6.6:
Adrenergic Agonists: Indirect-Acting Agents
Indirect-acting adrenergic agonists enhance the effect of endogenous catecholamines through varied mechanisms.
Agonists such as amphetamine and tyramine are termed "displacers" as they induce catecholamine release by depleting their stores from the synaptic vesicle.
They resemble noradrenaline but lack a catechol moiety. Due to this resemblance, they are actively transported into synaptic vessels and, eventually, replace noradrenaline.
The cytosolic noradrenaline is then exchanged for another displacer molecule and released to act on postsynaptic adrenoceptors.
Another mechanism involves catecholamine reuptake inhibition. Cocaine blocks the transporter involved in catecholamine reuptake, thus potentiating sympathomimetic action.
Additionally, selegiline—a MAO inhibitor, and entacapone —a COMT inhibitor, are indirect-acting sympathomimetics as they prevent metabolism and subsequent excretion of circulating catecholamines.
Indirect-acting agonists like cocaine and amphetamine are often abused due to their central effects, like euphoria resulting from dopamine and serotonin release.
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.