Mechanism of action of adrenergic drugs and recent updates

Direct-acting, indirect-acting, and mixed-acting sympathomimetics are the three types of sympathomimetic drugs. Direct-acting sympathomimetic medications bind to one or more adrenergic receptors directly. These drugs may have high selectivity for a single receptor subtype (e.g., phenylephrine for α1, terbutaline for β2) or no or low selectivity and operate on a variety of receptor types [e.g., epinephrine for α1, α2, β1, β2, and β3 receptors; norepinephrine (NE) for α1, α2, and β1 receptors]. The availability of NE or epinephrine (EP) to excite adrenergic receptors is increased by indirect acting. Mixed-acting sympathomimetic medications are those that release NE indirectly while also activating receptors directly (e.g., ephedrine, dopamine). Despite the convenience of this classification, there is likely a continuum of action from mostly direct-acting to predominantly indirect-acting medications. As a result, rather than being absolute, this classification is relative. Prior treatment with reserpine or guanethidine, which depletes NE from sympathetic neurons, has little effect on the responses of direct-acting sympathomimetic medications. Because the loss of the neurotransmitter causes compensatory alterations that up-regulate receptors or boost the signaling pathway, the activities of direct-acting sympathomimetic medications may actually increase after transmitter depletion. Prior treatment with reserpine or guanethidine, on the other hand, eliminates the effects of indirect-acting sympathomimetic medications (e.g., amphetamine, tyramine). Prior therapy with reserpine or guanethidine has the effect of blunting, but not eliminating the effects of mixed-acting sympathomimetic medications because the effects of NE are stronger on α and β1 receptors than on β2 receptors. The actions of noncatecholamines (CAs) that produce NE are mostly receptor mediated and cardiac. Non-CAs having direct and indirect adrenergic receptor actions, on the other hand, have considerable β2 activity and are employed clinically for these effects. Although part of its actions is dependent on the release of NE, ephedrine reduces bronchospasm by acting on β2 receptors in bronchial smooth muscle, an effect not seen with NE. Non-CAs, such as phenylephrine, also act predominantly and directly on target cells. As a result, predicting the effects of non-CAs merely based on their potential to cause NE release is impossible.