William H. Frishman, MD, Department of Medicine, Munger Pavilion, New York Medical College, Valhalla, NY 10595 E-mail: email@example.com
The introduction of β-adrenergic-blocking drugs into clinical medicine in the early 1960s represented a major advance in pharmacotherapy. The use of these drugs highlighted the importance of the sympathetic nervous system in contributing to the pathophysiology of a wide variety of cardiovascular and noncardiovascular disorders. This article summarizes the history of β-blocking agents and reviews the applications of this therapeutic class. These drugs may be useful as primary protection against cardiovascular morbidity and mortality in hypertensive patients and have proved to be beneficial in other cardiovascular conditions. Not all β-blockers have the same mechanism of action and, among them, there are pharmacologic differences that may be of clinical importance.
Catecholamines are neurohormonal substances that mediate a wide variety of physiologic and metabolic activities. The effects of various catecholamines ultimately depend on their chemical interactions with adrenergic receptors, which are discrete macromolecular structures located on the cell membrane.1 The finding that the relative potency of a series of sympathomimetic amines varied with the effector organs or systems led Ahlquist2 to originally conclude that there were 2 distinct types of adrenergic receptors; these were classified as α- and β-adrenergic receptors. Subsequent studies revealed that β-adrenergic receptors exist as 3 discrete subtypes: β1, β2, and β3 (Table I).3,4 It is now appreciated that there are 2 subtypes of α-receptors, designated as α1 and α2(Table I). In addition, at least 3 subtypes of both α1- and α2-adrenergic receptors are known, but their functions and locations are not well-defined.1
Table I. Characteristics of Subtypes of Adrenergic Receptors*
Increased force and rate of contraction and atrioventricular-nodal conduction velocity
Increased renin secretion
Positive inotropic and chronotropic effects; submaximal increases in force of contraction
Smooth muscle (vascular, bronchial, gastrointestinal, and genitourinary)
Glycogenolysis; uptake of K+
*Drugs that act on adrenergic receptors and the location of subtypes of adrenergic receptors. †At least 3 subtypes of each α1- and α2-adrenergic receptors are known, but their mechanisms of action and tissue locations have not been clearly defined. ‡In some species (eg, rat), metabolic responses in the liver are mediated by α1-adrenergic receptors, whereas in others (eg, dog), β2-adrenergic receptors are predominantly involved. Both types of receptors appear to contribute to responses in human beings. §Metabolic responses in adipocytes and certain other tissues with atypical pharmacologic characteristics may be mediated by this subtype of receptor. Most β-adrenergic receptor antagonists (including propranolol) do not block these responses. Adapted from Hoffman and Taylor3 with addictional data from Brodde et al.4
Once the β-adrenergic receptor was described, the concept of pharmacologic β-adrenergic blockade became feasible, leading to a major advance and the eventual awarding of the Nobel Prize in Medicine and Physiology to James Black in 1988.5 In this article, the historical development of the β-adrenergic blockers will be described, along with a discussion of the applications of this therapeutic class to a variety of cardiovascular and noncardiovascular conditions.
EARLY DEVELOPMENT OF β-ADRENERGIC BLOCKADE
Ahlquist's adrenergic receptor theories were the subject of skepticism until the discovery of dichloroisoproterenol (DCI) by Powell and Slater in 1958.6 The discovery that DCI selectively blocked the physiologic responses of isoproterenol, which according to Ahlquist were mediated by β-receptors, was the proof of principle that these receptors actually existed in humans. DCI as a β-blocker, however, possessed intrinsic sympathomimetic activity (ISA), which limited its clinical development.6 Black recognized that the inhibition of the sympathetic nervous system with the right competitive β-adrenergic blocker compound might benefit patients with cardiac arrhythmias and angina pectoris.5,7 His subsequent work led to the development of 2 nonselective β-adrenergic blocker compounds, pronethalol8 (which also had ISA and the potential for carcinogenesis in animals) and propranolol7 (a compound without ISA). The latter agent became the prototype drug for early clinical use in patients with angina, arrhythmias, and pheochromocytoma.
THE DIFFERENT PHARMACODYNAMIC AND PHARMACOKINETIC EFFECTS OF β-BLOCKERS
The potential adverse effects related to heart rate, myocardial contractility, and bronchial tone9 with propranolol led to refinements in the pharmacologic structure and drug delivery systems of β-blocker compounds (Figure 1). The evolution of drugs in the β-blocker class was marked by compounds with features such as relative β1-adrenergic receptor activity, partial adrenergic activity, and/or α1-adrenergic-blocking activity. Compounds also emerged that had favorable pharmacokinetic effects (Table II),10 allowing for once-daily oral dosing and rapid, short-acting intravenous use.
Table II. Pharmacodynamic Effects of β-Adrenergic-Blocking Drugs
β1-Blockade Potency Ratio (Propranolol=1.0)
Intrinsic Sympathomimetic Activity
+ Indicates modest effect; ++, strong effect; 0, absent effect. *Bisoprolol is also approved as initial antihypertensive therapy in combination with a very low-dose diuretic. †Carvedilol has peripheral vasodilating activity and additional α1-adrenergic-blocking activity. ‡Labetalol has additional α1-adrenergic-blocking activity and direct vasodilatory activity. §Sotalol has an additional type of antiarrhythmic activity. Adapted from Frishman.10
In 1967, Lands and colleagues11 described 2 types of β-adrenergic receptors, β1 and β2. β-Adrenergic blockers are now further classified as being β1-selective or β1-nonselective, according to their relative abilities to antagonize the actions of sympathomimetic amines at lower doses in some tissues than in other tissues. When used in low doses, β1-selective-blocking drugs inhibit cardiac β1-receptors but have less influence on β2-receptors in bronchial and vascular locations12; in higher doses, β1-selective agents also block β2-receptors. Accordingly, β1-selective agents may be safer than nonselective ones in patients with bronchospastic disease, since β2-receptors are still able to be stimulated and, in the process, mediate adrenergic bronchodilation. Even selective β-blockers, however, must be used with caution in patients with reversible bronchospasm.12
A second theoretic advantage is that unlike nonselective β-blockers, β1-selective blockers in low doses may not block the β2-receptors that mediate dilation of arterioles.1 During the infusion of epinephrine, nonselective blockers can cause a pressure response by blocking β2-receptor-mediated vasodilation, since α-adrenergic vasoconstrictor responses are still operative and relatively unopposed. Selective β1-antagonists may not induce the pressor effect in the presence of epinephrine and may lessen the risk of decreasing peripheral blood flow. It is possible that leaving β2-receptors unblocked (and responsive to epinephrine) may be functionally important in a subset of patients with asthma, drug-induced hypoglycemia, and/or peripheral vascular disease who require β-blocking drugs.1
Practolol was introduced in 1970 as the first β1-selective blocker, but, after 4 years of clinical use, it was found to cause a unique toxicity (the oculomucocutaneous syndrome) manifested by keratoconjunctivitis, sclerosing peritonitis, and pleurisy13; it was ultimately removed from the market. Subsequently, other β1-selective blockers without this toxicity were introduced, including metoprolol, atenolol, betaxolol, bisoprolol, esmolol, and acebutolol.
Intrinsic Sympathomimetic Activity
The 2 earliest β-blocking drugs that were synthesized, DCI and pronethalol, were found to inhibit the effects of catecholamines while at the same time stimulate adrenergic receptors, although with less potency (partial agonist activity). These were abandoned as clinical agents. Subsequently, other agents with less ISA (pindolol, carteolol, and penbutolol) were synthesized and approved for clinical use. The level of ISA with these particular β-blockers causes a minor stimulation of the receptor (in the absence of catecholamines), which can be blocked by propranolol (Figure 2). In the presence of catecholamines, β-blockers with ISA are effective antihypertensive agents; however, it is still debated whether a β-blocker with the potential for ISA constitutes an overall advantage or disadvantage in cardiac therapy.14,15 Drugs with ISA cause less slowing of the heart rate at rest than propranolol and metoprolol, although the increases in heart rate with exercise are similarly blunted.15β-Blocking agents with ISA directly reduce peripheral vascular resistance and may also cause less depression of atrioventricular conduction than drugs lacking this action.15,16 Some investigators have made claims that ISA in a β-blocker protects against myocardial depression, adverse lipid changes, bronchial asthma, and peripheral vascular complications that may be noted in some patients on a compound such as propranolol without ISA.15 The evidence to support this claim still remains unconvincing.17
Labetalol and carvedilol are 2 β-blocking agents that have antagonistic effects at both α- and β- adrenoceptors and both have direct vasodilator effects.1 Labetalol has been shown to be 6 to 10 times less potent than phentolamine on α-adrenergic receptors and 1.5 to 4 times less potent than propranolol at β-adrenergic receptors.1,18 Labetalol is itself much less potent at α- than at β-receptors. The additional α-blocking effect, however, may lead to a reduction in peripheral vascular resistance and better preservation of cardiac output than observed with propranolol. The drug is useful as a parenteral agent for treating hypertensive urgencies or emergencies and as an oral drug for chronic hypertension management in the patient receiving multiple antihypertensive agents.19
Although carvedilol has somewhat lower α-adrenergic-blocking potency than labetalol (the ratio of α1- to β-adrenergic blockade for carvedilol is 1:10, compared with 1:4 for labetalol),20 it is useful as a treatment of systemic hypertension and for patients with symptomatic congestive heart failure related to ischemic and nonischemic causes.20 Unlike labetalol, carvedilol also has been shown to have antioxidant and antiproliferative effects.20
Although β-adrenergic-blocking drugs as a group have similar therapeutic or pharmacodynamic actions in patients with systemic hypertension, angina pectoris, and arrhythmias, these compounds have varied pharmacokinetic actions and are available in a multitude of different delivery systems.12,21 For example, propranolol is a compound first introduced in an intravenous form for the treatment of angina pectoris. In its intravenous form it is fully bioavailable. Alternatively, when given orally there is a large first-pass effect, which clearly influences its absolute bioavailability. Its pharmacologic half-life is approximately 3 to 4 hours, requiring that the drug be given in 4 divided doses for the treatment of angina pectoris.16,22 The drug also is highly lipophilic and as such readily crosses the blood-brain barrier.16,22 Subsequently, 2 sustained-release formulations of propranolol, including 1 with delayed-release action, were developed to reduce the drug's dosing intervals, allowing for once-daily use.1 A delayed-release form of metoprolol is also now available, and a once-daily form of carvedilol has recently been introduced for use in patients with hypertension and congestive heart failure.23,24
β1-Selective agents have similar pharmacokinetic actions. The nonselective β-blocker nadolol and β1-selective blocker atenolol are also intrinsically longer-acting agents and are excreted unchanged by the kidney.25,26 In addition, they are much less lipid soluble and will concentrate to a lesser extent in the brain.25,26
Since intravenous propranolol was introduced for arrhythmias, intravenous forms of atenolol and metoprolol have become available for use in the hyperacute phase of myocardial infarction (MI),27 and intravenous labetalol has been approved for use in hypertensive emergencies. Esmolol, an ultra-short-acting β1-selective agent with a unique metabolic pathway related to hepatic and blood esterases, is also available for the treatment of arrhythmias.28,29 Recently, it has been observed that there are genetic polymorphisms that can influence the hepatic metabolism of various β-blocking drugs including propranolol, metoprolol, timolol, and carvedilol.20,23,30,31
The therapeutic efficacy and safety of β-adrenergic-blocking drugs has been well established after 40 years of use in human beings. Their clinical utility has been documented in patients with angina pectoris, cardiac arrhythmias, congestive cardiomyopathy, and hypertension, and for reducing the risk of mortality and possibly nonfatal reinfarction in survivors of acute MI. Not all of the β-blockers have been proved to be beneficial in each of the clinical applications listed above. These drugs may be useful as primary protection against cardiovascular morbidity and mortality in hypertensive patients and have also been found to be of use in other cardiovascular (Table III) and noncardiac (Table IV) disorders.1
Table III. Reported Cardiovascular Indications for β-Adrenoceptor-Blocking Drugs
Hypertension* (systolic and diastolic)
Isolated systolic hypertension in the elderly
Silent myocardial ischemia
Reducing the risk of mortality and reinfarction in survivors of acute myocardial infarction*
Reducing the risk of mortality following percutaneous coronary revascularization*
Hyperacute phase of myocardial infarction*
Dissection of aorta
Reversing left ventricular hypertrophy
Digitalis intoxication (tachyarrhythmias)*
Mitral valve prolapse
Prolonged QT interval syndrome
Tetralogy of Fallot
*Indications formally approved by the United States Food and Drug Administration for some agents. Adapted from Frishman.1
Table IV. Some Reported Noncardiovascular Indications for β-Adrenoceptor-Blocking Drugs
Alcohol withdrawal (delirium tremens)
Pheochromocytoma (after α-blockers)*
Portal hypertension and gastrointestinal bleeding
*Indications formally approved by the United States Food and Drug Administration for some agents. Adapted from Frishman.1
β-Blockers were first conceived as possible treatment for patients with angina pectoris; oral propranolol was approved for this use 35 years ago.32 By blunting catecholamine-induced increases in heart rate, blood pressure, and myocardial contractility, myocardial oxygen consumption is reduced, allowing patients to increase their exercise capacity.33 This compound can also be used in combination with nitrates and calcium channel blockers to increase antianginal effectiveness beyond what is seen with these compounds individually. In addition, β-blockers and nitrates have been shown to be first-step treatments for patients with unstable angina (preinfarction angina).1
Virtually all available β-blockers, whether or not they have ISA, α-adrenergic action, or nonselective or β1-selective actions, produce some form of increased work capacity without pain in patients with angina pectoris.1 The orally active β-blockers that have been approved for use in angina pectoris include propranolol, metoprolol, atenolol, and nadolol.23,34–36
Intravenous propranolol was approved almost 40 years ago for the treatment of arrhythmias and, shortly thereafter, it became available in an oral form for the same indication.1 The antiarrhythmic effects of propranolol result from its anticatecholamine electrophysiologic actions and not from the weak “quinidine-like” effect that propranolol manifests at very high doses.1,37 Although β-blockers were thought to have their greatest effect on the prevention and treatment of supraventricular arrhythmias, it quickly became apparent that they were also safe and effective for the prevention and treatment of ventricular arrhythmias.1
Subsequently, oral acebutolol, a drug with both β1-selectivity and ISA, was approved as a treatment for patients with ventricular arrhythmias,1 and intravenous esmolol, a β1-adrenergic blocker, was approved for intravenous use to treat supraventricular arrhythmias.28,38 Finally, oral sotalol, a nonselective β-blocker with unique type III antiarrhythmic effects, was approved as a treatment for both supraventricular and ventricular arrhythmias.1,39,40
As antiarrhythmic drugs, no other group of agents have shown the long-term safety profile exhibited by β-blocking agents.
The β-adrenergic blocker pronethalol was studied as a possible treatment of hypertension in the early 1960s.41 Prichard and Gillam42 demonstrated that propranolol had antihypertensive actions and, after resistance by some investigators, the drug was approved for clinical use as an oral antihypertensive agent. Propranolol was also used as adjunct therapy to phentolamine in the treatment of pheochromocytoma.34 Subsequently, labetalol in its intravenous form was determined to be useful in the treatment of hypertensive emergencies and in an oral form for hypertensive urgencies.19
Thirteen β-blockers have received approval for oral use in patients with systemic hypertension: the nonselective β-blockers without ISA (propranolol, nadolol, and timolol); the β1-selective agents (metoprolol, atenolol, betaxolol, acebutolol, and bisoprolol); the β-blockers with ISA (pindolol, carteolol, and penbutolol); and the α-/β-blockers (labetalol and carvedilol). Sustained-release formulations of metoprolol, propranolol, and carvedilol have allowed these shorter-acting β-blockers to be used once daily in hypertension.
The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure has considered β-blockers to be a first-step alternative treatment for hypertension.43 Recent meta-analyses with atenolol, however, have shown that this compound is less efficacious than other antihypertensive drugs,44 and some have considered this a class effect of all β-blockers. Atenolol may not be an effective drug when used once daily, and more frequent oral dosing may be necessary to achieve blood pressure control at a level seen with other β-blockers and other antihypertensive medications. In patients with angina pectoris and hypertension or congestive heart failure and hypertension, and in patients who are post-MI with hypertension, β-blockers remain important first-step treatments. When compared with other antihypertensive agents for primary prevention, however, they may be less effective in preventing strokes.
The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial45 compared the effects of β-blockers with different pharmacologic profiles on glycemic and metabolic control in participants with hypertension and diabetes already receiving renin-angiotensin system blockade. This trial compared the effects of carvedilol and metoprolol tartrate on glycemic control after equivalent blood pressure-lowering; the mean hemoglobin A1c levels increased significantly with metoprolol but not with carvedilol. Insulin sensitivity significantly improved with carvedilol but not metoprolol. Progression to microalbuminuria occurred more often with metoprolol than with carvedilol. Based on this study, it appears that the pharmacologic differences among β-blockers can affect the utility of these agents in hypertensive patients with diabetes.
Survivors of Acute Infarction
β-Blockers were the first class of pharmacologic agents to be shown conclusively to reduce mortality and reinfarction in survivors of acute MI. In the early 1980s, a series of trials using the nonselective β-blockers timolol and propranolol demonstrated survival benefit in survivors of infarction.27 While the β1-selective agents atenolol and metoprolol have demonstrated survival benefit in post-infarction patients as well, there is conflicting evidence regarding the duration of effect.27,46–48 Both oral propranolol and timolol received approval as long-term postinfarction therapy and, subsequently, the β1-selective agents atenolol and metoprolol were approved for both early intravenous use and long-term oral use. Oral carvedilol given twice daily was approved for use in survivors of acute MI with clinical evidence of left ventricular dysfunction with or without symptoms of heart failure who were also on standard treatments receiving angiotensin-converting enzyme inhibition and other contemporary post-MI treatments.49 Carvedilol is now available as a once-daily sustained-release formulation.24
For 25 years, β-blockers were contraindicated in patients with acute or chronic congestive heart failure because of fears that the negative inotropic effect of adrenergic blockade would further reduce myocardial function. Preliminary studies by Swedish investigators in the 1980s demonstrated the benefits and tolerability of β-blockers in patients with congestive heart failure.50 Subsequent placebo controlled studies with the β1-selective agents bisoprolol and metoprolol and the nonselective α-/β-blocker carvedilol demonstrated the efficacy and safety of using β-blockers to reduce the mortality risk in patients with symptomatic heart failure who were already receiving diuretics and angiotensin-converting enzyme inhibitors.51 Sustained-release metoprolol is approved for clinical use in patients with New York Heart Association (NYHA) class II and III heart failure, and carvedilol is approved for mild to severe heart failure in both its twice-daily and sustained-release once-daily formulations. Carvedilol is also approved for reducing mortality in patients with left ventricular dysfunction who have survived an MI. Not all β-blockers tested have been shown to significantly reduce mortality in heart failure patients (eg, bucindolol, nebivolol).52,53 Recently it was suggested that β-blockers might reduce accelerated myocardial apoptotic cell death seen in patients with cardiac dilatation and high levels of circulating plasma catecholamines.1
Other Cardiovascular Uses
Some β-blockers are also approved for the treatment of hypertrophic cardiomyopathy to reduce the symptoms of dyspnea, angina, and syncope.1,54 Since the introduction of propranolol in the 1960s, β-blockers have been shown to be useful treatments for patients with mitral valve prolapse,55 with the hereditary prolonged QT syndrome,56 and for children with tetralogy of Fallot.57
In the treatment of acute aortic dissection, β-blockers are often combined with α-blockers to reduce the extent of injury.58 The α-/β-blocker labetalol has been used as monotherapy in acute dissection.58 In addition, β-blockers can be useful for preventing first dissections in high-risk individuals with Marfan syndrome59 and for preventing recurrent dissection in patients who have had a first dissection.58 These medications are often used to reduce tachycardia and hypertension in patients with high levels of anxiety and atypical chest pain.60 and to possibly prevent cardiovascular events in high-risk patients undergoing general surgery.61
Since the introduction of β-blockers almost 40 years ago, their use has extended beyond cardiovascular disorders. Because β-adrenergic receptors are ubiquitous in the body, these agents have been approved for the prevention and treatment of migraine headache (propranolol),62 essential tremor (propranolol),63 intraocular pressure (topical timolol, betaxolol, carteolol),26,64 thyrotoxicosis (propranolol),37 and pheochromocytoma (propranolol).37 These drugs have also been used to treat alcohol withdrawal65 and relieve the symptoms of situational anxiety (stage fright).60 More recently, β-blockers have been used for reducing aberrant behaviors in children with autism.57
After 40 years of clinical use, β-blockers remain safe drugs when employed in the appropriate dose and in the appropriate patient populations. Definite contraindications to β-blocker use include active bronchospasm, Raynaud phenomenon, and acute pulmonary edema.1 Patients with bradyarrhythmias and heart block can be treated with these medications if there is concurrent artificial pacemaker use. Chronic heart failure is no longer a contraindication with carvedilol or metoprolol succinate (other agents still carry a contraindication in their prescribing information for patients with overt cardiac failure), and patients with intermittent claudication may be given the drugs, with caution.
β-Blockers may cause a slight increase in body weight and can worsen mild hypoglycemia, hyperglycemia, and hyperlipidemia.66,67 The α-/β-blocker carvedilol has been shown to cause fewer metabolic problems when compared with metoprolol.45 For years there was a fear that continued β-blocker use just before coronary artery bypass surgery would put patients undergoing general anesthesia at risk of myocardial depression; however, studies with continuous perioperative β-blocker use have shown the opposite to occur: better clinical outcomes and fewer postoperative arrhythmias.68 Indeed, abrupt β-blocker withdrawal in patients with ischemic heart disease can be associated with an unfavorable rebound effect and increased mortality and should be avoided whenever possible.69
Since their introduction into clinical medicine in the early 1960s, β-adrenergic-blocking drugs have proved to be useful in the treatment of several cardiac and noncardiac diseases. Use of these drugs has clarified the importance of the sympathetic nervous system in the pathophysiology of a wide variety of cardiovascular and noncardiovascular disorders. β-Blockers are not always interchangeable within the class, however, with pharmacologic differences that may be of clinical importance.