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