Comparison of Oral Beta-Blockers

Full update March 2017

Agent
Pharmacokinetics**

FDA-labeled Regimensb

Clinical Benefit in…*

Comments

Availability
Cost of 30-day supplya

Noncardioselective Agents (beta-1 and beta-2 antagonist activity) More likely to cause peripheral vasoconstriction or bronchoconstriction, delay recovery from hypoglycemia in type 1 diabetes, and impair exercise performance.4

Nadolol
Corgard

Low lipophilicity

Renal excretion

Long half-life

Angina/ HTN: Start with 40 mg once daily. Usual dose 40-80 mg once daily.

Max dose: 160-240 mg once daily for angina, 240-320 mg once daily for HTN.

A fib: For rate control. Usual dose 10-240 mg once daily.1

Migraine prevention: Probably effective.2 Usual dose 80 mg once daily.3 Max 240 mg once daily.3

Adjust dosing interval for CrCl ≤50 mL/min

20, 40, 80 mg scored tabs

$127.84 for 80 mg once daily (generic)

Propranolol, immediate-release
Inderal

(brand no longer available)

High lipophilicity

Extensive first-pass hepatic metabolism

Bioavailability variable; increased 50% by high-protein food

Hepatic elimination

Angina: 80-320 mg/day, divided BID-QID

A Fib: 10-30 mg TID-QID

Essential tremor: Start with 40 mg BID. Usual dose 120 mg/day. Max dose 320 mg/day.

HTN: Start with 40 mg BID. Usual dose 120-240 mg/day, divided BID or TID. Max dose 640 mg/day.

Hypertrophic subaortic stenosis: 20-40 mg TID-QID

Post-MI: 40 mg TID, titrated to target dose of 180-240 mg/day divided BID-QID.

Migraine prevention: Start with 80 mg/day, divided. Usual dose 160-240 mg/day.

Pheochromocytoma (with alpha-blocker): 60 mg/day, divided, for 3 days before surgery, or 30 mg/day, divided, for inoperable tumors.

A Fib: For rate control. Usual maintenance dose 10-40 mg TID-QID.1

Post-MI: Reduces cardiovascular and total mortality (BHAT)

Migraine prevention: Established efficacy2

Substrate of CYP2D6, CYP1A2, CYP2C19, and P-gp

Caution with renal or hepatic impairment

Continue for up to three years post-MI6,7

Low concentrations in breast milk.8

Risk of fatigue slightly higher than newer agents5

Wide dosing range may lead to more dosage adjustments than other agents4

10, 20, 40, 60, 80 mg scored tabs; 20 mg/5 mL, 40 mg/5 mL oral solution

$5.49 for 40 mg TID (generic tabs)

IV formulation available

Propranolol, extended-release
Inderal LA, Inderal XL

Once-daily sustained-release formulation

High lipophilicity

Extensive first-pass hepatic metabolism

Inderal LA produces lower blood levels than immediate-release formulation at the same dose.

Hepatic elimination

Inderal LA

Angina: Start with 80 mg once daily. Usual dose 160 mg once daily. Max dose 320 mg once daily.

HTN: Start with 80 mg once daily. Usual dose 120-160 mg once daily. Max dose 640 mg once daily.

Hypertrophic subaortic stenosis: Usual dose 80-160 mg once daily.

Migraine prevention: Start with 80 mg once daily. Usual dose 60-240 mg once daily.

Inderal XL

HTN: Start with 80 mg HS. May increase up to 120 mg HS.

Migraine prevention: Established efficacy3

Substrate of CYP2D6, CYP1A2, CYP2C19, and P-gp

Caution with renal or hepatic impairment

Risk of fatigue slightly higher than newer agents5

Inderal LA 60, 80, 120, 160 mg extended-release caps

Inderal XL 80, 120 mg extended-release caps

$72.67 for 120 mg once daily (generic) ***can’t be substituted for Inderal XL***

$681.40 for 120 mg once daily (Inderal XL)

Timolol
Blocadren

(brand discontinued)

Low to moderate lipophilicity4

Moderate first-pass

hepatic metabolism

Hepatic elimination4

HTN: Start with 10 mg BID. Usual dose of 20-40 mg/day. Max dose 60 mg/day, divided BID.

Post-MI: 10 mg BID

Migraine prevention: Start with 10 mg BID. Can give 20 mg once daily as maintenance dose. Max dose 30 mg/day, divided BID. Some patients may only need 10 mg once daily.

Post-MI: Reduces cardiovascular and total mortality, including sudden death, and reduces risk of nonfatal reinfarction (NMS)17

Migraine prevention: Established efficacy2

Substrate of CYP2D64

Caution with renal or hepatic impairment.

Continue for up to three years post-MI6,7

Risk of fatigue slightly higher than newer agents5

5 mg tabs; 10, 20 mg scored tabs

$188.52 (average wholesale price) for 20 mg BID (generic)

Cardioselective Agents (beta-1 antagonist activity only) Selectivity is not absolute and is lost with higher doses.

Atenolol
Tenormin

Low lipophilicity4

Bioavailability about 50%

Renal elimination

Angina: Start with 50 mg once daily. May increase to 100 mg once daily. Max dose 200 mg once daily.

HTN: Start with 50 mg once daily. May be increased to 100 mg once daily.

Post-MI: 50 mg BID or 100 mg once daily

A fib: For rate control. Usual maintenance dose 25-100 mg once daily.1

HTN: Atenolol not better than placebo for CV outcomes.18 Losartan had fewer strokes and greater regression of LVH than atenolol in LIFE study.9 Amlodipine +/− perindopril had lower mortality and stroke than atenolol +/− bendroflumethiazide in ASCOT.10

Migraine prevention: Probably effective.2 Usual dose 100 mg once daily.3

Reduce dose for CrCl ≤35 mL/min

Continue for up to three years post-MI6,7

Experts emphasize that atenolol may not reduce CV risk in patients with hypertension.12

FDA-approved for early use post-MI after IV beta-blockade. Due to increased risk of cardiogenic shock in COMMIT/CCS-2 trial of IV metoprolol, IV beta-blockade is used selectively.16

25, 50 (scored), 100 mg tabs

<$1 for 50 mg once daily (generic)

Betaxolol (generic only)

Moderate lipophilicity4

Low first-pass hepatic elimination

Bioavailability ~90%

Mostly hepatic elimination

HTN: Start 10 mg once daily. May increase to 20 mg once daily. Max dose 40 mg once daily.


Reduce dose in severe renal impairment

10 mg scored tabs, 20 mg tabs

$15.32 for 10 mg once daily (generic)

Bisoprolol
Zebeta

Low lipophilicity4

Low first-pass

Bioavailability 80%

50% renal elimination

HTN: Start 5 mg once daily. Increase to 10 mg, then 20 mg once daily if needed.

A Fib: For rate control. Usual maintenance dose 2.5-10 mg once daily.1

Angina: Effective. Doses of 5 to 20 mg once daily have been studied.3

HF: Reduces mortality (CIBIS-II). Usual starting dose is 1.25 mg once daily titrated to target dose of 10 mg once daily.13

Reduce starting dose to 2.5 mg once daily for CrCl
<40 mL/min, liver disease, or bronchospastic disease

5 mg scored tabs, 10 mg tabs

$21.38 for 10 mg once daily (generic)

Metoprolol tartrate, immediate-release

Lopressor

Moderate lipophilicity4

Bioavailability about 40%-50% due to first-pass hepatic metabolism4

Hepatic elimination

Angina: Start with 50 mg BID. Max dose 400 mg/day.

HTN: Start with 100 mg once daily or divided. Max dose 450 mg/day. If effect does not last 24 h with once-daily dosing, divide dose.

Post-MI: Start with 50 mg every six hours, decreasing to 25 mg if not tolerated, for 48 hours. Thereafter, dose is 100 mg BID.

A fib: For rate control. Usual maintenance dose is 25-100 mg BID.1

HF: Greater reduction in mortality with carvedilol than with immediate-release metoprolol tartrate in COMET.14

Post-MI: Reduces total mortality, sudden death, and reinfarction (Goteborg).15

Migraine prevention: Established efficacy.2 Usual dose is 25 mg BID to 200 mg/day, divided.3

Substrate of CYP2D6

Half-life prolonged in hepatic impairment

Continue for up to three years post-MI6,7

FDA-approved for early use post-MI after IV beta-blockade. Due to increased risk of cardiogenic shock in COMMIT/CCS-2 trial of IV metoprolol, IV beta-blockade is used selectively.16

50, 100 mg scored tabs

$2.36 for 100 mg BID (generic)

IV formulation available

Metoprolol succinate, extended-release

Toprol-XL

Moderate lipophilicity4

Sustained-release formulation that maintains therapeutic plasma concentrations for 24 hours

Bioavailability about 40%-50% due to first-pass hepatic metabolism4

Hepatic elimination

Angina: Start with 100 mg once daily. Max dose 400 mg/day.

HF: Start with 25 mg once daily for Class II HF, or 12.5 mg once daily for more severe HF. Target dose is highest dose tolerated. Max dose 200 mg/day.

HTN: Start with 25-100 mg once daily. Max dose 400 mg/day.

A fib: For rate control. Usual maintenance dose is 50-400 mg once daily.1

HF: Reduces mortality and cardiovascular hospitalization (MERIT-HF).

Reduce starting dose in hepatic impairment

25, 50, 100, 200 mg scored extended-release tabs

$45.30 for 200 mg once daily (generic)

Nebivolol
Bystolic

Low lipophilicity4

Bioavailability not determined

HTN: Start with 5 mg once daily. Max dose 40 mg/day.

HF: Reduced composite endpoint of mortality and cardiovascular hospitalizations in the elderly (SENIORS)11 Start with 1.25 mg once daily, titrated to target dose of 10 mg once daily.11

Migraine prevention: Possibly effective.2 Dose is 5 mg once daily.3

Substrate of CYP2D6

Starting with 2.5 mg once daily for CrCl <30 mL/min or moderate hepatic impairment. Contraindicated in severe liver impairment.

Causes peripheral vasodilation by increasing nitric oxide production4

2.5, 5, 10, 20 mg tabs

$119.46 for 5 mg once daily

Agents with alpha-1 antagonist activity
These agents cause peripheral vasodilation4

Carvedilol, immediate-release
Coreg

Not cardioselective4

Moderate lipophilicity4

Bioavailability 25% to 35% due to first-pass hepatic metabolism

Hepatic elimination

HF: Start with 3.125 mg BID, titrated to target dose of 25 mg BID (can use 50 mg BID for patients over 85 kg with mild-moderate HF). Reduce dose if HR <55.

HTN: Start with 6.25 mg BID. Max dose 25 mg BID.

LVD after MI: Start with 6.25 mg BID, titrated to target dose of 25 mg BID.

A Fib: For rate control. Usual maintenance dose 3.125-25 mg BID.1

HF: Reduces mortality in NYHA stage 2-4; has the strongest evidence for benefit in severe failure (COPERNICUS). Greater reduction in mortality than with immediate-release metoprolol tartrate in COMET.14

Post-MI with LVD: Reduces mortality and reinfarction in patients taking an ACEI (CAPRICORN)

Substrate of CYP2D6

Contraindicated in severe hepatic impairment

Continue for up to three years post-MI6,7

3.125, 6.25,12.5, 25 mg tabs

$3.51 for 12.5 mg BID (generic)

Carvedilol phosphate, extended-release
Coreg CR

Sustained-release formulation that maintains therapeutic plasma concentrations for 24 hours

Not cardioselective4

Moderate lipophilicity4

Bioavailability 25% to 35% due to first-pass hepatic metabolism

Hepatic elimination

HF Start with 10 mg once daily, titrated to a target dose of 80 mg once daily (equal to 25 mg BID immediate-release product). Reduce dose if HR <55.

HTN Start 20 mg once daily. Max dose 80 mg once daily.

LVD after MI: Start with

10-20 mg once daily. Max dose 80 mg once daily.

None

Should not be used in patients with severe hepatic impairment.

When switching from carvedilol immediate-release 12.5 mg BID or 25 mg BID, consider a starting dose of Coreg CR 20 mg or 40 mg once daily, respectively, especially in patients at increased risk of hypotension, dizziness, or syncope (e.g., the elderly).

Continue for up to three years post-MI6,7

10, 20, 40, 80 mg

extended-release caps

$275.27 for 40 mg QD

Labetalol
Trandate

Not cardioselective4

Low lipophilicity4

Bioavailability 20% to 40% due to first-pass metabolism.
Bioavailability may be increased by food.4

Hepatic elimination4

HTN: Start with 100 mg BID. Usual dose 200-400 mg BID. Max dose 2,400 mg/day. If nausea and/or dizziness occur, consider TID dosing.


Wide dosing range may lead to more dosage adjustments than other agents

Caution with hepatic impairment

Rare hepatic injury

A preferred antihypertensive in pregnancy. Low concentrations in breast milk.

100, 200, 300 mg scored tabs

$26.67 for 200 mg BID (generic)

IV formulation available for hypertensive emergencies

Agents with intrinsic sympathomimetic activity (ISA)
Decrease in resting heart rate and negative inotropic activity may be less than with other beta-blockers.4

Acebutolol
Sectral

Cardioselective

Mild ISA

Low lipophilicity4

Bioavailability 40% due to first-pass metabolism to active metabolite which is excreted in urine

HTN: Start with 400 mg/day once daily or divided BID. Usual dose 400-800 mg/day. Max dose 600 mg BID.

Ventricular arrhythmias: Start with 200 mg BID. Max dose 300-600 mg BID.

Reduce dose for CrCl <50 mL/min.

Migraine prevention: possibly ineffective; avoid.2

Agents without ISA are preferred for hypertension in patients with angina.16

200, 400 mg caps

$14.46 for 200 mg BID (generic)

Penbutolol
Levatol

Not cardioselective4

High lipophilicity4

Hepatic metabolites excreted in urine

HTN: Start with 20 mg once daily. Benefit of increasing dose to 40 or 80 mg/day not demonstrated.

None

20 mg scored tabs

$101.70 for 20 mg once daily

Pindolol
Visken

(brand no longer available)

Not cardioselective

Low lipophilicity4

HTN: Start with 5 mg BID. Max dose 60 mg/day.

Migraine prevention: Possibly effective.2

5, 10 mg scored tabs

$71.91 for 10 mg BID (generic)

Abbreviations: ACEI = angiotensin converting-enzyme inhibitor; ACS = acute coronary syndrome; A fib = atrial fibrillation; BID = twice daily; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P450; HF = heart failure; HR = heart rate; HS = at bedtime; HTN = hypertension; ISA = intrinsic sympathomimetic activity; LVD = left ventricular dysfunction; LVH = left ventricular hypertrophy; MI = myocardial infarction; NYHA = New York Heart Association; P-gp = P-glycoprotein; QID = four times daily; TID = three times daily.

  1. Cost is wholesale acquisition cost (WAC) unless otherwise noted.
  2. Consider reducing starting doses in elderly patients.11

* Clinical Trial Acronyms: ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial, BHAT = Beta-Blocker Heart Attack Trial, CAPRICORN = Carvedilol Post Infarction Survival Control in Left Ventricular Dysfunction, CIBIS-II = Cardiac Insufficiency Bisoprolol Study II, COMET = Carvedilol or Metoprolol European Trial, COMMIT/CCS-2 = Clopidogrel and Metoprolol in Myocardial Infarction Trial – Second Chinese Cardiac Study, COPERNICUS = Carvedilol Prospective Randomized Cumulative Survival, LIFE = Losartan Intervention For Endpoint Reduction in Hypertension, MERIT-HF = Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure, NMS = Norwegian Multicenter Study, SENIORS = Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure.

** Sotalol (Betapace) excluded from chart because of restrictions for use and the fact that it is not considered a “typical beta-blocker.” Esmolol (Brevibloc) is not included, as it is available only as an IV formulation.

U.S. product labeling used for the above chart (unless otherwise noted): Corgard (July 2013); propranolol immediate-release (Impax, May 2016); Inderal LA (June 2012); Inderal XL (November 2013), timolol (Mylan, August 2006); Tenormin (December 2014); betaxolol (Marlex, July 2016); Zebeta (October 2015); Lopressor (August 2015); Toprol-XL (June 2016) Bystolic (January 2014); Coreg (October 2015); Coreg CR (October 2015); Trandate (November 2010); Sectral (April 2008); Levatol (May 2011); pindolol (Mylan, November 2016).

Project Leader in preparation of this clinical resource (330356): Melanie Cupp, Pharm.D., BCPS; last modified September 2017

References

  1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2014;130:e199-267.
  2. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78:1337-45.
  3. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2017. http://www.clinicalpharmacology.com. (Accessed January 23, 2017).
  4. Westfall TC, Westfall DP. Adrenergic agonists and antagonists. In: Chabner BA, Brunton LL, Knollmann BC, Eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011.
  5. Ko DT, Hebert PR, Coffey CS, et al. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288:351-7.
  6. Cefalu WT, Bakris G, Blonde L, et al. American Diabetes Association standards of medical care in diabetes – 2017. Diabetes Care 2016;40:S1-112.
  7. Clinical Resource, Improving Outcomes After Myocardial Infarction. Pharmacist’s Letter/Prescriber’s Letter. August 2017.
  8. American College of Obstetricians and Gynecologists. Task Force on Hypertension in Pregnancy 2013. http://www.acog.org/Resources-And-Publications/Task-Force-and-Work-Group-Reports/Hypertension-in-Pregnancy. (Accessed January 28, 2017).
  9. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003.
  10. Ostergren J, Poulter NR, Sever PS, et al. The Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-lowering limb: effects in patients with type II diabetes. J Hypertens 2008;26:2103-11.
  11. Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005;26:215-25.
  12. Karagiannis A, Athyros VG, Papageorgiou A, et al. Should atenolol still be recommended as first-line therapy for primary hypertension? Hellenic J Cardiol 2006;47:298-307.
  13. [No authors listed]. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9-13.
  14. Poole-Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol OR Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362:7-13.
  15. Hjalmarson A, Herlitz J, Holmberg S, et al. The Goteborg metoprolol trial. Effects on mortality and morbidity in acute myocardial infarction. Circulation 1983;67(6 Pt 2):i26-32.
  16. Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. J Am Soc Hypertens 2015;9:453-98.
  17. Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801-7.
  18. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet 2004;364:1684-9.

Cite this document as follows: Clinical Resource, Comparison of Oral Beta-Blockers. Pharmacist’s Letter/Prescriber’s Letter. March 2017.

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