BETA-ADRENERGIC RECEPTOR BLOCKERS

Beta-adrenergic receptor blockers are competitive inhibitors; hence, the intensity of blockade is dependent on both the dose of the blocker and receptor concentrations of catecholamines, primarily epinephrine and norepinephrine. This competitive interaction between beta-blocking agents and catecholamines can be demonstrated in normal human volunteers and in isolated tissues. [198 ] The presence of disease and other drugs modify responses to beta-blocking agents observed in patients, but the underlying competitive interaction is still operative. Successful utilization of beta-adrenergic receptor blockers requires titrating the dose to a desired effect. Excessive inhibition can be overcome by (1) administering a catecholamine to compete at the blocked receptors and/or (2) administering other drugs to reduce unopposed, counterbalancing autonomic mechanisms. An example of the latter remedy is propranolol-induced bradycardia, which produces unopposed vagal cholinergic dominance on cardiac nodal tissue. Atropine relieves the excessive bradycardia by blocking cholinergic receptors in the sinus and atrioventricular (AV) nodes.

Knowledge of the type, location, and action of beta receptors is fundamental to understanding and predicting effects of beta-adrenergic receptor blocking drugs (Table 8-6) . [199 ] The net effect of stimulating beta receptors depends on several variables. For example, in the heart, increased automaticity and conduction velocity in nodal and conduction tissues is opposed by stimulating cholinergic receptors usually by vagal acetylcholine. Therefore, beta1 blockade decreases heart rate as the vagal actions are unopposed. If both beta1 and cholinergic receptors are blocked completely, the intrinsic heart rate dominates (normally greater than 100 bpm). The increase in automaticity usually is not apparent in the normal heart because the rate of spontaneous depolarization in myofibrils is lower than in nodal and conducting tissues. When these are diseased, increased automaticity in myocardial muscle cells becomes apparent with beta1 receptor stimulation, and beta-blocking agents are needed as antidysrhythmics (see the preceding). Increased automaticity can also occur in myocardial ischemia by interrupting normal conduction pathways that usually produce coordinated myofibril depolarization at a rate faster than spontaneous depolarization of individual myofibrils. As is evident in Table 8-6 , many actions of beta receptor stimulation are opposed by stimulation of alpha-adrenergic or cholinergic receptors in the same tissues. With cholinergic receptors, opposing effects are usually produced by acetylcholine spontaneously released from cholinergic nerves or released by giving a cholinomimetic drug. With adrenergic receptors, norepinephrine and epinephrine are released from sympathetic nerve terminals and from the adrenal medulla. Administration of sympathomimetic drugs with varying preferences for different adrenergic receptors can modify responses to beta receptor stimulation and blockade.

Beta-adrenergic receptor antagonists (blockers) include many drugs (Table 8-7) that are typically classified by their relative selectivity for beta1 and beta 2 receptors (i.e., cardioselective and nonselective); the presence or absence of agonistic activity; membrane-stabilizing properties, alpha-receptor blocking efficacy, and various pharmacokinetic features (e.g., lipid solubility, oral bioavailability, elimination half-

time). [200 ] The practitioner must realize that the selectivity of individual drugs for beta1 and2 receptors is relative, not absolute. Although the risk of inducing bronchospasm with a beta1 (cardioselective) adrenergic blocker (e.g., metoprolol) may be relatively less than with a nonselective blocker (e.g., propranolol), the risk is still present. With respect to alpha-adrenergic receptor blocking properties, only labetalol has that action and is used primarily for hypertension. Membrane-stabilizing effects of beta-adrenergic blockers generally occur at much higher doses than those given clinically; therefore, other drugs are usually chosen to produce membrane stabilization (e.g., local anesthetics, antidysrhythmics). The reader is referred to pharmacology textbooks and drug compendia for pharmacokinetic details.

Clinical Indications

The list of clinical indications and uses of beta-adrenergic receptor blockers is long (Table 8-8) . [200 ] In some of these clinical uses, the mechanisms principally responsible for the desired effects appear obvious and logical but are, in fact, not always proven. In some instances, there are actions that appear to oppose the desirable ones. In the end, the success of therapy has to be judged in terms of the balance of beneficial and undesirable effects. Some considerations in the use of beta-adrenergic receptor blockers for specific diseases treated by cardiac surgery are discussed in the following.

ANGINA PECTORIS

The primary goal of beta-blocking agent therapy is to reduce cardiac responses to sympathetic nervous system activation by exertion, emotion, and other types of stress. Limiting or preventing sympathetically induced increases in heart rate, contractility, and systolic blood pressure minimizes increases in myocardial oxygen demand. Doses required to achieve these goals often reduce resting heart rate. This effect may slightly increase ventricular end-systolic volume and myocardial oxygen demand, but this concern is not a clinically important problem. Also, nonselective beta-blocking agents risk coronary vasospasm owing to unopposed alpha-adrenergic receptor responses, but this too is not a clinically important problem, possibly because of routine use of coronary vasodilators (e.g., nitroglycerin). Side-effects of antianginal therapy with beta-blocking agents are considered in the following, but the most common complaints from chronic ingestion are mental depression, fatigue, limited work capacity, and impotence.

ACUTE MYOCARDIAL INFARCTION

Clinical trials of intravenous beta-adrenergic blockers in the early phases of acute myocardial infarction suggest that mortality decreases 10 percent. Following myocardial infarction, chronic oral beta-blocking agents reduce the incidence of recurrent myocardial infarction. The major risk of beta-blocking agents after acute myocardial infarction is congestive heart failure, since the heart may be dependent on sympathetic tone to maintain cardiac output.

SUPRAVENTRICULAR TACHYCARDIAS AND VENTRICULAR DYSRHYTHMIAS

Adrenergic beta-blocking agents are Class II antidysrhythmics that primarily block cardiac responses to catecholamines. Beta-blocking agents decrease spontaneous depolarization in the sinus and atrioventricular (AV) nodes, decrease automaticity in Purkinje fibers, increase AV nodal refractoriness, increase the threshold for fibrillation (but not for depolarization), and decrease ventricular slow responses that are dependent on catecholamines. There is evidence that beta-blocking agents also decrease intramyocardial conduction in ischemic tissue and reduce the risks of dysrhythmias, to the extent that they decrease myocardial ischemia. Beta-adrenergic blockers are not particularly effective in controlling dysrhythmias that are not induced or maintained by catecholamines. Membrane stabilizing effects of beta-adrenergic blockers occur at doses much higher than those tolerated by patients.

HYPERTENSION

Our understanding of the mechanisms for the antihypertensive effects of beta-adrenergic receptor blockers is incomplete, yet it is clear that these effects are caused by beta blockade. During the early phases of therapy there is a decrease in cardiac output, a rise in systemic vascular resistance (SVR), and relatively little change in mean arterial blood pressure. Within hours to days SVR normalizes and blood pressure declines. In addition, the release of renin from the juxtaglomerular apparatus in the kidney is inhibited (beta 1

blockade). Presumably, beta-blocking agents with intrinsic agonistic activity reduce systemic vascular resistance below pretreatment levels, presumably by activating beta 2

receptors in vascular smooth muscle. In addition, labetalol has the ability to block alpha-adrenergic receptors on vascular smooth muscle. Most often beta-adrenergic receptor blockers are used with other drugs in the treatment of chronic hypertension. When combined with a vasodilator, beta-blocking agents limit reflex tachycardia. When propranolol is combined with intravenous nitroprusside, the beta-blocking agent prevents reflex release of renin and reflex tachycardia induced by the vasodilator.

PHEOCHROMOCYTOMA

The presence of catecholamine-secreting cells is tantamount to continuous or intermittent infusion of a varying mixture of norepinephrine and epinephrine. It is absolutely essential that virtually complete alpha-adrenergic receptor blockade be established before beta receptor blocker is given to prevent hypertensive episodes owing to unopposed alpha-adrenergic receptor activity in vascular smooth muscle. [201 ]

ACUTE DISSECTING AORTIC ANEURYSM

The primary goal in the management of these patients is to reduce stress on the dissected aortic wall by reducing systolic acceleration of blood flow. Beta receptor blockers reduce cardiac inotropy and acceleration of blood during ventricular ejection. Beta-blocking

agents also limit reflex sympathetic responses to vasodilating drugs used to lower systemic arterial pressure.

OTHER INDICATIONS

Other clinical applications of beta-adrenergic receptor blockers listed in Table 8-8 are based largely on symptomatic treatment or empiric trials of beta-adrenergic receptor blocking therapy.

Side Effects and Toxicity

The most obvious and immediate evidence of a toxic overdose of a beta-adrenergic receptor blocker is hypotension, bradycardia, decreased AV conduction, and a widened QRS complex on the electrocardiogram. Treatment is aimed at blocking cholinergic receptor responses to vagal nerve activity (e.g., atropine) and administering a sympathomimetic to compete with the beta-blocking agents at adrenergic receptors. Bronchospasm is uncommon in the absence of preexisiting pulmonary disease, and hypoglycemia is rare.

Side effects of chronic beta-adrenergic receptor blockade include mental depression, physical fatigue, altered sleep patterns, excessive bradycardia, exacerbation of congestive heart failure, increased symptoms of peripheral vascular disease, exacerbation of bronchospasm in patients with pulmonary disease, masking hypoglycemic episodes in diabetics, delayed recovery from hypoglycemia, sexual dysfunction, and gastrointestinal symptoms that include indigestion, constipation, and diarrhea.

Drug Interactions

Pharmacokinetic drug interactions include reduced gastrointestinal absorption of the beta-blocking agent (aluminum-containing antacids, cholestyramine), increased biotransformation (phenytoin, phenobarbital, rifamtin, smoking), and increased bioavailability caused by decreased biotransformation (e.g., cimetidine, hydralazine). Pharmacodynamic interactions include an additive effect with calcium channel blockers to decrease intracardiac conduction and reduced antihypertensive effect of beta-blocking agents when administered with some nonsteroidal antiinflammatory drugs.