetalol Yes No Yes (Beta ) 2 Low Moderate IV 20 mg 3 to 4 Orally 100-400 mg two or three times per day Metoprolol tartrate No Yes No Low Moderate IV 1.25 to 5 mg 3 to 4 (7 to 9 h in poor Orally 25 to 100 mg two metabo times per day Metoprolol succinate No Yes No Low Moderate Orally 50 to 400 mg once Apparen half-life (extended daily prolong release) continu osmotic release ~20 hou Nadolol No No No No Low 40 to 160 mg 20 to 24 once daily Nebivolol No Yes No No High 5 to 40 mg once daily 10 to 12 (19 to 32 poor metabo Oxprenolol No No Yes Yes Moderate 40 to 80 mg three times per day 1.5 Penbutolol No No Yes No High 10 to 40 mg once daily 5 Pindolol No No Yes Low Moderate 5 to 30 mg 3 to 4 twice per day Propranolol No No No Yes High IV 1 to 5 mg 3 to 4 Orally 10 to 80 mg two to four times daily Sotalol No No No No Low 80 to 160 mg 12 twice per day Timolol No No No No Moderate 10 to 30 mg 4 to 5 twice per day https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 15/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate ISA: intrinsic sympathomimetic activity; MSA: membrane stabilizing activity; IV: intravenous. Range of usual, oral, anti-hypertensive dose, unless "IV" noted. Duration of hypotensive effect, in general, is longer than may be predicted by serum half-life. Usual initial IV dose. Subsequent dosing generally needed. See drug monograph for detail. Not available in US. Sotalol has independent class III antiarrhythmic activity. Prepared with data from: 1. Frishman WH, Alwarshetty M. -Adrenergic blockers in systemic hypertension pharmacokinetic considerations related to current guidelines. Clin Pharmacokinet 2002; 41:505. 2. Brubacher JR. -Adrenergic Antagonists. In: Goldfrank's Toxicologic Emergencies, 9th ed, Nelson LS (Ed), McGraw-Hill, New York 2010. Graphic 82571 Version 11.0 https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 16/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Major drug interactions with beta blockers Drug Possible effects Precautions Aluminum hydroxide gel Decreased beta-blocker Avoid beta-blocker-aluminum adsorption and therapeutic effect hydroxide combination Aminophylline Mutual inhibition Observe patient's response Amiodarone May induce cardiac arrest Combination should be used with extreme caution Antidiabetic agents Enhanced hypoglycemia; Monitor for altered diabetic response hypertension Calcium channel inhibitors Potentiation of bradycardia, Avoid use, although few patients show (verapamil, diltiazem) myocardial depression, and hypotension ill effects Cimetidine Prolongs half-life of Combination should be used with propranolol caution Clonidine Hypertension during clonidine withdrawal Monitor for hypertensive response; withdraw beta blocker before withdrawing clonidine Digitalis glycosides Potentiation of bradycardia Observe patient's response; interactions may benefit angina patients with abnormal ventricular function Epinephrine Hypertension; bradycardia Administer epinephrine cautiously; cardioselective beta blocker may be safer Ergot alkaloids Excessive vasoconstriction Observe patient's response; few patients show ill effects Glucagon Inhibition of hyperglycemic Monitor for reduced response effect Halofenate Reduced beta-blocking activity; induction of Observe for impaired response to beta blockade propranolol withdrawal rebound Indomethacin Inhibition of antihypertensive Observe patient's response response to beta blockade Isoproterenol Mutual inhibition Avoid concurrent use or choose cardiac-selective beta blocker https://www.uptodate.com/contents/major-side-effects-of-beta-blockers/print 17/19 7/5/23, 8:23 AM Major side effects of beta blockers - UpToDate Levodopa Antagonism of levodopa's hypotensive and positive Monitor for altered response; interaction may have favorable results inotropic effects Lidocaine Propranolol pretreatment increases lidocaine levels with Combination should be used with caution; use lower doses of lidocaine potential toxicity Methyldopa Hypertension during stress Monitor for hypertensive episodes MAO inhibitors Uncertain, theoretical Manufacturer of propranolol considers concurrent use contraindicated Phenothazines Additive hypotensive effects Monitor for altered response, especially with high doses of phenothiazines Phenylpropranolamine Severe hypertensive reaction Phenytoin Additive cardiac depressant effects Administer IV phenytoin with great caution Quinidine Additive cardiac depressant Observe patient's response; few effects patients show ill effects Reserpine Excessive sympathetic Observe patient's response blockade Rifampin Increased metabolism of beta blockers Observe patient's response Smoking Increased metabolism of beta blockers Observe patient's response Tricyclic antidepressants Inhibits negative inotropic and chronotropic effects of beta blockers