Tachyphylaxis and phenylephrine

[EazyE1907]

got a world question about tachyphylaxis due to phenylephrine use as a topical decongestant for rhinits

it says the drug efficacy of phenylephrine decreases due to a negative feedback mechansim leading to decreased levels of NE production in presynpatic nerve terminals and thus decreased vasoconstriction and worsening of rhinitis symptoms. I get the general idea here.

However,what i don't understand is where the negative feedback is coming from. I know that NE regulates it's own release by acting on a2 receptors, but NE would not be increased in this case. Is it because there is increased a1 receptor stimulation by phenylephrine which is leading to the negative feedback. That's the only thing i can think of. unless i am missing something. Thanks!

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[ChessMaster3000]

with repeated phenylephrine stimulation, fewer receptors are translocated to the surface of the cell, which means a higher phenylephrine dose is required to achieve the same effect. (or, at the extreme, it will just stop working at all). the phenylephrine example is classic for this, there are others, but i wouldn't delve too far into it.