BETA-BLOCKERS


 

Category Agent Dosing Comments (apply to specific agent)
Without ISA Atenolol*
Betaxolol
Bisoprolol*
Metoprolol tartrate*
Metoprolol succinate (XL)
Nadolol
Propanolol*, **
Timolol*
25-100mg divided QD-BID
5-40mg QD
5-20mg QD
50-200mg divided BID
50-400mg QD
20-240mg QD
40-240mg divided BID
10-40mg divided BID
Cardioselective
Cardioselective
Cardioselective
Cardioselective
Cardioselective
Noncardioselective
Noncardioselective
Noncardioselective
With ISA Acebutolol
Carteolol**
Penbutolol**
Pindolol
200-1200mg divided QD-BID
2.5-10mg QD
10-20mg QD
10-60mg divided BID
Acebutolol is cardioselective &
ass'd with drug-induced lupus; others
are non-cardioselective
Combined alpha-
and beta-
blocker
Carvedilol**
Labetolol
12.5-50mg divided BID
200-1200mg divided BID
Both ass'd with hepatotoxicity; don't
affect serum lipids
Combined beta-
blocker and K-
blocker
Sotalol   Noncardioselective; no ISA

*--Available in combination with diuretics as of 1999 (chlorthalidone or HCTZ)
**--High lipid solubility

I. Pharmacology

  1. Cardioselectivity--Have greater affinity for beta1-adrenergic receptors (cardiac) than beta2-adrenergic receptors (bronchi, peripheral blood vessels)--At high doses, much of this selectivity is lost
  2. "Intrinsic sympathomimetic activity" (ISA)
    1. Beta-blockers with ISA actually act as beta-agonisis, BUT block the more sig. agonist effect of endogenous catecholamines
    2. They slow heart rate less than beta-blockers without ISA
    3. They are less likely to increase triglycerides or decrease HDL
    4. Med. Letter advises against use of Beta-blockers with ISA in pts with Angina Pectoris or prior MI; possibly b/c of the advantage post-MI in mortality reduction (see below)
  3. Lipid-solubility
    1. Beta-blockers with low lipid solubility cross the blood-brain barrier less readily than others
    2. However, never been shown clinically to have lower incidence of CNS side effects
  4. Sotalol--In addition to beta-blockade, acts as a potassium-channel blocker

II. Indications

  1. Hypertension--All beta-blockers equally effective for this (Med. Lett. 43:9, 2001)
  2. Coronary Artery Disease
    1. Reduces sx in Stable Angina
    2. Reduces mortality when administered long-term after Myocardial Infarction
  1. Norwegian Multicenter Study Group ("NMS"; NEJM 304:801, 1981)
  1. Pts randomized 7-28d post-MI to timolol 10 BID vs. placebo for mean 17mos.
  2. Timolol group had 36% reduction in mortality
  1. Beta-blocker Heart Attack Trial ("BHAT"; JAMA 247:1707, 1982)
  1. 3800 pts randomized 5-21d post-MI to propanolol titrated to 180-240mg/d vs. placebo for mean 25mos.
  2. 26% reduction in mortality with propanolol
  3. No decrease in mortality in subgroup with non-Q-wave MI
  1. Meta-analysis of 25 studies of long-term beta-blockers after MI (BMJ 318:1730, 1999???)
  1. Pooled data showed 23% reduction in mortality with beta-blockers vs. Placebo
  2. Benefits shown with timolol, propanolol, metoprolol, atenolol, and acebutolol
  3. Nonsig. Advantage of beta-blockers without intrinsic sympathomimetic activity over those with ISA
  4. Benefits seem to be maintained for at least 6y with continued administration, and discontinuation of beta-blockers ass'd with acceleration of mortality.
  1. Congestive Heart Failure
  2. Tx of Arrhythmias including rate-control in Atrial Fibrillation and tx of ventricular arrhythmias (Sotalol useful for maintenance of sinus rhythm in AFib, unlike other Beta-blockers)
  3. Prophylaxis of Migraine
  4. Prevention of Intraoperative Cardiac Events
  5. May reduce risk of Osteoporosis
  6. Essential Tremor
  7. Hypertrophic Cardiomyopathy
  8. Pheochromocytoma

 

III. Adverse effects:

  1. Fatigue & emotional depression-The latter probably not a real effect of beta-blockers
    1. In a meta-analysis of 15 RCT's looking at incidence of depression, fatigue, or sexual dysfunction with beta-blockers.  Beta-blockers were not associated with increased risk of depressive sx; they were ass'd with a sig. increase in risk of reported fatigue (annual excess incidence 1.8%) and sexual dysfunction (annual excess incidence 0.5%).  No diff based on degree of lipid solubility of the specific beta-blocker tested, but incidence of fatigue was sig. higher for "early-generation" (propranolol & timolol) than for "late-generation" beta-blockers (metoprolol, atenolol, pindolol, acebutolol, and carvedilol), and in fact the association for the latter was barely statistically significant. (JAMA 288:351, 2002)
  2. Bradycardia, especially in combination with nondihydropyridine Ca-channel blockers
  3. Bronchospasm
    1. Use with caution in patients with asthma or COPD
    2. The "cardioselective" beta-blockers celiprolol and bisoprolol may have the least effect on pulmonary function in pts w/COPD, but the "cardioselectivity" of such agents may be reduced at higher doses (Chest 23:222, 2003)
  4. May worsen Congestive heart failure acutely, though may improve outcomes long-term
  5. Lipids: May reduce HDL by about 10% (less so with cardioselective agents and agents with ISA; don't affect LDL or total chol.)
  6. Worsening of PVD (theoretical) with non-cardioselective agents b/c beta-2 blockade can cause increased smooth mm. tone in arteries/arterioles
  7. Generally believed to blunt sx of hypoglycemia in diabetics, but in a retrospective study of 13,000 pts using insulin or sulfonylureas, there were no sig. differences in risk for severe hypoglycemia between pts on beta-blockers and pts not on antihypertensives (same for ACEIs and thiazides) after adjustment for age & comorbid conditions (JAMA 278:40, 1997-JW)
  8. Adverse effects on glucose metabolism
    1. In a 6y prospective trial of 12,550 adults w/o DM at beginning of trial, hypertensive pts who took beta-blockers were 28% more likely to develop DM than hypertensive pts who didn't use any antihypertensives. No such association was seen for thiazides, ACEI, or Ca-blockers (NEJM 342:905, 2000--JW)
    2. In a randomized trial in 1,235 pts 36-85yo with HTN and type 2 DM on ACEIs or ARBs randomized to carvedilol (titrated from 6.25-25mg BID) vs. metoprolol tartrate (titrated from 50-200mg BID), over 5mos, the metoprolol, but not the carvedilol group had sig. increases in mean HbA1c (absolute increase 0.15%); also, carvedilol had lower incidence of progression to microalbuminuria (6.4% vs. 10.3%) ("The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives" ("GEMINI") Trial; JAMA 292:2227, 2004--abst)
    3. In a study using data from the Nurses' Health Study and Health Professionals Follow-Up Study, in which about 75,000 pts with HTN but no DM were followed for 8-16y, incidence of new-onset DM (after adjustment for potential counfounders) was sig. higher in users of beta-blockers diuretics c/w non-use (RR 1.2-1.3 depending on the cohort). (Diab. Care 29:1065, 2006--JW)
  9. Depression
  10. Erectile Dysfunction
  11. In pts on Beta-blockers, sympathomimetics can cause unopposed alpha-adrenergic vasoconstriction and thus cause very high BP's!