Chapter 13

Autonomic and Cardiac Pharmacology

Cardiovascular medicine continues to be one of the most rapidly changing specialties in modern clinical practice. Management guidelines are continuously being refined as data from large-scale clinical trials are reported. The number of patients requiring noncardiac surgery who have had coronary interventions is increasing. Many patients are being managed with complex management plans that require consultation with their cardiologists. Providing high-quality anesthetic care involves continuous monitoring of all the body’s systems, with a special emphasis on the cardiovascular status of the patient. Complex anesthetic plans and invasive surgical intervention can produce profound stress on patients’ cardiovascular balance and require careful manipulation of vital signs. The array of diagnostic tests, monitors, and drugs available makes a thorough understanding of autonomic and cardiac pharmacology essential. A well-devised treatment plan will make the anesthetic course flow smoothly. Intraoperative planning for the immediate and late postoperative periods is critical to avoiding untoward outcomes. The number and variety of medications in a patient’s profile require a delicate balance between the anesthetic requirements and maintaining a successful continuum of therapy for the long-term needs of the patient. This chapter presents a broad overview of the many autonomic and cardiovascular medicines that may be encountered during the perioperative period and their important anesthetic considerations.

Autonomic Drugs—Sympathomimetic Amines

The sympathomimetic amines include the three naturally occurring catecholamines epinephrine, norepinephrine, and dopamine and a number of synthetic agents such as phenylephrine and dobutamine. These drugs are used in a variety of situations, including the treatment of anesthesia-induced hypotension, bradycardia, anaphylaxis, shock, heart failure, and cardiac resuscitation.

The basic structure of the sympathomimetic amines is β-(3,4-dihydroxyphenyl)-ethylamine. This structure consists of a substituted benzene ring and an ethylamine side chain.¹ The effects elicited by this pharmacologic class are the result of the stimulation of β-adrenergic, α-adrenergic, and dopamine adrenergic receptors. The innervation of the effector organs by the autonomic system is outlined in Table 13-1.

TABLE 13-1

Typical Autonomic Influences on Peripheral Effector Organs

α, Alpha receptor; β, beta receptor; GI, gastrointestinal; M, muscarinic receptor.

The efficacy of a particular sympathomimetic amine depends on its concentration at the receptor site, its affinity for specific receptors, and the population of receptors available for binding. The effects of the common autonomic drugs are summarized in Table 13-2.

TABLE 13-2

Effects of Autonomic Drugs

↑, Increase; ↓ decrease; GI, gastrointestinal; NCRE, no clinically relevant effect.

Epinephrine

Epinephrine, one of the naturally occurring catecholamines, is the final product in the chain of catecholamine synthesis. (See Chapter 33 for a complete description of catecholamine synthesis.) Although both epinephrine and norepinephrine have agonistic activity at both α- and β-receptors, norepinephrine has minimal β₁ activity in low doses, whereas epinephrine strongly stimulates both β₁– and β₂-receptors.

Epinephrine is useful not only in the treatment of anaphylaxis and cardiopulmonary resuscitation, but also its combination of α and β effects makes it an appropriate choice for the treatment of some shock states in which poor tissue oxygen delivery and hypotension are combined. In small doses, epinephrine may well be useful as a sympathomimetic agent in patients unresponsive to indirect-acting agents and in those in whom simultaneous β₁ (cardiac stimulation) and β₂-receptor stimulation (vasodilation) may be helpful. With epinephrine, the dominance of α or β effects is dose related.

Epinephrine’s β₁ effect produces marked positive inotropic (force of contraction), chronotropic (heart rate), and dromotropic (conduction velocity) actions. It should be noted that as heart rate, left ventricular stroke work, stroke volume, and cardiac output increase, so does myocardial oxygen consumption. In addition, the corresponding increased automaticity of all foci, including those that are ectopic, may lead to arrhythmia. Marked vigilance must be maintained in an effort to ensure that an imbalance of myocardial oxygen supply and demand does not occur. It should be recalled that the effects resulting from epinephrine administration are capable of both increasing myocardial demand and decreasing supply.

Beneficial effects of β₂ stimulation include bronchodilation, vasodilation, and stabilization of mast cells, with a resultant diminution of histamine release. Concurrently, α stimulation promotes a decrease in bronchial secretion. The net effect is a decrease in airway resistance with an improvement in oxygenation.

With low doses of epinephrine (10 mcg/min) the peripheral vasculature promotes the redistribution of blood flow to skeletal muscle, thereby producing a decrease in systemic vascular resistance. As the dose of epinephrine is increased, the α effect predominates, with resultant vasoconstriction and an increase in systemic pressures. The systolic pressure is increased, whereas the diastolic pressure remains relatively unchanged, with a resultant increase in pulse pressure. It should be noted that if the coronary arteries are not obstructed, autoregulation increases oxygen delivery to meet the increased demand.² However, in the presence of a coronary artery lesion, oxygen delivery may be insufficient to meet demand, and myocardial ischemia results.³

The increased α effect that occurs with greater doses of epinephrine also results in renal and splanchnic vasoconstriction. Renal vascular resistance and ultimately renal blood flow are decreased. Beta stimulation leads to activation of the renin-angiotensin system and also to an increase in lipolysis, glycogenolysis, gluconeogenesis, ketone production, and lactate release by skeletal muscle. Insulin secretion is inhibited by an overriding β₂ stimulation. Epinephrine-induced β₂ stimulation also can cause a transient hyperkalemia as potassium follows glucose out of hepatic cells. This is followed by a longer hypokalemia as β₂ stimulation then forces this extracellular potassium into red blood cells.⁴

Norepinephrine

Norepinephrine is a potent vasopressor. Although it is not as potent as epinephrine in stimulating α-receptors in equal doses, it has little β₂ activity at low doses, and the end result is, for the most part, unopposed α stimulation. The chronotropic effect seen with β₁ stimulation is generally absent with norepinephrine in low doses because of the increase in systemic vascular resistance, which induces reflex vagal activity.

The aforementioned combination of adrenergic stimulation results in a decrease in vital organ flow; however, coronary artery perfusion may be increased because of the increase in diastolic pressure. Renal vascular resistance is increased, and urine output may fall. An increase in preload may be seen because norepinephrine is a venoconstrictor.5,6

Both norepinephrine and dopamine are used as first-line therapy for shock. There is an ongoing debate as to whether one is superior. A recent large multicenter clinical trial suggests that they are equally effective, although dopamine produces more adverse events such as arrhythmias.⁷ Norepinephrine is generally used in patients with adequate cardiac output but low systemic vascular resistance. In this group of patients, however, the underlying problem of peripheral tissue perfusion-oxygenation may be exacerbated by the intense norepinephrine-induced peripheral vasoconstriction, even if adequate blood pressure has been achieved.

Norepinephrine does have some generalized metabolic effects, such as a decrease in insulin production, but these metabolic effects are present to a lesser degree than those seen with epinephrine. Adverse effects are usually a result of the intense vasoconstriction associated with norepinephrine.

Dopamine

Dopamine is an endogenous central and peripheral neurotransmitter that is derived from dopa in the chain of catecholamine synthesis. Pharmacologically, dopamine stimulates dopamine receptors, β-receptors, and α-receptors in a dose-dependent manner because of differing receptor affinities. Dopaminergic receptors are stimulated with low doses of less than 2 mcg/kg/min. At moderate doses of 2 to 5 mcg/kg/min, β effects are elicited, and α effects are seen with high infusion rates of greater than 10 mcg/kg/min. Dopamine also has an indirect sympathomimetic effect, eliciting the release of norepinephrine via β₁ stimulation.⁸

Dopamine is often the first inotropic agent chosen for a patient in shock. Some clinicians have found dopamine to have a poor response in cases of gram-negative sepsis because of a down-regulation in which the sensitivity of β-receptors is diminished.9,10

During surgery and anesthesia, dopamine is administered for its dopaminergic effect. The stimulation of dopamine receptors in the renal artery promotes an increase in renal blood flow and a resultant increase in glomerular filtration rate and urine output. Benefits, however, of so-called “renal” dopamine are in doubt, and many clinicians have abandoned the practice.11–14 The urine output is increased but long-term morbidity and mortality are not improved. Dopamine also inhibits aldosterone, resulting in an increase in sodium excretion and urine output.

Dopamine has been implicated in several cases of severe limb ischemia. If dopamine is administered through a peripheral line, increased vigilance in pediatric patients and in patients with any type of vascular disease such as diabetes, atherosclerosis, or Raynaud’s phenomenon is advised. The presence of an arterial line in the affected limb also increases the incidence of limb ischemia with concurrent dopamine infusion. Other metabolic and central nervous system (CNS) effects, similar to those seen with epinephrine but less extensive, have been attributed to dopamine administration.⁴

The monoamine oxidase enzymes metabolize dopamine; therefore, the effects of dopamine can be prolonged in patients receiving a monoamine oxidase inhibitor. Tricyclic antidepressants may also augment the activity of sympathomimetic drugs.

Isoproterenol

Isoproterenol is a synthetic catecholamine with the same underlying chemical structure as the endogenous catecholamines. It is a potent nonselective agonist of β₁– and β₂-receptors but has no agonistic activity at α-receptors or dopamine receptors. The current use of isoproterenol is limited since the emergence of dobutamine and milrinone. In current practice, it is occasionally used in the treatment of bradycardia with heart block and torsades de pointes ventricular tachycardia.¹⁵ Isoproterenol is also used after heart transplant for chronotropic support. The mechanism is in part due to β₂-receptor stimulation.¹⁶

The profound β₁ stimulation of isoproterenol results in both positive inotropic and chronotropic effects. In combination with the peripheral β₂-induced vasodilation and resultant drop in systemic vascular resistance, an increase in cardiac output is seen. However, the positive inotropic and chronotropic effects dramatically increase myocardial oxygen consumption, which may already be compromised by the β₂-induced peripheral vasodilation, causing a decrease in diastolic blood pressure and ultimately a decrease in coronary artery perfusion. These effects are especially detrimental in patients with coronary artery disease. Isoproterenol is also a potent bronchial dilator and pulmonary vasodilator.

The detrimental effects of isoproterenol on the heart, such as excessive tachycardia, induction of myocardial ischemia, and arrhythmia production are the major factors limiting its use to the treatment of significant heart block unresponsive to atropine. Other side effects are similar to those seen with epinephrine but occur to a lesser extent.

Dobutamine

Dobutamine is a synthetic sympathomimetic amine. It is a modification of isoproterenol, but its use is much more widespread. Dobutamine is primarily a β₁-agonist with some β₂ effects.¹⁷ Dobutamine displays a strong inotropic response with minimal chronotropy. It also produces a slight drop in systemic vascular resistance, owing to peripheral vasodilation. The resultant increase in cardiac output compensates for the decrease in systemic vascular resistance, and the blood pressure is increased or, at low doses, relatively unchanged. Pulmonary artery pressure decreases, and an increase in left ventricular stroke work index is observed.¹⁸

The positive inotropic effects, coupled with the lack of chronotropy and maintenance of normal blood pressure, have made this agent an option in cardiogenic and septic shock and in select patients with mild heart failure.¹⁹ It is also frequently used for heart stimulation for cardiac stress testing.¹⁵ Recent evidence indicates significant adverse effects when dobutamine is used in cardiac surgery, and clinicians have stopped using it for inotropic support in this situation.²⁰

Direct-Acting α-Agonists

α₁-Agonists

Phenylephrine

Phenylephrine (Neo-Synephrine) is the most commonly employed pure α-agonist. Phenylephrine has strong α-stimulating effects, with virtually no β stimulation. A sharp rise in blood pressure is produced as a result of a significant increase in peripheral resistance secondary to the α₁ stimulation. A reflex bradycardia can be elicited secondary to baroreceptor stimulation. Careful titration of intravenous (IV) boluses of phenylephrine is necessary to avoid large changes in blood pressure and decreases in heart rate. The onset of action of IV phenylephrine is immediate, with the duration of action ranging from 5 to 20 minutes. Because of its vasoconstricting effects, phenylephrine is frequently used topically for the prevention of nosebleeds during nasal intubation or for a reduction in bleeding in ear, nose, and throat surgery. Severe hypertension may occur with excessive doses. It is recommended that the topical dose should not exceed 0.5 mg (4 drops of 0.25% in adults) and 20 mcg/kg in children.²¹

Other Inotropes

Vasopressin

Arginine vasopressin is an endogenous hormone that is produced in the hypothalamus, stored in the posterior pituitary, and released from the magnocellular neurons of the hypothalamus. It functions to control osmoregulation. Its release is stimulated by an increased osmolality and hypovolemia. It is also referred to as antidiuretic hormone. Vasopressin deficiency and down-regulation of vasopressin receptors are common in septic shock.²² Vasopressin is a potent vasoconstrictor; however, it selectively dilates renal afferent, pulmonary, and cerebral arterioles. Low-dose vasopressin infusion (0.03 to 0.04 units/min) increases blood pressure, urine output, and creatinine clearance and decreases the dosage of norepinephrine required to maintain blood pressure in patients with septic shock. It is mostly used as an add-on therapy with catecholamine vasopressors. Increases in blood pressure occur in the first hour of administration, and the catecholamine vasopressor can then be titrated down. In a randomized trial, low-dose vasopressin added to norepinephrine was not significantly better than as-needed norepinephrine alone although added vasopressin may be useful in patients with less severe shock. Complications of vasopressin include gastrointestinal ischemia, decreased cardiac output, skin or digital necrosis, and cardiac arrest (especially at doses greater than 0.04 units/min).^23–25 Vasopressin agonists such as terlipressin and desmopressin have a variety of uses including bleeding reduction, antidiuresis in diabetes insipidus, and treatment of enuresis.²⁶

Phosphodiesterase Inhibitors

Milrinone

The phosphodiesterase 3 (PDE 3) inhibitors, also known as nonglycoside noncatecholamines, include milrinone (Primacor). They differ structurally and functionally from the catecholamines and are generally used as alternatives or adjuncts to the standard inotropes in cardiac surgery and heart failure.27–30

Phosphodiesterases (PDEs) are a group of enzymes that play a role in a variety of physiologic actions. Eleven subfamilies have been identified.³¹ They break down the second messengers, cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP), in various cells. The PDE 3 inhibitors such as milrinone prevent the breakdown of cAMP and thus enhance its action. Milrinone produces a positive inotropic action and vasodilation without producing tachycardia. It is occasionally referred to as an inodilator.³² Milrinone substantially improves left ventricular function in association with an acceleration of calcium uptake by the sarcoplasmic reticulum. This acceleration appears to result from an inhibition of membrane-bound PDE 3 in the sarcoplasm, which induces a local elevation of cAMP. This allows for the buildup of cAMP and a subsequent increase in the uptake of intracellular calcium. Adrenergic receptors are not used to achieve the inotropic effect. It follows that these drugs retain their inotropic effect even in the presence of β-blocking agents or the phenomenon of β-receptor down-regulation, situations frequently encountered in patients with heart failure. Therefore PDE 3 inhibitors may be used, by virtue of their alternative pathway, to augment the effect of direct-acting β-agonists such as dobutamine or dopamine. Milrinone improves weaning of high-risk patients from cardiopulmonary bypass.^29,30

These agents act as vasodilators because of the differential mechanism of cAMP in the smooth muscle versus its actions in the myocardium. In the smooth muscle, cAMP causes an efflux of calcium, with a resultant relaxation of the muscle and vasodilation. The clinical result is a decrease in both preload and afterload. This effect, along with the absence of an associated increase in heart rate, probably contributes to the absence of an increase in myocardial oxygen consumption. Sildenafil (Viagra, Revatio) is a PDE 5 inhibitor that produces vasodilation and is being used to treat pulmonary arterial hypertension. Pulmonary vasodilation reduces the workload of the right ventricle and improves symptoms of right-sided heart failure.

Milrinone acts to enhance diastolic function, increases cardiac output, and decreases pulmonary wedge pressure. Side effects can include arrhythmias. Elimination is via the kidney; therefore, milrinone should be used with caution in patients in renal failure because of the potential for life-threatening arrhythmias. The current manufacturer’s recommendation for the administration of milrinone is an IV loading dose of 50 mcg/kg, administered slowly over 10 minutes, followed by an infusion of 0.5 mcg/kg as needed. Table 13-3 outlines the current vasopressors and some of their uses.

TABLE 13-3

Vasopressor Agents

From Rivers EP. Approach to patient with shock. In: Goldman L, Schafer AI. Goldman’s Cecil Medicine. 24th ed. Philadelphia: Saunders; 2012:645-653.

Mixed Function Agonists

Ephedrine

Ephedrine is a synthetic noncatecholamine sympathomimetic commonly used in anesthesia practice. It stimulates both α- and β-receptors directly, and it indirectly causes release of endogenous catecholamines, leading to multiple mechanisms of action. It has both central and peripheral actions. Ephedrine’s effects are similar to those seen with epinephrine; however, they are lesser and not accompanied by a dramatic increase in serum glucose concentrations. The duration of action of ephedrine is also longer than that of epinephrine, owing to its lack of a basic catechol structure; this characteristic makes it resistant to metabolism by monoamine oxidase.¹⁵

Ephedrine produces dose-related increases in blood pressure, cardiac output, heart rate, and systemic vascular resistance. Ephedrine often is the first sympathomimetic chosen for alleviation of hypotension because of the cardiac-depressant effects of anesthetic agents or vasodilation resulting from spinal anesthesia. Intravenously administered ephedrine, in doses ranging from 5 to 25 mg, has an immediate onset and a duration of action of 15 minutes to 1.5 hours depending on dose. This drug should be used cautiously in patients with questionable coronary perfusion, because myocardial oxygen consumption may be more dramatically increased than is anticipated as a result of ephedrine’s positive inotropic effect. In obstetrics, ephedrine has long been considered the drug of choice to address maternal hypotension after regional anesthesia because it was felt that it maintains uterine blood flow better than phenylephrine. Newer data are questioning this long-standing practice, with phenylephrine being recommended over ephedrine.33–35 Ephedrine produces increases in fetal metabolic rate leading to fetal acidosis due to beta stimulation and phenylephrine does not.³⁶ As with any indirect-acting agent, tachyphylaxis may develop with subsequent dosing, because catecholamine stores become depleted.³⁷ Ephedrine also may be administered by oral, intramuscular, or subcutaneous routes.

Selective β₂-Agonists

The β₂-agonists include albuterol (Proventil, Ventolin, others), levalbuterol (Xopenex), pirbuterol (Maxair), and salmeterol (Serevent). These “selective” β₂-agonists are effective in treating obstructive airway diseases such as asthma, chronic obstructive pulmonary disease, and acute bronchospasm. Long-acting formulations include formoterol (Foradil) and salmeterol (Serevent).38,39

The selectivity of these agents for β₂-receptors results in the desired response of bronchodilation and a lower incidence of the undesired β₁ responses of tachycardia and arrhythmia. None of these agents are, however, completely selective. These agents are available in aerosol form, and it is widely accepted that aerosol delivery is as effective as subcutaneous or other means of administration. Drugs of this class also have an increased duration of action because of their noncatecholamine structure; this renders them resistant to methylation by catechol-O-methyltransferase. Two puffs of nebulized or metered-dose inhaler–administered albuterol, or salmeterol, 10 to 15 minutes before exercise have been shown to have similar efficacy in preventing exercise-induced asthma. Long-acting β₂-agonists should be used in combination with an inhaled corticosteroid.⁴⁰

Chronic use of these agents can result in tachyphylaxis secondary to down-regulation (i.e., diminished quantity) of β-receptors. Increased hyperresponsiveness of the airway also has been suspected with chronic use of these agents. A black box warning about a higher risk of asthma-related death was added to the package inserts of all preparations containing a long-acting β₂-agonist.41,42

The β₂-agonists have been given to delay premature labor although there use has declined dramatically because of a high frequency of adverse events and lack of efficacy. This is referred to as a tocolytic effect. Uterine relaxation is achieved through increases in the levels of cAMP; this decreases intracellular calcium levels and ultimately diminishes the level of actin-myosin coupling. Terbutaline is the agonist used.

The effectiveness of tocolytic therapy was recently reviewed, with the following practice points: (1) β₂-agonists are effective in delaying delivery for 48 hours but have no effect on perinatal mortality. (2) There is no evidence to support the use of magnesium sulfate or the nitric oxide donors such as nitroglycerin. (3) Indomethacin is an effective tocolytic, but there are concerns about possible fetal and neonatal effects. (4) Nifedipine is an effective tocolytic with a low maternal side effect profile and positive effects on neonatal outcomes. (5) The oxytocin receptor antagonist atosiban is no better than other tocolytics in delaying or preventing preterm birth and has significant side effects.43,44 Women with failed tocolysis often need emergency surgery. In such cases, regional anesthesia may be preferable. Epidural blockade produces less hypotension than spinal anesthesia and is preferred. If vasopressors are necessary, phenylephrine is the drug of choice because it does not increase the heart rate.⁴⁵ Doses of selected vasoactive drugs are listed in Table 13-4. A complete discussion of tocolysis is in Chapter 46.

TABLE 13-4

Doses of Select Vasoactive Drugs

α₂-Agonists

Clonidine

Clonidine (Catapres) is a presynaptic α₂-agonist. Clonidine decreases blood pressure by acting as an agonist at peripheral presynaptic α₂-receptors and central α₂-receptors. Stimulation of the peripheral presynaptic α₂-receptors causes inhibition of catecholamine release, with subsequent vasodilation. Stimulation of the central α₂-receptors, which is considered the main antihypertensive mechanism of action, results in diminished sympathetic outflow and a resultant decrease in circulating catecholamines and renin activity. It is usually reserved for short-term oral treatment of severe hypertension as an add-on drug.⁴⁶ Rebound hypertension, seen after abrupt discontinuation of clonidine use, is a major concern. The resultant increase in catecholamine levels manifests as tachycardia and hypertension. Continuing the medication throughout the perioperative period is essential. Tapering the dose and discontinuation may occasionally be indicated. Patches may also be used during surgery to prevent withdrawal.

Clonidine is available in oral, transdermal, and epidural forms. The transdermal form is frequently encountered and administered at a fixed rate for a period of 1 week. Additional uses of clonidine include premedicant sedative, an analgesic combined with opiates for epidural treatment of severe pain (Duraclon), and suppression of alcohol withdrawal symptoms.⁴⁷ Clonidine is used as a catecholamine suppression test in the diagnosis of pheochromocytoma.

Dexmedetomidine

Dexmedetomidine is an α₂-agonist that is marketed for short-term sedation in critical care. It is being used as an adjunct to anesthesia in a variety of situations.⁴⁸ Dexmedetomidine provides dose-dependent sedation, analgesia, sympatholysis, and anxiolysis without significant respiratory depression. The side effects are predictable from the pharmacologic profile of α₂-adrenoceptor agonists and include hypotension, bradycardia, oversedation, and delayed recovery. Dexmedetomidine is discussed in detail in Chapter 9. The mechanism of presynaptic α₂-agonism is shown in Figure 13-1.

FIGURE 13-1 Presynaptic α₂-agonism. (From Page C, et al. Integrated Pharmacology. 3rd ed. Edinburgh: Mosby; 2006:420.)

α-Receptor Antagonists

The α-receptor antagonists are used for treatment of hypertension, benign prostatic hyperplasia, pheochromocytoma, Raynaud’s phenomenon, and ergot alkaloid toxicity.⁴⁹ Common side effects include orthostatic hypotension and baroreceptor-mediated reflex tachycardia, which may make their use in the treatment of hypertension somewhat difficult in the ambulatory patient. In addition, because of the significantly longer duration of action of the α-receptor antagonists, other agents are considered more predictable in the treatment of emergent episodes of hypertension.

β-Adrenergic Blocking Agents

The β-blockers are one of the most widely prescribed classes of drugs. Common applications of these agents include the treatment of angina pectoris, hypertension, postmyocardial infarctions, supraventricular tachycardias (including Wolff-Parkinson-White syndrome), and atrial fibrillation; the suppression of increased sympathetic activity (e.g., as occurs with intubation); the management of hypertrophic obstructive cardiomyopathies and congestive heart failure (CHF); the treatment of migraine headaches; and the preoperative preparation of hyperthyroid patients. They are also effective in the treatment of digitalis-induced arrhythmias and in the management of select atrial and ventricular arrhythmias.⁵⁸ The perioperative use of β-blockers in vascular and select general surgery patients to reduce morbidity and mortality has been an area of tremendous discussion, and many large-scale clinical trials have been reported. They also prevent detrimental cardiac remodeling, which occurs in many cardiac diseases.⁵⁹ The use of perioperative β-blockade in high-risk patients is discussed as follows and in Chapter 25.

The β-blockers are structurally related to isoproterenol. They bind β-receptors in a competitive manner and prevent the actions of catecholamines and other β-agonists. Because these agents are competitive antagonists if an agonist is present in sufficient concentration at the receptor, the blocking actions of the β-antagonists can be overcome.

The β-blockers are subdivided on the basis of their selectivity for cardiac β₁-receptors and other notable clinical differences such as their ability to vasodilate by additional mechanisms or whether they have partial agonist activity. Table 13-5 lists the beta blockers according to classification subtype.⁶⁰

TABLE 13-5

Antihypertensive Drugs

AV, Atrioventricular; CNS, central nervous system; GI, gastrointestinal; HDL, high-density lipoprotein.

From Medical Letter Treatment Guidelines. Drugs for hypertension. Med Lett. 2012;10(113):1-10; Azilsartan medoximil (Edarbi)-the eighth ARB. Med Lett 2011;53(1364):39-40; Nebivolol (Bystolic) for hypertension. Med Lett. 2008;50(1281):17-19.

The degree of receptor selectivity is important because antagonism of β₁-receptors results in lowered heart rate, decreased myocardial contractility, and diminished atrioventricular conduction velocity; it also has beneficial effects with regard to decreasing myocardial oxygen consumption and the treatment of arrhythmias. However, antagonism of β₂-receptors can result in adverse effects such as bronchoconstriction, hypoglycemia, and peripheral vasoconstriction. It is important to note that as the dose of the selective β-blockers is increased, the degree of selectivity is diminished.

Some of the β-blockers act as partial agonists and as such possess intrinsic sympathomimetic activity. A partial agonist does not stimulate β-receptors to the extent that a full agonist does, and in the presence of a full agonist, the partial agonist acts as a competitive antagonist. It follows that β-blockers with intrinsic sympathomimetic activity (ISA) competitively antagonize the effects of a full agonist (e.g., endogenous catecholamines released during times of maximal sympathetic tone) down to the activity level of its partial agonist component. Intrinsic sympathomimetic activity minimizes the risk of bronchoconstriction in patients with reactive airway disease who require β-blockade. Pindolol, acebutolol, penbutolol, and carteolol are β-adrenergic blocking agents that possess intrinsic sympathomimetic activity.

Membrane-stabilizing activity is another property of some β-blockers. These agents diminish arrhythmogenicity by exerting a quinidine-like effect in the heart. However, membrane-stabilizing activity is seen only with high drug concentrations.⁶¹ Propranolol and pindolol are two β-blockers with membrane-stabilizing activity. Labetalol and carvedilol are mixed β- and α-receptor antagonists. The added α-receptor blockade makes them vasodilators. Nebivolol (Bystolic) is a new cardioselective β-blocker approved for the treatment of hypertension. It is unique in that it has nitric oxide–mediated vasodilating properties.⁶²

Some potential problems with β-adrenergic blocking agents have already been mentioned. β-blockade can result in both bronchospasm and the development of overt cardiac failure in some patients with high doses or IV administration. Other potential problems arise with β₂-receptor blockade in patients with peripheral vascular disease and Raynaud’s disease because of the possible potentiation of peripheral vasoconstriction. In diabetic patients, signs of hypoglycemia may be masked, and the patient’s ability to increase serum glucose levels may be impaired. Serum potassium levels may also become elevated with β₂-blockade, because uptake into skeletal muscle is inhibited. In patients whose heart rate is controlled to maintain cardiac output, β-blockade may have a significant impact on blood pressure.

The β-receptors are considered to be “labile” receptors—that is, they are subject to significant up- and down-regulation. Chronic therapy with β-blockers can lead to up-regulation of β-receptors or an increase in the absolute number and activity of receptors. This phenomenon is suspected to be the underlying cause of the withdrawal syndrome seen with abrupt discontinuation of β-adrenergic antagonist use. Raynaud’s phenomenon is characterized by increased sympathetic activity for up to 2 days. Obviously this means the patient receiving β-blockers should continue to receive them without interruption throughout the perioperative period. The effects of the β-blocking agents on the ischemic heart are summarized in Figure 13-2.

FIGURE 13-2 Cardiac effects of beta adrenergic blocking drugs. A, Negative chronotropic. B, Negative dromotropic. C, Negative inotropic. D, Antiarrhythmic. E, Antiischemic.

Anesthetic Uses

Metoprolol, Esmolol, and Labetalol

Three β-adrenergic blocking agents, which are available IV, are especially useful in the perioperative period. They are metoprolol, esmolol, and labetalol. Esmolol has replaced propranolol in most instances of β-blocker application in anesthesia because of its rapid onset and short duration of action. Esmolol has an onset time of 2 minutes and an elimination half-life of approximately 9 minutes. Its rapid onset and short half-life, as well as its duration of action of 10 to 15 minutes, make it easily and reliably titratable in acute-care situations. The recommended IV loading dose of esmolol is 500 mcg/kg; this is followed by an infusion of 100 to 300 mcg/kg/min as needed. Small boluses of 10 to 15 mg may be given with repeat administration according to patient response. Esmolol is metabolized by nonspecific plasma esterases found in the cytosol of red blood cells. Metoprolol is frequently used after myocardial infarction or in some types of angina and hypertension, once the patient is stable, to normalize vital signs. Administration of 5-mg doses intravenously at 5-minute intervals to a maximum dose of 15 mg is recommended.⁶⁰

Labetalol (Normodyne, Trandate) is classified as a nonselective β-blocker but is unique in that it also possesses an α-blocking component. It provides β-blockade along with α-blockade in a ratio of 7:1. Unlike the standard β-blocker, labetalol produces vasodilation secondary to its α-blocking properties. This action can be extremely beneficial in situations in which an acute rise in blood pressure could be devastating to the clinical outcome. The usual IV dose of labetalol is 0.25 mg/kg; this dose can be repeated every few minutes as indicated and followed by an infusion, if indicated, at a rate of 2 mg/min. In clinical practice, a bolus dose of labetalol (5-10 mg) is titrated and repeated on the basis of patient response. Labetalol can have a duration of action ranging from 2 to 6 hours, depending on dose. Because labetalol provides both β- and α-blockade, an adequate heart rate must be present before labetalol can be used in the acute management of hypertension. It is recommended for hypertensive episodes in obstetric patients. Uterine blood flow is not affected in obstetric patients, even in the event of a dramatic decrease in systemic blood pressure.⁶² Labetalol undergoes hepatic metabolism and renal elimination.⁶³

Prophylactic β-blockers showed a positive benefit in reducing major postoperative cardiac events in select high-risk patients. A large-scale clinical trial (POISE) of extended-release metoprolol indicated that there was a lower incidence of perioperative myocardial infarction (MI), clinically significant atrial fibrillation, and the need for coronary revascularization, but an increase in strokes and overall mortality secondary to more hypotension and bradycardia.⁶⁴ There are concerns that anemia might complicate perioperative β-blockade by further limiting oxygen delivery. β-blockade is associated with worse outcomes when hemoglobin levels are decreased by greater than 35%. In elderly patients, this is a potential mechanism for the increased stroke rate found in the POISE trial. Gender differences exist as well. Men benefited from β-blockade with reduced MI, but women suffered from clinically significant increases in CHF. Evidence for pharmacogenetic variation in metabolism suggests that metoprolol might not be the best choice of β-blocker in the perioperative period.⁶⁵ Many other studies have noted conflicting results, and the proper use of β-blockers has been a much discussed and researched area.^66,67 The American College of Cardiology Foundation and the American Heart Association (ACCF/AHA) have issued revised guidelines on the use of perioperative β-blockers.⁶⁸

In general, β-blockers should be continued in surgical patients who are already taking them. β-blockers may benefit vascular surgery patients at high risk for MI but not for stroke. They are more likely to be beneficial when started at a lower dose well in advance of surgery and titrated to a heart rate of 55 to 70 beats per minute (bpm). Avoid starting β-blockers immediately before surgery, in emergency surgery, or in patients with prior cerebrovascular disease or sepsis. A protocol for perioperative β-blocker therapy is listed in Box 13-1. The detailed recommendations for the use of β-blockers in noncardiac surgery can be found in the ACCF/AHA guidelines.⁶⁸ In situations where β-blockers are contraindicated, such as patients with asthma, bradyarrhythmias, acute heart failure, or advanced heart block, an α₂-adrenergic agonist such as clonidine may have some benefit.⁶⁹

BOX 13-1 Protocols for Prophylactic Perioperative β-Blockers

General Principles