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Beta Adrenergic Receptor Blockers (BBs)

This pharmacologic review was prompted by the entry of a new third generation beta-blocker, Bystolic© (nebivolol), as well as recent meta-analysis questioning the use of BBs as first line therapy for essential HTN. Although safe for most patients, BBs have been associated recently with an increase in mortality and a decrease in effectiveness for certain indications compared to other medications (1,2).

Are Beta-blockers still first line therapy for numerous disease states? • Are there differences between BBs that may affect first line indications? • What do the variations in Beta receptor selectivity and lipid solubility mean clinically?

BBs are old drugs, what’s new in the last year? • Bystolic© (nebivolol) • New generics; Toprol XL© (metoprolol ER), Coreg© (carvedilol)

BBs: • BBs function by blocking the action of endogenous catecholamine’s (Epinephrine and norepinephrine) by

blocking beta-adrenergic receptors (BARs). Blocking of BARs have an effect on regulation of circulation through a number of mechanisms which include a reduction in myocardial contractility, HR & CO(1,2).

• An important mechanism of BBs to highlight is the blockade of BARs in the juxtaglomerular complex, reducing rennin secretion and decreasing production of circulating angiotensin II(1,2).

• BBs have been shown to increase risk for new onset diabetes mellitus (DM), most commonly atenolol. Literature Highlights: (3)

Bangalore et al conducted a meta-analysis on the risk of new onset DM after initiation of BB for treatment of HTN. A search of RCTs of patients taking BBs as 1st line therapy for HTN with follow-up of at least 1 year from 1966 to 2007. o 2 studies (total of 16,372 patients) compared a BB (1,102 atenolol, 4,403 propranolol) and placebo. There was a 33% increased

risk for new onset DM (RR:1.33, p=0.05). This was more pronounced in the elderly (>60yo:RR:2.13) than the younger groups (<60yo:RR:1.01).

7 studies (total of 65,765 patients) comparing BBs (19,097 patients took atenolol, 405 patients took metoprolol) with a nondiuretics antiHTN agent (ACEI, CCB or ARB), BBs therapy resulted in 22%, 21% and 19% increase risk of new onset DM compared to a CCB, ACEI or ARB respectively.

Dahlof et al (4) conducted prospective, multicenter, RCT 19,257 patients (40-79yo) w/HTN & least 3 other CV risk factors. o Incidence of developing new onset diabetes was lower for amlodipine (567 (6%)) vs atenolol (799(15.9%)) (HR: 0.70, p<0.0001).

• BBs were less effective than CCBs in preventing morbidity and stroke. They were also less effective in preventing cardiac events compared to other antiHTN agents.

Literature Highlight: (Dahlof et al) (4) Amlodipine group showed significant decrease in fatal & non-fatal stroke (Amlodipine: 327(3%), Atenolol 422(4%); HR: 0.77, p=0.0003) Total CV events and procedures (Amlodipine: 1362 (14%) vs. Atenolol: 1602(17%); HR: 0.84, p<0.0001) All-cause mortality (Amlodipine: 738 (8%) vs Atenolol: 820(9%); HR: 0.89, p=0.025)

• BBs found less effective than CCBs to prevent stroke. Comparison relative to other antiHTN agents (diuretics, ACEI, ARB) necessary to figure out if BBs should be considered alternative to CCB or 3rd line.

Literature Highlight: (Wiysonge et al) (2) Risk of all-cause mortality NO different 1st line BBs vs. placebo, diuretics or ACEI/ARB, but higher for BBs compared to CCB (P<0.04). Patients taking a BB had more stroke events than those treated with a CCB, ACEI or ARB.

• The newest BB, nebivolol, has the highest affinity for ß1 receptors among BBs & might reduce BB side effects & be more effective for HTN management and stroke prophylaxis (5,6).

• Even though atenolol & nebivolol are both ß1 selective BB, the higher affinity for ß1 receptor & NO mediated vasodilatory actions may prove nebivolol a better alternative than atenolol to control HTN (5-7).

• Studies on nebivolol gave promising results (reduction of BP without causing new onset of DM); however, studies on long-term effects needed to confirm use of nebivolol as 1st line therapy for HTN (5-7).

• Pending future studies, BBs should NOT be used as 1st line therapy for essential HTN unless patients have other co-morbidities (post-MI, CHF, and Afib) (5-9).

PHARMACOLOGIC CLASS REVIEWSMarch 2008 Disclaimer: Specific agents may have variations

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Insurance Information* Generic (Trade)

FDA-Approved Indications

Available Strengths Elimination Lipophilicity Misc. Properties

IHA(10) BCBS(11) Univera(12)

Non selective β-adrenergic antagonists

Nadolol (Corgard®)

Angina, Hypertension

20, 40, 80, 120, 160mg tablet Renal Low

Brand: Tier 3

Generic: Tier 1

Brand: Tier 3

Generic: Tier 1

Brand: Not listed Generic: Tier 1

Penbutolol (Levatol®) Hypertension 20mg tablet Hepatic High Not listed Not listed Not listed

Pindolol (Visken®)

Angina, Hypertension 5, 10mg tablet Renal, Hepatic Moderate High ISA

Brand: Tier 3

Generic: Tier 1

Brand: Not listed Generic: Tier 1

Brand: Not listed Generic: Tier 1

Propranolol (Inderal®,

Inderal LA®; Propranolol )

Angina; Atrial Fibrillation/Flutter;

Hypertension; IHSS; Migraine prophylaxis;

Pheochromocytoma; PSVT;

Thyrotoxicosis; Post-MI; Tremor

10, 20, 40, 60, 80mg tablet 60, 120, 160 extended rel

capsule 20mg-40mg/5ml

oral solution 1mg/1ml soln for

inj

Hepatic High High MSA

Brand: Tier 3

Generic: Tier 1

Brand: Tier 2/3 Generic: Tier 1

Brand: Tier 3

Generic: Tier 1

Sotalol (Betapace®; Sotalol AF®)

Atrial fibrillation, Atrial flutter, Ventricular tachycardia

80,120,160, 240mg tablet 80, 120,160,

240mg ER tablet

Renal Low Class III antiarrhythmic

Brand: Tier 3

Generic: Tier 1

Brand: Tier 3

Generic: Tier 1

Brand: Not listed Generic: Tier 1

Timolol (Blocadren®)

Hypertension, migraine

prophylaxis; MI prophylaxis

5, 10, 20mg tablet Renal Moderate

Available as ophthalmic solution to treat glaucoma

and ocular hypertension

Brand: Tier 3

Generic: Tier 1

Brand: Tier 3

Generic: Tier 1

Brand: Not listed Generic: Tier 1

Mixed α1-β adrenergic antagonists

Carvedilol (Coreg®,

Coreg CR®)

Acute MI, Cardiomyopathy, HF, Hypertension,

MI prophylaxis

3.125, 6.25, 12.5, 25mg tablet

10, 20, 40, 80mg ER capsule

Hepatic High MSA

Brand: Tier 3

Generic: Tier 1

Brand: Tier 2/3 Generic: Tier 2

Brand: Tier 3

Generic: Tier 2

Labetalol (Normodyne®) Hypertension

100, 200, 300mg tablet

5mg/ml solution of injection

Hepatic Moderate MSA

Brand: Tier 3

Generic: Tier 1

Brand: Not listed Generic: Tier 1

Brand: Not listed Generic: Tier 1

*Current through February 2008 MSA: Membrane Stability Activity ISA: Intrinsic sympathomimetic activity

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Insurance Information* Generic (Trade)

FDA-Approved Indications

Available Strengths Elimination Lipophilicity Misc. Properties

INDEP(10) BCBS(11) Univera(12)

selective β1-adrenergic antagonists

Acebutolol (Sectral®) Hypertension, PVC 200, 400mg tablet Renal, Hepatic low ISA, MSA

Brand: Tier 3

Generic: Tier 1

Brand: Not listed Generic: Tier 1

Brand: Not listed Generic: Tier 1

Atenolol (Tenormin®)

Acute MI, Angina, Hypertension, MI

prophylaxis, post-MI

25, 50, 100mg tablets

0.5ml/1ml solution for injection

Renal low

Brand: Tier 3

Generic: Tier 1

Brand: Not listed Generic: Tier 1

Brand: Not listed Generic: Tier 1

Betaxolol (Kerlone®) Hypertension 10, 20mg tablet Renal Moderate

Available as ophthalmic solution to treat glaucoma

and ocular hypertension (Betoptic®).

MSA

Brand: Not listed Generic: Not listed

Brand: Tier 3

Generic: Tier 1

Brand: Not listed Generic: Tier 1

Bisoprolol (Zebeta®) Hypertension 5, 10mg tablet Renal, Hepatic Moderate

Brand: Tier 3

Generic: Tier 1

Brand: Not listed Generic: Tier 1

Brand: Not listed Generic: Tier 1

Esmolol (Brevibloc®)

Atrial fibrillation, Atrial flutter, PSVT, perioperative/post

operative HTN.

10mg/ml solution for injection Blood Esterase Low Available only IV;

Short half life (9 min)

Generic: Not

available

Generic: Not

available

Generic: Not

available

Metoprolol (Lopressor®,

Toprol®, Toprol XL®)

Acute MI, Angina, Cardpomyopathy,

Heart failure, hypertension, MI

prophylaxis, post MI

25, 50, 100mg tablet

25, 50, 100mg ER tablet

1mg/ml solution for injection

Renal Moderate MSA

Brand: Tier 3

Generic: Tier 1

Brand: Tier 3

Generic: Tier 1

Brand: Not listed Generic: Tier 1

Nebivolol (Bystolic®)

Hypertension 2.5, 5, 10mg tablet Renal, hepatic High Possess antioxidant

properties.

Brand: Not

available

Brand: Not available

Brand: Not available

*Current through February 2008 MSA: Membrane Stability Activity, ISA: Intrinsic sympathomimetic activity

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Beta Blockers – FDA-Approved Adult Doses* and Maximum Daily Doses (1) Non selective β-adrenergic antagonists

(class representatives) Mixed α1-β adrenergic antagonists

(class representatives) selective β1-adrenergic antagonists

(class representatives) ‘3rd Gen’ selective

Indication Nadolol Propanolol Carvedilol Labetalol Atenolol Bisoprolol Metoprolol Nebivolol

Angina 40mg qd IR: 10mg po bid-qid ER: 80mg po qd

** ** 50mg po qd ** IR: 50mg po bid ER: 100mg po qd

usual effective dose range 100 – 400mg qd

**

Hypertension 40mg qd IR: 40mg po bid ER: 80mg po qd

IR: 6.25mg po bid ER: 20mg po qd

100mg bid 25mg po qd 5mg po qd IR: 50mg po bid-tid ER: 25mg po qd

5mg qd (titrate at 2-

week intervals)

Cardiomyopathy/ Heart Failure

** ** IR: 6.25mg po bid ER: 20mg po qd

** ** ** ER: Initially - 12.5mg qd (Class III);

25mg qd (Class II); double dose q 2 weeks

until target dose of 200mg daily (if tolerated)

** OFF-label;

1.25qd up to 10qd in

SENIORS trial

Post-MI / MI prophylaxis

** IR: 80mg po bid-tid ER: 120mg po qd

IR: 6.25mg po bid ER: 20mg po qd

** 50mg po qd ** IR: 100mg bid x at least 3months;

maintenance dose 50 – 100mg bid

**

Migraine Prophylaxis

** IR: 80mg/day div 2-3x ER: 80mg po qd

** ** ** ** ** **

Pheochromocytoma ** IR: 80mg po bid-tid ER: 80mg po qd

** ** ** ** ** **

Atrial fibrillation/flutter

** IR: 10mg po tid-qid ** ** ** ** ** **

PSVT ** IR: 10mg po tid-qid

** ** ** ** ** **

IHSS ** IR: 20mg po tid-qid ER: 80mg po qd

** ** ** ** ** **

Essential Tremor ** IR: 40mg po bid ** ** ** ** ** **

Thyrotoxicosis ** IR: 10mg po qid ** ** ** ** ** **

Usual Maximum Daily Dose

HTN: 320mg Angina: 240mg

IHSS: 160 Angina: 320 HTN: 640

IR: 50/100mg ER: 80mg

2400mg HTN: 100mg Angina: 200mg

20mg IR: 450mg ER: 400mg

40mg

HTN: Hypertension, MI: Myocardial Infarction, PSVT: Paroxysmal Supraventricular Tachycardia, IHSS: Idiopathic Hypertrophic Subaortic Stenosis, PVC: Premature Ventricular Contraction

(*Unless otherwise noted, all doses are the FDA-approved starting dose) (**Not FDA-approved for this indication)

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Points of Interest (8,9,13) BBs are indicated to treat hypertension, per Joint National Committee (JNC 7), for patients with heart failure, postmyocardial infarction, high coronary disease risk or diabetes. Based on recent meta-analyses, two new hypertension guidelines, NICE (National Institute for Health and Clinical Excellence) and BHS (British Hypertension Society) have proposed that beta blockers were no longer suitable first line therapy for patients without complications. Two issues contributed to these recent changes:

One main issue is the association between beta blockers with new onset diabetes mellitus compared to other antihypertensive regimens: Calcium Channel Blockers (CCB), Angiotensin Converting Enzyme Inhibitors (ACEI), Angiotensin Receptor Blockers (ARB).

The second issue is related to the result of the ASCOT (4) study which showed an increase in cardiovascular deaths, cardiac events and cerebrovascular events compared to other medications

Properties of variability in BBs: (1,14) Although all beta blockers are effective as antihypertensive agents, they differ in the pharmacokinetics, β1 affinity, spectrum of adverse effects and indications.

Lipid solubility Beta blockers vary in their lipid solubility, the more lipid soluble the more likely CNS ADRs will occur

β receptor selectivity BBs have differing affinity for β receptors. β1-blocking effects provide protection from ischemic metabolic changes &

contribute to BP reduction. More β1 selective, less likely to adversely effect lung function or cause hyperkalemia.

Intrinsic sympathomimetic activity (ISA) Agents w/ISA capable of exerting low level agonist activity at β-adrenergic receptor while simultaneously acting as receptor

antagonist. BBs w/ISA may be less likely to impair myocardial function or adversely affect lung function.

Membrane stabilizing effects (MSAs) MSAs involve the inhibition of action potential propagation across the membrane, producing a nerve block.

BBs and new onset DM? (3,4,15)

BBs, in particular atenolol, may be associated with new onset DM. Despite being ß1 selective, atenolol has shown to have adverse effects both on carbohydrate and lipid metabolism, reducing insulin sensitivity. It has been shown that BBS can inhibit pancreatic insulin secretion via ß2, worsen insulin resistance and cause weight gain. All of these factors lead to more difficult glycemic control. However, other studies gave conflicting results.

Bangalore et al, “A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus” (3)

• Out of 805 studies, only 12 studies were evaluated, containing a total of 94,492 patients. Only randomized controlled trials w/ beta blockers as first line therapy for hypertension and with data for new onset DM were included. Trials included comparisons of a BB w/either placebo or thiazide diuretic.

Two studies (total of 16,372 patients) compared a beta blocker (1,102 patients took atenolol, 4,403 patients took propanolol) and placebo, there was a 33% increased risk for new onset DM (RR: 1.33, p=0.05). More pronounced in elderly (>60: RR: 2.13) than younger groups (<60yo: RR: 1.01).

Five studies (total of 17,860 patients) compared beta blockers (4,399 patients receive either atenolol or metoprolol and 4,581 patients receive propranolol) with thiazide diuretics (bendrofluazide, HCTZ or amiloride). Beta blocker therapy resulted in a 26% decreased risk for new onset DM (RR:0.64; p=0.002).

Seven studies (total of 65,765 patients) comparing beta blockers (19,097 patients took atenolol, 405 patients took metoprolol) with a nondiuretics antihypertensive agent (ACEI, CCB or ARB), beta blockers therapy resulted in 22%, 21% and 19% increase risk of new onset DM compared to a CCB, ACEI or ARB respectively.

• There was an increase risk for new onset DM when using BB. The excess risk was greater for elderly patients (>60yo). While BBs have shown less risk than thiazide diuretics to develop new onset DM, other antihypertensive agents (CCB, ACEI, ARB) have shown to be more efficacious in decreasing blood pressure as well as prevent new onset of DM.

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BBs give higher risk for cardiac and cerebrovascular events than CCBs?

While beta blockers are often used as first line treatment for hypertension, recent meta-analysis and retrospective studies have shown a higher risk for coronary heart disease (CHD) events after using beta-blockers or diuretics compared to ACEI or CCB.

Dahlof et al, “Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicenter randomized controlled trial” (4)

Prospective, multicenter, randomized controlled trial in 19 257 patients (40-79yo) with hypertension and had at least three other cardiovascular risk factors. The primary endpoint was non-fatal or fatal myocardial infarction. Secondary end points were all-cause mortality, non-fatal or fatal stroke, heart failure. Tertiary end points were new onset of DM, angina, and arrhythmia.

Patients were assigned either amlodipine 5–10 mg ± perindopril 4–8 mg (CCB + ACEI group; n=9639) or atenolol 50–100 mg ± bendroflumethiazide 1·25–2·5 mg (± potassium as required) (BB + Diuretics group; n=9618).

After a 5.5 years follow up, there was no significant difference in non-fatal or fatal myocardial infarction between the 2 groups (Amlodipine: 429 (5%) vs Atenolol: 474(5%); HR: 0·90, p=0.1052).

However, the amlodipine group showed a significant decrease in fatal and non-fatal stroke(Amlodipine: 327(3%), Atenolol 422(4%); HR: 0.77, p=0.0003), total cardiovascular events and procedures (Amlodipine: 1362 (14%) vs Atenolol: 1602(17%);HR: 0.84, p<0.0001), and all-cause mortality (Amlodipine: 738 (8%) vs Atenolol: 820(9%); HR: 0.89, p=0.025).

New onset DM was lower for amlodipine (567 (6%)) vs atenolol (799(15.9%)) (HR: 0.70, p<0.0001).

No significant change in fatal and non-fatal heart failure events was observed (amlodipine: 134 (1%) vs atenolol: 159 (2%): HR: 0.84, p=0.1257).

Nebivolol (Bystolic®) properties (5,6)

Nebivolol has unique pharmacologic properties including high specificity for the β1 receptor and a nitric oxide (NO) mediated vasodilatory effect. Those combined mechanisms may potentiate the blood pressure lowering effect and provide a favorable metabolic profile compared to other beta blockers. Nebivolol has been recently FDA approved for management of hypertension and studies have shown its efficacy in elderly patients with HF (SENIORS trial).

Higher β1 affinity than other beta blockers (321 fold higher affinity for β1 vs β2 compared to bisoprolol (103), metoprolol (74), carvedilol and propanolol (1)).

Augments endothelium-dependent vasodilation through the L-Arginine/NO pathway. It increases NO concentrations by decreasing NO deactivation. NO increases blood flow which is beneficial for coronary heart disease. This increase in NO also has some antioxidant effect similar to carvedilol.

Devoid of ISA, possesses no negative inotropic properties, and is highly lipophilic.

Well absorbed w/ peak plasma concentration within 0.5-4h. Its half life varies from 13-56h.

It is metabolized hepatically and is a CYP2D6 and CYP3A4 (minor) substrate. Hepatically-impaired individuals may need a dose-adjustment. Although not excreted renally, it can be eliminated through the urine in poor metabolizers. Severely renally-impaired patients may need dose-adjustment.

It increases the ventricular fibrillation threshold and reduces the occurrence of ventricular arrhythmias.

It provides significant BP reduction from baseline values compared with placebo (systolic: -15-20.5mmHg). Clinical trials have demonstrated that nebivolol reduces blood pressure similarly to atenolol, bisoprolol, amlodipine, nifedipine, lisinopril, and HCTZ.

Nebivolol is well tolerated; common adverse effects (similar to placebo) are fatigue, headache, dyspnea.

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Comparison between Nebivolol and other BBs (7)

Nebivolol is the newest beta blocker, considered to be a 3rd generation of BB with carvedilol.

Poirier et al conducted a prospective, randomized, crossover study to compare the effects of nebivolol and atenolol in 25 ambulatory hypertensive patients with impaired glucose tolerance.

Patients 40-65years old w/ essential HTN given 4 weeks of single-blind placebo then given either nebivolol 2.5-5mg/day or atenolol 50-100mg/day for 16 weeks separated w/4 week single-blind placebo washout.

Clinic and ambulatory blood pressure, insulin sensitivity (CLAMP), glucose tolerance (IV glucose tolerance test), systemic and regional hemodynamics were measured after each placebo and medication treatment period.

Nebivolol and atenolol have similarly reduced clinic and ambulatory blood pressure ∗ (Nebivolol: -14mmHg/9mmHg; Atenolol: -16mmHg/12mmHg with P < 0.001).

Clinic and ambulatory heart rate was reduced to a greater extent by atenolol than nebivolol (Nebivolol: -9beats/min; Atenolol: -14beats/min with P < 0.01).

Atenolol showed 20% reduction in insulin sensitivity (Placebo: 0.74; Atenolol: 0.58 with P< 0.01)) while Nebivolol do not show a significant reduction in insulin sensitivity (Nebivolol: 0.65).

Cardiac output was reduced similarly by both medications at rest (P < 0.05). However, forearm blood flow, vascular resistance and total peripheral resistance were unaffected by both medications. While there was a significant inverse correlation between cardiac output and insulin sensitivity at baseline (r=-0.46; P=0.04), the correlation was unaffected by nebivolol (r=-0.53; P=0.008) but lost with atenolol (r=-.031; p=0.14). This correlation implied that a compensatory increase in systemic blood flow occurs in hypertensive patients with progressively more marked insulin resistance.

These results confirm the detrimental effects of atenolol on insulin sensitivity but also show that insulin sensitivity was not modified significantly by nebivolol. Blood pressure was decreased to the same extent by both agents. Atenolol also decreased heart rate to a higher extent compared to nebivolol.

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