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A. Adrenergic Receptors and Transporters

  1. Alpha-1
    1. Three subtypes are known (1a, 1b, 1d); unclear functional distinctions
    2. Selective Agonist: phenylephrine (Neosynephrine®)
    3. Mixed Agonists: epinephrine (EPI) > norepinephrine (NE) >> isoproterenol
    4. Selective Antagonists: prazosin, doxazosin, terazosin, tamsulosin
    5. Agonists cause vascular and genitourinary smooth muscle contraction
    6. Stimulation of liver glycogenolysis and gluconeogenesis
    7. Cardiac increased contractile force (may precipitate arrhythmias)
    8. Associated with Gq proteins, increase phospholipase C, D and A2
    9. May increase calcium channel activity
  2. Alpha-2
    1. Three subtypes are known (2a, 2b, 2c); unclear functional distinctions
    2. Selective Agonist: clonidine, oxymetazoline
    3. Mixed Agonists: epinephrine (EPI) > norepinephrine (NE) >> isoproterenol
    4. Selective Antagonist: yohimbine, prazosin (2b and 2c)
    5. Agonists reduce insulin secretion by pancreatic ß cells
    6. Increase platelet aggregation
    7. Decrease release of NE at nerve terminals (central actions)
    8. Induces some smooth muscle contraction (relatively week)
    9. Associated with Gi proteins which reduce adenylyl cyclase
    10. Gi also Increase potassium channels
    11. Go reduces L- and N-type calcium channels
    12. Gi/o may increase phospholipase A2 and C
  3. Beta-1
    1. Selective Agonist: dobutamine
    2. Mixed Agonists: isoproterenol > EPI = NE
    3. Selective Antagonists: metoprolol, atenolol
    4. Non-selective Antagonists: propranolol, naldolol
    5. Agonists increase cardiac contraction and AV nodal conduction (rate)
    6. Increased renin secretion by juxtaglomerular cells
    7. Chronic ß-antagonists can improve cardiac remodelling in congestive heart failure (CHF)
    8. ß-antagonists reduce angiotensin I and II levels in CHF patients on ACE-I [1]
    9. Adrenergic neurohormonal activation in CHF appears detrimental in long term
    10. Gs protein linked to increased adenyl cyclase and increased L-type Ca channels
  4. Beta-2
    1. Selective Agonists: terbutaline, albuterol
    2. Mixed Agonists: isoproterenol > EPI >> NE
    3. Non-selective Antagonists: propranolol, naldolol
    4. Agonists cause smooth muscle relaxation (diffusely)
    5. Increase skeletal muscle glycogenolysis and uptake of K+
    6. Increase liver glycogenolysis and gluconeogenesis
    7. Gs protein linked to increased adenyl cyclase
    8. ß2-adrenergic receptor genotype is correlated with survival after acute coronary syndromes in patients treated with ß-blockers [11]
  5. Beta-3
    1. Selective agonists and antagonists are being developed
    2. Mixed agonists: isoproterenol = NE > EPI (other agents above do not bind to ß3)
    3. Increase lipolysis in adipose tissue
    4. Gs protein linked to increased adenyl cyclase
  6. Transporters
    1. Uptake of NE and other neurotransmitters mediated by specific transporters
    2. These are 12-transmembrane spanning proteins
    3. The NE reuptake system has some affinity for EPI but essentially none for isoproterenol
    4. Transporters also exist for dopamine, serotonin, and various amino acids

B. ß-Adrenergic Receptor Blockers [2]

  1. Overview of Indications [2]
    1. Hypertension (HTN) - no longer first line in most patients [15]
    2. Angina
    3. Documented coronary artery disease (CAD) or after myocardial infarction (MI)
    4. Congestive Heart Failure (CHF) [34]
    5. Anti-arrhythmic agents
    6. Perioperative use
    7. Migraine prophylaxis
    8. Social phobia prophylaxis
    9. Essential tremor treatment
    10. Hypertrophic cardiomyopathy
  2. Therapeutic Benefits
    1. Proved reduction in morbidity and moratility in many long term cardiovascular studies
    2. Very effective and well tolerated in patients with stable angina [27]
    3. ß-blockers should be used patients peri- and post-MI who tolerate them [33]
    4. When used within 24 hours of MI in all patients, reduces arrhythmias and reinfarction but increases risk of cardiogenic shock [23]
    5. Likely that ß-blockers should be delayed for 36-48 hours in acute MI until hemodynamic status has stabilized [23]
    6. ß-adrenergic receptor blockers cause actual atherosclerotic plaque regression [5]
    7. ß-Blocker use associated with (up to 70%) reduced risk of incident MI [7]
    8. Not first line therapy in HTM unless coronary disease (CAD) present
    9. Excellent and safe anti-arrhythmics: suppresses PVC, prevents sudden cardiac death
    10. Bisoprolol given perioperatively to high risk patients undergoing vascular surgery reduced death and MI by >80% [31]
    11. Associated with up to 40% reduced risk of death in high risk patients undergoing non- cardiac surgery [13]
    12. In low to moderate noncardiac surgery patients, ß-blockers reduced cardiac events but increased mortality as well as hypotension and bradycardia requiring treatment [3,10]
    13. Very effective in rate control of atrial fibrillation
    14. Should be used in combination therapy in patients with CHF [29,34]
    15. Improve exercise tolerance and mortality in Class II and III systolic CHF
    16. Improve exercise tolerance in hypertrophic cardiomyopathy of any cause
    17. Thiazide diuretics and calcium blockers should be used for HTN first line in elderly
    18. Use of ß-adrenergic blockers associated with ~20% reduced risk for fractures [19]
  3. Mechanisms of Action
    1. Slow heart rate and contractility, with good anti-ischemic properties
    2. Reduce cardiac oxygen demand
    3. Reduce rate of atheroma formation
    4. Reduce ventricular ectopy with stabilization of normal and injured cardiac muscle
    5. Alter gene expression (increased sarcoplasmic calcium ATPase and alpha-myosin heavy chain mRNA, reduced ß-myosin heavy chain mRNA) in dilated cardiomyopathy [41]
  4. Non-Selective Agents
    1. Propranolol (Inderal®, Inderal LA®): t1/2 6-7 hours; dose 80-240mg bid or qd for LA form
    2. Naldolol (Corgard®): nonselective ß-blocker, t1/2 ~22 hours; dose 20-240qd
    3. Esmolol (iv agent): t1/2 ~9 minutes (broken down by RBCs); useful in ICU setting
    4. Carvidilol (see below)
  5. ß1-Selective Agents
    1. Atenolol (see below)
    2. Metoprolol (see below)
    3. Betaxolol (Kerlone®): t1/2 ~18 hours; dose 5-40mg po qd
    4. Bisoprolol (Zebeta®): Highly ß1-selective; t1/2 ~18 hours; dose 5-20mg qd
    5. Bisoprolol has been shown to reduce risk of hospitalization and mortality in CHF [2]
    6. These cardioselective agents do not adversely affect patients with asthma or other hyperactive airways disease [8]
  6. Atenolol (Tenoramin®)
    1. Long acting: t1/2 ~18hr
    2. Dose 25-100mg po qd to bid
    3. Overall questionable efficacy as antihypertensive [20]
  7. Metoprolol (Lopressor®; Toprol®, Toprol® XL)
    1. Short acting: t1/2 ~3-7hr
    2. Long acting (Toprol® XL): t1/2~18-24 hr
    3. Dose is divided bid or tid for short acting, once daily for XL
    4. Total daily dose is 25-200mg
    5. Approved for HTN, angina, and CHF
  8. ß-Blockers with Intrinsic Sympathomimetic Activity (ISA)
    1. May be useful in patients with bradycardias who cannot tolerate usual ß-blockers
    2. Note that these agents have not been shown to improve survival post-MI
    3. Acebutolol (Sectral®): excellent PVC control; initiate dose 200mg po bid
    4. Pindolol (Visken®): 10-60mg po in divided doses
    5. Labetolol also has ISA activity
  9. Carvidilol (Coreg®) [4]
    1. Non-selective ß-blocker, alpha-1 blocker activity (vasodilator), anti-oxidant
    2. ß-blocker activity ~10 fold higher than alpha-1 blocker activity
    3. The S-isomer is the major mixed activity; R-carvidilol is only a ß-blocker
    4. Approved for CHF, improves LV EF, exercise tolerance [17]
    5. Safe and reduces mortality in patients with severe symptomatic CHF [38]
    6. Reduced mortality 65% in CHF alone; synergistic with ACE inhibitors
    7. During first 8 weeks of therapy in severe CHF, shows trend toward mortality benefit [9]
    8. Appears more effective than metoprolol in CHF patients [18]
    9. More effective than metoprolol on metabolic parameters in patients with Type 2 diabetes and HTN [28]
    10. Some effect on LV EF may be improvement in ischemic or hybernating myocardium [17]
    11. Effective in both black and non-black patients with CHF [35]
    12. Carvidilol 3-21 days after MI in patients with LV EF <40% reduces mortality [36]
    13. Improves glucose and lipid metabolism in type II diabetics
    14. Initial dose 3.125mg bid in CHF with progressively increase to maximum 25-50mg po bid
    15. Metabolized by CYP 2D6; levels increase in CYP 2D6 deficient patients
  10. Bucindolol
    1. Blockade of ß-receptors with direct vasodilatory activity
    2. Ongoing evaluations in CHF, MI, other ischemic disease
    3. Bucindolol did not improve survival in Class III/IV CHF patients [39]
  11. Nebivolol (Bystolic®) [46]
    1. ß-blocker and nitric oxide inducing vasodilator; no alpha-adrenergic activity
    2. Mainly ß1-blockade and no sympathomimetic activity
    3. No increase in insulin resistance
    4. Approved for HTN treatment, but also effective in CHF
    5. Dose usually 5mg po qd; maximum 40mg; hepatic impairment 2.5mg
  12. Bisoprolol-Hydrochlorothiazide (HCTZ) (Ziac®) [6]
    1. Bisopropol (ß1 selective, Zebeta®) 2.5-10mg and HCTZ 6.25mg
    2. Low dose of each agent may have fewer side effects
  13. Pindolol
    1. ß-blocker with serotonin autoreceptor antagonism
    2. Increases efficacy of fluoxetine in depression and anxiety
  14. Adverse Effects
    1. Minimized by starting at low dose and increasing gradually over weeks
    2. Symptomatic hypotension, particularly orthostatic hypotension
    3. Bradycardia / heart block
    4. Bronchospasm
    5. Aggrevation of CHF when used at high doses
    6. Increase riskfor new onset diabetes by >10% compared with non-diuretic anti-HTN drugs [47]
    7. May mask some symptoms of hypoglycemia in diabetics
    8. Mild risk of fatigue, impotence, anorgasmia, depression, insomnia, delirium
    9. May exacerbate or induce Raynaud's phenomenon

C. Summary of Effects

Drug / Activityß-blocking*ß1-selectiveISA*alpha-blockvasodilatorCHF*
Propranolol1.0nonononono
Bucindolol1.0nononoyesyes
Carvidolol2.4nonoyesnoyes
Labetolol0.3noyesyesnono
Pindolol6.0noyesnonono
Bisoprololyesyesnononoyes
Metoprololyesyesnononoyes
*ß-blocking relative potency *ISA=intrinsic sympathomimetic activity

D. Ophthalmic ß-Adrenergic Blockers
  1. Topical agents are usual first line therapy for open angle glaucoma
    1. Timolol (Timoptic®) - 0.5% solution
    2. Levobunolol (Betagan®)
    3. Betaxolol (Betoptic®)
    4. Metipranolol
  2. Mechanism of Action
    1. Aqueous production is stimulating by sympathetic output
    2. ß-adrenergic receptor blockade reduces aqueous production by ciliary body
    3. This leads to reduced optic pressures by 20-30%
    4. Reduction in intraocular pressue is additive with other agents
  3. Drug Interactions
    1. Timolol side effects may be worsened by poor P450 enzyme CYP2D6 metabolism
    2. Quinidine also blocks CYP2D6 function
    3. Therefore, quinidine and timolol should not be given concurrently

E. ß-Blocker Side Effects

  1. Cardiac
    1. Mainly due to ß1-blocking effects
    2. Bradycardia, hypotension, and CHF exacerbation can occur
    3. ß1-blocking effects can reduce exercise tolerance
    4. ß2-blocking effects can increase claudication and reduce exercise tolerance
  2. Pulmonary
    1. Exacerbates bronchospasm mainly due to ß2-blocking effects
    2. Betaxolol is ß1-selective and may be helpful in patients with history of bronchospasm
    3. However, caution must be used when giving ß-blockers to any patient with bronchospasm
  3. Central Nervous System (CNS)
    1. Fatigue - questionable association [42]
    2. Weakness
    3. Confusion
    4. Memory loss
    5. Headaches
    6. Anxiety
    7. Depression risk is not increased with ß-blocker use [42]
    8. Overall, ~5% of patients discontinue topical ß-blockers due to CNS side effects
  4. Sexual dysfunction is not increased with ß-blocker use [42]
  5. ß-blockade may reduce symptoms of hypoglycemia in diabetics, which can increase risks

F. Mixed ß-Adrenergic Agonists

  1. These are mainly inotropic (or chronotropic) agents
  2. Dopamine (Intropin®)
    1. Acts on D1-, ß1-, and alpha-receptors depending on the concentration used
    2. Low dose increases renal and mesenteric blood flow
    3. Moderate "cardiac" doses are inotropic, with increased heart rate and cardiac output
    4. At high doses (>10-15µg/kg/min), alpha-adrenergic vasoconstrictor effect predominates
    5. Excellent first line agent for hypotension
    6. Primary agent for severe refractory CHF
  3. Dobutamine (Dobutrex®)
    1. Synthetic catecholamine with non-selective ß-adrenergic activity
    2. Increased myocardial contractility via ß1-agonist activity
    3. Afterload reduction due to ß2-agonist activity
    4. This afterload reduction can prevail leading to hypotension

G. Comparison Of Commonly Used Inotropic Agents

Drug / Agonist Activityalphaß1ß2
Phenylephrine++/+++------
Norepinephrine+++++++++/++
Epinephrine+++++++++++
Dopamine++/+++++++++
Dobutamine+++++++

H. ß2-Adrenergic Agonists [12]
  1. Actions
    1. ß2-receptor activation prevents smooth muscle constriction
    2. Act in 3-5 minutes to bronchodilate in asthmatics
    3. Stereoisomers may have very different activities in asthma
    4. Polymorphisms in ß2-adrenergic receptor (ADRB2) may affect desensitization to ß2-agonists and may play small role in susceptibility to asthma [24]
    5. May act synergistically with glucocorticoids to reduce inflammation [43]
  2. Use [16]
    1. Very potent bronchodilator effects
    2. Short acting ß2-agonists are only used on an as needed (prn) basis
    3. Long acting agents are generally for chronic asthma or COPD control
    4. Short acting ß2-agonists must be provided to patients on long acting ß2-agonists
  3. Albuterol (Ventolin®)
    1. Short acting requiring qid use (also for prn use) in most patients
    2. R-albuterol may be active form
    3. S-albuterol may have bronchial irritant activity
    4. For mild asthma, prn use of albuterol is as effective as regularly scheduled use
  4. Levalbuterol (Xopenex®) [12]
    1. This is the pure R-isomer of albuterol
    2. Approved for prevention and treatment of bronchospasm
    3. No clear benefit compared to mixed (racemic) albuterol [14]
  5. Metoproterenol (Alupent®) - short acting (qid)
  6. Pirbuterol (Maxair®) - short acting (qid)
  7. Terbutaline (Brethine®) - short acting (qid)
  8. Bitolterol (Tornalate®) - short acting, more expensive than others
  9. Salmeterol (Serevent®) [30]
    1. Delayed onset but long duration (~12 hours) of action
    2. Usually given qhs or bid
    3. Longer acting agents may be useful for overnight asthma exacerbations
    4. Eformoterol also long acting
    5. No particular advantages to any agent in each specific class
    6. When long acting agents are prescribed, short acting agents should be used prn as well
    7. Long acting agents should absolutely NOT be used for acute symptoms
    8. Salmeterol - increased FEV1 and duration of action versus albuterol
    9. Chronic salmeterol use does not reduce efficacy of acute albuterol therapy [30]
  10. Formoterol (Foradil®, Perforomist®) and Arformoterol (Brovana®) [37]
    1. Long acting (12 hour) agent with rapid (1-3 minute) onset of action
    2. Dose is 1 puff bid or, for nocturnal symptoms, 1 puff qhs
    3. Nebulized arformoterol (Brovana®) and formoterol (Perforomist®) are available for patients who cannot tolerate dry powder inhalers [26]
    4. Indicated for chronic asthma control in patients already on inhaled glucocorticoid
    5. Of clear benefit alone (not recommended) or with inhaled glucocorticoids in mild-moderate asthma [25]
    6. Should NOT be used for acute exacerbation
    7. Also useful for prevention of excercise-induced bronchospasm
    8. Approved for chronic treatment of COPD
    9. Formoterol added to budesonide is safe and highly effective in moderate asthma, with both agents independently contributing to improved outcomes [25]
  11. Oral ß2-Agonists
    1. Agents for tid-qid dosing
    2. Useful for patients who will/can not use inhalers
    3. Albuterol caplets, 200µg/dose - 1-2 caps q4-6 hours
  12. Tolerance [16]
    1. Long term salmeterol or terbutaline causes tolerance to anticonstrictor effects
    2. Thus, the long term efficacy of these agents may jeopardized by constant use
    3. Tachyphylaxis and ß2-receptor down regulation may occur, mainly short acting agents
    4. Chronic salbutamol (short acting) use for 1 year did not lead to reduced asthma control [32]
    5. Mutations in the ß-adrenergic receptor (ADRB2) do not affect responses of asthmatic patients to long acting ß2-agonist therapy [40]
  13. Side effects
    1. Tremor, headache, tachycardia, palpitations, tachyarrhythmias (atrial fibrillation)
    2. Side effects increased with oral forms and large inhaled doses
    3. Side effects generally decline with continued use

I. Other Drugs with Adrenergic Effects

  1. Venlafaxine (Effexor®) [21]
    1. Mixed serotonin and norepinephrine reuptake inhibitor (weak on dopamine receptors)
    2. Reduced anti-cholinergic, anti-histaminergic and anti-adrenergic effects
    3. Dose: start 37.5mg po bid, maximum 225-3375mg/day
    4. Mild diastolic HTN has been reported at higher doses
    5. May be effective in patients who respond poorly to other SSRI's
    6. Desvenlafaxine (Pristique®) also now approved for major depression
    7. Abrupt withdrawal leads to irritability, headache, dizziness, lethargy, vomiting
  2. Duloxetine (Cymbalta®) [44,45]
    1. Mixed serotonin and norepinephrine (NE) reuptake inhibitor
    2. Minimal activities on other receptors
    3. Dose 30-40mg bid or 60mg qd
    4. Similar side effects as venlafaxine
    5. Approved in depression and diabetic neuropathic pain
    6. As or slightly more effective than fluoxetine or paroxetine
    7. Side effects: nausea, dizziness, somnolence, constipation, asthenia, erectile dysfunction
    8. Abrupt withdrawal leads to irritability, headache, vomiting, insomnia
  3. Nefazodone (Serzone®) [22]
    1. Serotonin and neurepinephrine reuptake inhibitor
    2. Blockade at serotonin 5-HT2A and alpha1-adrenergic receptors
    3. Dose 50-100mg po bid initially, up to 300mg po bid
    4. Better tolerated than imipramine
    5. Side effects include headache, insomnia, orthostasis
    6. Improves symptoms of anxiety and restores sleep patterns
    7. Inhibits cytochrome P450-3A4; increases benzodiazepine, MAO-inhibitor levels
    8. Contraindicated for use with astemizole (Hismanal®), terfenadine (Seldane®), cisapride

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