Agonists indirect-acting

Figure 7.7 Dopamine-induced rotation in the rat in which one (left) nigrostriatal dopamine pathway from the substantia nigra (SN) to the caudate putamen (CP) has been lesioned by a prior injection (14 days) of 6-hydroxydopamine. Amphetamine, an indirectly acting amine, releases DA and so can only act on the right side. Since the animal moves away from the dominating active side it induces ipsilateral rotation (i.e. towards the lesioned side). By contrast, the development of postS5maptic supersensitivity to DA on the lesioned side ensures that apomorphine, a directly acting agonist, is actually more active on that side and so the animal turns away from it (contralateral rotation)...

Functional antagonism is a term used to represent the interaction of two agonists that act independently of each other but happen to cause opposite effects. Thus, indirectly, each tends to cancel out or reduce the effect of the other. A classic example is acetylcholine and epinephrine. These agonists have opposite effects on several body functions. Acetylcholine slows the heart, and epinephrine accelerates it. Acetylcholine stimulates intestinal movement, and epinephrine inhibits it. Acetylcholine constricts the pupil, and epinephrine dilates it and so on. 

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). 

Cholinesterase inhibitors have less marked effects on vascular smooth muscle and on blood pressure than direct-acting muscarinic agonists. This is because indirect-acting drugs can modify the tone of only those vessels that are innervated by cholinergic nerves and because the net effects on vascular tone may reflect activation of both the parasympathetic and sympathetic nervous systems. The cholinomimetic effect at the smooth muscle effector tissue is minimal since few vascular beds receive cholinergic innervation. Activation of sympathetic ganglia may increase vascular resistance. 

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. 

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. 

Triadimefon binds to hepatic cytochrome P450 and inhibits microsomal enzyme activities. It inhibits sterol demethylation and thus sterol synthesis. Fungi sensitive to triadimefon utilize ergosterol as the primary sterol, the production of which is inhibited. It is also thought that triadimefon may have actions similar to those caused by indirect-acting dopamine agonists. 

Indirect-acting adrenoceptor agonists act only on effector tissues innervated by SANS. 

Figure II-4-12 Classic example showing that denervated tissues do not respond to indirect-acting agonists. In this case, tyramine fails to cause mydriasis in the left eye, but this eye is more responsive than the right eye to epinephrine (denervation supersensitivity).

Indirect-acting adrenoceptor agonists act only on effector tissues innervated by SANS. Denervated effector tissues are nonresponsive because these drugs act to either release transmitter from nerve terminals or to inhibit neurotransmitter reuptake. 

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