Beta-blocking agents Flashcards

Question

Cardiovascular effects of β-blockade: β-blockers were originally designed by the Nobel prize winner Sir James Black to counteract the adverse cardiac effects of adrenergic stimulation. The latter, he reasoned, increased myocardial oxygen demand and worsened angina. His work led to the design of the prototype β-blocker, propranolol. By blocking the cardiac β-receptors, he showed that these agents could induce the now well-known inhibitory effects on the sinus node, atrioventricular (AV) node, and on myocardial contraction. These are respectively the negative chronotropic, dromotropic, and inotropic effects (Fig. 1-3). Of these, it is especially bradycardia and the negative inotropic effects that are relevant to the therapeutic effect in angina pectoris because these changes decrease the myocardial oxygen demand (Fig. 1-4).

Answer 1

Cardiovascular effects of β-blockade: β-blockers were originally designed by the Nobel prize winner Sir James Black to counteract the adverse cardiac effects of adrenergic stimulation. The latter, he reasoned, increased myocardial oxygen demand and worsened angina. His work led to the design of the prototype β-blocker, propranolol. By blocking the cardiac β-receptors, he showed that these agents could induce the now well-known inhibitory effects on the sinus node, atrioventricular (AV) node, and on myocardial contraction. These are respectively the negative chronotropic, dromotropic, and inotropic effects (Fig. 1-3). Of these, it is especially bradycardia and the negative inotropic effects that are relevant to the therapeutic effect in angina pectoris because these changes decrease the myocardial oxygen demand (Fig. 1-4).

Answer 2

The inhibitory effect on the AV node is of special relevance in the therapy of supraventricular tachycardias (SVTs; see Chapter 8), or when β-blockade is used to control the ventricular response rate in atrial fibrillation.

Answer 3

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. 3-2).

Answer 4

Thus during exercise the heart pumps faster and more forcefully and the coronary flow is increased—a logical combination. Conversely, β-blockade should have a coronary vasoconstrictive effect with a rise in coronary vascular resistance. However, the longer diastolic filling time, resulting from the decreased heart rate in exercise, leads to better diastolic myocardial perfusion, to give an overall therapeutic benefit.

Answer 5

The effects previously described explain why β-blockers are antianginal as predicted by their developers. Antihypertensive effects are less well understood. In the absence of the peripheral dilatory actions of some β-blockers (see Fig. 1-11), it initially decrease the resting cardiac output by approximately 20% with a compensatory reflex rise in the peripheral vascular resistance. Thus within the first 24 hours of therapy, the arterial pressure is unchanged. The peripheral resistance then starts to fall after 1 to 2 days and the arterial pressure now starts to fall in response to decreased heart rate and cardiac output.

Answer 6

Additional antihypertensive mechanisms may involve (1) inhibition of those β-receptors on the terminal neurons that facilitate the release of norepinephrine (prejunctional β-receptors), hence lessening adrenergic mediated vasoconstriction; (2) central nervous effects with reduction of adrenergic outflow; and (3) decreased activity of the renin-angiotensin system (RAS) because β-receptors mediate renin release (the latter mechanism may explain part of the benefit in heart failure).

Answer 7

β-blockers for hypertension β-blockers are no longer recommended as first-line treatment for hypertension by the Joint National Council (JNC) of the USA and have been relegated to fourth- or even fifth-line choices by the National Institute of Clinical Excellence of the UK.33 β-blockers are the least effective of the standard antihypertensive drug classes at preventing major cardiovascular events, especially stroke. β-blockers are more likely to predispose to new diabetes and they are the least cost-effective of the major classes of antihypertensive agents (the costs of hospitalization, clinical events, and therapy of new diabetes).

Answer 8

The crucial study was ASCOT, in which the much better cardiovascular outcomes of amlodipine with or without perindopril compared with the atenolol with or without diuretic34 could be explained by the lower central aortic pressures with amlopidine.37 In 2003 JNC 7 listed the following as “compelling indications” for the use of β-blockers: heart failure with hypertension, post-MI hypertension, high coronary risk, and diabetes.38 JNC 8 is due to appear this year and its view of β-blockers will elicit great interest.

Answer 9

The exact mechanism of BP lowering by β-blockers remains an open question (see Fig. 7-10). A sustained fall of cardiac output and a late decrease in peripheral vascular resistance (after an initial rise) are important. Inhibition of renin release also contributes, especially to the late vasodilation. Of the large number of β-blockers now available, all are antihypertensive agents but few have outcome studies.39

Answer 10

For patients at high risk of coronary artery disease, such as those with diabetes, chronic renal disease, or a 10-year Framingham risk score of 10% or more, first-line antihypertensive choices should exclude β-blockers, according to the AHA.40

Answer 11

Combination antihypertensive therapy. To reduce the BP, β-blockers may be combined with CCBs, α-blockers, centrally active agents, and cautiously with diuretics. Because β-blockers reduce renin levels, combination with ACE inhibitors or an ARB is not so logical. Increased new diabetes is a risk during β-blocker-thiazide cotherapy. Much less well tested is the use of carvedilol that may increase insulin sensitivity. Ziac is bisoprolol (2.5 to 10 mg) with a very low dose of hydrochlorothiazide (6.25 mg). This drug combination has been approved as first-line therapy (starting with bisoprolol 2.5 mg plus thiazide 6.25 mg) for systemic hypertension by the Food and Drug Administration, an approval rarely given to a combination product. Metabolic side effects of higher thiazide doses were minimized and there was only a small increase in fatigue and dizziness. In the United States, atenolol and chlorthalidone (Tenoretic) and metoprolol tartrate and hydrochlorothiazide (Lopressor HCT) are combinations widely used, yet they often contain diuretic doses that are higher than desirable (e.g., chlorthalidone 25 mg; see Chapter 7). Combinations of such prodiabetic doses of diuretics with β-blockade, in itself a risk for new diabetes,50 is clearly undesirable.

Answer 12

Note that standard doses of β-blocker or diuretic even separately predispose to new diabetes.35 In the ASCOT hypertension study, amlodipine with or without perindopril gave better outcomes than atenolol with or without bendroflumethiazide, including less new diabetes (see Chapter 7).

Answer 13

β-blockers have multiple antiarrhythmic mechanisms (Fig. 1-5) and are effective against many supraventricular and ventricular arrhythmias. Basic studies show that they counter the arrhythmogenic effects of excess catecholamine stimulation by countering the proarrhythmic effects of increased cAMP and calcium-dependent triggered arrhythmias.

Answer 14

Logically, β-blockers should be particularly effective in arrhythmias caused by increased adrenergic drive (early phase AMI, heart failure, pheochromocytoma, anxiety, anesthesia, postoperative states, and some exercise-related arrhythmias, as well as mitral valve prolapse) or by increased cardiac sensitivity to catecholamines (thyrotoxicosis).

Answer 15

β-blockade may help in the prophylaxis of SVTs by inhibiting the initiating atrial ectopic beats and in the treatment of SVT by slowing the AV node and lessening the ventricular response rate. Perhaps surprisingly, in sustained ventricular tachyarrhythmias the empirical use of metoprolol was as effective as electrophysiologically guided antiarrhythmic therapy. Likewise, in ventricular tachyarrhythmias, the ESVEM study showed that sotalol, a β-blocker with added Class III activity (Fig. 1-5), was more effective than a variety of Class I antiarrhythmics.

Answer 16

In patients with atrial fibrillation, current management practices often aim at control of ventricular rate (“rate control”) rather than restoration and maintenance of sinus rhythm (“rhythm control”). β-blockers, together with low-dose digoxin, play an important role in rate control in such patients.

Answer 17

In postinfarct patients, β-blockers outperformed other antiarrhythmics and decreased arrhythmic cardiac deaths. In postinfarct patients with depressed LV function and ventricular arrhythmias, a retrospective analysis of data from the CAST study shows that β-blockade reduced all-cause mortality and arrhythmia deaths.56 Although the mechanism of benefit extends beyond antiarrhythmic protection,57 it is very unlikely that β-blockers can match the striking results obtained with an implantable defibrillator (23% mortality reduction in Class 2-3 heart failure).57,58 In perioperative patients, β-blockade protects from atrial fibrillation.59

Answer 18

Intravenous esmolol is an ultrashort-acting agent esmolol that has challenged the previously standard use of verapamil or diltiazem in the perioperative period in acute SVT, although in the apparently healthy person with SVT, adenosine is still preferred (see Chapter 8). Intravenous esmolol may also be used acutely in atrial fibrillation or flutter to reduce the rapid ventricular response rate (see later).

Answer 19

β-blockers in heart failure That β-blockers, with their negative inotropic effects, could increase cardiac contraction and decrease mortality in heart failure is certainly counterintuitive, especially bearing in mind that the β1-receptor is downregulated (Fig. 1-6). Not only does the cardiac output increase, but abnormal patterns of gene expression revert toward normal.60 Several mechanisms are proposed, of which the first three are well-studied.

Answer 20

1. Improved β-adrenergic signaling. Myocardial β-receptors respond to prolonged and excess β-adrenergic stimulation by internalization and downregulation (see Fig. 1-6), so that the β-adrenergic inotropic response is diminished. This is a self-protective mechanism against the known adverse effects of excess adrenergic stimulation. The first step in β1-receptor internalization is the increased activity of β1ARK, now renamed GRK2. GRK2 then phosphorylates the β1-receptor, which in the presence of β-arrestin becomes uncoupled from Gs and internalizes (Fig. 1-7).4

Answer 21

If the β-stimulation is sustained, then the internalized receptors may undergo lysosomal destruction with true loss of receptor density or downregulation. However, downregulation is a term also often loosely applied to any step leading to loss of receptor response.

Answer 22

Experimental β-blockade decreases the expression of GRK2 and increases the activity of AC, thereby improving contractile function. Relative upregulation of the β2-receptor may have inhibitory effects (see Fig. 1-6), including continued excessive formation of Gi and hyperphosphorylated SR (see Fig. 1-7). However, the role of the β2-receptor in advanced heart failure is still not fully clarified.8 Thus not surprisingly in clinical heart failure studies carvedilol with its blockade of β1, β2,and β3 receptors is superior to the β1-selective blocker metoprolol.

Answer 23

Self-regulation. There is a potent and rapid physiologic switch-off feedback mechanism that mutes β-adrenergic receptor stimulation and avoids perpetuated activation of this receptor (see Fig. 1-7). Physiologically, this very rapid desensitization of the β-receptor occurs within minutes to seconds. Sustained β-agonist stimulation rapidly induces the activity of the GRK2, thereby increasing the affinity of the β-receptor for another protein family, the arrestins that dissociate the agonist-receptor complex.

Answer 24

β-arrestin not only lessens the activation of AC, thereby inhibiting is activity,63 but furthermore switches the agonist coupling from Gs to inhibitory Gi.64

Answer 25

Resensitization of the receptor occurs if the phosphate group is split off by a phosphatase so that the receptor may then more readily be linked to Gs. β-arrestin signaling can also evoke an alternative counterbalancing protective path by activating the epidermal growth factor receptor that leads to the protective ERK/MAP kinase path (see item 7 in Fig. 1-7).65 β-blocker drugs may have complex effects by β-arrestin agonism.

Answer 26

Although receptor-arrestin effects are best described for the β2-receptor, they also occur to a lesser extent with the β1-receptor.63

Answer 27

In heart failure, prolonged hyperadrenergic β-receptor stimulation is linked to adverse end results, both impairing contractile function and enhancing adverse signaling.

Answer 28

There is long-term compensatory desensitization of the β-adrenergic receptor in chronic heart failure. Conversely, transgenic mice with GRK2 (previously Beta-adrenergic receptor kinase, BARK) overexpression are protected from heart failure.67 Of note, the desensitization process is reversible as occurs during experimental cardiac resynchronization therapy, when specific suppressors of the inhibitor G protein (see Gi in Fig. 1-6) are much increased in activity so that β-adrenergic signaling becomes more normal.

Answer 29

3. The hyperphosphorylation hypothesis. The proposal is that continued excess adrenergic stimulation leads to hyperphosphorylation of the calcium-release channels (also known as the ryanodine receptor) on the SR. This causes defective functioning of these channels with excess calcium leak from the SR, with cytosolic calcium overload. Because the calcium pump that regulates calcium uptake into the SR is simultaneously downregulated, the pattern of rise and fall of calcium ions in the cytosol is impaired with poor contraction and delayed relaxation. These abnormalities are reverted toward normal with β-blockade, which also normalizes the function of the calcium release channel.

Answer 30

4.Bradycardia. β-blockade may act at least in part by reduction of the heart rate (Fig. 1-8). Multiple studies have suggested that a high resting heart rate is an independent risk factor for cardiovascular disease, which could reflect the role of excess adrenergic tone. Bradycardia may improve coronary blood flow and decrease the myocardial oxygen demand. Experimentally, long-term heart rate reduction lessens extracellular matrix collagen, besides improving the LV EF. To achieve adequate bradycardia, the addition of ivabradine may be required (see Chapter 6, p. 195).

Answer 31

. Protection from catecholamine myocyte toxicity. The circulating concentrations of norepinephrine found in severe heart failure are high enough to be directly toxic to the myocardium, experimentally damaging the membranes and promoting subcellular destruction, acting at least in part through cytosolic calcium overload.

Answer 32

Antiarrhythmic effects. In experimental heart failure, ventricular arrhythmias are promoted via increased formation of cAMP and calcium-mediated afterpotentials.

Answer 33

7. Antiapoptosis. Coupling of the β2-receptor to the inhibitory G-protein, G1, may be antiapoptotic

Answer 34

8. Renin-angiotensin inhibition. When added to prior ACE inhibitor or ARB therapy, β-blockade by metoprolol increases the blockade of the RAS.

Answer 35

1. Improved β-adrenergic signaling. 2. Self-regulation. 3. The hyperphosphorylation hypothesis. 4. Bradycardia. 5. Protection from catecholamine myocyte toxicity. 6. Antiarrhythmic effects 7. Antiapoptosis. 8. Renin-angiotensin inhibition.

Answer 36

How to apply β-blockers in heart failure β-blockers are now recognized as an integral part of anti–heart failure therapy based on neurohumoral antagonism with coherent molecular mechanisms (see Fig. 1-8). They benefit a wide range of patients with stable systolic heart failure. The principles are the following: (1) Select patients with stable heart failure; start slowly and uptitrate gradually (Table 1-2), while watching for adverse effects. If necessary cut back on the dose or titrate more slowly. (2) The usual procedure is to add β-blockade to existing therapy, including ACE inhibition and diuretics, and, optionally in some studies, digoxin, when the patient is hemodynamically stable and not in Class IV or severe Class III failure. (3) However, in several recent studies, β-blockers were also given before ACE inhibitors, which is logical, considering that excess baroreflex-mediated adrenergic activation may be an important initial event in heart failure (see Fig. 5-8). (4) Never stop the β-blocker abruptly (risk of ischemia and infarction). (5) Use only β-blockers with doses that are well understood and clearly delineated, and with proven benefit, notably carvedilol, metoprolol, bisoprolol, and nebivolol (see Table 1-2). The first three of these drugs have reduced mortality in large trials by approximately one third. Of these, only carvedilol and long-acting metoprolol are approved in the United States. However, data for carvedilol are strongest in the COMET trial; carvedilol reduced mortality more than metoprolol. Thus far there is no evidence that diastolic heart failure improves.

Answer 37

For every heart rate reduction of 5 beats/min with β-blockade, there is an 18% reduction (cardiac index, 6%-29%) in the risk for death as occurred in the 23 β-blocker trials in 209 patients, of whom more than 95% had systolic dysfunction. Perhaps unexpectedly, the dose of β-blocker did not relate to any benefit. The initiation of β-blockade is a slow process that requires careful supervision and may temporarily worsen the heart failure; we strongly advise that only the proven β-blockers be used in the exact dose regimens that have been tested (see Table 1-2). Propranolol, the original gold-standard β-blocker, and atenolol, two commonly used agents, have not been well studied in heart failure.

Answer 38

Other cardiac indications: 1. In hypertrophic obstructive cardiomyopathy, high-dose propranolol is standard therapy although verapamil and disopyramide are effective alternatives. 2. In catecholaminergic polymorphic ventricular tachycardia high-dose β-blockers prevent exercise-induced ventricular tachycardia (VT), although most patients continue to have ventricular ectopy during exercise, so that heart rate–reducing calcium blockers may give added benefit. 3. In mitral stenosis with sinus rhythm, β-blockade benefits by decreasing resting and exercise heart rates, thereby allowing longer diastolic filling and improved exercise tolerance. In mitral stenosis with chronic atrial fibrillation, β-blockade may have to be added to digoxin to obtain sufficient ventricular slowing during exercise. Occasionally β-blockers, verapamil, and digoxin are all combined. Heart block is a risk during co-therapy of β-blockers with verapamil. 4. In mitral valve prolapse, β-blockade is the standard procedure for control of associated arrhythmias. 5. In dissecting aneurysms, in the hyperacute phase, intravenous propranolol has been standard, although it could be replaced by esmolol. Thereafter, oral β-blockade is continued. 6. In Fallot’s tetralogy, propranolol 2 mg/kg twice daily is usually effective against the cyanotic spells, probably acting by inhibition of right ventricular contractility. 7. Congenital QT-prolongation syndromes are now classified both on the basis of genotype and phenotype. β-blocker therapy is theoretically most effective when the underlying mutation affects K+ channel–modulated outward currents. β-blockers reduce the overall frequency of major and minor cardiac events by approximately 60%, thus not eliminating the need for implantable defibrillator insertion in high-risk patients. In the related condition of catecholaminergic polymorphic VT, β-blockers are also moderately effective. 8. In postural tachycardia syndrome (POTS), both low-dose propranolol (20 mg)86 and exercise training are better than high-dose propranolol (80 mg daily).

Answer 39

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. 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.

Answer 40

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 can be given at a rate of 1 mg/min (to a total of 5 mg at a time); 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.

Answer 41

β-blocker “generations.” First-generation nonselective agents, such as propranolol, block all the β-receptors (both β1 and β2). Second-generation cardioselective agents, such as atenolol, metoprolol, acebutolol, bisoprolol, and others, have, when given in low doses, relative selectivity for the β1 (largely cardiac) receptors (Fig. 1-9). Third-generation vasodilatory agents have added properties (Fig. 1-10), acting chiefly through two mechanisms: first, direct vasodilation, possibly mediated by release of nitric oxide as for carvedilol (see Fig. 1-10) and nebivolol, and, second, added α-adrenergic blockade, as in labetalol and carvedilol. A third vasodilatory mechanism, as in pindolol and acebutolol, acts via β2-intrinsic sympathomimetic activity (ISA), which stimulates arterioles to relax; however, these agents are less used at present and do not neatly fit into the division of the three “generations.” Acebutolol is a cardioselective agent with less ISA than pindolol that was very well tolerated in a 4-year antihypertensive study.

Answer 42

The prototype β-blocker is propranolol, which is still often used worldwide and is a World Health Organization essential drug. By blocking β1-receptors, it affects heart rate, conduction, and contractility, yet by blocking β2-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.

Answer 43

Combined β1–β2–α-blocker. 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

Answer 44

``` Cardioselective agents (β1-selectivity). Cardioselective agents (acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, and metoprolol) are as antihypertensive as the nonselective ones (see Fig. 1-9). ```

Answer 45

Selective agents are preferable in patients with chronic lung disease or chronic smoking, insulin-requiring diabetes mellitus, and in stroke prevention. Cardioselectivity varies between agents, but is always greater at lower doses.

Answer 46

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 hypertension, cardioselective agents are just as effective as noncardioselective agents.

Answer 47

Vasodilating β-blockers. Carvedilol and nebivolol are the prototypes (see Fig. 1-10). 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.

Answer 48

Antiarrhythmic β-blockers. All β-blockers are potentially antiarrhythmic by virtue of Class II activity (see Fig. 1-6). Sotalol is a unique β-blocker with prominent added Class III antiarrhythmic activity (see Fig. 1-6; Chapter 8).

Answer 49

Esmolol, given intravenously, has the shortest of all half-lives at only 9 min. Esmolol may therefore be preferable in unstable angina and threatened infarction when hemodynamic changes may call for withdrawal of β-blockade.

Answer 50

The half-life of propranolol (Table 1-3) 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.

Answer 51

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.

Answer 52

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

Answer 53

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.

Answer 54

First-pass metabolism varies greatly among patients and alters the dose required. In liver disease or low-output states the dose should be decreased.

Answer 55

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 P450 2D6–mediated hydroxylation and is subject to marked genetic variability.

Answer 56

Acebutolol produces large amounts of diacetolol, and is also cardioselective with ISA, but with a longer half-life and chiefly excreted by the kidneys (Fig. 1-11). Lipid-insoluble hydrophilic compounds (atenolol, sotalol, nadolol) are excreted only by the kidneys (see Fig. 1-11) and have low brain penetration.

Answer 57

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 1-3).

Answer 58

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.

Answer 59

β-blockers depress hepatic blood flow so that the blood levels of lidocaine increase with greater risk of lidocaine toxicity.

Answer 60

Cardioselective β1-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.

Answer 61

In patients with sick sinus syndrome, pure β-blockade can be dangerous. Added ISA may be best. In active peripheral vascular disease, β-blockers are generally contraindicated, although the evidence is not firm.

Answer 62

The logical choice should be a β-blocker eliminated by the liver rather than the kidney (see Fig. 1-11). Of those, the vasodilating β-blocker nebivolol conserved the estimated glomerular filtration rate in patients with heart failure better than did metoprolol.

Answer 63

Diabetes mellitus. In diabetes mellitus, the risk of β-blockade in insulin-requiring diabetics is that the symptoms of hypoglycemia might be masked. There is a lesser risk with the cardioselective agents.

Answer 64

In type 2 diabetics with hypertension, initial β-blocker therapy by atenolol was as effective as the ACE inhibitor, captopril, in reducing macrovascular end points 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 (see Chapter 5, p. 136). Carvedilol combined with 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.

Answer 65

The β-blocker and diuretics pose 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.

Answer 66

(1) smooth muscle spasm (bronchospasm and cold extremities), (2) exaggeration of the cardiac therapeutic actions (bradycardia, heart block, excess negative inotropic effect), (3) central nervous system penetration (insomnia, depression), and (4) adverse metabolic side effects.

Answer 67

The mechanism of fatigue is not clear. When compared with propranolol, however, it is reduced by use of either a cardioselective β-blocker or a vasodilatory agent, so that both central and peripheral hemodynamic effects may be involved.

Answer 68

When patients are appropriately selected, double-blind studies show no differences between a cardioselective agent such as atenolol and placebo. This may be because atenolol is not lipid soluble and should have lesser effects on bronchial and vascular smooth muscle than propranolol.

Answer 69

When propranolol is given for hypertension, the rate of serious side effects (bronchospasm, cold extremities, worsening of claudication) leading to withdrawal of therapy is approximately 10%.101 The rate of withdrawal with atenolol is considerably lower (approximately 2%), but when it comes to dose-limiting side effects, both agents can cause cold extremities, fatigue, dreams, worsening claudication, and bronchospasm. Increasing heart failure remains a potential hazard when β-blockade therapy is abruptly started at normal doses in a susceptible patient and not tailored in.

Answer 70

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.

Answer 71

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.

Answer 72

Severe bradycardia, preexisting high-degree heart block, sick sinus syndrome, and overt LV failure unless already conventionally treated and stable (Fig. 1-12).

Answer 73

Pulmonary contraindications are overt asthma or severe bronchospasm; depending on the severity of the disease and the cardioselectivity of the β-blocker used, these may be absolute or relative contraindications.

Answer 74

The central nervous system contraindication is severe depression (especially for propranolol). Active peripheral vascular disease with rest ischemia is another contraindication. The metabolic syndrome suggests caution.

Answer 75

Bradycardia may be countered by intravenous atropine 1 to 2 mg; if serious, temporary transvenous pacing may be required. When an infusion is required, glucagon (2.5 to 7.5 mg/h) is logical because it stimulates formation of cAMP by bypassing the occupied β-receptor. However, evidence is only anecdotal. Logically an infusion of a phosphodiesterase inhibitor, such as amrinone or milrinone, should help cAMP to accumulate. Alternatively, dobutamine is given in doses high enough to overcome the competitive β-blockade (15 mcg/kg/min). In patients without ischemic heart disease, an infusion (up to 0.10 mcg/kg/min) of isoproterenol may be used.

Answer 76

(1) advantageous pharmacokinetics (simplicity, agents not metabolized in liver); (2) a high degree of cardioselectivity (bisoprolol); (3) long duration of action (several) (4) a favorable metabolic profile, especially when associated with vasodilatory properties (carvedilol and nebivolol).

Answer 77

Propranolol (Inderal) is the historical gold standard because it is licensed for so many different indications, including angina, acute-stage MI, postinfarct follow-up, hypertension, arrhythmias, migraine prophylaxis, anxiety states, and essential tremor. However, propranolol is not β1-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.

Answer 78

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 postinfarct protection, 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.

Answer 79

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, atenolol was inferior to the ARB losartan in the therapy of hypertensives with LVH

Answer 80

Bisoprolol (Zebeta in the United States, Cardicor or Emcor in the United Kingdom) is a highly β1-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 In CIBIS-3, bisoprolol compared well with enalapril as first-line agent in heart failure.

Answer 81

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.

Answer 82

Metoprolol (Toprol-XL) is cardioselective and particularly well studied in AMI and in postinfarct protection. It is also registered for hypertension and angina. Lopressor, shorter acting, is licensed for angina and MI.

Answer 83

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.

Answer 84

Ultrashort-acting intravenous β-blockade Esmolol (Brevibloc) is an ultrashort-acting β1-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. I

Answer 85

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.

Answer 86

Doses are as follows: For SVT, loading by 500 mcg/kg/min over 1 minute, followed by a 4-minute infusion of 50 mcg/kg/min (US package insert). If this fails, repeat loading dose and increase infusion to 100 mcg/kg/min (over 4 minutes). If this fails, repeat loading dose and then infuse at rates up to 300 mcg/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 mcg/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 mcg/kg/min may be tried.119 Cautions include extravasation of the acid solution with risk of skin necrosis.

Answer 87

Summary 1. Despite some setbacks in recent hypertension trials, β-blockers still come closest to providing all-purpose cardiovascular therapy with the conspicuous absence of any benefit for lipid problems. Licensed indications include angina, hypertension, AMI, postinfarct follow-up, arrhythmias, and now heart failure. Data for postinfarct protection and for mortality reduction in CHF are particularly impressive. Other data are less compelling (Table 1-5). 2. In heart failure, solid data support the essential and earlier use of β-blockers in stable systolic heart failure, to counter the excessive adrenergic drive. Only three agents have been studied in detail, namely carvedilol, metoprolol, and bisoprolol, of which only the first two are approved for heart failure in the United States. In older adults, nebivolol improved EF in systolic but not diastolic heart failure. Following the recommended protocol with slow, incremental doses of the chosen agent is essential. 3. For coronary heart disease, β-blockade is very effective symptomatic treatment, alone or combined with other drugs, in 70% to 80% of patients with classic effort angina. However, atenolol-based therapy was no better at lessening major outcomes than verapamil-based therapy, and worse for some minor outcomes. β-blockers are part of the essential postinfarct protection armamentarium. For ACSs, indirect evidence suggests a quadruple follow-up regime of aspirin, statin, ACE inhibitor, and β-blockade, but there are no compelling outcome trials. Overall, there is no clinical evidence that β-blockers slow the development of coronary artery disease. 4. In hypertension β-blockers have lost their prime position, although they reduce the BP effectively in 50% to 70% of those with mild to moderate hypertension. The crucial study showed that for equal brachial pressures, the aortic pressure was less reduced with atenolol than with the CCB amlodipine, which could explain why β-blockers reduce stroke less than several other agents. Older adults with hypertension, especially those of the black ethnic group, respond less well to β-blocker monotherapy. The previously recommended combination of β-blockers and diuretics may provoke new diabetes, with lesser risk if the diuretic dose is truly low. 5. In arrhythmias β-blockers are among the more effective ventricular antiarrhythmics. 6. Metabolic side-effects, including new diabetes, have come to the fore. β-blockers can be diabetogenic even without diuretics. The vasodilatory β-blockers carvedilol and nebivolol appear to be exceptions and have outcome studies only in heart failure. 7. Is there still a role for propranolol? There is no particular advantage for this original “gold standard” drug, with its poor quality-of-life outcomes, unless hypertension or angina with some other condition in which experience with propranolol is greater than with other β-blockers (e.g., POTS, hypertrophic cardiomyopathy, migraine prophylaxis, anxiety, or essential tremor) is also occurring. 8. Other b-blockers are increasingly used because of specific attractive properties: cardioselectivity (acebutolol, atenolol, bisoprolol, metoprolol), vasodilatory capacity and possible metabolic superiority (carvedilol and nebivolol), positive data in heart failure (carvedilol, metoprolol, bisoprolol, nebivolol) or postinfarct protection (metoprolol, carvedilol, timolol), lipid insolubility and no hepatic metabolism (atenolol, nadolol, sotalol), long action (nadolol) or long-acting formulations, ISA in selected patients to help avoid bradycardia (pindolol, acebutolol), and well-studied antiarrhythmic properties (sotalol). Esmolol is the best agent for intravenous use in the perioperative period because of its extremely short half-life. 9. Evidence-based use directs the use of those agents established in large trials because of the known doses and clearly expected benefits. For example, for postinfarct protection propranolol, metoprolol, carvedilol, and timolol are the best studied, of which only carvedilol has been studied in the reperfusion era. For stabilized heart failure, carvedilol, metoprolol, and bisoprolol have impressive data from large trials. Carvedilol especially merits attention, being licensed for a wide clinical range, from hypertension to LV dysfunction to severe heart failure, and having best trial data in heart failure. For arrhythmias, sotalol with its class III properties stands out.