AHFS Class:

• beta-Adrenergic Blocking Agents 24:20

Generic Name(s):

• Atenolol

Atenolol is a β₁-selective adrenergic blocking agent (β-blocker).111,118,120

Atenolol is used for the management of hypertension,111,118,171,172,234,501,1200 angina,111,112 and acute myocardial infarction (MI).111,113,120,122,123,124 The drug also has been used for the management of supraventricular and ventricular tachyarrhythmias†,300,401 management of acute alcohol withdrawal (in conjunction with a benzodiazepine)†,101,229 and prophylaxis of migraine headache†.228

The choice of a β-adrenergic blocking agent (β-blocker) depends on numerous factors, including pharmacologic properties (e.g., relative β-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance.232,262,263,264,265,266,267,268,269,270,271,272,273 While specific pharmacologic properties and other factors may appropriately influence the choice of a β-blocker in individual patients,1235 evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited.262,264,265,266,267,268,269,270,271,272,273 Patients who do not respond to or cannot tolerate one β-blocker may be successfully treated with a different agent.264,265,266,267,270,272,273

In the management of hypertension or chronic stable angina pectoris in patients with chronic obstructive pulmonary disease (COPD) or type 1 diabetes mellitus, many clinicians prefer to use low dosages of a β₁-selective adrenergic blocking agent (e.g., atenolol, metoprolol), rather than a nonselective agent (e.g., nadolol, pindolol, propranolol, timolol). However, selectivity of these agents is relative and dose dependent. Some clinicians also will recommend using a β₁-selective agent or an agent with intrinsic sympathomimetic activity (ISA) (e.g., pindolol), rather than a nonselective agent, for the management of hypertension or angina pectoris in patients with peripheral vascular disease, but there is no evidence that the choice of β-blocker substantially affects efficacy.

Hypertension

Atenolol is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.108,109,110,153,154,155,156,157,158,159,171,172,501,502,503,504,515,1200β-Blockers often are used concurrently with a diuretic because of their additive effects. β-Blockers also have been combined with vasodilators (e.g., hydralazine, minoxidil) to counteract the reflex tachycardia that occurs with vasodilators.

Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).501,502,503,504,1200 Most guidelines no longer recommend β-blockers as first-line therapy for hypertension because of the lack of established superiority over other recommended drug classes and evidence from at least one study (with atenolol) demonstrating that β-blockers may be less effective than angiotensin II receptor antagonists in preventing cardiovascular death, MI, or stroke.237,501,502,503,504,515,1200 (See Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.) However, therapy with a β-blocker may still be considered in hypertensive patients who have a compelling indication (e.g., prior MI, ischemic heart disease, heart failure) for their use or as add-on therapy in those who do not respond adequately to the preferred drug classes.501,502,503,504,523,524,527,800,1200 (See Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors, under Uses: Hypertension.) Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs).501,502,503,504,515,1200,1201

General Considerations for Initial and Maintenance Antihypertensive Therapy

Nonpharmacologic Therapy

Nonpharmacologic measures (i.e., lifestyle/behavioral modifications) that are effective in lowering blood pressure include weight reduction (for those who are overweight or obese), dietary changes to include foods such as fruits, vegetables, whole grains, and low-fat dairy products that are rich in potassium, calcium, magnesium, and fiber (i.e., adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), sodium reduction, increased physical activity, and moderation of alcohol intake.1200 Such lifestyle/behavioral modifications, including smoking cessation, enhance antihypertensive drug efficacy and decrease cardiovascular risk and remain an indispensable part of the management of hypertension.502,504,1200 Lifestyle/behavioral modifications without antihypertensive drug therapy are recommended for individuals classified by a 2017 multidisciplinary hypertension guideline of the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations as having elevated blood pressure (systolic blood pressure 120-129 mm Hg and diastolic blood pressure less than 80 mm Hg) and in those with stage 1 hypertension (systolic blood pressure 130-139 mm Hg or diastolic blood pressure 80-89 mm Hg) who do not have preexisting cardiovascular disease or an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk of 10% or greater.1200

Initiation of Drug Therapy

Drug therapy in the management of hypertension must be individualized and adjusted based on the degree of blood pressure elevation while also considering cardiovascular risk factors.171,173,226,227,234,257,502,1200,1201 Drug therapy generally is reserved for patients who respond inadequately to nondrug therapy (i.e., lifestyle modifications such as diet [including sodium restriction and adequate potassium and calcium intake], regular aerobic physical activity, moderation of alcohol consumption, and weight reduction) or in whom the degree of blood pressure elevation or coexisting risk factors, especially increased cardiovascular risk, requires more prompt or aggressive therapy; however, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.504,505,506,507,508,515,523,530,1200,1201,1207,1209

The 2017 ACC/AHA hypertension guideline and many experts currently state that the treatment of hypertension should be based not only on blood pressure values but also on patients' cardiovascular risk factors.502,1200,1219 For secondary prevention of recurrent cardiovascular disease events in adults with clinical cardiovascular disease or for primary prevention in adults with an estimated 10-year ASCVD risk of 10% or higher, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at an average systolic blood pressure of 130 mm Hg or an average diastolic blood pressure of 80 mm Hg or higher.1200 For primary prevention of cardiovascular disease events in adults with a low (less than 10%) estimated 10-year risk of ASCVD, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive drug therapy in conjunction with lifestyle/behavioral modifications at a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher.1200 After initiation of antihypertensive drug therapy, regardless of the ASCVD risk, the 2017 ACC/AHA hypertension guideline generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults.1200 In addition, a systolic blood pressure goal of less than 130 mm Hg also is recommended for noninstitutionalized ambulatory patients 65 years of age or older.1200 While these blood pressure goals are lower than those recommended for most patients in previous guidelines, they are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of systolic blood pressure.1200,1202,1210

Most data indicate that patients with a higher cardiovascular risk will benefit the most from tighter blood pressure control; however, some experts state this treatment goal also may be beneficial in those at lower cardiovascular risk.1200 Other clinicians believe that the benefits of such blood pressure lowering do not outweigh the risks in those patients considered to be at lower risk of cardiovascular disease and that reclassifying individuals formerly considered to have prehypertension as having hypertension may potentially lead to use of drug therapy in such patients without consideration of cardiovascular risk.1201,1222,1223,1229 Previous hypertension guidelines, such as those from the JNC 8 expert panel, generally have recommended initiation of antihypertensive treatment in patients with a systolic blood pressure of at least 140 mm Hg or diastolic blood pressure of at least 90 mm Hg, targeted a blood pressure goal of less than 140/90 mm Hg regardless of cardiovascular risk, and used higher systolic blood pressure thresholds and targets in geriatric patients.501 Some clinicians continue to support the target blood pressures recommended by the JNC 8 expert panel because of concerns that such recommendations in the 2017 ACC/AHA hypertension guideline are based on extrapolation of data from the high-risk population in the SPRINT study to a lower-risk population.1223,1224 Also, because more than 90% of patients in SPRINT were already receiving antihypertensive drugs at baseline, data are lacking on the effects of initiating drug therapy at a lower blood pressure threshold (130/80 mm Hg) in patients at high risk of cardiovascular disease.1223 The potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs should be considered when deciding a patient's treatment goal.1200,1220,1229

The 2017 ACC/AHA hypertension guideline recommends an ASCVD risk assessment for all adults with hypertension; however, experts state that it can be assumed that patients with hypertension and diabetes mellitus or chronic kidney disease (CKD) are at high risk for cardiovascular disease and that antihypertensive drug therapy should be initiated in these patients at a blood pressure of 130/80 mm Hg or higher.1200 ACC/AHA also recommends a blood pressure goal of less than 130/80 mm Hg in patients with hypertension and diabetes mellitus or CKD.1200 These recommendations are based on a systematic review of high-quality evidence from randomized controlled trials, meta-analyses, and post hoc analyses that have demonstrated substantial reductions in the risk of important clinical outcomes (e.g., cardiovascular events) regardless of comorbid conditions or age when systolic blood pressure is lowered to less than 130 mm Hg.1200,1213 However, some clinicians have questioned the generalizability of findings from some of the trials (e.g., SPRINT) used to support the 2017 ACC/AHA hypertension guideline.1224 For example, SPRINT included adults (mean age: 68 years) without diabetes mellitus who were at high risk of cardiovascular disease.1209,1210 While benefits of intensive blood pressure control were observed in this patient population, some clinicians have questioned whether these findings apply to younger patients who have a low risk of cardiovascular disease.1223 In patients with CKD in the SPRINT trial, intensive blood pressure management (achieving a mean systolic blood pressure of approximately 122 mm Hg compared with 136 mm Hg with standard treatment) provided a similar beneficial reduction in the composite cardiovascular disease primary outcome and all-cause mortality as in the full patient cohort.1200,1210 Because most patients with CKD die from cardiovascular complications, the findings of this study further support a lower blood pressure target of less than 130/80 mm Hg.1200 Data are lacking to determine the ideal blood pressure goal in patients with hypertension and diabetes mellitus; also, studies evaluating the benefits of intensive blood pressure control in patients with diabetes mellitus have provided conflicting results.521,1200,1213

Clinical studies reviewed for the 2017 ACC/AHA hypertension guideline have shown similar quantitative benefits from blood pressure lowering in hypertensive patients with or without diabetes mellitus.1213 In a randomized, controlled study (ACCORD-BP) that compared a higher (systolic blood pressure less than 140 mm Hg) versus lower (systolic blood pressure less than 120 mm Hg) blood pressure goal in patients with diabetes mellitus, there was no difference in the incidence of cardiovascular outcomes (e.g., composite outcome of cardiovascular death, nonfatal MI, and nonfatal stroke).521,1214 However, some experts state that this study was underpowered to detect a difference between the 2 treatment groups and that the factorial design of the study complicated interpretation of the results.1200,1216 Although SPRINT did not include patients with diabetes mellitus, patients in this study with prediabetes demonstrated a similar cardiovascular benefit from intensive treatment of blood pressure as normoglycemic patients.1200 A meta-analysis of data from ACCORD and SPRINT suggests that the findings of both studies are consistent and that patients with diabetes mellitus benefit from more intensive blood pressure control.1202,1217 These data support the 2017 ACC/AHA hypertension guideline recommendation of a blood pressure treatment goal of less than 130/80 mm Hg in patients with hypertension and diabetes mellitus.1200 Alternatively, the American Diabetes Association (ADA) recommends a blood pressure goal of less than 140/90 mm Hg in patients with diabetes mellitus.1214 The ADA states that a lower blood pressure goal (e.g., less than 130/80 mm Hg) may be appropriate for patients with a high risk of cardiovascular disease and diabetes mellitus if it can be achieved without undue treatment burden.1214

Further study is needed to more clearly define optimum blood pressure goals in patients with hypertension, particularly in high-risk groups (e.g., patients with diabetes mellitus, cardiovascular disease, or cerebrovascular disease; black patients); when determining appropriate blood pressure goals, individual risks and benefits should be considered in addition to the evidence from clinical studies.503,507,515,526,530,1200

Experts state that in patients with stage 1 hypertension (especially the elderly, those with a history of hypotension, or those who have experienced adverse drug effects), it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target blood pressure.1200 However, although some patients can begin treatment with a single antihypertensive agent, the 2017 ACC/AHA hypertension guideline recommends initiation of antihypertensive therapy with 2 drugs from different pharmacologic classes (either as separate agents or in a fixed-dose combination) in patients with stage 2 hypertension and an average blood pressure more than 20/10 mm Hg above their target blood pressure.1200 Such combined therapy may increase the likelihood of achieving goal blood pressure in a more timely fashion, but also may increase the risk of adverse effects (e.g., orthostatic hypotension) in some patients (e.g., elderly).234,257,1200 Drug regimens with complementary activity, where a second antihypertensive agent is used to block compensatory responses to the first agent or affect a different pressor mechanism, can result in additive blood pressure lowering and are preferred.1200 Drug combinations that have similar mechanisms of action or clinical effects (e.g., the combination of an ACE inhibitor and an angiotensin II receptor antagonist) generally should be avoided.1200 Many patients who begin therapy with a single antihypertensive agent will subsequently require at least 2 drugs from different pharmacologic classes to achieve their blood pressure goal.1200 Experts state that other patient-specific factors, such as age, concurrent medications, drug adherence, drug interactions, the overall treatment regimen, cost, and comorbidities, also should be considered when deciding on an antihypertensive drug regimen.1200 For any stage of hypertension, antihypertensive drug dosages should be adjusted and/or other agents substituted or added until goal blood pressure is achieved.1200 (See Follow-up and Maintenance Drug Therapy under Hypertension: General Considerations for Initial and Maintenance Antihypertensive Therapy, in Uses.)

Follow-up and Maintenance Drug Therapy

Several strategies are used for the titration and combination of antihypertensive drugs; these strategies, which are generally based on those used in randomized controlled studies, include maximizing the dosage of the first drug before adding a second drug, adding a second drug before achieving maximum dosage of the initial drug, or initiating therapy with 2 drugs simultaneously (either as separate preparations or as a fixed-dose combination).1200 Combined use of an ACE inhibitor and angiotensin II receptor antagonist should be avoided because of the potential risk of adverse renal effects.1200 After initiating a new or adjusted antihypertensive drug regimen, patients should have their blood pressure reevaluated monthly until adequate blood pressure control is achieved.1200 Effective blood pressure control can be achieved in most hypertensive patients, but many will ultimately require therapy with 2 or more antihypertensive drugs.244,1200 In addition to measuring blood pressure, clinicians should evaluate patients for orthostatic hypotension, adverse drug effects, adherence to drug therapy and lifestyle modifications, and the need for drug dosage adjustments.1200 Laboratory testing such as electrolytes and renal function status and other assessments of target organ damage also should be performed.1200

Considerations for Drug Therapy in Patients with Underlying Cardiovascular and Other Risk Factors

Drug therapy in patients with hypertension and underlying cardiovascular or other risk factors should be carefully individualized based on the underlying disease(s), concomitant drugs, tolerance to drug-induced adverse effects, and blood pressure goal.234,502,1200 (See Table 2 on Compelling Indications for Drug Classes based on Comorbid Conditions, under Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.)

Ischemic Heart Disease

The selection of an appropriate antihypertensive agent in patients with ischemic heart disease should be based on individual patient characteristics and may include a β-blocker, with the addition of other drugs (e.g., ACE inhibitors, thiazide diuretics, calcium-channel blockers) as necessary to achieve blood pressure goals.523,525,1200 Because of the demonstrated mortality benefit of β-blockers following MI, these drugs should be administered in all patients who have survived an MI.141,253,523,527,1200 The 2017 ACC/AHA hypertension guideline states that β-blockers used for ischemic heart disease/angina that are also effective in lowering blood pressure include bisoprolol, carvedilol, metoprolol succinate, metoprolol tartrate, nadolol, propranolol, and timolol.1200 However, ACC/AHA state that the use of atenolol for the management of hypertension in patients with stable ischemic heart disease should be avoided because the drug has been shown to be less effective than placebo in reducing cardiovascular events and is not as effective in treating hypertension as other antihypertensive agents.237,1200

Heart Failure

While β-blockers as single therapies are not superior to other antihypertensive agents in the reduction of all cardiovascular outcomes,524 certain β-blockers (bisoprolol, carvedilol, extended-release metoprolol succinate) have been shown to be effective in reducing the incidence of heart failure† and associated morbidity and mortality.193,246,252,524,1200 (See Uses: Heart Failure, in Carvedilol 24:24.)

Other Special Considerations for Antihypertensive Drug Therapy

Race

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 In general, black hypertensive patients tend to respond better to monotherapy with thiazide diuretics or calcium-channel blocking agents than to monotherapy with β-blockers, ACE inhibitors, or angiotensin II receptor antagonists.226,227,232,259,260,501,504,1200 However, such diminished response to a β-blocker is largely eliminated when the drug is administered concomitantly with a thiazide diuretic.504 In addition, some experts state that when use of β-blockers is indicated in hypertensive patients with underlying cardiovascular or other risk factors, these indications should be applied equally to black hypertensive patients.232

For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.

Chronic Stable Angina

Atenolol is used for the management of chronic stable angina pectoris.111,112,600,1101β-Blockers are recommended as the anti-ischemic drugs of choice in most patients with chronic stable angina; despite differences in cardioselectivity, intrinsic sympathomimetic activity, and other clinical factors, all β-blockers appear to be equally effective for this indication.1101 Long-term use of β-blockers in patients with chronic stable angina pectoris has been shown to reduce the frequency of anginal attacks, allow a reduction in nitroglycerin dosage, and increase exercise tolerance.

Combination therapy with a β-blocker and a nitrate appears to be more effective than either drug alone because β-blockers attenuate the increased sympathetic tone and reflex tachycardia associated with nitrate therapy while nitrate therapy (e.g., nitroglycerin) counteracts the potential increase in left-ventricular wall tension associated with a decrease in heart rate.1101 Combined therapy with a β-blocker and a dihydropyridine calcium-channel blocker also may be useful because the tendency to develop tachycardia with the calcium-channel blocker is counteracted by the β-blocker.1101 However, caution should be exercised in the concomitant use of β-blockers and the nondihydropyridine calcium-channel blockers verapamil or diltiazem because of the potential for excessive fatigue, bradycardia, or atrioventricular (AV) block.1101 (See Drug Interactions: Cardiovascular Drugs.)

Non-ST-Segment-Elevation Acute Coronary Syndromes

β-Blockers are used as part of the standard therapeutic measures for managing non-ST-segment-elevation acute coronary syndromes (NSTE ACS).1100 Patients with NSTE ACS have either unstable angina or non-ST-segment-elevation MI (NSTEMI); because these conditions are part of a continuum of acute myocardial ischemia and have indistinguishable clinical features upon presentation, the same initial treatment strategies are recommended.805,1100 The American Heart Association/American College of Cardiology (AHA/ACC) guideline for the management of patients with NSTE ACS recommends an early invasive strategy (angiographic evaluation with the intent to perform revascularization procedures such as percutaneous coronary intervention [PCI] with coronary artery stent implantation or coronary artery bypass grafting [CABG]) or an ischemia-guided strategy (initial medical management followed by cardiac catheterization and revascularization if indicated) in patients with definite or likely NSTE ACS; standard medical therapies for all patients should include a β-blocker, antiplatelet agents (aspirin and/or a P2Y12-receptor antagonist), anticoagulant agents (e.g., low molecular weight or unfractionated heparin), nitrates (e.g., nitroglycerin), and analgesic agents regardless of the initial management approach.1100 The guideline states that oral β-blocker therapy should be initiated within the first 24 hours in patients who do not have manifestations of heart failure, evidence of a low-output state, increased risk of cardiogenic shock, or any other contraindications to β-blocker therapy; use of IV β-blockers is potentially harmful in patients with risk factors for cardiogenic shock.1100 Continued therapy with a β-blocker proven to reduce mortality (bisoprolol, carvedilol, or metoprolol succinate) is recommended in patients with stabilized heart failure and reduced systolic function.1100 (See Uses: Heart Failure, in Carvedilol 24:24.)

Acute Myocardial Infarction

Atenolol is used to reduce the risk of cardiovascular mortality in hemodynamically stable patients with definite or suspected acute MI.111,113,120,122,123,124,134,135,147,527,600,1100 The term MI is used when there is evidence of myocardial necrosis in the setting of acute myocardial ischemia.807 ST-segment-elevation MI (STEMI) is distinguished from NSTEMI based on the presence or absence of ST-segment elevation on ECG.527,807,808,1100 Patients with STEMI typically have complete arterial occlusion; therefore, immediate reperfusion therapy (with primary PCI or thrombolytic agents) is the current standard of care for such patients.527,803,805,808 Because the clinical presentation of NSTEMI is similar to that of unstable angina, these conditions are considered together in current expert guidelines.1100 (See Uses: Non-ST-Segment-Elevation Acute Coronary Syndromes.) During the early stage of a definite or suspected MI, atenolol has been initiated with IV doses (no longer commercially available in the US), followed by continued oral dosing; however, experts currently recommend that early IV use of β-blockers be limited to selected patients.113,527,1100

Because β-blockers can reduce myocardial oxygen demand during the first few hours of an acute MI by reducing heart rate, arterial blood pressure, and myocardial contractility, and also have been shown to reduce mortality, early IV therapy with these drugs was routinely recommended following acute MI.122,132,134,135,136,149,802,803,1100 Evidence supporting this recommendation was generally based on studies conducted prior to the reperfusion era demonstrating a reduction in mortality and other clinical benefits (i.e., reduced infarct size, incidence of ventricular arrhythmias, chest pain, and cardiac enzyme elevations) with early use of β-blockers during MI.113,120,124,803,804 In one such study (the First International Study of Infarct Survival; ISIS-1), therapy with atenolol (initiated IV within the first 12 hours of symptom onset and continued orally for 7 days) was shown to reduce cardiovascular mortality by approximately 15% during the first few days of therapy, but did not substantially reduce cardiovascular mortality beyond this initial period.113,120 The difference in vascular mortality rate between those receiving atenolol or placebo was evident almost entirely during the first 2 days of therapy.113,120,122,123 Analysis of data from a subset of patients who died during early treatment in ISIS-1 suggested that the principal mechanism of early mortality reduction associated with atenolol therapy was prevention of cardiac rupture and of cardiac electromechanical dissociation.122,123 However, the relevance of these study findings to current clinical practice has been questioned since patients did not receive reperfusion therapy and only 5% received an antiplatelet agent.802

Studies conducted after the widespread use of reperfusion therapy generally have demonstrated more attenuated benefits with early β-blocker therapy in patients with acute MI; while β-blockers may still confer benefits (e.g., reduction in the risk of reinfarction and ventricular arrhythmias), there is less certainty regarding the drugs' effects on mortality in patients receiving contemporary revascularization and pharmacologic therapies (antiplatelet agents, ACE inhibitors, and lipid-lowering therapies).527,801,802,804,1100 In addition, early use of β-blockers (particularly when administered IV) has been associated with an increased risk of cardiogenic shock.527,801,804,1100 (See Uses: Acute Myocardial Infarction in Metoprolol 24:24.) Based on the currently available evidence, the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guideline for the management of STEMI recommends oral β-blocker therapy in all patients who do not have manifestations of heart failure, evidence of a low-output state, increased risk of cardiogenic shock, or any other contraindications to β-blocker therapy.527 Such therapy should be initiated within the first 24 hours following acute MI and continued during and after hospitalization.527 Because of conflicting evidence of benefit and the potential for harm, the guidelines recommend limiting use of IV β-blockers to patients with refractory hypertension or ongoing ischemia.527

Although the efficacy of atenolol in reducing cardiovascular mortality has been established only during the first 7 days after an acute MI,113,120,600 the benefits of long-term β-blocker therapy for secondary prevention have been well established in numerous clinical studies.527,804,806,1101 Patients with MI complicated by heart failure, left ventricular dysfunction, or ventricular arrhythmias appear to derive the most benefit from long-term β-blocker therapy.527 Data from studies using other β-blockers suggest that optimum benefit may be achieved if treatment with these agents is continued for at least 1-3 years if not indefinitely after infarction unless contraindicated.120,122,134,135,136,138,139,140,141,142,525,527 Several large, randomized studies have demonstrated that prolonged oral therapy with a β-blocker can reduce the rates of reinfarction and mortality (e.g., sudden and nonsudden cardiac death) following acute MI.134,135,136,138,139,140,141,142,527 It is estimated that such therapy could result in a relative reduction in mortality of about 25% annually for years 1-3 after infarction, with high-risk patients exhibiting the greatest potential benefit;122,134,135,136,138,139,140,141,142,143,144,147 the benefit of continued therapy may persist for at least several years beyond this period, although less substantially.134,138,146,147 Therefore, atenolol, like other β-blockers, can be used for secondary prevention following acute MI to reduce the risk of reinfarction and mortality.111,113,120,122,123,124,134,135,147,527 The AHA/ACCF secondary prevention guideline recommends β-blocker therapy in all patients with left ventricular systolic dysfunction (ejection fraction of 40% or less) and a prior MI; use of a β-blocker with proven mortality benefit (bisoprolol, carvedilol, or metoprolol succinate) is recommended.525 (See Uses: Heart Failure, in Carvedilol 24:24.) Although the benefits of long-term β-blockade in post-MI patients with normal left ventricular function are less well established, the guideline recommends continued β-blocker therapy for at least 3 years in such patients.525 Further studies are needed to establish the optimal duration of β-blocker therapy for secondary prevention of MI.527,802,804

Supraventricular Arrhythmias

β-Blockers, including atenolol, have been used to slow ventricular rate in patients with supraventricular tachycardia (SVT)†.300,301 The American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guideline for the management of adult patients with supraventricular tachycardia recommends the use of β-adrenergic blocking agents in the treatment of various SVTs (e.g., atrial flutter, junctional tachycardia, focal atrial tachycardia, atrioventricular nodal reentrant tachycardia [AVNRT]); in general, an IV β-blocker is recommended for acute treatment, while an oral preparation is recommended for ongoing management of these arrhythmias.300,301 Vagal maneuvers and/or IV adenosine are considered first-line interventions for the acute treatment of patients with SVT and should be attempted prior to other therapies when clinically indicated; if such measures are ineffective or not feasible, an IV β-blocker may be considered in hemodynamically stable patients.300 Although evidence of efficacy is limited, experts state that the overall safety of β-adrenergic blockers warrants their use in patients with SVT.300 Patients should be closely monitored for hypotension and bradycardia during administration of these drugs.300

Atrial Fibrillation and Flutter

β-Blockers are recommended as one of several drug therapy options for ventricular rate control in patients with nonpreexcited atrial fibrillation or flutter†.300,301 For acute treatment of atrial fibrillation or flutter, an IV β-adrenergic blocking agent (e.g., esmolol, propranolol, metoprolol) may be used for ventricular rate control in patients without preexcitation; an oral β-blocker such as atenolol may be used for ongoing rate control in such patients.300,301 Choice of a specific β-blocker should be individualized based on the patient's clinical condition.301

Atrial Tachycardia

IV β-blockers may be used for the treatment of patients with hemodynamically stable focal atrial tachycardia† (i.e., regular SVT arising from a localized atrial site), and an oral β-blocker may be used for ongoing management.300 Multifocal atrial tachycardia, characterized by a rapid, irregular rhythm with at least 3 distinct P-wave morphologies, is commonly associated with an underlying condition (e.g., pulmonary, coronary, or valvular heart disease) and is generally not responsive to antiarrhythmic drug therapy.300 Antiarrhythmic drug therapy usually is reserved for patients who do not respond to initial attempts at correcting or managing potential precipitating factors (e.g., exacerbation of chronic obstructive pulmonary disease or congestive heart failure, hypoxemia, anemia) or in whom a precipitating factor cannot be identified.300

Paroxysmal Supraventricular Tachycardia

IV β-blockers may be used for the acute treatment of hemodynamically stable patients with paroxysmal supraventricular tachycardia (PSVT), including AVNRT†, that is uncontrolled or unconverted by vagal maneuvers and adenosine; an oral β-blocker may be used for the ongoing management of such patients who are not candidates for, or prefer not to undergo, catheter ablation.300

Junctional Tachycardia

β-Blockers are considered one of several drug therapy options that may be used for the treatment of junctional tachycardia† (i.e., nonreentrant SVT originating from the AV junction), a rapid, occasionally irregular, narrow-complex tachycardia.300 While evidence is limited, there is some data indicating that β-blockers (specifically propranolol) are modestly effective in terminating and/or reducing the incidence of junctional tachycardia.300

Ventricular Arrhythmias

β-Blockers also have been used in patients with cardiac arrest precipitated by ventricular fibrillation or pulseless ventricular tachycardia†.400 However, AHA states that routine administration of β-blockers after cardiac arrest is potentially harmful (e.g., may worsen hemodynamic instability, exacerbate heart failure, or cause bradyarrhythmias) and is therefore not recommended.400

β-Blockers may be useful in the management of certain forms of polymorphic ventricular tachycardia† (e.g., associated with acute ischemia).401

Vascular Headache

Migraine

Atenolol has been used for the prophylaxis of migraine headache†.228 When used prophylactically, atenolol can prevent migraine or reduce the number of attacks in some patients.228 However, the US Headache Consortium states that the quality of evidence for atenolol is not as compelling as it is for propranolol for this indication.228 Atenolol is not recommended for the treatment of a migraine attack that has already started.228 For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.

Alcohol Withdrawal

Atenolol has been used in conjunction with a benzodiazepine in the management of acute alcohol withdrawal†.101,229β-Blockers such as atenolol appear to be effective in reducing manifestations of the hyperadrenergic state associated with alcohol withdrawal, including elevated blood pressure, increased heart rate, and anxiety.229,230 However, β-blockers have not been shown to prevent delirium or seizures, and such drugs should be used only as adjuncts to benzodiazepines (not as monotherapy) for the treatment of alcohol withdrawal.229,230 (See Uses: Alcohol Withdrawal, in the Benzodiazepines General Statement 28:24.08.) Some clinicians state that the use of β-blockers may be particularly helpful in patients with certain coexisting conditions (e.g., coronary artery disease).230

Administration

Atenolol is administered orally; the drug also has been administered by IV injection, however a parenteral preparation no longer is commercially available in the US.111,120,401

Oral administration of atenolol more frequently than once daily for the management of hypertension usually is not necessary. If atenolol is used in patients with bronchospastic disorders, therapy should be initiated cautiously; concomitant administration of a β₂-adrenergic agonist and twice-daily dosing of atenolol may minimize the risk of bronchospasm in some patients.

Extemporaneous Liquid Formulation

An oral liquid formulation containing 2 mg/mL of atenolol has been extemporaneously prepared using the commercially available tablets and various vehicles (e.g., simple syrup, Ora-Sweet, Ora-Plus, Ora-Sweet SF, methylcellulose-based vehicle).276,277

Standardize 4 Safety

Standardized concentrations for an extemporaneously prepared oral liquid formulation of atenolol have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 275Multidisciplinary expert panels were convened to determine recommended standard concentrations. 275Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 275 For additional information on S4S (including updates that may be available), see [Web].

Dosage

Dosage of atenolol must be individualized and adjusted according to the patient's response and tolerance.111 If atenolol therapy is to be discontinued, dosage of the drug should be reduced gradually over a period of about 2 weeks.111,120 (See Cautions: Precautions and Contraindications.)

Hypertension

Atenolol Therapy

The manufacturer recommends an initial adult atenolol dosage of 50 mg once daily, either alone or in combination with diuretic therapy; the full antihypertensive effect may not be evident for 1-2 weeks.600 If response is inadequate after a sufficient trial at the initial dosage, the manufacturer states that dosage should be increased to 100 mg once daily.600 Some experts state that the usual adult dosage range for treatment of hypertension is 25-100 mg daily administered in 2 divided doses.1200 Dosages exceeding 100 mg daily usually do not result in further improvement in blood pressure control.600

If atenolol is used for the management of hypertension in children†, some experts have recommended an initial oral dosage of 0.5-1 mg/kg daily given as a single dose or in 2 divided doses.258 Such experts have suggested that dosage may be increased as necessary to a maximum dosage of 2 mg/kg (up to 100 mg) daily given as a single dose or in 2 divided doses.258 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Atenolol/Chlorthalidone Fixed-combination Therapy

When combination therapy is required, commercially available preparations containing atenolol in combination with chlorthalidone should not be used initially. Dosage should first be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in the commercial combination preparation, such a preparation may be used. If the fixed-combination preparation is used, the manufacturer recommends an initial dosage of 50 mg of atenolol and 25 mg of chlorthalidone once daily.118 If an optimal response is not achieved, the fixed-combination preparation containing 100 mg of atenolol and 25 mg of chlorthalidone may be used once daily.118

Blood Pressure Monitoring and Treatment Goals

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200,1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with atenolol, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 While other hypertension guidelines have based target blood pressure goals on age and comorbidities,501,504,536 the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) for all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220 (See General Considerations for Initial and Maintenance Antihypertensive Therapy under Uses: Hypertension.)

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

Chronic Stable Angina

For the management of chronic stable angina pectoris, the initial adult oral dosage of atenolol is 50 mg once daily.111 If an optimum response is not achieved within one week, oral dosage should be increased to 100 mg once daily.111 Some patients may require an oral atenolol dosage of 200 mg once daily for optimum effect.111 Dosage of β-blockers in angina pectoris usually is adjusted according to clinical response and to maintain a resting heart rate of 55-60 beats/minute. Control of angina pectoris over a 24-hour period with once-daily dosing of atenolol is achieved by the use of doses larger than those necessary to achieve an immediate maximum effect.111 The maximum early effect on exercise tolerance occurs with oral atenolol doses of 50-100 mg, but the effect at 24 hours is attenuated at these doses, averaging about 50-75% of that observed with once-daily oral doses of 200 mg.111

Acute Myocardial Infarction

Early Treatment

Atenolol therapy may be initiated as soon as possible after an acute myocardial infarction (MI) when the patient's hemodynamic condition has stabilized.600 During the early stage of a definite or suspected MI, atenolol has been initiated with IV doses, followed by continued oral dosing; 113,120 however, a parenteral preparation of atenolol is no longer commercially available in the US. When IV dosing is excluded, atenolol can be administered orally at a dosage of 50 mg twice daily or 100 mg once daily for at least 7 days.111,120

The American College of Cardiology Foundation (ACCF)/AHA guideline for the management of ST-segment-elevation MI (STEMI) recommends initiation of oral β-blocker therapy within the first 24 hours of an acute MI in all patients who do not have manifestations of heart failure, evidence of a low-output state, increased risk of cardiogenic shock, or any other contraindications to β-blocker therapy.527

Long-term Secondary Prevention

The optimal duration of β-blocker therapy following MI remains to be clearly established.111,120,527,802,804 Experts generally recommend that such therapy be continued long-term in post-MI patients with left ventricular systolic dysfunction, and for at least 3 years in those with normal left ventricular function.525,802,804,1101

Supraventricular Arrhythmias

For the ongoing treatment of various supraventricular tachycardias (SVTs)† (e.g., atrial flutter†, atrial tachycardia† , junctional tachycardia†) or atrial fibrillation† after initial IV therapy in adults, some experts recommend an initial oral atenolol dose of 25-50 mg daily and usual maintenance dosage of 25-100 mg daily.300,301

Vascular Headaches

Migraine

Although oral dosage of atenolol for the prophylaxis of migraine† in adults has not been established, the usual effective dosage of the drug in clinical studies was 100 mg daily.228

Dosage in Renal Impairment

In patients with impaired renal function, doses and/or frequency of administration of atenolol must be modified in response to the degree of renal impairment. Because decreased renal function is a physiologic consequence of aging, the possibility that modification of atenolol dosage may be necessary in geriatric patients should be considered.111 Initiation of oral atenolol therapy at 25 mg daily may be necessary in some renally impaired or geriatric patients being treated for hypertension; if this dosage is employed, measurement of blood pressure just prior to a dose is recommended to ensure persistence of adequate blood pressure reduction.111 Although similar, low-dose initial therapy may be warranted for other conditions, data currently are not available.111

A maximum oral atenolol dosage of 50 mg daily is recommended for patients with creatinine clearances of 15-35 mL/minute per 1.73 m²; 25 mg daily or 50 mg every other day is recommended when creatinine clearance is less than 15 mL/minute per 1.73 m².111,118,120 In patients undergoing hemodialysis, a 25- or 50-mg oral dose of atenolol may be administered after each dialysis; since marked reductions in blood pressure may occur, it is recommended that the supplemental dose be given under careful supervision.111,120

Atenolol shares the toxic potentials of β-adrenergic blocking agents (β-blockers). In therapeutic dosage, atenolol usually is well tolerated and has a low incidence of adverse effects. The incidence and severity of adverse reactions may occasionally be obviated by a reduction in dosage. Abrupt withdrawal of the drug should be avoided, especially in patients with coronary artery disease, since it may exacerbate angina or precipitate myocardial infarction (MI).

Cardiovascular Effects

Potentially serious adverse cardiovascular effects of atenolol include bradycardia,274 which occurs in 3% of patients; profound hypotension;274 second- or third-degree atrioventricular (AV) block;274 and precipitation of severe heart failure, which is more likely to occur in patients with preexisting left ventricular dysfunction. Sick sinus syndrome has been reported during postmarketing experience in patients receiving atenolol-containing therapy.111,118,120 Atenolol-containing therapy is not recommended for use in patients with untreated pheochromocytoma.111,118,120 Bradycardia and hypotension usually can be reversed with an antimuscarinic agent like IV atropine. Isoproterenol or a transvenous cardiac pacemaker may be required for AV block. Other adverse cardiovascular effects include coldness of the extremities, reportedly occurring in 0-12% of patients; postural hypotension (which may be associated with syncope), in 2-4% of patients; and leg pain, in 0-3% of patients. When IV and oral atenolol were used in the early post-MI infarction period (for up to 10 days after onset of symptoms) in clinical trials, the principal adverse effects were bradycardia and hypotension, which occurred in up to 25% of patients receiving the drug (often combined with other therapy) and required reduction in dosage or discontinuance of atenolol in many patients.111,113,120,124 In addition, analysis of data from a subset of patients who died during early treatment in the First International Study of Infarct Survival (ISIS-1) revealed evidence of a small but not statistically significant increase in early death secondary to bradycardia and shock associated with atenolol therapy, but this potential adverse effect was outweighed substantially by beneficial effects of the drug on reduction of mortality from other causes.123 Atenolol may aggravate peripheral arterial circulatory disorders.111,118,120

CNS Effects

Adverse CNS effects of atenolol include dizziness, fatigue, and mental depression. Lethargy, drowsiness, unusual dreams, lightheadedness, and vertigo usually occur in less than 3% of patients. Headache and hallucinations also have been reported in patients receiving atenolol. Adverse CNS effects seen with other β-blockers that may occur with atenolol include visual disturbances, disorientation, short-term memory impairment, emotional lability, psychoses, catatonia, and impaired performance on neuropsychometric tests.

GI Effects

Adverse GI reactions include diarrhea and nausea, which reportedly occur in 2-4% of patients receiving atenolol. A few cases of mesenteric arterial thrombosis and ischemic colitis have been reported in patients receiving other β-blockers. Dry mouth also has been reported in patients receiving atenolol.184

Endocrine Effects

Results of a large prospective cohort study of nondiabetic adults 45-64 years of age indicate that use of β-blockers in hypertensive patients is associated with increased risk (about 28%) of developing type 2 diabetes mellitus compared with hypertensive patients who were not receiving hypotensive therapy.205,206 In this study, the number of new cases of diabetes per 1000 person-years was 33.6 or 26.3 in patients receiving a β-blocker or no drug therapy, respectively.205 The association between the risk of developing diabetes mellitus and use of β-blockers reportedly was not confounded by weight gain, hyperinsulinemia, or differences in heart rate.205,206 It is not known if the risk of developing type 2 diabetes is affected by β-receptor selectivity.205 Further studies are needed to determine whether concomitant use of ACE inhibitors (which may improve insulin sensitivity) would abrogate β-blocker-induced adverse effects related to glucose intolerance.206 Therefore, until results of such studies are available, the proven benefits of β-blockers in reducing cardiovascular events in hypertensive patients must be weighed carefully against the possible risks of developing type 2 diabetes mellitus.205

Hypoglycemia,204 which may result in loss of consciousness, also may occur in nondiabetic patients receiving β-blockers. Patients most at risk for the development of β-blocker-induced hypoglycemia are those undergoing dialysis, prolonged fasting, or severe exercise regimens.204

β-Blockers may mask signs and symptoms of hypoglycemia (e.g., palpitation, tachycardia, tremor) and potentiate insulin-induced hypoglycemia.204 Although it has been suggested that nonselective β-blockers are more likely to induce hypoglycemia than selective β-blockers, such an adverse effect also has been reported with selective β-blocking agents (e.g., atenolol).204 In addition, selective β-blockers are less likely to mask symptoms of hypoglycemia or delay recovery from insulin-induced hypoglycemia than nonselective β-blockers because of their vascular sparing effects; however, selective β-blockers can decrease insulin sensitivity by approximately 15-30%, which may result in increased insulin requirements.204

Other Adverse Effects

Wheezing and dyspnea have occurred in patients receiving atenolol and are more likely to occur when dosage of the drug exceeds 100 mg daily. Rashes (which may be psoriasiform),111,118,120,184 exacerbation of psoriasis,111,118,120,184 lupus syndrome,111,118,120,184 drying of the eyes,111 visual disturbances,184 reversible alopecia,111,184 Peyronie's disease,111,118,120,184 antinuclear antibodies (ANA),111,118,120,184 impotence,111,184 elevated serum concentrations of hepatic enzymes and bilirubin,111,184 purpura,111,118,120,184 and thrombocytopenia111,184 also have been reported with atenolol.

The possibility that other adverse effects associated with other β-blockers may occur during atenolol therapy should be considered. These include hematologic reactions (e.g., agranulocytosis, nonthrombocytopenic or thrombocytopenic purpura); allergic reactions characterized by fever, sore throat, laryngospasm, and respiratory distress; Raynaud's phenomenon; conjunctivitis sicca; otitis; sclerosing serositis; and erythematous rash.

Precautions and Contraindications

Atenolol shares the toxic potentials of β-blockers, and the usual precautions of these agents should be observed. When atenolol is used as a fixed-combination preparation that includes chlorthalidone, the cautions, precautions, and contraindications associated with thiazide diuretics must be considered in addition to those associated with atenolol.115,116,117,118

In patients with heart failure, sympathetic stimulation is vital for the support of circulatory function. Atenolol should be used with caution in patients with inadequate cardiac function, since heart failure may be precipitated by blockade of β-adrenergic stimulation when atenolol therapy is administered. In addition, in patients with latent cardiac insufficiency, prolonged β-adrenergic blockade may lead to cardiac failure. Although β-blockers should be avoided in patients with overt heart failure, atenolol may be administered cautiously, if necessary, to patients with well-compensated heart failure (e.g., those controlled with cardiac glycosides and/or diuretics). Patients receiving atenolol therapy should be instructed to consult their physician at the first sign or symptom of impending cardiac failure and should be adequately treated (e.g., with a cardiac glycoside and/or diuretic) and observed closely; if cardiac failure continues, atenolol should be discontinued, gradually if possible. In patients with acute MI, use of atenolol is contraindicated in those whose congestive heart failure cannot be controlled promptly and effectively with a parenteral loop diuretic or comparable therapy.120 In addition, good clinical judgment suggests that patients whose cardiac output and/or blood pressure depends on sympathetic stimulation are not good candidates for β-adrenergic blocker therapy for acute MI, and such use is not recommended for patients whose systolic blood pressure or heart rate persistently is less than 100 mm Hg or 50-60 beats/minute, respectively.120,123,274

Since β-blockers may inhibit bronchodilation produced by endogenous catecholamines, the drugs generally should not be used in patients with bronchospastic disease;274 however, because of its relative β₁-selective adrenergic blocking activity, atenolol may be used with caution in patients with bronchospastic disease who do not respond to or cannot tolerate other hypotensive agents. If atenolol is used in such patients, the initial dosage should be 50 mg daily and the smallest effective dosage should be used. In patients who develop symptoms of bronchospasm, atenolol dosage should be reduced or the drug discontinued (gradually if possible), and supportive treatment administered. In patients with bronchospastic disease, concomitant administration of a β₂-adrenergic agonist and/or twice-daily dosing of the drug may minimize the risk of bronchospasm.

Abrupt withdrawal of atenolol may exacerbate angina symptoms and/or precipitate MI and ventricular arrhythmias in patients with coronary artery disease, or may precipitate thyroid storm in patients with thyrotoxicosis. Therefore, patients receiving atenolol (especially those with ischemic heart disease) should be warned not to interrupt or discontinue therapy without consulting their physician. Because coronary artery disease is common and may be undiagnosed, abrupt withdrawal also should be avoided in patients receiving atenolol for other conditions (e.g., hypertension).111,118 When atenolol is discontinued in patients with coronary artery disease or suspected thyrotoxicosis, the patients should be observed carefully; patients with coronary artery disease should be advised to temporarily limit their physical activity.111,118,120 If exacerbation of angina occurs or acute coronary insufficiency develops after atenolol therapy is interrupted or discontinued, treatment with the drug should be reinstituted, at least temporarily.111,120

Patients who have a history of anaphylactic reactions to a variety of allergens reportedly may be more reactive to repeated accidental, diagnostic, or therapeutic challenges with such allergens while taking β-blockers.111,118,120 These patients may be unresponsive to usual doses of epinephrine or may develop a paradoxical response to epinephrine when used to treat anaphylactic reactions.111,118,120

Atenolol should be used with caution in patients undergoing major surgery involving general anesthesia. The necessity of withdrawing β-adrenergic blocking therapy prior to major surgery is controversial. Severe, protracted hypotension and difficulty in restarting or maintaining a heart beat have occurred during surgery in some patients who have received β-blockers. As with other β-blockers, the effects of atenolol can be reversed by administration of β-agonists (e.g., dobutamine, isoproterenol).111,120 If atenolol is discontinued, this should be done 2 days before surgery. If patients continue to receive atenolol prior to or during surgery in which anesthetics with negative inotropic activity are used, the patients should be observed for signs and symptoms of heart failure; if vagal stimulation occurs, atropine may be administered.111,118,120

Atenolol should be used with caution in patients with hyperthyroidism since the drug may mask the tachycardia associated with hyperthyroidism. In addition, it is recommended that atenolol be used with caution in patients with diabetes mellitus since β-blockers may mask the tachycardia associated with hypoglycemia (a few cases have been reported in patients with type 2 diabetes mellitus), and β-blockers, especially nonselective ones, may potentially precipitate severe, acute hyperglycemia. (See Cautions: Endocrine Effects.) However, many clinicians state that patients with diabetes mellitus may be particularly likely to experience a reduction in morbidity and mortality with the use of these drugs.185β-Blockers usually will not mask dizziness and sweating seen with hypoglycemia.

Atenolol should be used with caution and in reduced dosage in patients with impaired renal function, especially when creatinine clearance is less than 35 mL/minute per 1.73 m². The manufacturers recommend that patients receiving atenolol after hemodialysis be administered the drug under close supervision in a hospital setting, since marked hypotension may occur.

Atenolol is contraindicated in patients with sinus bradycardia, AV block greater than first degree, cardiogenic shock, known hypersensitivity to any component of the drug formulations, and overt or decompensated cardiac failure.111,118,120,220 Atenolol-containing therapy is not recommended for use in patients with untreated pheochromocytoma.111,118,120

Pediatric Precautions

Safety and efficacy of atenolol in pediatric patients have not been established;111,118,120 however, some experts have suggested dosages for hypertension based on clinical experience.258

Geriatric Precautions

Clinical studies of atenolol (used for angina pectoris associated with coronary atherosclerosis or hypertension) and of atenolol in fixed combination with chlorthalidone (used for hypertension) did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults.111,118,120 In addition, in a large clinical study (ISIS-1) evaluating atenolol in 8037 patients for the management of suspected acute MI, 2644 patients (about 33%) were 65 years of age or older, and there were no overall differences in safety or efficacy observed between geriatric individuals and younger adults; however, geriatric patients with systolic blood pressure below 120 mmHg seemed less likely to benefit from atenolol therapy.111,120 Although other clinical experience has not revealed age-related differences in response to the drug, care should be taken in dosage selection of atenolol.111,118,120 Because of greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, the manufacturers suggest that patients in this age group receive initial dosages of the drug in the low end of the usual range.111,118,120

The manufacturers state that evaluation of geriatric patients with hypertension or MI always should include assessment of renal function.111,120

Pregnancy, Fertility, and Lactation

Pregnancy

Atenolol has been shown to cause a dose-related increase in embryonal and fetal resorptions in rats when given at dosages 25 or more times the maximum human antihypertensive dosa similar effects were not observed in rabbits receiving atenolol dosages up to 12.5 times the maximum human antihypertensive dosage. Atenolol crosses the placenta102,111,118,120 and has been detected in cord blood.111,118,120 Atenolol can cause fetal harm when administered to pregnant women.111,118,120 There are no studies on use of the drug during the first trimester of pregnancy and the possibility of fetal injury cannot be excluded.111,118,120 Atenolol therapy initiated in the second trimester of pregnancy has been associated with birth of infants who were small for gestational age.111,118,120 Atenolol has been used effectively under close supervision for the management of hypertension during the third trimester108,109,110 in a limited number of women and was well tolerated, and apparently did not adversely affect the fetus.108,109,110 However, use of the drug for longer periods of time for the management of mild to moderate hypertension in pregnant women has been associated with intrauterine growth retardation.164,165 Neonates born to mothers who receive atenolol at parturition may be at risk for developing hypoglycemia and bradycardia.111,118,120 Caution is recommended when atenolol is administered during pregnancy.111,118,120 If atenolol is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.111,118,120

Fertility

Reproduction studies in male and female rats using atenolol dosages up to 200 mg/kg daily (100 times the maximum recommended human antihypertensive dosage) have not revealed evidence of impaired fertility.

Lactation

Atenolol is distributed into milk.103,107,111,118,120,125,129 The drug distributes into milk in concentrations 1.5-6.8 times those in maternal serum.103,111,118,120,131 In at least one infant, potentially toxic serum atenolol concentrations (2 mcg/mL) have been reported 48 hours after discontinuance of breast-feeding.125 Neonates of mothers who receive atenolol during breast-feeding may be at risk of developing hypoglycemia and adverse β-adrenergic effects (e.g., bradycardia).111,118,120 125 Therefore, the manufacturers state that atenolol should be used cautiously in nursing women.111,118,120,151 Because clearance of the drug may be substantially impaired, premature neonates, and infants with impaired renal function, may be at increased risk of developing adverse effects from ingested atenolol during breast-feeding.111,117,129,130,131 If a woman receiving atenolol breast-feeds, the infant should be monitored closely for potential systemic effects of the drug.103,107,125,129 Alternatively, β-blockers that distribute less extensively into milk (e.g., propranolol) can be considered, although caution still must be exercised.125,129,131

Cardiovascular Drugs

Concomitant administration of atenolol with reserpine may increase the incidence of hypotension and bradycardia as compared with atenolol alone, because of reserpine's catecholamine-depleting activity. Atenolol also is additive with and may potentiate the hypotensive actions of other hypotensive agents (e.g., calcium-channel blockers, hydralazine, methyldopa). This effect usually is used to therapeutic advantage, but dosage should be carefully adjusted when these drugs are used concurrently. Because β-blockers may exacerbate rebound hypertension that may occur following discontinuance of clonidine therapy, atenolol should be discontinued several days before clonidine when clonidine therapy is to be discontinued in patients receiving atenolol and clonidine concurrently.

Patients currently receiving another β-blocker must be evaluated carefully prior to initiating atenolol therapy.111,120 Depending on clinical findings (e.g., blood pressure, pulse), initial and subsequent atenolol dosage can be adjusted downward.111,120

Slowing or complete suppression of SA node activity with development of slow ventricular rates (e.g., 30-40 bpm), often misdiagnosed as complete AV block, has been reported in patients receiving the nondihydropyridine calcium-channel blocking agent mibefradil (no longer commercially available in the US), principally in geriatric patients and in association with concomitant β-adrenergic blocker therapy.167,168

Parenteral atenolol should be used with caution in patients who recently have received another drug that also may have a negative inotropic effect on the myocardium.111,120 Concomitant therapy with a β-blocker and verapamil can result in potentially serious adverse reactions, particularly in patients with severe cardiomyopathy, heart failure, or recent myocardial infarction (MI).111,120 (See Drug Interactions: β-Adrenergic Blocking Agents, in Verapamil Hydrochloride 24:28.92.)

Nonsteroidal Anti-inflammatory Agents

Concurrent use of cyclooxygenase (prostaglandin synthase) inhibitors (e.g., indomethacin) may decrease the hypotensive effects of β-blockers.111,118,120 However, information on concomitant use of atenolol and aspirin is limited.111,120 Evidence from several studies (e.g., Thrombolysis in Myocardial Infarction Phase II [TIMI-II],126 Second International Study of Infarct Survival [ISIS-2])127 suggests a lack of any clinically important adverse interaction and that the drugs can be used safely and effectively together in patients with MI.111,120,122

Acute Toxicity

Manifestations

Limited information is available on atenolol overdosage.104,105,106,119 In one woman who reportedly ingested 1.2 g of the drug, no unusual effects occurred and the patient's recovery was uncomplicated,104 and adults have survived acute doses up to 5 g;111,118,120 however, in a woman 15 years of age who reportedly ingested a single 500-mg dose of atenolol, severe sinus bradycardia, hypotension, and marked hypoglycemia occurred,119 and death occurred in a man who may have ingested up to 10 g acutely.111,118,120 In general, overdosage of atenolol may be expected to produce effects that are mainly extensions of pharmacologic effects, including symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure; hypoglycemia, impaired conduction, decreased cardiac contractility, heart block, shock, and cardiac arrest may also occur.105,106,119

Treatment

In acute atenolol overdose, the stomach should be emptied immediately by gastric lavage. Supportive and symptomatic treatment should be initiated. For symptomatic bradycardia, IV atropine sulfate may be given and for second- or third-degree AV block, IV isoproterenol hydrochloride274 or a transvenous cardiac pacemaker may be used. A vasopressor (e.g., dobutamine, dopamine, epinephrine, norepinephrine) may be given for severe hypotension; IV glucagon may be useful if hypotension is refractory to vasopressors.105,106 For heart failure, a cardiac glycoside, diuretic, and oxygen should be used; IV glucagon also may be useful.105,106 Hypoglycemia should be treated with IV dextrose. Hemodialysis may be useful in enhancing elimination of atenolol in patients with severe overdosage.

Pharmacology

Atenolol has pharmacologic actions similar to those of other β-blockers. The principal physiologic action of atenolol is to competitively block adrenergic stimulation of β-adrenergic receptors within the myocardium and within vascular smooth muscle. Like metoprolol, low doses of atenolol selectively inhibit cardiac and lipolytic β₁-adrenergic receptors while having little effect on the β₂-adrenergic receptors of bronchial and vascular smooth muscle. At high doses (e.g., greater than 100 mg daily), this selectivity of atenolol for β₁-adrenergic receptors usually diminishes, and the drug will competitively block β₁- and β₂-adrenergic receptors. Atenolol does not exhibit the intrinsic sympathomimetic activity seen with pindolol or the membrane-stabilizing activity possessed by propranolol or pindolol.

By inhibiting myocardial β₁-adrenergic receptors, atenolol produces negative chronotropic and inotropic activity. The negative chronotropic action of atenolol on the sinoatrial (SA) node results in a decrease in the rate of SA node discharge and an increase in recovery time, thereby decreasing resting and exercise-stimulated heart rate and reflex orthostatic tachycardia by about 25-35%. High doses of the drug may produce sinus arrest, especially in patients with SA node disease (e.g., sick sinus syndrome). Atenolol also slows conduction in the atrioventricular (AV) node. Although stroke index may be increased moderately by about 10%, atenolol usually reduces cardiac output by about 20%, probably secondary to its effect on heart rate. The decrease in myocardial contractility and heart rate, as well as the reduction in blood pressure, produced by atenolol generally lead to a reduction in myocardial oxygen consumption which accounts for the effectiveness of the drug in chronic stable angina pectoris; however, atenolol can increase oxygen requirements by increasing left ventricular fiber length and end-diastolic pressure, particularly in patients with cardiac failure.111

Atenolol suppresses plasma renin activity and suppresses the renin-aldosterone-angiotensin system. The renin-lowering effect of β-blockers may lead to a minimal reduction in glomerular filtration rate and occasionally may reduce renal blood flow; however, other mechanisms (e.g., decreased cardiac output, unopposed α-mediated renal vasoconstriction) also probably contribute to these effects. Because of the suppression of aldosterone production, β-blockers usually produce no measurable increases in plasma volume or sodium and water retention.

The precise mechanism of atenolol's hypotensive effect has not been determined. Single doses of atenolol may increase peripheral vascular resistance at rest and with exercise. It has been postulated that β-blockers reduce blood pressure by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renal renin release.

Because of its β₁-receptor selectivity, low doses (100 mg or less) of atenolol usually have little effect on bronchial airway resistance. Higher doses of atenolol may result in an increase in airway resistance (as measured by decreasing forced expiratory volume in 1 second), especially in patients with asthma and/or chronic obstructive pulmonary disease (COPD).

Low doses of atenolol produce no changes in serum insulin concentrations or in time to recover from insulin-induced hypoglycemia, and little change in free fatty acid response to hypoglycemia. The drug reduces serum free fatty acid concentrations and slightly increases serum triglyceride concentrations.

Pharmacokinetics

Absorption

Atenolol is rapidly but incompletely absorbed from the GI tract. Only about 50-60% of an oral dose of atenolol is absorbed. In healthy adults, peak plasma concentrations of 1-2 mcg/mL are achieved 2-4 hours after oral administration of a single 200-mg dose of atenolol. An approximately fourfold interindividual variation in plasma concentrations attained has been reported with a specific oral dose of atenolol. In geriatric patients, plasma concentrations are increased.111,118,120 Peak plasma atenolol concentrations are achieved within 5 minutes following direct IV injection of the drug, and decline rapidly during an initial distribution phase; after the first 7 hours, plasma concentrations reportedly decline with an elimination half-life similar to that of orally administered drug.111,120

The effect of atenolol on heart rate usually has an onset of 1 hour, peaks at 2-4 hours, and persists for 24 hours following oral administration of the drug. Following IV administration of a single 10-mg dose, the effect on heart rate usually peaks within 5 minutes and generally is negligible by 12 hours after the dose.120 The antihypertensive and β-adrenergic blocking effect of a single 50- to 100-mg oral dose usually persists for 24 hours. Atenolol's effect on heart rate, but not on blood pressure, correlates linearly with plasma atenolol concentrations of 0.02-200 mcg/mL.

Distribution

In animals, atenolol is well distributed into most tissues and fluids except brain and CSF. Unlike propranolol, only a small portion of atenolol is apparently distributed into the CNS.

Approximately 6-16% of atenolol is bound to plasma protein.111,118,120

Atenolol readily crosses the placenta102,111,118,120 and has been detected in cord blood.111,118,120 During continuous administration, fetal serum concentrations of the drug are probably equivalent to those in maternal serum.102 Atenolol is distributed into milk;103,107,111,118,120,125,129 peak milk concentrations of the drug are higher than peak serum concentrations after an individual dose,103,107 and the area under the milk concentration-time curve (AUC) is substantially greater than that of the serum AUC in lactating women receiving the drug continuously.103,111,118,120,125,129 (See Cautions: Pregnancy, Fertility, and Lactation.)

Elimination

In patients with normal renal function, atenolol has a plasma half-life (t_½) of 6-7 hours. Children with normal renal function may exhibit a shorter elimination half-life.133 In one study in children 5-16 (mean: 8.9) years of age with arrhythmias and normal renal and hepatic function, the terminal elimination half-life averaged 4.6 hours.133 The plasma half-life(t_½) of atenolol is markedly prolonged in geriatric patients compared with that in younger patients.111,118,120 Plasma t_½ of the drug increases to 16-27 hours in patients with creatinine clearances of 15-35 mL/minute per 1.73 m² and exceeds 27 hours with progressive renal impairment. Little or no metabolism of atenolol occurs in the liver. Approximately 40-50% of an oral dose of the drug is excreted in urine unchanged. The remainder is excreted unchanged in feces, principally as unabsorbed drug. About 1-12% of atenolol is reportedly removed by hemodialysis.

In geriatric patients, total plasma clearance of atenolol is reduced by about 50% compared with that in younger patients, resulting in higher plasma concentrations of the drug.111,118,120 The decreased clearance in geriatric adults may be related to decreased renal function in this age group.111,118,120

Chemistry and Stability

Chemistry

Atenolol is a β₁-selective adrenergic blocking agent.111,118,120 The drug occurs as a white, crystalline powder and has a solubility of 26.5 mg/mL in water at 37°C.111,118,120

Stability

Atenolol tablets alone or in fixed combination with chlorthalidone should be protected from heat, light, and moisture and stored in well-closed, light-resistant containers at 20-25°C.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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