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Catecholamines and sympathomimetic drugs are classified as direct-acting, indirect-acting, or mixed-acting sympathomimetics (Figure 12-1).

figure 12–1

Classification of adrenergic receptor agonists (sympathomimetic amines) and drugs that produce sympathomimetic-like effects. For each category, a prototypical drug is shown. (*Not actually sympathetic drugs but produce sympathomimetic-like effects.)

Direct-acting sympathomimetic drugs act directly on 1 or more of the adrenergic receptors. These agents may exhibit considerable selectivity for a specific receptor subtype (e.g., phenylephrine for α1, terbutaline for β2) or may have no or minimal selectivity and act on several receptor types (e.g., epinephrine for α1, α2, β1, β2, and β3 receptors; norepinephrine for α1, α2, and β1 receptors).

Indirect-acting drugs increase the availability of norepinephrine (NE) or epinephrine (EPI) to stimulate adrenergic receptors by several mechanisms:

  • By releasing or displacing NE from sympathetic nerve varicosities

  • By inhibiting the transport of NE into sympathetic neurons (e.g., cocaine), thereby increasing the dwell time of the transmitter at the receptor

  • By blocking the metabolizing enzymes, monoamine oxidase (MAO) (e.g., pargyline) or catechol-O-methyltransferase (COMT) (e.g., entacapone), effectively increasing transmitter supply

Drugs that indirectly release NE and also directly activate receptors are referred to as mixed-acting sympathomimetic drugs [e.g., ephedrine, dopamine (DA)].

A feature of direct-acting sympathomimetic drugs is that their responses are not reduced by prior treatment with reserpine or guanethidine, which deplete NE from sympathetic neurons. After transmitter depletion, the actions of direct-acting sympathomimetic drugs actually may increase because the loss of the neurotransmitter induces compensatory changes that upregulate receptors or enhance the signaling pathway. In contrast, the responses of indirect-acting sympathomimetic drugs (e.g., amphetamine, tyramine) are abolished by prior treatment with reserpine or guanethidine. The cardinal feature of mixed-acting sympathomimetic drugs is that their effects are blunted, but not abolished, by prior treatment with reserpine or guanethidine.

Because the actions of NE are more pronounced on α and β1 receptors than on β2 receptors, many non-catecholamines that release NE have predominantly α receptor–mediated and cardiac effects. However, certain non-catecholamines with both direct and indirect effects on adrenergic receptors show significant β2 activity and are used clinically for these effects. Thus, ephedrine, although dependent on release of NE for some of its effects, relieves bronchospasm by its action on β2 receptors in bronchial smooth muscle, an effect not seen with NE. Moreover, some non-catecholamines (e.g., phenylephrine) act primarily and directly on target cells. It therefore is impossible to predict precisely the effects of non-catecholamines solely on their ability to provoke NE release.

CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIP OF SYMPATHOMIMETIC AMINES. β-Phenylethylamine (Table 12-1) can be viewed as the parent compound of the sympathomimetic amines, consisting of a benzene ring ...

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