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.
What I am after is which effects tachyphylax and which persist, because the answer explains why tolerability improves while the appetite effect keeps working.
I have searched first, so if this is covered somewhere point me at it and I will read it.
sarah_nash92 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…
Receptor pharmacology relevant to the pharmacology: semaglutide is a GLP-1R agonist with a C-18 fatty acid chain that enables albumin binding (>99%), creating a depot effect with a ~168-hour half-life enabling weekly dosing[1].
Tirzepatide is a dual GIP/GLP-1R agonist with higher GIP affinity (5:1 GIP:GLP-1 potency ratio). The GIP component may enhance beta-cell function and adipocyte lipid metabolism beyond what GLP-1 alone achieves.
For the pharmacology, the pharmacology explains the clinical differences between these agents.
[1] Lau J, et al. J Med Chem. 2015;58(18):7370-7380.
MikeFit_NJ said:Receptor pharmacology relevant to the pharmacology: semaglutide is a GLP-1R agonist with a C-18 fatty acid chain that enables albumin binding (>99%),…
Agreeing with MikeFit_NJ, and the qualification matters more than the agreement. 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.
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Browse GL Biochemsarah_nash92 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 experience, arrived at from the opposite direction. I had assumed I was the exception until I read this.
Clinical perspective, offered as context rather than as advice.
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.