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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 86) . [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 alphaadrenergic 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).

. emotion. Limiting or preventing sympathetically induced increases in heart rate. in fact. the risk is still present. Clinical Indications The list of clinical indications and uses of beta-adrenergic receptor blockers is long (Table 8-8) . Also. possibly because of routine use of coronary vasodilators (e. The major risk of beta-blocking agents after acute myocardial infarction is congestive heart failure. there are actions that appear to oppose the desirable ones.g. With respect to alpha-adrenergic receptor blocking properties. fatigue. [200 ] In some of these clinical uses. only labetalol has that action and is used primarily for hypertension. not absolute. ACUTE MYOCARDIAL INFARCTION Clinical trials of intravenous beta-adrenergic blockers in the early phases of acute myocardial infarction suggest that mortality decreases 10 percent. .[200 ] The practitioner must realize that the selectivity of individual drugs for beta1 and2 receptors is relative. and other types of stress. but this concern is not a clinically important problem.g.. not always proven. therefore. and systolic blood pressure minimizes increases in myocardial oxygen demand. ANGINA PECTORIS The primary goal of beta-blocking agent therapy is to reduce cardiac responses to sympathetic nervous system activation by exertion. since the heart may be dependent on sympathetic tone to maintain cardiac output. metoprolol) may be relatively less than with a nonselective blocker (e. nitroglycerin). This effect may slightly increase ventricular end-systolic volume and myocardial oxygen demand. Although the risk of inducing bronchospasm with a beta1 (cardioselective) adrenergic blocker (e. other drugs are usually chosen to produce membrane stabilization (e.g. Doses required to achieve these goals often reduce resting heart rate. In some instances.. and impotence. but the most common complaints from chronic ingestion are mental depression. propranolol). Some considerations in the use of beta-adrenergic receptor blockers for specific diseases treated by cardiac surgery are discussed in the following. the success of therapy has to be judged in terms of the balance of beneficial and undesirable effects.g. nonselective beta-blocking agents risk coronary vasospasm owing to unopposed alpha-adrenergic receptor responses. but this too is not a clinically important problem. local anesthetics. In the end.. chronic oral beta-blocking agents reduce the incidence of recurrent myocardial infarction. Following myocardial infarction. the mechanisms principally responsible for the desired effects appear obvious and logical but are. Side-effects of antianginal therapy with beta-blocking agents are considered in the following. Membrane-stabilizing effects of beta-adrenergic blockers generally occur at much higher doses than those given clinically. antidysrhythmics). limited work capacity. contractility. The reader is referred to pharmacology textbooks and drug compendia for pharmacokinetic details.

Presumably. During the early phases of therapy there is a decrease in cardiac output. There is evidence that beta-blocking agents also decrease intramyocardial conduction in ischemic tissue and reduce the risks of dysrhythmias. and decrease ventricular slow responses that are dependent on catecholamines. Beta-blocking . When propranolol is combined with intravenous nitroprusside. PHEOCHROMOCYTOMA The presence of catecholamine-secreting cells is tantamount to continuous or intermittent infusion of a varying mixture of norepinephrine and epinephrine. Most often beta-adrenergic receptor blockers are used with other drugs in the treatment of chronic hypertension. labetalol has the ability to block alphaadrenergic receptors on vascular smooth muscle.SUPRAVENTRICULAR TACHYCARDIAS AND VENTRICULAR DYSRHYTHMIAS Adrenergic beta-blocking agents are Class II antidysrhythmics that primarily block cardiac responses to catecholamines. a rise in systemic vascular resistance (SVR). [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-blocking agents decrease spontaneous depolarization in the sinus and atrioventricular (AV) nodes. and relatively little change in mean arterial blood pressure. 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 alphaadrenergic receptor activity in vascular smooth muscle. In addition. When combined with a vasodilator. the beta-blocking agent prevents reflex release of renin and reflex tachycardia induced by the vasodilator. decrease automaticity in Purkinje fibers. HYPERTENSION Our understanding of the mechanisms for the antihypertensive effects of beta-adrenergic receptor blockers is incomplete. In addition. beta-blocking agents with intrinsic agonistic activity reduce systemic vascular resistance below pretreatment levels. increase the threshold for fibrillation (but not for depolarization). yet it is clear that these effects are caused by beta blockade. Membrane stabilizing effects of beta-adrenergic blockers occur at doses much higher than those tolerated by patients. beta-blocking agents limit reflex tachycardia. the release of renin from the juxtaglomerular apparatus in the kidney is inhibited (beta 1 blockade). presumably by activating beta 2 receptors in vascular smooth muscle. Beta receptor blockers reduce cardiac inotropy and acceleration of blood during ventricular ejection. Beta-adrenergic blockers are not particularly effective in controlling dysrhythmias that are not induced or maintained by catecholamines. to the extent that they decrease myocardial ischemia. increase AV nodal refractoriness. Within hours to days SVR normalizes and blood pressure declines.

smoking). and increased bioavailability caused by decreased biotransformation (e. Bronchospasm is uncommon in the absence of preexisiting pulmonary disease. and a widened QRS complex on the electrocardiogram. cimetidine. Drug Interactions Pharmacokinetic drug interactions include reduced gastrointestinal absorption of the betablocking agent (aluminum-containing antacids. and hypoglycemia is rare. Treatment is aimed at blocking cholinergic receptor responses to vagal nerve activity (e. increased symptoms of peripheral vascular disease. sexual dysfunction. delayed recovery from hypoglycemia. increased biotransformation (phenytoin. exacerbation of bronchospasm in patients with pulmonary disease. masking hypoglycemic episodes in diabetics. excessive bradycardia. atropine) and administering a sympathomimetic to compete with the beta-blocking agents at adrenergic receptors. . physical fatigue. hydralazine). Side effects of chronic beta-adrenergic receptor blockade include mental depression. 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.. altered sleep patterns. decreased AV conduction. 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.agents also limit reflex sympathetic responses to vasodilating drugs used to lower systemic arterial pressure.g. bradycardia. phenobarbital. exacerbation of congestive heart failure.. cholestyramine). Side Effects and Toxicity The most obvious and immediate evidence of a toxic overdose of a beta-adrenergic receptor blocker is hypotension. and gastrointestinal symptoms that include indigestion. rifamtin. and diarrhea.g. constipation.