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Agents or drugs that act on the adrenergic system may mimic the actions of endogenous catecholamines, block their synthesis or release, or antagonize their effects at the level of adrenergic receptors on cell membranes. Catecholamines are released from neurons within the sympathetic nervous system and adrenal medulla. Norepinephrine (NE) is the primary catecholamine neurotransmitter in the peripheral sympathetic nervous system while epinephrine (EPI) is the primary catecholamine hormone released from the adrenal medulla. NE therefore acts in innervated tissues locally and EPI, secreted into blood circulation, acts as a hormone, with effects dependent upon its circulating concentration. NE and EPI are released and activated by several stimuli including physical and psychological stress. The diversity of their actions accounts for the fact that drugs acting to alter sympathetic and adrenergic responses are used for a myriad of clinical disorders including hypertension, asthma, heart failure, and anaphylactic reactions. Many of these uses are discussed elsewhere (see Chapters 32, 33, and 44). Dopamine is a third endogenous catecholamine; it is predominantly located in the central nervous system (CNS), and its central effects are discussed elsewhere (see Chapter 15), although there are some dopamine receptors in the periphery.

Actions of agents that activate or antagonize adrenergic receptors primarily follow known physiological effects of endogenous catecholamines. Most available adrenergic agonists are structural analogues of EPI and NE. Although EPI and NE are sometimes used, modifications of these parent structures offer therapeutic benefits including improved bioavailability, duration of action, and receptor subtype specificity. The actions of NE and EPI are similar at some sites but quite different at others due to subtypes of adrenergic receptors that are expressed by different organs and tissues. There are nine adrenergic receptor subtypes, and these can dictate specific effects of adrenergic agonists and antagonists throughout the body. Subtype selectivity of newer agonists and antagonists adds to the therapeutic benefits.


The pressor effects of adrenal extracts were first demonstrated by Oliver and Schafer in 1895. The active component was named epinephrine by J.J. Abel in 1899, who isolated the monobenzoyl derivative. Takamine isolated the “pure, stable, crystalline form” and termed it adrenalin (see Arthur, 2015). Henry Dale worked on a series of synthetic amines related to EPI that were termed sympathomimetics (Barger and Dale, 1910). Cannon and Rosenblueth described the actions of the body’s “fight and flight” mechanisms, observations that later led to the discovery that NE is the sympathetic neurotransmitter (see Bacq, 1983). In the mid-20th century, Ahlquist hypothesized that the myriad organ-level effects of catecholamines were mediated by activation of two distinct populations of receptors, which he termed distinct α and β receptors. This theory, although not universally embraced at the time (see Lefkowitz, 2018), provided the initial impetus for the synthesis and pharmacological evaluation of β receptor antagonists. The first β-selective agent was dichloroisoproterenol, a partial agonist. James Black and his colleagues ...

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