Sympathomimetics

All sympathomimetics are derived from β-phenylethylamine. The presence of hydroxyl groups on the 3- and 4-carbons in the benzene ring designates a compound as a catecholamine, which may be endogenous or synthetic (Fig. 3-1). The noncatecholamine sympathomimetics include a diverse range of drugs, such as the asthma medication albuterol and the central nervous system stimulant amphetamine. Two commonly used vasoactive noncatecholamine sympathomimetics are ephedrine and phenylephrine.

Figure 3.1 Classification of sympathomimetics. All sympathomimetics have a benzene ring and an ethylamine group in position 1. Catecholamines have hydroxyl substitutions in positions 3 and 4 of the benzene ring. Noncatecholamine sympathomimetics may also have substitutions in the benzene ring (e.g., phenylephrine has a single hydroxyl substitution in position 4).

α Receptors.

α₁ Receptors are widely distributed in vascular smooth muscle, particularly in the arterioles of skeletal muscle and the gastrointestinal tract. They are also present on the radial muscle of the eye, the smooth muscle of the uterus, and the sphincters of the bladder and gastrointestinal tract. Stimulation of α₁ receptors causes vasoconstriction, pupillary dilatation (mydriasis), and sphincter contraction.

Peripheral α₂ receptors are located on sympathetic nerve terminals. Stimulation of these receptors inhibits norepinephrine release and therefore causes vasodilation. Stimulation of central α₂ receptors causes sedation, analgesia, and reduced sympathetic outflow. The last effect contributes to vasodilation.

β Receptors.

β1 Receptors are present on the heart; their stimulation results in increased heart rate (chronotropy), increased conduction (dromotropy), reduced refractoriness within the atrioventricular (AV) node, and increased contractility (inotropy). The β1 receptors are also found on the juxtaglomerular cells of the kidney; their stimulation leads to increased renin release.

β₂ Receptors are found on the heart and throughout the vasculature, particularly the arterioles of skeletal muscle, the coronary circulation, and the liver. Their stimulation leads to vasodilation and enhanced diastolic relaxation (lusitropy). Outside of the cardiovascular system, β₂ receptor activation causes bronchodilation, uterine and bladder relaxation, and decreased gastrointestinal motility.

Epinephrine.

Epinephrine is a potent catecholamine with actions at both α and β receptors. At lower doses (0.01 to 0.03 μg/kg/min) β effects predominate, resulting in an increase in contractility and heart rate. Despite β₂ receptor-mediated vasodilation, a fall in blood pressure is uncommon. As the dose increases, α receptor-mediated vasoconstriction predominates, such that at higher doses (>0.05 to 0.1 μg/kg/min) vasoconstriction occurs in most vascular beds. In the acutely failing heart, epinephrine has the advantage of providing increased cardiac output while maintaining coronary perfusion pressure. Epinephrine can cause sinus tachycardia, atrial and ventricular arrhythmias, and marked metabolic disturbance, particularly hypokalemia, hyperglycemia, and lactic acidosis.

Norepinephrine.

Norepinephrine causes potent stimulation at α and β₁ receptors, but unlike epinephrine, it has minimal effect at β₂ receptors. Blood pressure is reliably increased but the effect on cardiac output is variable. Although β₁ receptor stimulation has a direct inotropic effect, in the setting of hypovolemia or impaired ventricular function, increased left ventricular afterload due to α₁ receptor stimulation can cause cardiac output to fall. Similarly, the effect on heart rate is variable: direct β₁ stimulation has a chronotropic effect but increased blood pressure can cause baroreceptor-mediated bradycardia.

Norepinephrine is useful following cardiac surgery to counter the vasodilatory effects of cardiopulmonary bypass and sedation. However, doses above 0.05 to 0.1 μg/kg/min should be avoided in patients with impaired ventricular function unless cardiac output is being measured. Norepinephrine is commonly combined with an inodilator such as dobutamine or milrinone. Norepinephrine is typically commenced at a dose of 0.01 to 0.05 μg/kg/min and titrated to blood pressure. There is no maximum dose, but infusions greater than 0.1 to 0.2 μg/kg/min are rarely needed in cardiac surgery patients except in the presence of vasoplegic syndrome (Chapter 2) or septic shock, in which case doses as high as 0.5 to 1 μg/kg/min may be required. Troublesome metabolic effects, particularly lactic acidosis, are much less common with norepinephrine than with epinephrine.²

Dopamine.

Dopamine is a precursor to norepinephrine and is itself an important neurotransmitter in the peripheral and central nervous systems. Dopamine stimulates α and β receptors and type 1 and 2 dopamine (DA) receptors. DA-1 receptors are found in the renal, mesenteric, and cerebral circulations,³ and their stimulation results in vasodilation. DA-1 receptors are also found in the renal tubule, where they mediate natriuresis. DA-2 receptors are analogous to α₂ receptors in that they are found presynaptically and inhibit the release of norepinephrine. Dopamine also has an indirect mechanism of action.

At low doses (<3 μg/kg/min), dopaminergic effects predominate. At higher doses, initially β receptor effects predominate; then α receptor effects predominate. The widely accepted dose range is 3 to 10 μg/kg/min for β effects and more than 10 μg/kg/min for α effects. However, these dose ranges must be viewed with skepticism. There is huge individual variability in the pharmacokinetics of dopamine such that dramatically different plasma concentrations may occur in different patients who are receiving the same dose.⁴ Furthermore, the clinical effects of a given plasma concentration are dependent on the functional activity of the adrenergic receptors. β Receptors are desensitized in a variety of clinical settings, including after cardiac surgery and with heart failure.^5–7 Because of its indirect action, dopamine has reduced effectiveness in patients with heart failure or shock. Despite these caveats, it is generally true that as the dose of dopamine increases, there is a progressive increase in blood pressure and heart rate.

Dopamine at a dose of 1 to 3 μg/kg/min has been termed “renal-dose dopamine” and has traditionally been used to provide selective renal vasodilation in patients at risk for renal dysfunction. However, it is now clear that although low-dose dopamine may increase blood flow to the renal cortex, blood flow to the renal medulla may actually decrease.⁸ Given the relatively hypoxic environment of the renal medulla under normal circumstances (Chapter 1), this effect is potentially harmful. Furthermore, the increase in urine output that occurs with low-dose dopamine is due primarily to a direct tubular natriuretic effect rather than to renal vasodilation. In a well-conducted, large, randomized trial, low-dose dopamine did not reduce the incidence of acute renal failure in patients with early renal dysfunction.⁹ Dopamine has a number of other potentially detrimental effects, including inhibition of hypoxic ventilatory drive, impairment of ventilation-perfusion matching in the lung, and suppression of the secretion of some anterior pituitary hormones, such as prolactin, growth hormone, and thyrotropin.⁸

Isoproterenol.

Isoproterenol is a potent β receptor agonist that has virtually no effect at α receptors. The principal actions of isoproterenol are increased contractility, increased heart rate, and vasodilation. Cardiac output is reliably increased and blood pressure typically falls. In patients with coronary artery disease, isoproterenol can precipitate myocardial ischemia. The main indication for isoproterenol is the treatment of symptomatic bradycardia or heart block, but its use is limited by the development of arrhythmias, hypotension, and metabolic disturbances. The usual dose is 0.01 to 0.05 μg/kg/min.

Dobutamine.

Dobutamine is a synthetic catecholamine with relative specificity for β₁ receptors. Although heart rate is increased, tachycardia is less pronounced than with isoproterenol. Modest β₂ receptor-mediated vasodilation may occur. Cardiac output is reliably increased, but the effect on blood pressure is unpredictable; it may increase, remain stable, or occasionally fall.

Dobutamine is useful for treating low cardiac output following cardiac surgery,¹⁰ and it may be used in combination with norepinephrine for treating septic shock.¹¹ The dose range is 1 to 10 μg/kg/min. At higher doses tachyarrhythmias become common. Metabolic side effects are minimal.

Ephedrine.

Ephedrine is a synthetic noncatecholamine sympathomimetic that has effects at both α and β receptors. It is not metabolized by COMT and therefore has a longer duration of action than the catecholamines. For the most part, ephedrine acts indirectly; thus, its efficacy is reduced in patients with shock or heart failure and after prolonged administration. Ephedrine is not suitable for continuous infusion but may be administered as an intravenous bolus of 5 to 20 mg to treat acute hypotension.

Phenylephrine.

Phenylephrine is a noncatecholamine, direct-acting α receptor agonist that does not possess any significant β receptor activity. Bolus doses of 50 to 100 μg are commonly used during induction of anesthesia in patients with aortic stenosis to counteract the vasodilation produced by anesthetic drugs. In this situation phenylephrine has the advantage of increasing coronary perfusion pressure without increasing heart rate. Cardiac output may fall due to increased afterload and baroreceptor-mediated reflex bradycardia. Phenylephrine has a slightly longer duration of action than norepinephrine. The drug may be administered as a continuous infusion at a dose of 0.1 to 1 μg/kg/min.

Milrinone.

Milrinone is a bipyridine derivative with an elimination half-time of about 2.5 hr. It is administered as a loading dose of 50 μg/kg over 30 min, followed by an infusion of 0.25 to 0.75 μg/kg/min. In patients at risk for hypotension, the loading dose should be reduced or given very slowly. Milrinone is eliminated via the kidneys, and the rate of infusion should be adjusted in patients with severe renal dysfunction so as to avoid excessive vasodilation.

Amrinone.

Amrinone was the first selective PDE-III inhibitor introduced into clinical practice. Like milrinone, it is a bipyridine derivative and is eliminated by the kidneys. Amrinone can cause thrombocytopenia, and for this reason is no longer widely used.

Enoximone.

Enoximone is an imidazolone derivative, and is metabolized primarily by the liver. It is therefore less affected by renal function than the bipyridines. The elimination half-time of enoximone is about 4 hours. Enoximone is administered as a loading dose of 0.5 to 1 mg/kg over 30 minutes, followed by an infusion of 5 to 20 μg/kg/min.

Calcium.

An intravenous bolus dose of calcium chloride of 5 mg/kg (or 0.035 mmol/kg) increases blood pressure but has little effect on myocardial contractility.¹⁵ The duration of effect following a bolus dose is 5 to 10 minutes. The pressor effect is much more pronounced in the presence of hypocalcemia. Calcium chloride does not improve outcome after cardiac arrest¹⁶ and is no longer included in routine resuscitation protocols. However, calcium is useful in the management of hyperkalemia because it reduces potassium-induced arrhythmias, and in the treatment of hypocalcemia.

Vasopressin.

Vasopressin (V; antidiuretic hormone) is a peptide hormone released from the posterior pituitary in response to an increase in serum osmolarity or hypovolemia (Chapters 1 and Chapter 32). Stimulation of V1 receptors within vascular smooth muscle results in vasoconstriction (via the IP₃/DAG second-messenger system), whereas stimulation of V2 receptors in the kidney results in water retention (via the cAMP second-messenger system). An additional action of vasopressin is to increase the release of the von Willebrand factor from the vascular endothelium, which increases platelet aggregation. The elimination half-time of vasopressin is 10 to 30 minutes.

Exogenously administered vasopressin is used to treat catecholamine-resistant vasodilatory shock. In early shock, endogenous stores of vasopressin are released from the posterior pituitary, but as shock progresses, these stores become depleted. In patients with advanced vasodilatory shock, vasopressin infusion at 4 units/hr combined with norepinephrine has been shown to be superior to norepinephrine alone in terms of hemodynamics and markers of splanchnic perfusion.¹⁷ However, higher doses of vasopressin, sufficient to replace rather than augment norepinephrine, can cause a marked reduction in cardiac output and may worsen splanchnic perfusion.¹⁸ In animal models, vasopressin is associated with relatively less vasoconstriction within the coronary, cerebral, and pulmonary circulations than is associated with catecholamines.^19,20 Despite an antidiuretic effect, in patients with vasodilatory shock urine output may actually improve with vasopressin,²¹ presumably due to an improvement in renal blood flow. As with all vasoconstrictors, precipitous reductions in cardiac output can occur with vasopressin, particularly in the settings of hypovolemia and impaired ventricular function. Current recommendations are that vasopressin, in a dose of 0.01 to 0.04 units/min, should be considered in patients with vasodilatory shock who have adequate volume resuscitation and are refractory to high doses of catecholamines.²²

Levosimendan.

Levosimendan is an inotropic drug that acts by stabilizing the interaction between calcium and tropo-nin, so-called calcium sensitization. In addition, levosimendan functions as a vasodilator, partly through PDE-III inhibition and partly by opening adenosine triphosphate gated potassium channels. Because the effect of levosimendan is not mediated by β₁ receptors or increased cAMP, it does not increase myocardial oxygen consumption and is not arrhythmogenic. Levosimendan may be a particularly useful inotropic agent in patients who are receiving β blockers. In the treatment of heart failure, levosimendan is more effective than dobutamine in improving cardiac output and, in one study, was associated with better mortality compared to dobutamine.²³

Levosimendan has an elimination half-time of 1 hour, but it has pharmacologically active metabolites with elimination half-times of up to 80 hours. The drug is usually administered as a continuous infusion of 0.1 to 0.2 μg/kg/min for 24 hours, which may be preceded by a loading dose of 12 to 24 μg/kg. Following a 24-hour infusion, a positive inotropic effect is sustained for several days. Side effects are typically modest and include mild tachycardia and hypotension. So far, levosimendan has been used primarily in patients with decompensated heart failure, but there is some limited experience in its use in patients after cardiac surgery.²⁴

Esmolol.

Esmolol is an intravenously administered, cardioselective β blocker that undergoes very rapid metabolism by plasma esterases. A single bolus dose has a peak effect within 2 to 6 minutes and a duration of effect of less than 20 minutes. The drug may be given as repeated bolus doses of 25 mg or as an intravenous infusion (25 to 300 μg/kg/min). Esmolol is useful for heart rate control of atrial fibrillation or as an adjuvant for suppressing life-threatening ventricular arrhythmias. Esmolol may be used as a “test” β blocker in patients who are at risk for bronchospasm or ventricular decompensation. Esmolol is usually ineffective in treating acute hypertension.

Labetalol.

Labetalol is an α₁ blocker and a nonselective β blocker that is formulated for intravenous and oral use. Labetalol is a useful drug for the treatment of postoperative hypertension. Intravenously, labetalol may be administered as repeated bolus doses of 5 to 10 mg. Labetalol undergoes significant hepatic metabolism and has low oral bioavailability; thus, the oral dose is much higher than the intravenous dose.

Metoprolol.