Graham Patrick explains the mechanism for the activity of tyramine, amphetamine and ephedrine in his book Introduction to Medicinal Chemistry as follows:

Some amines such as tyramine , amphetamine , and ephedrine closely resemble noradrenaline in structure and are transported into the nerve cell by noradrenaline’s transport proteins. Once in the cell, they are taken up into the vesicles. Because these amines are competing with noradrenaline for transport proteins, noradrenaline is more slowly reabsorbed into the nerve cells. Moreover, as the foreign amines are transported into the nerve cell, noradrenaline is transported out by those same transport proteins. Both of these facts mean that more noradrenaline is available to interact with its receptors. Therefore, amphetamines and similar amines have an indirect agonist effect on the adrenergic system.

I have two question concerning this explanation:

  • When these foreign amines have been taken up into the vesicles how do they proceed? Do they re-enter the synaptic cleft by exocytosis, so that they can re-exercise their negative influence on noradrenaline re-uptake? How are they eventually cleared from the synaptic area?

  • Why do the noradrenaline re-uptake proteins transport noradrenaline out of the axonal terminal under the influence of these foreign amines?

  • 1
    $\begingroup$ Well, it's probably on-topic but imo it would be better to ask that on Biology SE $\endgroup$
    – Mithoron
    Aug 21, 2015 at 20:15

1 Answer 1


Question: When these foreign amines have been taken up into the vesicles how do they proceed?...Do they re-enter the synaptic cleft by exocytosis...How are they eventually cleared from the synaptic area?

Here is the mode of action of these agents (indirectly acting sympathomimetics):

enter image description here

The most important drugs in the indirectly acting sympathomimetic amine category are tyramine, amphetamine and ephedrine, which are structurally related to noradrenaline. Amphetamine enters the nerve terminal via the noradrenaline transporter (NET) and enters synaptic vesicles via the vesicular monoamine transporter (VMAT), in exchange for noradrenaline (NA), which accumulates in the cytosol.

Some of the NA is degraded by monoamine oxidase (MAO) within the nerve terminal and some escapes, in exchange for amphetamine via the noradrenaline transporter, to act on postsynaptic receptors. Amphetamine also reduces NA reuptake via the transporter, so enhancing the action of the released NA.

Exocytosis is not involved in the release process, so their actions do not require the presence of Ca2+. They are not completely specific in their actions, and act partly by a direct effect on adrenoceptors, partly by inhibiting NET (thereby enhancing the effect of the released noradrenaline) and partly by inhibiting MAO.

These agents are cleared by metabolism via oxidative deamination with monoamine oxidase(MAO) enzyme, however are poor substrates for MAO and, thus, show a prolonged duration of action.

Amphetamine is an example of a drug metabolized through oxidative deamination: enter image description here

Question: Why do the noradrenaline re-uptake proteins transport noradrenaline out of the axonal terminal under the influence of these foreign amines?

I am not really sure about the “why” part but instead the “how” part AFAICT, this is more of a displacement mechanism:

These drugs, do block reuptake 1(NET) releasing stored transmitter from noradrenergic nerve endings and they displace vesicular norepinephrine into the cytoplasm. The norepinephrine is then transported out of the nerve terminal by the reverse action of reuptake 1 and activates adrenoceptors. So essentially the drugs increase the availability of noradrenaline to stimulate adrenergic receptors by:

i. releasing or displacing NE (noradrenaline) from sympathetic nerve endings,

ii. blocking the transport of NE into sympathetic neurons or

iii. blocking the metabolizing enzymes, MAO or COMT.

How this helps


  1. Rang and Dale’s Pharmacology 8th Edition. Section 2: Chemical Mediators

  2. Medical Pharmacology at a Glance M. JNeal: Drugs acting on the sympathetic system

  3. Lippincott Illustrated Reviews: Pharmacology 6th Edition: Adrenergic Agonists

  4. Goodman and Gilman Manual of Pharmacology and Therapeutics: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia

  5. Principles of Clinical Pharmacology 2nd Ed Atkinson etal Basic and Clinical Pharmacology B. Katsung et al.


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