Chapter 14: Adrenergic Agonists & Antagonists

Adrenergic agonists and antagonists produce their clinical effects by interacting with the adrenergic receptors (ie, adrenoceptors). The clinical effects of these drugs can be deduced from an understanding of the adrenoceptor physiology and a knowledge of which receptors each drug activates or blocks.

The term adrenergic originally referred to the effects of epinephrine (adrenaline), although norepinephrine (noradrenaline) is the primary neurotransmitter responsible for most of the adrenergic activity of the sympathetic nervous system. With the exception of eccrine sweat glands and some blood vessels, norepinephrine is released by postganglionic sympathetic fibers at end-organ tissues (Figure 14–1). In contrast, acetylcholine is released by preganglionic sympathetic fibers and all parasympathetic fibers.

Norepinephrine is synthesized in the cytoplasm of sympathetic postganglionic nerve endings and stored in the vesicles (Figure 14–2). After release by a process of exocytosis, the action of norepinephrine is primarily terminated by reuptake into the postganglionic nerve ending. Norepinephrine transporter located on neuronal cell membranes facilitates removal of norepinephrine from the synapse. Other transporters facilitate uptake of dopamine and serotonin. Tricyclic antidepressants, cocaine, and amphetamines can inhibit these transporters leading to their clinical effects. Norepinephrine may diffuse from receptor sites where it is taken up by nonneuronal cells and is metabolized by catechol-O-methyltransferase (Figure 14–3). In neurons norepinephrine may be metabolized by monoamine oxidase or repackaged into vesicles. Prolonged adrenergic activation leads to desensitization and hyporesponsiveness to further stimulation.

Adrenergic receptors are divided into two general categories: α and β. Each of these has been further subdivided into at least two subtypes: α₁ and α₂, and β₁, β₂, and β₃. The α-receptors have been further divided using molecular cloning techniques into α_1A, α_1B, α_1D, α_2A, α_2B, and α_2C. These receptors are linked to G proteins (Figure 14–4)—heterotrimeric receptors with α, β, and γ subunits. The different adrenoceptors are linked to specific G proteins, each with a unique effector, but each using guanosine triphosphate (GTP) as a cofactor. α₁ is linked to G_q, which activates phospholipases; α₂ is linked to G_i, which inhibits adenylate cyclase (also termed adenyl or adenylyl cyclase); and β is linked to G_s, which activates adenylate cyclase.

α₁-Receptors

α₁-Receptors are postsynaptic adrenoceptors located in smooth muscle throughout the body (in the eye, lung, blood vessels, uterus, gut, and genitourinary system). Activation of these receptors increases intracellular calcium ion concentration, which leads to contraction of smooth muscles. Thus, α₁-agonists are associated with mydriasis (pupillary dilation due to contraction of the radial eye muscles), bronchoconstriction, vasoconstriction, uterine contraction, and constriction of sphincters in the gastrointestinal and genitourinary tracts. Stimulation of α₁-receptors also inhibits insulin secretion and lipolysis. The myocardium possesses α₁-receptors that have a positive inotropic effect, which might play a role in catecholamine-induced arrhythmia. During myocardial ischemia, enhanced α₁-receptor coupling with agonists is observed. Nonetheless, the most important cardiovascular effect of α₁ stimulation is vasoconstriction, which increases peripheral vascular resistance, left ventricular afterload, and arterial blood pressure.

α₂-Receptors

In contrast to α₁-receptors, α₂-receptors are located primarily on the presynaptic nerve terminals. Activation of these adrenoceptors inhibits adenylyl cyclase activity. This decreases the entry of calcium ions into the neuronal terminal, which limits subsequent exocytosis of storage vesicles containing norepinephrine. Thus, α₂-receptors create a negative feedback loop that inhibits further norepinephrine release from the neuron. In addition, vascular smooth muscle contains postsynaptic α₂-receptors that produce vasoconstriction. More importantly, stimulation of postsynaptic α₂-receptors in the central nervous system causes sedation and reduces sympathetic outflow, which leads to peripheral vasodilation and lower blood pressure.

β₁-Receptors

β-Adrenergic receptors are classified into β₁, β₂, and β₃ receptors. Norepinephrine and epinephrine are equipotent on β₁ receptors, but epinephrine is significantly more potent than norepinephrine on β₂ receptors.

The most important β₁-receptors are located on the postsynaptic membranes in the heart. Stimulation of these receptors activates adenylyl cyclase, which converts adenosine triphosphate to cyclic adenosine monophosphate and initiates a kinase phosphorylation cascade. Initiation of the cascade has positive chronotropic (increased heart rate), dromotropic (increased conduction), and inotropic (increased contractility) effects.

β₂-Receptors

β₂-Receptors are primarily postsynaptic adrenoceptors located in smooth muscle and gland cells, but are also located in ventricular myocytes. Their relative contribution to the response to intravenous catecholamines increases in patients with chronic heart failure. They share a common mechanism of action with β₁-receptors: adenylyl cyclase activation. Despite this commonality, β₂ stimulation relaxes smooth muscle, resulting in bronchodilation, vasodilation, and relaxation of the uterus (tocolysis), bladder, and gut. Glycogenolysis, lipolysis, gluconeogenesis, and insulin release are stimulated by β₂-receptor activation. β₂-Agonists also activate the sodium–potassium pump.

β₃-Receptors

β₃-Receptors are found in the gallbladder and brain adipose tissue. Their role in gallbladder physiology is unknown, but they are thought to play a role in lipolysis, thermogenesis in brown fat, and bladder relaxation.

Dopaminergic Receptors

Dopamine (DA) receptors are a group of adrenergic receptors that are activated by dopamine; these receptors are classified as D₁ and D₂ receptors. Activation of D₁ receptors mediates vasodilation in the kidney, intestine, and heart. D₂ receptors are believed to play a role in the antiemetic action of droperidol.

Adrenergic agonists interact with varying specificity (selectivity) at α- and β-adrenoceptors (Tables 14–1 and 14–2).

Overlapping of activity complicates the prediction of clinical effects. For example, epinephrine stimulates α₁-, α₂-, β₁-, and β₂-adrenoceptors. Its net effect on arterial blood pressure depends on the dose-dependent balance between α₁-vasoconstriction, α₂- and β₂-vasodilation, and β₁-inotropic influences (and, to a minor degree, β₂-inotropic influences).

Adrenergic agonists can be categorized as direct or indirect. Direct agonists bind to the receptor, whereas indirect agonists increase endogenous neurotransmitter activity. Mechanisms of indirect action include increased release or decreased reuptake of norepinephrine. The differentiation between direct and indirect mechanisms of action is particularly important in patients who have abnormal endogenous norepinephrine stores, as may occur with use of some antihypertensive medications or monoamine oxidase inhibitors. Intraoperative hypotension in these patients should be treated with direct agonists, as their response to indirect agonists will be unpredictable.

Another feature distinguishing adrenergic agonists from each other is their chemical structure. Adrenergic agonists that have a 3,4-dihydroxybenzene structure (Figure 14–5) are known as catecholamines. These drugs are typically short-acting because of their metabolism by monoamine oxidase and catechol-O-methyltransferase. Patients taking monoamine oxidase inhibitors or tricyclic antidepressants may therefore demonstrate an exaggerated response to catecholamines. The naturally occurring catecholamines are epinephrine, norepinephrine, and DA. Changing the side-chain structure (R₁, R₂, R₃) of naturally occurring catecholamines has led to the development of synthetic catecholamines (eg, isoproterenol and dobutamine), which tend to be more receptor specific.

Adrenergic agonists commonly used in anesthesiology are discussed individually below. Note that the recommended doses for continuous infusion are expressed as mcg/kg/min for some agents and mcg/min for others. In either case, these recommendations should be regarded only as guidelines, as individual responses are quite variable.

PHENYLEPHRINE

Phenylephrine is a noncatecholamine with selective α₁-agonist activity. The primary effect of phenylephrine is peripheral vasoconstriction with a concomitant rise in systemic vascular resistance and arterial blood pressure. Reflex bradycardia mediated by the vagus nerve can reduce cardiac output. Phenylephrine is also used topically as a decongestant and a mydriatic agent.

Small intravenous boluses of 50 to 100 mcg (0.5 to 1 mcg/kg) of phenylephrine rapidly reverse reductions in blood pressure caused by peripheral vasodilation (eg, spinal anesthesia). The duration of action is short, lasting approximately 15 min after administration of a single dose. Tachyphylaxis may occur with phenylephrine infusions and require upward titration of the infusion. Phenylephrine must be diluted from a 1% solution (10 mg/1-mL ampule), usually to a 100 mcg/mL solution and titrated to effect.

α₂-AGONISTS

Clonidine is an α₂-agonist that is commonly used for its antihypertensive and negative chronotropic effects. More recently, it and other α₂-agonists are increasingly being used for their sedative properties. Various studies have examined the anesthetic effects of oral (3–5 mcg/kg), intramuscular (2 mcg/kg), intravenous (1–3 mcg/kg), transdermal (0.1–0.3 mg released per day), intrathecal (15–30 mcg), and epidural (1–2 mcg/kg) clonidine administration.

Clonidine decreases anesthetic and analgesic requirements (decreases minimum alveolar concentration) and provides sedation and anxiolysis. During general anesthesia, clonidine reportedly enhances intraoperative circulatory stability by reducing catecholamine levels. During regional anesthesia, including peripheral nerve block, clonidine prolongs the duration of the block. Direct effects on the spinal cord may be mediated by α₂-postsynaptic receptors within the dorsal horn. Other possible benefits include decreased postoperative shivering, inhibition of opioid-induced muscle rigidity, attenuation of opioid withdrawal symptoms, and the treatment of acute postoperative pain and some chronic pain syndromes. Side effects include bradycardia, hypotension, sedation, respiratory depression, and dry mouth.

Dexmedetomidine has a higher affinity for α₂-receptors than clonidine. Compared with clonidine, dexmedetomidine is more selective for α₂-receptors (α₂:α₁ specificity ratio is 200:1 for clonidine and 1600:1 for dexmedetomidine). Dexmedetomidine has a shorter half-life (2–3 h) than clonidine (12–24 h). It has sedative, analgesic, and sympatholytic effects that blunt many of the cardiovascular responses seen during the perioperative period. The sedative and analgesic effects are mediated by α₂-adrenergic receptors in the brain (locus ceruleus) and spinal cord. When used intraoperatively, dexmedetomidine reduces intravenous and volatile anesthetic requirements; when used postoperatively, it reduces concurrent analgesic and sedative requirements. Dexmedetomidine is useful in sedating patients in preparation for awake fiberoptic intubation. It is also a useful agent for sedating patients postoperatively in postanesthesia and intensive care units, because it does so without significant ventilatory depression. Rapid administration may elevate blood pressure, but hypotension and bradycardia can occur during ongoing therapy. The recommended dosing of dexmedetomidine consists of a loading dose at 1 mcg/kg over 10 min followed by an infusion at 0.2 to 0.7 mcg/kg/h, although we recognize that clinicians administer this agent in a great many ways (including intranasally for sedation in children).

Although these agents are adrenergic agonists, they are also considered to be sympatholytic because sympathetic outflow is reduced. Long-term use of these agents, particularly clonidine and dexmedetomidine, leads to super-sensitization and upregulation of receptors; with abrupt discontinuation of either drug, an acute withdrawal syndrome including hypertensive crisis can occur. Because of the increased affinity of dexmedetomidine for the α₂-receptor, compared with that of clonidine, this syndrome may manifest after only 48 h of dexmedetomidine use when the drug is discontinued.

EPINEPHRINE

Epinephrine is an endogenous catecholamine synthesized in the adrenal medulla. Direct stimulation of β₁-receptors of the myocardium by epinephrine raises blood pressure, cardiac output, and myocardial oxygen demand by increasing contractility and heart rate (increased rate of spontaneous phase IV depolarization). α₁ Stimulation decreases splanchnic and renal blood flow but increases coronary perfusion pressure by increasing aortic diastolic pressure. Systolic blood pressure rises, although β₂-mediated vasodilation in skeletal muscle may lower diastolic pressure. β₂ Stimulation also relaxes bronchial smooth muscle.

Administration of epinephrine is the principal pharmacological treatment for anaphylaxis and can be used to treat ventricular fibrillation. Complications include cerebral hemorrhage, myocardial ischemia, and ventricular arrhythmias. Volatile anesthetics, particularly halothane, potentiate the arrhythmic effects of epinephrine.

In emergency situations (eg, cardiac arrest and shock), epinephrine is administered as an intravenous bolus of 0.5 to 1 mg, depending on the severity of cardiovascular compromise. In major anaphylactic reactions, epinephrine should be used at a dose of 100 to 500 mcg (repeated, if necessary) followed by infusion. To improve myocardial contractility or heart rate, a continuous infusion is prepared (1 mg in 250 mL [4 mcg/mL]) and run at a rate of 2 to 20 mcg/min (30–300 ng/kg/min). Epinephrine local infiltration is also used to reduce bleeding from the operative sites. Some local anesthetic solutions containing epinephrine at a concentration of 1:200,000 (5 mcg/mL) or 1:400,000 (2.5 mcg/mL) are characterized by less systemic absorption and a longer duration of action. Epinephrine is available in vials at a concentration of 1:1000 (1 mg/mL) and prefilled syringes at a concentration of 1:10,000 (0.1 mg/mL [100 mcg/mL]). A 1:100,000 (10 mcg/mL) concentration is available for pediatric use.

EPHEDRINE

The cardiovascular effects of ephedrine, a noncatecholamine sympathomimetic, are similar to those of epinephrine: increase in blood pressure, heart rate, contractility, and cardiac output. Likewise, ephedrine is also a bronchodilator. There are important differences, however: Ephedrine has a longer duration of action, is much less potent, has both indirect and direct actions, and stimulates the central nervous system (it raises minimum alveolar concentration). The indirect agonist properties of ephedrine may be due to peripheral postsynaptic norepinephrine release or inhibition of norepinephrine reuptake.

Ephedrine is commonly used as a vasopressor during anesthesia. As such, its administration should be viewed as a temporizing measure while the cause of hypotension is determined and remedied. Unlike direct-acting α₁-agonists, ephedrine in sheep experiments did not decrease uterine blood flow; thus, for many years it was the preferred vasopressor in obstetric anesthesia. Currently phenylephrine is widely used in obstetric patients undergoing neuroaxial anesthesia due its faster onset, shorter duration of action, easier titration, and lack of adverse effects on fetal pH relative to ephedrine.

In adults, ephedrine is administered as a bolus of 2.5 to 10 mg; in children, it is given as a bolus of 0.1 mg/kg. Subsequent doses are increased to offset the development of tachyphylaxis, which is probably due to depletion of norepinephrine stores. Ephedrine is available in 1-mL ampules containing 25 or 50 mg of the agent.

NOREPINEPHRINE

Direct α₁ stimulation with limited β₂ activity (at the doses used clinically) induces intense vasoconstriction of arterial and venous vessels. Increased myocardial contractility from β₁ effects, along with peripheral vasoconstriction, contributes to a rise in arterial blood pressure. Both systolic and diastolic pressures usually rise, but increased afterload and reflex bradycardia may prevent any elevation in cardiac output. Decreased renal and splanchnic blood flow and increased myocardial oxygen requirements are concerns, yet norepinephrine is the agent of choice in the management of refractory (particularly septic) shock. Extravasation of norepinephrine at the site of intravenous administration can cause tissue necrosis.

Norepinephrine is administered usually as a continuous infusion due to its short half-life at a rate of 2 to 20 mcg/min (30–300 ng/kg/min). Ampules contain 4 mg of norepinephrine in 4 mL of solution.

DOPAMINE

The clinical effects of DA, an endogenous nonselective direct and indirect adrenergic and dopaminergic agonist, vary markedly with the dose. At low doses (0.5–3 mcg/kg/min), DA primarily activates dopaminergic receptors (specifically, DA₁ receptors); stimulation of these receptors vasodilates the renal vasculature and promotes diuresis and natriuresis. Although this action increases renal blood flow, use of this “renal dose” does not impart any beneficial effect on kidney function. When used in moderate doses (3–10 mcg/kg/min), β₁ stimulation increases myocardial contractility, heart rate, systolic blood pressure, and cardiac output. Myocardial oxygen demand typically increases more than supply. The α₁ effects become prominent at higher doses (10–20 mcg/kg/min), causing an increase in peripheral vascular resistance and a fall in renal blood flow. The exact dose–response curve for dopamine and these several actions is far more unpredictable than the preceding paragraph would suggest! The indirect effects of DA are due to release of norepinephrine from presynaptic sympathetic nerve ganglion.

DA was formerly a first-line treatment for shock to improve cardiac output, support blood pressure, and maintain renal function. The chronotropic and proarrhythmic effects of DA limit its usefulness in some patients, and it has been replaced by norepinephrine for many situations in critical illness. DA is administered as a continuous infusion at a rate of 1 to 20 mcg/kg/min. It is most commonly supplied in 5 to 10 mL vials containing 200 or 400 mg of DA.

ISOPROTERENOL

Isoproterenol is of interest because it is a pure β-agonist. β₁ effects increase heart rate, contractility, and cardiac output. Systolic blood pressure may increase or remain unchanged, but β₂ stimulation decreases peripheral vascular resistance and diastolic blood pressure. Myocardial oxygen demand increases while oxygen supply falls, making isoproterenol or any pure β-agonist a poor inotropic choice in most situations.

DOBUTAMINE

Dobutamine is a racemic mixture of two isomers with affinity for both β₁- and β₂-receptors, with relatively higher selectivity for β₁-receptors. Its primary cardiovascular effect is a rise in cardiac output as a result of increased myocardial contractility. A decline in peripheral vascular resistance caused by β₂ activation usually prevents much of a rise in arterial blood pressure. Left ventricular filling pressure decreases, whereas coronary blood flow increases.

Dobutamine increases myocardial oxygen consumption and should not be routinely used without specific indications to facilitate separation from cardiopulmonary bypass. It is often employed in pharmacological stress testing. Dobutamine is administered as an infusion at a rate of 2 to 20 mcg/kg/min. It is supplied in 20-mL vials containing 250 mg.

FENOLDOPAM

Fenoldopam is a selective D₁-receptor agonist that has many of the benefits of DA but with little or no α- or β-adrenoceptor or D₂-receptor agonist activity. Fenoldopam has been shown to exert hypotensive effects characterized by a decrease in peripheral vascular resistance, along with an increase in renal blood flow, diuresis, and natriuresis. It is indicated for patients undergoing cardiac surgery and aortic aneurysm repair with potential risk of perioperative kidney impairment. Fenoldopam exerts an antihypertensive effect, but helps to maintain renal blood flow. It is also indicated for patients who have severe hypertension, particularly those with renal impairment. Along with its recommended use in hypertensive emergencies, fenoldopam is also indicated in the prevention of contrast media-induced nephropathy. Fenoldopam has a fairly rapid onset of action and is easily titratable because of its short elimination half-life. The ability of fenoldopam to “protect” the kidney perioperatively remains the subject of ongoing debate, but there is no good evidence for efficacy.

Fenoldopam is supplied in 1-, 2-, and 5-mL ampules, 10 mg/mL. It is started as a continuous infusion of 0.1 mcg/kg/min, increased by increments of 0.1 mcg/kg/min at 15- to 20-min intervals until target blood pressure is achieved. Lower doses have been associated with less reflex tachycardia.

Adrenergic antagonists bind but do not activate adrenoceptors. They act by preventing adrenergic agonist activity. Like the agonists, the antagonists differ in their spectrum of receptor interaction.

α-BLOCKERS: PHENTOLAMINE

Phentolamine produces a competitive (reversible) blockade of both α₁- and α₂-receptors. α₁ Antagonism and direct smooth muscle relaxation are responsible for peripheral vasodilation and a decline in arterial blood pressure. The drop in blood pressure provokes reflex tachycardia. This tachycardia is augmented by antagonism of presynaptic α₂-receptors in the heart because α₂ blockade promotes norepinephrine release by eliminating negative feedback. These cardiovascular effects are usually apparent within 2 min and last up to 15 min. As with all of the adrenergic antagonists, the extent of the response to receptor blockade depends on the degree of existing sympathetic tone. Reflex tachycardia and postural hypotension limit the usefulness of phentolamine to the treatment of hypertension caused by excessive α stimulation (eg, pheochromocytoma, clonidine withdrawal). Prazosin and phenoxybenzamine are examples of other α-antagonists.

Phentolamine is administered intravenously as intermittent boluses (1–5 mg in adults) or as a continuous infusion. To prevent or minimize tissue necrosis following extravasation of intravenous fluids containing an α-agonist (eg, norepinephrine), 5 to 10 mg of phentolamine in 10 mL of normal saline can be locally infiltrated. Phentolamine has been used in combination with norepinephrine for inotropic support in heart surgery, to block excessive hypertension during resection of pheochromocytoma, and to facilitate cooling prior to circulatory arrest in children undergoing repair of congenital heart lesions.

MIXED ANTAGONISTS: LABETALOL

Labetalol blocks α₁-, β₁-, and β₂-receptors. The ratio of α blockade to β blockade has been estimated to be approximately 1:7 following intravenous administration. This mixed blockade reduces peripheral vascular resistance and arterial blood pressure. Heart rate and cardiac output are usually slightly depressed or unchanged. Thus, labetalol lowers blood pressure without reflex tachycardia because of its combination of α and β effects, which is beneficial to patients with coronary artery disease. Peak effect usually occurs within 5 min after an intravenous dose. Left ventricular failure, paradoxical hypertension, and bronchospasm have been reported.

The initial recommended dose of labetalol is 2.5 to 10 mg administered intravenously over 2 min. After the initial dose, and depending on the response, 5 to 20 mg may be given at 10-min intervals until the desired blood pressure response is obtained.

β-BLOCKERS

β-Receptor blockers have variable degrees of selectivity for the β₁-receptors. Those that are more β₁ selective have less influence on bronchopulmonary and vascular β₂-receptors (Table 14–3). Theoretically, a selective β₁-blocker would have less of an inhibitory effect on β₂-receptors and, therefore, might be preferred in patients with chronic obstructive lung disease or peripheral vascular disease. Patients with peripheral vascular disease could potentially have a decrease in blood flow if β₂-receptors, which dilate the arterioles, are blocked. β-Receptor blocking agents also reduce intraocular pressure in patients with glaucoma.

β-Blockers are also classified by the amount of intrinsic sympathomimetic activity (ISA) they have. Many of the β-blockers have some agonist activity; although they would not produce effects similar to full agonists (such as epinephrine).

β-Blockers can be further classified as those that are eliminated by hepatic metabolism (such as metoprolol), those that are excreted by the kidneys unchanged (such as atenolol), or those that are hydrolyzed in the blood (such as esmolol).

ESMOLOL

Esmolol is an ultrashort-acting selective β₁-antagonist that reduces heart rate and, to a lesser extent, blood pressure. It is used to prevent or minimize tachycardia and hypertension in response to perioperative stimuli, such as intubation, surgical stimulation, and emergence. For example, esmolol (0.5–1 mg/kg) attenuates the rise in blood pressure and heart rate that usually accompanies electroconvulsive therapy, without significantly affecting seizure duration. Esmolol is useful in controlling the ventricular rate of patients with atrial fibrillation or flutter. Although esmolol is considered to be cardioselective, at higher doses it inhibits β₂-receptors in bronchial and vascular smooth muscle.

The short duration of action of esmolol is due to rapid redistribution (distribution half-life is 2 min) and hydrolysis by red blood cell esterase (elimination half-life is 9 min). Side effects can be reversed within minutes by discontinuing its infusion. As with all β₁-antagonists, esmolol should be avoided in patients with sinus bradycardia, heart block greater than first degree, cardiogenic shock, or uncompensated, low ejection fraction heart failure.

Esmolol is administered as a bolus (0.2–0.5 mg/kg) for short-term therapy, such as attenuating the cardiovascular response to laryngoscopy and intubation. Long-term treatment is typically initiated with a loading dose of 0.5 mg/kg administered over 1 min, followed by a continuous infusion of 50 mcg/kg/min to maintain therapeutic effect. If this fails to produce a sufficient response within 5 min, the loading dose may be repeated and the infusion increased by increments of 50 mcg/kg/min every 5 min to a maximum of 200 mcg/kg/min.

Esmolol is supplied as multidose vials for bolus administration containing 10 mL of drug (10 mg/mL). Ampules for continuous infusion (2.5 g in 10 mL) are also available but must be diluted prior to administration to a concentration of 10 mg/mL.

METOPROLOL

Metoprolol is a selective β₁-antagonist with no intrinsic sympathomimetic activity. It is available for both oral and intravenous use. It can be administered intravenously in 1 to 5 mg increments every 2 to 5 min, titrated to blood pressure and heart rate.

PROPRANOLOL

Propranolol nonselectively blocks β₁- and β₂-receptors. Arterial blood pressure is lowered by several mechanisms, including decreased myocardial contractility, lowered heart rate, and diminished renin release. Cardiac output and myocardial oxygen demand are reduced. Propranolol slows atrioventricular conduction and slows the ventricular response to supraventricular tachycardia.

Side effects of propranolol include bronchospasm (β₂ antagonism), acute congestive heart failure, bradycardia, and atrioventricular heart block (β₁ antagonism). Concomitant administration of propranolol and verapamil (a calcium channel blocker) can synergistically depress heart rate, contractility, and atrioventricular node conduction.

Propranolol’s elimination half-life of 100 min is quite long compared with that of esmolol. Generally, propranolol is titrated to effect in 0.5 mg increments every 3 to 5 min. Total doses rarely exceed 0.15 mg/kg. Propranolol is supplied in 1-mL ampules containing 1 mg.

NEBIVOLOL

Nebivolol is a newer generation β-blocker with high affinity for β₁-receptors. The drug is unique in its ability to cause direct vasodilation via its stimulatory effect on endothelial nitric oxide synthase.

CARVEDILOL

Carvedilol is a mixed β- and α-blocker used in the management of chronic heart failure secondary to cardiomyopathy, left ventricular dysfunction following acute myocardial infarction, and hypertension. Carvedilol dosage is individualized and gradually increased up to 25 mg twice daily, as required and tolerated. Bisoprolol and sustained-release metoprolol are also used in long-term therapy to reduce mortality in patients with reduced ejection fraction heart failure.

PERIOPERATIVE β-BLOCKER THERAPY

Management of β-blockers perioperatively has been a key anesthesia performance indicator and is closely monitored by various “quality management” agencies. Although studies regarding the perioperative administration of β-blockers have yielded conflicting results as to benefit versus harm, maintenance of β-blockers in patients already being treated with them is essential, unless contraindicated by other clinical concerns. Initial small trials did not demonstrate adverse outcomes from initiation of perioperative β-blocker therapy. Subsequent studies either demonstrated no benefit or actual harm (eg, stroke) when β blockade was begun perioperatively. Consequently, guidelines continue to be revised as new evidence is evaluated.

The 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend continuation of β-blocker therapy during the perioperative period in patients who are receiving them chronically (class I benefit >>> risk). β-Blocker therapy postoperatively should be guided by clinical circumstances (class IIa benefit >> risk). Irrespective of when β-blocker therapy was started, therapy may need to be temporarily discontinued (eg, bleeding, hypotension, bradycardia). The ACC/AHA guidelines suggest that it may be is reasonable to begin perioperative β-blockers in patients at intermediate or high risk for myocardial ischemia (class IIb benefit ≥ risk). Other conditions such as risk of stroke or uncompensated heart failure should be considered in discerning if β-blockade should be initiated perioperatively. Additionally, in patients with three or more Revised Cardiac Risk Index risk factors (see Chapter 21), it may be reasonable to begin β-blocker therapy before surgery (class IIb). Lacking these risk factors, it is unclear whether preoperative β-blocker therapy is effective or safe. Should it be decided to begin β-blocker therapy, the ACC/AHA guidelines suggest that it is reasonable to start therapy sufficiently in advance of the surgical procedure to assess safety and tolerability of treatment (class IIb). Lastly, β-blockers should not be initiated in β-blocker naïve patients on the day of surgery (class III: harm).

Abrupt discontinuation of β-blocker therapy for 24 to 48 h may trigger a withdrawal syndrome characterized by rebound hypertension, tachycardia, and angina pectoris. This effect seems to be caused by an increase in the number of β-adrenergic receptors (upregulation).

GUIDELINES