Adrenergic receptors (adrenoceptors) are molecular structures present in plasma membranes. They all have seven transmembrane-spanning domains and are coupled to guanosine triphosphate–binding proteins (G proteins). After binding by specific extracellular ligands, they signal their biological effects through various cellular effector systems (Fig. 26-1). In the heart, adrenoceptors mediate changes in contractile function, pacemaker activity, and conduction velocity, leading to increases in cardiac output. In veins and arteries, adrenoceptors mediate changes in the tone of smooth muscle cells, prompting adaptive redistribution of blood flow through vasoconstriction or vasodilation of specific vascular beds. Adrenoceptors also mediate metabolic, endocrine, respiratory, gastrointestinal, urinary, and central nervous system function, but discussion of these effects exceeds the scope of this chapter. Adrenergic agonists include the endogenous catecholamines epinephrine and norepinephrine and sympathomimetic drugs such as isoproterenol, dobutamine, phenylephrine, and methoxamine (Table 26-1).

Two main adrenoceptors were originally described by Ahlquist¹ based on the vascular response to endogenous agonists. Adrenoceptors that mediated vasoconstriction were designated as alpha adrenoceptors and those that mediated vasodilation as beta adrenoceptors. Subsequently it was discovered that these primary adrenoceptors included multiple subtypes, totaling, at the time of this writing, nine distinctive adrenoceptors (Fig. 26-2).²

Dopamine (D) receptors are also G protein–coupled receptors. To date, five types have been identified and grouped into two main types based on whether they are coupled to stimulatory (Gsα) or inhibitory (Giα) G-proteins. Thus, D1 receptors (including D1 and D5) are coupled to Gsα and stimulate formation of cAMP by increasing adenylyl cyclase activity. D2 receptors (including D2, D3, and D4) are coupled to Giα and have the opposite effect reducing the formation of cAMP by inhibiting adenylyl cyclase. D receptors play an important role in neurologic processes such as the control of motivation, learning, and fine motor movement.¹³ They also mediate neuroendocrine signaling by modulating the release of prolactin and thyroid hormone from the pituitary gland. Abnormalities in D receptors and dopaminergic nerve function have been implicated in several neuropsychiatric disorders, such as Parkinson’s disease, drug addiction, compulsive behavior, attention-deficit/hyperactivity disorder, and schizophrenia.¹³

In the cardiovascular system, D receptors mediate selected vasodilatory responses along with inotropic and chronotropic cardiac responses. In the kidneys, D receptors mediate increased glomerular filtration, diuresis, and natriuresis.¹⁴ These cardiovascular and renal effects are mediated through D1 receptors located postsynaptically in vascular smooth muscle cells and kidney. D2 receptors are located presynaptically at various sites within the sympathetic nervous system. Their activation leads to inhibition of sympathetic nervous system activity.

The broad diversity of adrenoceptors presented above permits, at the cellular level, signaling of distinct responses contingent on cell type, effector systems, and target mechanisms. At the organ level, receptor density, specific subtypes, and relative ligand potency allow for specific responses to sympathetic stimulation, circulating catecholamines, and sympathomimetic agents. For example, beta₁ adrenoceptors—as discussed above—are distributed predominantly in cardiac tissue, mediating inotropic and chronotropic responses. Blood vessels express alpha and beta adrenoceptors in varying proportions and densities, leading to vasoconstrictive or vasodilatory responses after stimulation by endogenous catecholamines or sympathomimetic drugs contingent on the vascular bed and local concentration of the agonists. For example, cutaneous vessels express almost exclusively alpha adrenoceptors, such that stimulation by epinephrine or norepinephrine leads to vasoconstriction; whereas stimulation by isoproterenol has virtually no effects. Blood vessels that supply skeletal muscles express beta₂ and alpha adrenoceptors, such that the predominant effect becomes contingent on the dose of the adrenergic agent. Epinephrine at low doses causes vasodilation, reflecting the predominance of beta₂-agonist effect, given a higher receptor affinity, whereas at higher doses, the same epinephrine causes vasoconstriction as the
alpha-adrenoceptor effect predominates. This pharmacologic effect is useful during cardiac resuscitation when exogenous epinephrine is given to redistribute blood toward the heart and brain. Dopamine, the natural agonist of dopamine receptor and precursor of norepinephrine and epinephrine, mediates inotropic and vasodilatory responses at relatively low doses. However, as the dopamine dose increases, vasoconstrictive responses occur, related to increased production of norepinephrine in sympathetic nerve terminals.

Besides the primary effect of adrenergic stimulation, many additional factors influence the clinical response to adrenergic agonists, including the baroreflex response slowing the heart rate, activity of the parasympathetic nervous system, release of cotransmitters including ATP and neuropeptide Y from sympathetic nerve terminals, the effects of vasoactive platelet–mediated products such as thromboxane A₂ and prostacyclin, endothelial injury causing paradoxical responses to vasodilating stimuli, and interactions with other drugs.

Accordingly, the clinical effects of adrenergic agonists may vary widely from patient to patient and is further influenced by disease states, including whether the patient is in cardiac arrest. Because of this variability, these drugs may need to be titrated and the patient response closely monitored. In Table 26-1, a simplified selection of vasoactive drugs is summarized, identifying their major receptor sites and their effects on arterial vascular tone, heart rate, myocardial contractility, and the risk for inducing arrhythmias. Their usual clinical doses are also given.

Epinephrine is hemodynamically beneficial during cardiac resuscitation because of its alpha-adrenoceptor vasoconstrictive
effect.²⁷ In animal models, alpha-adrenergic stimulation during cardiac resuscitation increases coronary and cerebral blood flow and favors return of spontaneous circulation.²⁸ Experimentally, differences in the effects mediated through alpha₁ and alpha₂ adrenoceptors appear relevant. Alpha₁ adrenoceptors desensitize faster than alpha₂ adrenoceptors during ischemia and acidosis, such that there is a better alpha₂-mediated vasoconstrictive response after prolonged cardiac arrest. Alpha₁ adrenoceptors signal a modest inotropic effect through increases in cytosolic Ca²⁺, which can be detrimental by increasing myocardial energy requirements and inducing arrhythmias. In contrast, presynaptic alpha₂ adrenoceptors in the heart limit the release of norepinephrine, exerting a favorable antiadrenergic effect.⁸ Concomitant beta-adrenergic stimulation by epinephrine may be detrimental by increasing myocardial energy demands. Animal studies have shown that marked increases in myocardial blood flow by epinephrine during chest compression fail to attenuate ischemia, such that intramyocardial lactate and ATP depletion remain unchanged (Fig. 26-5).²⁹ In other studies, epinephrine has been shown to worsen postresuscitation myocardial function. Such detrimental effects can be reduced by concomitant use of beta-blockers or by use of selective alpha agonists instead of epinephrine.³⁰

Despite these considerations, epinephrine is the most used vasopressor agent for resuscitation from cardiac arrest. Previous investigators had suggested that higher initial doses or escalating doses could improve survival rates. However, eight randomized clinical studies—involving more than 9,000 cardiac arrest victims—failed to demonstrate that higher doses of epinephrine improve survival to hospital discharge or neurologic outcomes when compared with standard doses.^{31,32,33,34,35,}

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