Mechamisms of Indirect Acting Sympathomimetics

• An indirect acting sympathomimetic acts mainly by promoting norepinephrine release from nerve terminals.

• Mechanism: These amines, all substrates for uptake I, act by:

  • Competing with noradrenergic vesicular transport systems, thus making norepinephine more available for release.

• Indirect-acting agents, such as tyramine, produce tachyphylaxis in which repetitive doses of tyramine results in a progressively diminishing response.

  • Tachyphylaxis may result from depletion of a small pool of vesicular norepinphrine residing near the presynaptic membrane.

• Uptake II is an extraneuronal (glia, heart, liver, etc) amine translocator that exhibits low affinity for norepinephrine and higher affinities for epinephrine and isoproterenol. This system is of limited physiological significance, unless Uptake I is blocked.

• Metabolic Transformation

  • Besides reuptake and diffusion away from receptor sites, catecholamine action can end due to metabolic transformation.

  • Two primary degradative enzymes:

    • Monoamine Oxidase (MAO)

    • Catechol-O-Methyl Transferase (COMT)

  • Inhibitors of MAO, such as pargyline, phenelzine, and tranylcypromine increase norepinephrine, dopamine, and serotonin (5-HT) brain concentrations.

    • These concentration increases may be responsible for antidepressant action of MAO inhibitors.

Catecholamine Release (Adrenal medulla)

Release steps: Chromaffin Granule Adrenal medulla

• preganglion fiber releases Ach nicotinic receptor activationdepolarizationCa²⁺ entry exocytosis of granular content

• Ca²⁺ influx is important in excitation (depolarization)--release coupling

Category: Pharmacology Notes