Adrenergic receptors are part of a family of receptors known as G protein coupled receptors. Receptor stimulation by an agonist (see Chapter 4) facilitates the binding of the nucleotide guanosine triphosphate to a G protein, which activates it. The activated G protein then stimulates or inhibits one of a number of second messenger systems. Two second messenger systems mediate the actions of adrenergic receptors:

• Inositol triphosphate/diacylglycerol (IP₃/DAG). This second messenger system regulates the release of calcium from intracellular stores. An activated G protein stimulates the enzyme phospholipase C, which causes the hydrolysis of a membrane-bound phospholipid into IP₃ and DAG. IP₃ diffuses into the cytoplasm and triggers the release of calcium from the endoplasmic reticulum. The IP₃/DAG system mediates the actions of α₁ receptors. (It also mediates the actions of angiotensin II and vasopressin type-1 receptors.)

• Cyclic adenosine monophosphate (cAMP). Activation of stimulatory or inhibitory G proteins regulates the activity of the membrane-bound enzyme adenylate cyclase, which catalyzes the conversion of adenosine triphosphate into cAMP. Then cAMP activates protein kinases, which cause the phosphorylation of various intracellular enzymes, modulating their function. The cAMP system regulates the intracellular calcium concentration through protein-kinase-mediated phosphorylation of transmembrane calcium channels; cAMP is metabolized into an inactive form by phosphodiesterase, of which there are several types. The cAMP second-messenger system mediates the actions of β₁ and β₂ receptors via a stimulatory G protein and α₂ receptors via an inhibitory G protein. (An analogous second-messenger system based on cyclic guanosine monophosphate (cGMP) mediates the actions of the natriuretic peptides and nitric oxide.)

Receptor Effects

The direct cardiovascular effects of the adrenergic receptor subtypes are summarized in Table 3-1.

Table 3-1 Effects of Adrenergic Receptor Subtypes on the Cardiovascular System

Receptor	Location	Action
α₁	Systemic arterioles, mainly: Abdominal viscera Coronary Skin Skeletal muscle Veins Pulmonary arterioles	Vasoconstriction
α₂	Pre- and postsynaptic sympathetic nerve terminals Central nervous system	Vasodilation
β₁	Heart	Increased contractility Increased conduction velocity and reduced refractoriness (particularly within pacemaker cells) Increased automaticity
β₂	Veins	Vasodilation
	Pulmonary arterioles, mainly: Systemic arterioles Abdominal viscera Coronary Skeletal muscle

Individual Sympathomimetics

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.

Phosphodiesterase Type III Inhibitors

The phosphodiesterases (PDEs) are a family of enzymes that catalyze the breakdown of cyclic nucleotides, including cAMP and cGMP. There are multiple subtypes of PDE that have varying tissue distributions and actions.¹² Caffeine and theophylline are nonspecific PDE inhibitors that are used as bronchodilators. Papaverine is a vasodilator and nonspecific PDE inhibitor that is used by cardiac surgeons during coronary artery bypass graft (CABG) surgery to prevent spasm of the internal mammary artery.

Drugs that selectively inhibit PDE subtype III function as inodilators. The commercially available PDE-III inhibitors all have a similar pharmacologic profile: they increase contractility and cause pulmonary and systemic (arteriolar and venous) vasodilation. As such, PDE-III inhibitors are useful for treating low cardiac output, particularly in the presence of pulmonary edema or pulmonary hypertension. They are potent vasodilators of coronary grafts ¹³ and cause less tachycardia and atrial fibrillation than dobutamine.¹⁰ The inotropic effect is independent of the β₁ receptor, which is advantageous in patients with β₁ receptor desensitization (see earlier discussion). Also, by combining a PDE-III inhibitor with a β₁ receptor agonist, a dual mechanism of action is exploited. Arteriolar and venous dilation can cause modest hypotension. This can be treated with either fluid or low-dose norepinephrine, depending on the status of the patient’s intravascular volume. In patients with cardiogenic shock, the combination of a PDE-III and norepinephrine provides support for both cardiac output and blood pressure, but without the troublesome tachycardia and metabolic disturbance that can occur with epinephrine.

PDE-III inhibitors are available as intravenous formulations for short-term use. Unlike the sympathomimetics, they have durations of action measured in hours, so their effects cannot be readily judged. Oral formulations of PDE-III inhibitors for the treatment of chronic heart failure have been studied but have resulted in higher mortality rates.¹⁴

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.

Miscellaneous Vasoactive Drugs

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