6.6: Adrenergic Agonists: Indirect-Acting Agents
Indirect-acting adrenergic agonists potentiate the effects of endogenous catecholamines through different mechanisms without directly binding to adrenoceptors.
One mechanism involves depleting stored catecholamines by displacing them from synaptic vesicles. These agents, known as "displacers," are transported into vesicles at the expense of noradrenaline. Examples include amphetamine and tyramine, which lack a catechol moiety, resulting in prolonged action, improved oral bioavailability, and better penetration into the central nervous system. Amphetamine stimulates cardiac adrenoceptors and releases nonvesicular dopamine and noradrenaline. Tyramine, found in fermented foods, mimics sympathetic responses in individuals taking MAO inhibitors.
Another mechanism is the inhibition of catecholamine reuptake, enhancing the sympathetic response. Cocaine, a local anesthetic, blocks catecholamine transporters, acting as an indirect sympathomimetic. Drugs like cocaine and amphetamine can be addictive due to their CNS stimulatory effects, releasing dopamine and serotonin.
Enzyme inhibitors like MAO inhibitors (e.g., selegiline) and COMT inhibitors (e.g., entacapone) are also indirect-acting agents, as they prevent the breakdown and excretion of circulating neurotransmitters.
