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ForumsPharmacology & MechanismsTachyphylaxis vs tolerance — need advice

Tachyphylaxis vs tolerance — need advice

Dr.NateNeph Sat, Jun 14, 2025 at 3:20 AM 10 replies 1,406 viewsPage 1 of 2
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Dr.NateNeph
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Jun 14, 2025 at 3:20 AM#1

Reading about receptor desensitisation and trying to work out which of the effects adapt over time and which do not, because people clearly experience both.

Numbers worth memorising for this class: Tmax one to three days for the weekly peptides, terminal half-life about a week for semaglutide and about five days for tirzepatide, steady state at four to five half-lives, subcutaneous bioavailability high enough that site choice is irrelevant.

So the question, as narrowly as I can put it: which effects tachyphylax and which persist, because the answer explains why tolerability improves while the appetite effect keeps working.

Happy to be told the question itself is wrong.

37 7JakeSmashed95, NauseaFreeNow, SteveThurs and 34 others
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BenResearch_OR
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Jun 14, 2025 at 3:35 AM#2
Dr.NateNeph said:
Reading about receptor desensitisation and trying to work out which of the effects adapt over time and which do not, because people clearly experience…

Amycretin (AMY/GLP-1 dual agonist) emerging data relevant to the pharmacology: Phase 1 showed -13.1% body weight at only 12 weeks, the fastest trajectory ever seen for an anti-obesity agent[1].

Amylin receptor agonism enhances satiety signaling through the area postrema and reduces glucagon secretion. Combined with GLP-1R agonism, this dual mechanism may produce even greater efficacy than current agents.

Early-stage data — interpret with caution. But the trajectory is extraordinary.

References:
[1] Novo Nordisk investor presentation, September 2023.
36 6PharmD_Rodriguez, julia.endo, JessicaM_2024 and 33 others
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TrialTracker_MD
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Jun 14, 2025 at 3:50 AM#3
BenResearch_OR said:
Amycretin (AMY/GLP-1 dual agonist) emerging data relevant to the pharmacology: Phase 1 showed -13.1% body weight at only 12 weeks, the fastest…

That is correct as far as it goes, and here is where it stops going. The pharmacokinetics explain nearly every practical question asked here. Albumin binding above 99% slows clearance enough to make weekly dosing possible; a terminal half-life near a week means four to five weeks to steady state and therefore a four-week titration interval; subcutaneous bioavailability around 89% means injection site barely matters. Those three facts answer most timing questions before they are asked.

Last edited: Jun 14, 2025 at 8:50 AM
35 5maya_sedona, stefan_berlin, Dr.EM_Chicago and 32 others
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josh_phd_bmore
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Jun 14, 2025 at 4:05 AM#4
Dr.NateNeph said:
Reading about receptor desensitisation and trying to work out which of the effects adapt over time and which do not, because people clearly experience…

Same pattern here, and in the same order. I had assumed I was the exception until I read this.

Last edited: Jun 14, 2025 at 6:05 AM
34 4KarenAZ_mom, zoe_NC, Dr.ObesityLA and 31 others
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Dr.MetabolicMD
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Jun 14, 2025 at 5:25 AM#5

Adding the clinical framing, because it changes how the question reads.

Pharmacist here. I want to add the drug interaction perspective on the pharmacology.

Key points from a pharmacokinetic standpoint:

  • GLP-1 agonists delay gastric emptying, which can affect Tmax of co-administered oral medications
  • Monitor patients on warfarin (INR), levothyroxine (TSH), and oral contraceptives during dose titration
  • The albumin-binding mechanism of semaglutide (C-18 fatty acid linker) gives it the ~168-hour half-life that enables weekly dosing
  • Steady state is reached at approximately 4-5 weeks after dose initiation or adjustment

Re: the pharmacology specifically — the pharmacology here is well-characterized and the clinical implications are straightforward.

33 3GenomicsKate, Dr.ObesityMed, HealthEcon_DC and 30 others
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