The β ₁ -adrenoceptor and signal transduction

Situated on the cardiac sarcolemma, the β ₁ -receptor is part of the adenylyl (= adenyl) cyclase system ( Fig. 1.1 ) and is one of the group of G protein–coupled receptors. The G protein system links the receptor to adenylyl cyclase (AC) when the G protein is in the stimulatory configuration (G _s , also called Gαs). The link is interrupted by the inhibitory form (G _i or Gαi), the formation of which results from muscarinic stimulation following vagal activation. When activated, AC produces cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). The intracellular second messenger of β ₁ -stimulation is cAMP; among its actions is the “opening” of calcium channels to increase the rate and force of myocardial contraction (the positive inotropic effect) and increased reuptake of cytosolic calcium into the sarcoplasmic reticulum (SR; relaxing or lusitropic effect, see Fig. 1.1 ). In the sinus node the pacemaker current is increased (positive chronotropic effect), and the rate of conduction is accelerated (positive dromotropic effect). The effect of a given β-blocking agent depends on the way it is absorbed, the binding to plasma proteins, the generation of metabolites, and the extent to which it inhibits the β-receptor (lock-and-key fit).

β-adrenergic signal systems involved in positive inotropic and lusitropic (enhanced relaxation) effects. These can be explained in terms of changes in the cardiac calcium cycle. When the β-adrenergic agonist interacts with the β-receptor, a series of G protein-mediated changes lead to activation of adenylate cyclase and formation of the adrenergic second messenger, cyclic adenosine monophosphate (cAMP) . The latter acts via protein kinase A (PKA) to stimulate metabolism and to phosphorylate (P) the calcium channel protein, thus increasing the opening probability of this channel. More Ca ^{2 +} ions enter through the sarcolemmal channel, to release more Ca ^{2 +} ions from the sarcoplasmic reticulum (SR). Thus the cytosolic Ca ^{2 +} ions also increase the rate of breakdown of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) and inorganic phosphate (P _i ) . Enhanced myosin adenosine triphosphatase (ATPase) activity explains the increased rate of contraction, with increased activation of troponin-C explaining increased peak force development. An increased rate of relaxation (lusitropic effect) follows from phosphorylation of the protein phospholamban (PL) , situated on the membrane of the SR, that controls the rate of calcium uptake into the SR. AKAP , A-kinase-anchoring protein.

(Figure © L. H. Opie, 2012.)

β ₂ -receptors

The β-receptors classically are divided into the β ₁ -receptors found in heart muscle and the β ₂ -receptors of bronchial and vascular smooth muscle. If the β-blocking drug selectively interacts better with the β ₁ – than the β ₂ -receptors, then such a β ₁ -selective blocker is less likely to interact with the β ₂ -receptors in the bronchial tree, thereby giving a degree of protection from the tendency of nonselective β-blockers to cause pulmonary complications.

β ₃ -receptors

Endothelial β ₃ -receptors mediate the vasodilation induced by nitric oxide in response to the vasodilating β-blocker nebivolol (see Fig. 1.2 ).

Vasodilatory mechanisms and effects.

Vasodilatory β-blockers tend to decrease the cardiac output less as the systemic vascular resistance falls. Vasodilatory mechanisms include α-blockade (carvedilol), formation of nitric oxide (nebivolol and carvedilol), and intrinsic sympathomimetic activity (ISA). ISA, as in pindolol, has a specific effect in increasing sympathetic tone when it is low, as at night, and increasing nocturnal heart rate, which might be disadvantageous in nocturnal angina or unstable angina. cAMP, Cyclic adenosine monophosphate; NO, nitric oxide.

(Figure © L. H. Opie, 2012.)

Secondary effects of β-receptor blockade

During physiologic β-adrenergic stimulation, the increased contractile activity resulting from the greater and faster rise of cytosolic calcium ( Fig. 1.3 ) is coupled to increased breakdown of ATP by the myosin adenosine triphosphatase (ATPase). The increased rate of relaxation is linked to increased activity of the sarcoplasmic/endoplasmic reticulum calcium uptake pump. Thus, the uptake of calcium is enhanced with a more rapid rate of fall of cytosolic calcium, thereby accelerating relaxation. Increased cAMP also increases the phosphorylation of troponin-I, so that the interaction between the myosin heads and actin ends more rapidly. Therefore, the β-blocked heart not only beats more slowly by inhibition of the depolarizing currents in the sinoatrial (SA) node but has a decreased force of contraction and decreased rate of relaxation. Metabolically, β-blockade switches the heart from using oxygen-wasting fatty acids toward oxygen-conserving glucose. All these oxygen-conserving properties are of special importance in the therapy of ischemic heart disease. Inhibition of lipolysis in adipose tissue explains why gain of body mass may be a side effect of chronic β-blocker therapy.

The β-adrenergic receptor is coupled to adenyl (= adenylyl) cyclase (AC) via the activated stimulatory G-protein, G _s . Consequent formation of the second messenger, cyclic adenosine monophosphate (cAMP) activates protein kinase A (PKA) to phosphorylate (P) the calcium channel to increase calcium ion (Ca ^{2 +} ) entry. Activity of AC can be decreased by the inhibitory subunits of the acetylcholine (ACh) –associated inhibitory G-protein, G _i . cAMP is broken down by phosphodiesterase (PDE) so that PDE-inhibitor drugs have a sympathomimetic effect. The PDE is type 3 in contrast to the better-known PDE type 5 that is inhibited by sildenafil (see Fig. 2.6 ). A current hypothesis is that the β ₂ –receptor stimulation additionally signals via the inhibitory G-protein, G _i , thereby modulating the harm of excess adrenergic activity.

(Figure © L. H. Opie, 2012.)

Effects on coronary flow and myocardial perfusion

Enhanced β-adrenergic stimulation, as in exercise, leads to β-mediated coronary vasodilation. The signaling system in vascular smooth muscle again involves the formation of cAMP, but whereas the latter agent increases cytosolic calcium in the heart, it paradoxically decreases calcium levels in vascular muscle cells (see Fig. 1.6 ). Thus, during exercise, the heart pumps faster and more forcefully while coronary flow is augmented to meet the increased demand imposed by the increment in external workload. Conversely, while β-blockade should have a coronary vasoconstrictive effect with a rise in coronary vascular resistance, the longer diastolic filling time resulting from a decreased heart rate during exercise leads to more nutritive coronary blood flow and better diastolic myocardial perfusion.

Proposed comparative effects of β-blockade and calcium channel blockers (CCBs) on smooth muscle and myocardium.

The opposing effects on vascular smooth muscle are of critical therapeutic importance. cAMP, Cyclic adenosine monophosphate; SR, sarcoplasmic reticulum.

(Figure © L.H. Opie, 2012.)

Plasma half-lives

Esmolol, given intravenously, has the shortest of all half-lives at only 9 minutes. Esmolol may therefore be preferable in unstable angina and threatened infarction when hemodynamic changes may call for withdrawal of β-blockade. The half-life of propranolol ( Table 1.2 ) is only 3 hours, but continued administration saturates the hepatic process that removes propranolol from the circulation; the active metabolite 4-hydroxypropranolol is formed, and the effective half-life then becomes longer. The biological half-life of propranolol and metoprolol (and all other β-blockers) exceeds the plasma half-life considerably, so that twice-daily dosages of standard propranolol are effective even in angina pectoris. Clearly, the higher the dose of any β-blocker, the longer the biologic effects. Longer-acting compounds such as nadolol, sotalol, atenolol, and slow-release propranolol (Inderal-LA) or extended-release metoprolol (Toprol-XL) should be better for hypertension and effort angina.

Protein binding

Propranolol is highly bound, as are pindolol, labetalol, and bisoprolol. Hypoproteinemia calls for lower doses of such compounds.

First-pass hepatic metabolism

First-pass liver metabolism is found especially with the highly lipid-soluble compounds, such as propranolol, labetalol, and oxprenolol. Major hepatic clearance is also found with acebutolol, nebivolol, metoprolol, and timolol. First-pass metabolism varies greatly among patients and alters the dose required. In liver disease or low-output states the dose should be decreased. First-pass metabolism produces active metabolites with, in the case of propranolol, properties different from those of the parent compound. Metabolism of metoprolol occurs predominantly via cytochrome (CY) P450 2D6–mediated hydroxylation and is subject to marked genetic variability. Acebutolol produces large amounts of diacetolol, and is also cardioselective with intrinsic sympathomimetic activity (ISA), but with a longer half-life and chiefly excreted by the kidneys ( Fig. 1.7 ). Lipid-insoluble hydrophilic compounds (atenolol, sotalol, nadolol) are excreted only by the kidneys (see Fig. 1.7 ) and have low brain penetration. In patients with renal or liver disease, the simpler pharmacokinetic patterns of lipid-insoluble agents make dosage easier. As a group, these agents have low protein binding (see Table 1.2 ).

Comparative routes of elimination of β-blockers.

Those most hydrophilic and least lipid-soluble are excreted unchanged by the kidneys. Those most lipophilic and least water-soluble are largely metabolized by the liver. Note that the metabolite of acebutolol, diacetolol, is largely excreted by the kidney, in contrast to the parent compound. (For derivation of data in figure, see third edition. Estimated data points for acebutolol and newer agents added.)

(Figure © L. H. Opie, 2012.)

Pharmacokinetic interactions

Those drugs metabolized by the liver and hence prone to hepatic interactions are metoprolol, carvedilol, labetalol, and propranolol, of which metoprolol and carvedilol are more frequently used. Both are metabolized by the hepatic CYP2D6 system that is inhibited by paroxetine, a widely used antidepressant that is a selective serotonin reuptake inhibitor. To avoid such hepatic interactions, it is simpler to use those β-blockers not metabolized by the liver (see Fig. 1.7 ). β-blockers, in turn, depress hepatic blood flow so that the blood levels of lidocaine increase with greater risk of lidocaine toxicity.

Combination antiischemic therapy of angina pectoris

β-blockers are often combined with nitrate vasodilators and calcium channel blockers (CCBs) in the therapy of angina (see Table 1.3 ). However, the combined use of β-blockers with nondihydropyridine calcium antagonists (e.g., verapamil, diltiazem) should in general be avoided because of the risks of excess bradycardia and precipitation of heart failure, whereas the combination with long-acting dihydropyridines (DHPs) is well documented.

Combination therapy in angina

Angina is basically a vascular disease that needs specific therapy designed to give long-term vascular protection. The following agents should be considered for every patient with angina: (1) aspirin and/or clopidogrel for antiplatelet protection, (2) statins and a lipid-lowering diet to decrease lipid-induced vascular damage, and (3) an angiotensin converting enzyme (ACE) inhibitor that has proven protection from MI and with the doses tested. Combinations of prophylactic antianginal agents are necessary in some patients to suppress symptoms but have less clear-cut prognostic implications.

Vasospastic angina

β-blockade is commonly held to be ineffective and even harmful because of lack of efficacy. On the other hand, there is excellent evidence for the benefit of CCB therapy, which is the standard treatment. In the case of exercise-induced anginal attacks in patients with variant angina, a small prospective randomized study in 20 patients showed that nifedipine was considerably more effective than propranolol.

Cold intolerance and angina

During exposure to severe cold, effort angina may occur more easily (the phenomenon of mixed-pattern angina). Conventional β-blockade by propranolol is not as good as vasodilatory therapy by a CCB and may reflect failure to protect from regional coronary vasoconstriction in such patients.

Silent myocardial ischemia

Episodes of myocardial ischemia, for example detected by continuous electrocardiographic recordings, may be precipitated by minor elevations of heart rate, probably explaining why β-blockers are very effective in reducing the frequency and number of episodes of silent ischemic attacks. In patients with silent ischemia and mild or no angina, atenolol given for 1 year lessened new events (angina aggravation, revascularization) and reduced combined endpoints.

Early ST-elevation myocardial infarction

There are no good trial data on the early use of β-blockade in the reperfusion era. Logically, β-blockade should be of most use in the presence of ongoing pain, inappropriate tachycardia, hypertension, or ventricular rhythm instability. In the COMMIT trial, early intravenous metoprolol given to more than 45,000 Asiatic patients, about half of whom were treated by lytic agents and without primary percutaneous coronary intervention, followed by oral dosing, led to 5 fewer reinfarctions and 5 fewer ventricular fibrillations per 1000 treated. The cost was increased cardiogenic shock, heart failure, persistent hypotension, and bradycardia (in total, 88 serious adverse events). In the United States, metoprolol and atenolol are the only β-blockers licensed for intravenous use in AMI. Overall, however, no convincing data emerge for routine early intravenous β-blockade. With selected and carefully monitored exceptions, it is simpler to introduce oral β-blockade later when the hemodynamic situation has stabilized. The current American College of Cardiology (ACC)–American Heart Association (AHA) guidelines recommend starting half-dose oral β-blockade on day 2 (assuming hemodynamic stability) followed by dose increase to the full or the maximum tolerated dose, followed by long-term postinfarct β-blockade.

Postinfarction secondary prevention

(1) Administer β-blockade for all postinfarct patients with an ejection fraction (EF) of 40% or less unless contraindicated, with use limited to carvedilol, metoprolol succinate, or bisoprolol, which reduce mortality (Class 1, Level of Evidence A); (2) administer β-blockade for 3 years in patients with normal LV function after AMI or ACS; (Class I, Level B). It is also reasonable to continue β-blockade beyond 3 years (Class IIa, Level B).

Benefits of postinfarct β-blockade

In the postinfarct phase, β-blockade reduces mortality by 23% according to trial data and by 35% to 40% in an observational study on a spectrum of patients including diabetics. Timolol, propranolol, metoprolol, and atenolol are all effective and licensed for this purpose. Metoprolol has excellent long-term data. Carvedilol is the only β-blocker studied in the reperfusion era and in a population also receiving ACE inhibitors. As the LV dysfunction was an entry point, the carvedilol dose was gradually uptitrated, and all-cause mortality was reduced. The mechanisms concerned are multiple and include decreased ventricular arrhythmias and decreased reinfarction. β-Blockers with partial agonist activity are relatively ineffective, perhaps because of the higher heart rates.

The only outstanding questions are (1) whether low-risk patients really benefit from β-blockade (there is an increasing trend to omit β-blockade especially in patients with borderline hyperglycemic values); (2) when to start (this is flexible and, as data for early β-blockade are not strong, oral β-blocker may be started when the patient’s condition allows, for example from 3 days onward or even later at about 1 to 3 weeks); and (3) how long β-blockade should be continued. Bearing in mind the risk of β-blockade withdrawal in patients with angina, many clinicians continue β-blockade administration for the long term once a seemingly successful result has been obtained. The benefit in high-risk groups such as older adults or those with low EFs increases progressively over 24 months.

The high-risk patients who should benefit most are those often thought to have contraindications to β-blockade. Although CHF was previously regarded as a contraindication to β-blockade, postinfarct patients with heart failure benefited more than others from β-blockade. Today this category of patient would be given a β-blocker after treatment of fluid retention cautiously with gradually increasing doses of carvedilol, metoprolol, or bisoprolol. The SAVE trial showed that ACE inhibitors and β-blockade are additive reducing postinfarct mortality, at least in patients with reduced EFs. The benefit of β-blockade when added to combination therapy with ACE inhibitors reduces mortality by 23% to 40%. Concurrent therapy of CCBs or aspirin does not diminish the benefits of postinfarct β-blockade.

Despite all these strong arguments and numerous recommendations, β-blockers are still underused in postinfarct patients at the expense of many lives lost. In the long term, 42 patients have to be treated for 2 years to avoid one death, which compares favorably with other treatments.

Stroke

In an early trial the nonselective blocker propranolol was only modestly beneficial in reducing stroke (although ineffective in reducing coronary artery disease [CAD]). The β ₁ selective agents are more effective in stroke reduction.

Vascular and noncardiac surgery

β-blockade exerts an important protective effect in selected patients. Perioperative death from cardiac causes and MI were reduced by bisoprolol in high-risk patients undergoing vascular surgery. A risk-based approach to noncardiac surgery is proposed by a very large observational study on 782,969 patients. In those at no or very low cardiac risk, β-blockers were without benefit and in fact were associated with more adverse events, including mortality. In those at very high cardiac risk, mortality decreased by 42%, with a number needed to treat of only 33. Thus risk factor assessment is vital (see original article for revised cardiac risk index). In patients undergoing vascular surgery but otherwise not at very high risk, perioperative metoprolol gave no benefit yet increased intraoperative bradycardia and hypotension.

Impact of POISE study

In the major prospective PeriOperative ISchemic Evaluation (POISE) study on a total of 8351 patients, perioperative slow-release metoprolol decreased the incidence of nonfatal MI from 5.1% to 3.6% ( P < 0.001), yet increased total perioperative mortality from 2.3% to 3.1% ( P < 0.05), with increased stroke rates and markedly increased significant hypotension and bradycardia. Thus, routine perioperative inception of metoprolol therapy is not justified. As metoprolol exerts markedly heterogenous cardiovascular effects according to metabolic genotype, involving subtypes of CYP450 2D6, genetic differences may have accounted for part of the adverse cardiovascular findings in POISE and another study.

In an important focused update given by ACC-AHA, the major recommendations are the following: (1) Class I indication for perioperative β-blocker use in patients already taking the drug; (2) Class IIa recommendations for patients with inducible ischemia, coronary artery disease, or multiple clinical risk factors who are undergoing vascular (i.e. high-risk) surgery and for patients with CAD or multiple clinical risk factors who are undergoing intermediate-risk surgery; (3) Initiation of therapy, particularly in lower-risk groups, requires careful consideration of the risk/benefit ratio; (4) If initiation is selected, it should be started well before the planned procedure with careful perioperative titration to achieve adequate heart rate control while avoiding frank bradycardia or hypotension. In light of the POISE results, routine administration of perioperative β-blockers, particularly in higher fixed-dose regimens begun on the day of surgery, cannot be advocated.

Thyrotoxicosis

Together with antithyroid drugs or radioiodine, or as the sole agent before surgery, β-blockade is commonly used in thyrotoxicosis to control symptoms, although the hypermetabolic state is not decreased. β-blockade controls tachycardia, palpitations, tremor, and nervousness and reduces the vascularity of the thyroid gland, thereby facilitating operation. In thyroid storm, intravenous propranolol IV in slow 1–2 mg boluses may be repeated every 10–15 min until the desired effect is achieved. Alternatively, esmolol, 500 micrograms/Kg IV bolus, followed by 50–200 micrograms/Kg/min for maintenance may be administered; circulatory collapse is a risk, so that β-blockade should only be used in thyroid storm if LV function is normal as shown by conventional noninvasive tests.

Anxiety states

Although propranolol is most widely used in anxiety (and is licensed for this purpose in several countries, including the United States), probably all β-blockers are effective, acting not centrally but by a reduction of peripheral manifestations of anxiety such as tremor and tachycardia.

Glaucoma

The use of local β-blocker eye solutions is now established for open-angle glaucoma; care needs to be exerted with occasional systemic side effects such as sexual dysfunction, bronchospasm, and cardiac depression. Among the agents approved for treatment of glaucoma in the United States are the nonselective agents timolol (Timoptic), carteolol, levobunolol, and metipranolol. The cardioselective betaxolol may be an advantage in avoiding side effects in patients with bronchospasm.

Migraine

Propranolol (80 to 240 mg daily, licensed in the United States) acts prophylactically to reduce the incidence of migraine attacks in 60% of patients. The mechanism is presumably by beneficial vasoconstriction. The antimigraine effect is prophylactic and not for attacks once they have occurred. If there is no benefit within 4 to 6 weeks, the drug should be discontinued.

Esophageal varices

β-blockade has been thought to prevent bleeding by reducing portal pressure. No benefit was found in a randomized study.

β-blocker “generations.”

First-generation nonselective agents, such as propranolol, block all the β-receptors (both β ₁ and β ₂ ). Second-generation cardioselective agents, such as atenolol, metoprolol, acebutolol, bisoprolol, and others, have relative selectivity for the β ₁ (largely cardiac) receptors when given in low doses ( Fig. 1.10 ). Third-generation vasodilatory agents have added properties ( Fig. 1.2 ), acting chiefly through two mechanisms: first, direct vasodilation, possibly mediated by release of nitric oxide as for carvedilol (see Fig. 1.2 ) and nebivolol ; and, second, added α-adrenergic blockade, as in labetalol and carvedilol. A third vasodilatory mechanism, as in pindolol and acebutolol, acts via β ₂ -ISA, which stimulates arterioles to relax. Acebutolol is a cardioselective agent with less ISA than pindolol that was very well tolerated in a 4-year antihypertensive study.

β ₁ – versus β ₂ -cardioselectivity.

In general, note several advantages of cardioselective β-blockers (exception: heart failure). Cardioselectivity is greatest at low drug doses.

(Figure © L. H. Opie, 2012.)

Nonselective agents (combined β ₁ -β ₂ -blockers)

The prototype β-blocker is propranolol, which is still often used worldwide and is a World Health Organization essential drug. By blocking β ₁ -receptors, it affects heart rate, conduction, and contractility, yet by blocking β ₂ -receptors, it tends to cause smooth muscle contraction with risk of bronchospasm in predisposed individuals. This same quality might, however, explain the benefit in migraine when vasoconstriction could inhibit the attack. Among the nonselective blockers, nadolol and sotalol are much longer acting and lipid insoluble.

Combined β ₁ –β ₂ –α-blockers

Carvedilol is very well supported for preferential use in heart failure, in which this combination of receptor blockade should theoretically be ideal, as shown by better outcomes than with metoprolol in the COMET study.

Cardioselective agents (β ₁ -selectivity)

Cardioselective agents (acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, and metoprolol) exert antihypertensive effects equally to the nonselective ones (see Fig. 1.10 ). Selective agents are preferable in patients with chronic lung disease or chronic smoking, insulin-requiring diabetes mellitus, and in stroke prevention. Cardioselectivity varies among agents but is always greater at lower doses. Bisoprolol is among the most selective. Cardioselectivity declines or is lost at high doses. No β-blocker is completely safe in the presence of asthma; low-dose cardioselective agents can be used with care in patients with bronchospasm or chronic lung disease or chronic smoking. In angina and hypertension, cardioselective agents are just as effective as noncardioselective agents. In acute MI complicated by stress-induced hypokalemia, nonselective blockers theoretically should be better antiarrhythmics than β ₁ -selective blockers.

Vasodilating β-blockers

Carvedilol and nebivolol are the prototypes (see Fig. 1.2 ). These agents could have added value in the therapy of hypertension by achieving vasodilation and, in the case of nebivolol, better reduction of LVH is claimed.

Antiarrhythmic β-blockers

All β-blockers are potentially antiarrhythmic by virtue of Class II activity (see Fig. 1.11 ). Sotalol is a unique β-blocker with prominent added Class III antiarrhythmic activity (see Fig. 1.11 ; Chapter 9 ) and will be discussed in greater detail elsewhere.

β-adrenergic receptors in advanced heart failure.

Downregulation and uncoupling of β-adrenergic receptor signal systems results in depressed levels of cyclic adenosine monophosphate (cAMP) and decreased contractility, which may be viewed as an autoprotective from the adverse effects of cAMP. Note: (1) β-receptor downregulation starts as a result of inhibitory phosphorylation of the receptor mediated by G protein–coupled receptor kinase ( GRK ₂ ; previously β ₁ adrenergic receptor kinase [β ₁ ARK]), GRK ₂ increases in response to excess β-adrenergic stimulation of the receptor, (2) β-receptor uncoupling from G-protein, G _s results from β-arrestin activity, (3) β-receptor downregulation is a result of internalization, (4) increased inhibitory G-protein (G _i ) is a result of increased messenger ribonucleic acid activity, (5) β ₂ receptors are relatively upregulated and appear to exert an inhibitory effect on contractile via enhanced G _i . AC, Adenyl cyclase; ATP, adenosine triphophate.

(Figure © L. H. Opie, 2012. For details, see Opie LH, Heart Physiology from Cell to Circulation. Philadelphia: Lippincott Williams and Wilkins; 2004:508.)

Propranolol

(Inderal) is the historical gold standard because it is approved for so many different indications, including angina, acute MI, postinfarction secondary prevention, hypertension, arrhythmias, migraine prophylaxis, anxiety states, and essential tremor. However, propranolol is not β ₁ -selective. Being lipid soluble, it has a high brain penetration and undergoes extensive hepatic first-pass metabolism. Central side effects may explain its poor performance in quality-of-life studies. Propranolol also has a short half-life so that it must be given twice daily unless long-acting preparations are used. The other β-blockers agents are described below alphabetically:

Acebutolol

(Sectral) is the cardioselective agent with ISA that gave a good quality of life in the 4-year TOMH study in mild hypertension. In particular, the incidence of impotence was not increased.

Atenolol

(Tenormin) was one of the first of the cardioselective agents and now in generic form is one of the most widely used drugs in angina, in postinfarction secondary prevention, and in hypertension. However, its use as first-line agent in hypertension is falling into disfavor, with poor outcomes, including increased all-cause mortality when compared with the CCB amlodipine in ASCOT. There are very few trials with outcome data for atenolol in other conditions, with two exceptions: the ASIST study in silent ischemia and INVEST in hypertensives with coronary artery disease. Here atenolol had equality of major clinical outcomes with verapamil at the cost of more episodes of angina, more new diabetes, and more psychological depression. Note that atenolol was often combined with a diuretic and verapamil with an ACE inhibitor. In the British Medical Research Council trial of hypertension in older adults, atenolol did not reduce coronary events. More recently, in the LIFE Trial, atenolol was inferior to the ARB losartan in the therapy of hypertensives with LVH.

Bisoprolol

(Zebeta in the United States, Cardicor or Emcor in the United Kingdom) is a highly β ₁ -selective agent, more so than atenolol, licensed for hypertension, angina heart failure in the United Kingdom, but only for hypertension in the United States. It was the drug used in the large and successful CIBIS-2 study in heart failure, in which there was a large reduction not only in total mortality but also in sudden death. In CIBIS-3, bisoprolol compared well with enalapril as first-line agent in heart failure. A combination of low-dose bisoprolol and low-dose hydrochlorothiazide (Ziac) is available in the United States (see Combination Therapy, p. 13).

Carvedilol

(Coreg in the United States, Eucardic in the United Kingdom) is a nonselective vasodilator α-β-blocker with multimechanism vasodilatory properties mediated by antioxidant activity, formation of nitric oxide, stimulation β-arrestin-MAP-kinase and α-receptors, that has been extensively studied in CHF and in postinfarct LV dysfunction. Metabolically, carvedilol may increase insulin sensitivity. In the United States, it is registered for hypertension, for CHF (mild to severe), and for post-MI LV dysfunction (EF ≤ 40%), but not for angina.

Labetalol

(Trandate, Normodyne) is a combined α- and β-blocking antihypertensive agent that has now largely been supplanted by carvedilol except for acute intravenous use as in hypertensive crises (see Table 1.4 ).

Metoprolol

(Toprol-XL) is cardioselective and particularly well studied in AMI and in postinfarct protection. Toprol-XL is approved in the United States for stable symptomatic Class 2 or 3 heart failure. It is also registered for hypertension and angina. Lopressor, shorter acting, is licensed for angina and MI.

Nadolol

(Corgard) is very long acting and water soluble, although it is nonselective. It is particularly useful when prolonged antianginal activity is required.

Nebivolol

• 
  

  (Nebilet in the United Kingdom, Bystolic in the United States) is a highly cardioselective agent with peripheral vasodilating properties mediated by nitric oxide. Hepatic metabolites probably account for the vasodilation and the long biological half-life. Nebivolol reverses endothelial dysfunction in hypertension, which may explain its use for erectile dysfunction in hypertensives. There are also metabolic benefits. In a 6-month study, nebivolol, in contrast to atenolol and at equal BP levels, increased insulin sensitivity and adiponectin levels in hypertensives. Nebivolol given in the SENIORS trial to older adult patients with a history of heart failure or an EF of 35% or less reduced the primary composite end-point of all-cause mortality and cardiovascular hospitalizations, also increasing the EF and reducing heart size.

Penbutolol

(Levatol) has a modest ISA, similar to acebutolol, but is nonselective. It is highly lipid soluble and is metabolized by the liver.

Sotalol

(Betapace, Betapace AF) is a unique nonselective β-blocker that has Class 3 antiarrhythmic activity. It is licensed for life-threatening ventricular arrhythmias as Betapace, and now also as Betapace AF for maintenance of sinus rhythm in patients with symptomatic atrial fibrillation or atrial flutter. Sotalol is a water-soluble drug, excreted only by the kidneys, so that Betapace AF is contraindicated in patients with a creatinine clearance of less than 40 mL/min.

Timolol

(Blocarden) was the first β-blocker shown to give postinfarct protection and it is one of the few licensed for this purpose in the United States. Other approved uses are for hypertension and in migraine prophylaxis.

Esmolol

(Brevibloc) is an ultrashort-acting β ₁ -blocker with a half-life of 9 minutes, rapidly converting to inactive metabolites by blood esterases. Full recovery from β-blockade occurs within 30 minutes in patients with a normal cardiovascular system. Indications are situations in which on-off control of β-blockade is desired, as in SVT in the perioperative period, or sinus tachycardia (noncompensatory), or emergency hypertension in the perioperative period (all registered uses in the United States). Other logical indications are emergency hypertension (pheochromocytoma excluded) or in unstable angina. Doses are as follows: For SVT, loading by 500 μg/kg/min over 1 minute, followed by a 4-minute infusion of 50 μg/kg/min (US package insert). If this fails, repeat loading dose and increase infusion to 100 μg/kg/min (over 4 minutes). If this fails, repeat loading dose and then infuse at rates up to 300 μg/kg/min. Thereafter, to maintain control, infuse at adjusted rate for up to 24 hours. For urgent perioperative hypertension, give 80 mg (approximately 1 mg/kg) over 30 seconds and infuse at 150 to 300 μg/kg/min if needed. For more gradual control of BP, follow routine for SVT. Higher doses are usually required for BP control than for arrhythmias. After the emergency, replace with conventional antiarrhythmic or antihypertensive drugs. For older adult patients with non–ST-elevation MI requiring acute β-blockade despite symptoms of heart failure, a cautious infusion of 50–200 μg/kg/min may be tried. Cautions include extravasation of the acid solution with risk of skin necrosis.

Respiratory disease

Cardioselective β ₁ -blockers in low doses are best for patients with reversible bronchospasm. In patients with a history of asthma, no β-blocker can be considered safe.

Associated cardiovascular disease

For hypertension plus effort angina, see “β-blockers for hypertension” earlier in this chapter. In patients with sick sinus syndrome, pure β-blockade can be dangerous. β-blockers with ISA may be best. In patients with Raynaud phenomenon, propranolol with its peripheral vasoconstrictive effects is best avoided. In active peripheral vascular disease, β-blockers are generally contraindicated, although the evidence is not firm.

Renal disease

The logical choice should be a β-blocker eliminated by the liver rather than the kidney (see Fig. 1.7 ). Of those, the vasodilating β-blocker nebivolol conserved the estimated glomerular filtration rate in patients with heart failure better than did metoprolol.

Diabetes mellitus

In diabetes mellitus, the risk of β-blockade in insulin-requiring diabetics is that the premonitory symptoms of hypoglycemia might be masked. There is a lesser risk with the cardioselective agents. In type 2 diabetics with hypertension, initial β-blocker therapy by atenolol was as effective as the ACE inhibitor, captopril, in reducing macrovascular endpoints at the cost of weight gain and more antidiabetic medication. Whether diabetic nephropathy benefits as much from treatment with β-blockade is not clear. ARBs and ACE inhibitors have now established themselves as agents of first choice in diabetic nephropathy. Carvedilol combined with renin angiotensin system (RAS) blocker therapy in diabetic patients with hypertension results in better glycemic control and less insulin resistance than combination therapy that includes metoprolol. Although better glycemic control should theoretically translate into fewer cardiovascular events and other adverse outcomes, the short-term nature of this study does not allow conclusions on outcomes.

Those at risk of new diabetes

The use of β-blockers and diuretics poses a risk of new diabetes, which should be lessened by a truly low dose of the diuretic or by using another combination. Regular blood glucose checks are desirable.

Central side effects

An attractive hypothesis is that the lipid-soluble β-blockers (epitomized by propranolol) with their high brain penetration are more likely to cause central side effects. An extremely detailed comparison of propranolol and atenolol showed that the latter, which is not lipid soluble, causes far fewer central side effects than does propranolol. However, depression remains an atenolol risk. The lipid-solubility hypothesis also does not explain why metoprolol, which is moderately lipid soluble, appears to interfere less with some complex psychological functions than does atenolol and may even enhance certain aspects of psychological performance.

Quality of life and libido

In the first quality-of-life study reported in patients with hypertension, propranolol induced considerably more central effects than did the ACE inhibitor captopril. More modern β-blockers, with different fundamental properties, all leave the quality of life largely intact in hypertensives. However, there are a number of negatives. First, weight gain is undesirable and contrary to the lifestyle pattern required to limit cardiovascular diseases, including the metabolic syndrome and hypertension. Second, β-blockade may precipitate diabetes, a disease that severely limits the quality of life. Third, during exercise, β-blockade reduces the total work possible by approximately 15% and increases the sense of fatigue. Vasodilatory β-blockers may be exceptions but lack outcome studies in hypertension. Erectile dysfunction is an age-dependent complication of β-blockade. In a large group with mean age 48 years, erectile problems took place in 11% given a β-blocker, compared with 26% with a diuretic and 3% with placebo. β-blockers have consistently impaired sexual intercourse more than an ACE inhibitor or ARB, the latter improving sexual output. Changing to nebivolol may improve erections. Sildenafil (Viagra) or similar agents should also help, but are relatively contraindicated if the β-blocker is used for angina (because of the adverse interaction with nitrates, almost always used in those with angina).

Adverse metabolic side effects and new-onset diabetes

The capacity of β-blockers to increase new diabetes, whether given for hypertension or postinfarct, comes at a time when diabetes is increasingly recognized as major cardiovascular hazard (see Chapter 4 ). A wise precaution is to obtain fasting blood glucose levels and, if indicated, a glucose tolerance curve before the onset of chronic β-blockade and at annual intervals during therapy. Note that the vasodilatory β-blockers carvedilol and nebivolol both promote formation of nitric oxide and both have a better metabolic profile than comparator cardioselective agents, without, however, long-term outcome data in hypertension (see “Specific β-Blockers” later in this chapter, see also Fig. 1.2 ).

β-blockade withdrawal

Chronic β-blockade increases β-receptor density. When β-blockers are suddenly withdrawn, angina may be exacerbated, sometimes resulting in MI. Treatment of the withdrawal syndrome is by reintroduction of β-blockade. Best therapy is to avoid this condition by gradual withdrawal.