Adrenergic agonists indirect-acting

These are (3-adrenergic agonists that act by stimulation of the enzyme, adenylyl cyclase, thereby increasing intracellular cAMP. This indirectly increases intracellular calcium, by induction of the active form of protein kinase followed by an influx of Ca2+ through open voltage-dependent Ca2+ channels (Figure 8.4). 

Indirect-acting agonists These agents, which include amphetamine and tyramine, are taken up into the presynaptic neuron and cause the release of norepinephrine from the cytoplasmic pools or vesicles of the adrenergic neuron (see Figure 6.8). As with neuronal stimulation, the norepinephrine then traverses the synapse and binds to the a or p receptors. 

Sites of action of direct-, indirect-and mixed-acting adrenergic agonists. 

Indirect-acting adrenergic agonists cause norepinephrine release from presynaptic terminals (see Figure 6.8). They potentiate the effects of norepinephrine produced endogenously, but these agents do not directly affect postsynaptic receptors. 

Neurotransmission across adrenergic junctions is mediated by norepinephrine (NE). Adrenergic effectors may act indirectly by influencing NE synthesis, monoamine oxidase (MAO) enzymes, the mobile NE pool, the NE transporter, prejunctional a-adrenoceptors, granule uptake, or release of NE, or they may ad directly on the postjunctional receptor as agonists or antagonists. 

Metaraminol (aramine) is a mixed-acting agent an agonist at vascular a adrenergic receptors and an indirectly acting agent that stimulates the release ofNE. The drug has been used in the treatment of hypotensive states or off-label to relieve attacks of paroxysmal atrial tachycardia, particularly those associated with hypotension (see Chapter 34 for preferable treatments of this arrhythmia). 

A. PPA and phenylephrine are direct alpha-adrenergic agonists. In addition, PPA produces mild beta-1 adrenergic stimulation and acts in part indirectly by enhancing norepinephrine release. 

The atypical tricyclic antidepressant amineptine (Survector) is an indirect dopamine agonist, which selectively inhibits dopamine uptake and induces its release, with additional stimulation of the adrenergic system. Its antidepressant effects are similar to those of other tricyclic antidepressant drugs. However, it acts more rapidly, is better... 

As was noted on p. 68, some agonists, such as amphetamine and tyra-mine, do not act directly on the adrenoceptor. Instead, they exert their effects indirectly on the adrenergic neuron by causing the release of neurotransmitter from storage vesicles. Similarly, some agents act on the adrenergic neuron, to either interfere in neurotransmitter release or alter the uptake of the neurotransmitter into the adrenergic nerve. 

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