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.
What I actually want to know is 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.
LarryQC_SD 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…
PK/PD modeling for the pharmacology: understanding the pharmacokinetics helps optimize dosing. Semaglutide:
- Tmax: 24-72 hours post-injection
- T½: ~168 hours (7 days) — enables weekly dosing
- Steady state: reached at 4-5 weeks
- Bioavailability (SubQ): ~89%
- Volume of distribution: ~12.5L (primarily plasma)
The albumin binding (>99%) is the key pharmacological innovation — creating a sustained-release effect from a single injection. Previous GLP-1 agonists (exenatide) required BID dosing due to rapid clearance.
sarah.morrison said:PK/PD modeling for the pharmacology: understanding the pharmacokinetics helps optimize dosing.
That is correct as far as it goes, and here is where it stops going. The mechanism is more central than most summaries suggest. Receptor agonism in the arcuate nucleus activates POMC neurons and inhibits AgRP/NPY signalling, and the downstream MC4R pathway is the same one disrupted in monogenic obesity — convergent genetic evidence that the target is the right one. Peripherally there is glucose-dependent insulin secretion, glucagon suppression and delayed gastric emptying, but the gastric component largely adapts over months while the central effect persists, which is why the durable effect is appetite rather than fullness.
I would rather be corrected than agreed with, if it comes to it.
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Browse GL BiochemLarryQC_SD 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…
Second this. Nothing to add that would improve it.
From the other side of the consultation, briefly.
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.