A supply gap is a pharmacological event
Concentrations fall by half a week, so a month away leaves a small fraction of steady state. Resuming at the previous dose presents the receptor with a step it has not seen…
Pharmacology
Page 5 of 12 of this archive, newest first.
Page 5
Escalating past the approved maximum, examined honestly
Higher doses of these molecules have been studied. In general they produced modest additional efficacy and disproportionate additional symptom burden, which is why the…
Escalating onto a rising curve
What the published pharmacokinetics permit, what the labels state, and where the two diverge.
What the GIP receptor adds: reading orforglipron as two drugs in one sequence
The glucagon arm raises energy expenditure and also raises hepatic glucose output. Balancing those is the whole engineering problem.
The tolerability data everybody quotes and nobody reads
Severity in these tables is graded by interference with activity, not by how unpleasant the experience was. Those are different measurements.
The steps get smaller as the ladder gets higher, and that is deliberate
What the published pharmacokinetics permit, what the labels state, and where the two diverge.
Three receptors, one peptide: the design problem behind triple agonism
What adding GIP activity does, on the current evidence, and what remains unresolved.
Is liraglutide better than mazdutide, or differently balanced?
What adding GIP activity does, on the current evidence, and what remains unresolved.
Antiemetics, laxatives and the thin literature underneath them
Constipation is the most tractable of the effects and the most consistently under-managed.
The mechanism behind the mechanism
The receptor populations that produce satiety and the ones that produce nausea overlap substantially. That is why the ceiling of this drug class is where it is, and it is…
When to stop escalating and when to stop entirely
The ceiling varies severalfold between people, and nothing measurable at baseline predicts where it sits.
Gastric emptying is a mechanism, not a side effect
The central effects are not a bonus. On the current evidence they are the principal mechanism of weight loss.
What the trials counted as intolerance
Trial discontinuation figures are a floor, not an estimate: trial populations are supported in ways ordinary patients are not.
The restart nobody plans for
We work through the residual-exposure table so the decision can be made from numbers rather than from feel.
The mechanism behind the mechanism
The clinical effect profile is almost fully predictable from where the receptor is expressed, which is unusual and useful.
From cell to clinic: where the extrapolation stops being safe
Receptor pharmacology is strong on average effects and almost silent on individual variation. That gap is where most reader questions live.
The eighteenth month, and the conversation that should have happened in the third
What the trials measured was continuation against withdrawal. What patients want to know is continuation at a lower dose, and that study has largely not been done.
The mechanism behind the mechanism
The receptor populations that produce satiety and the ones that produce nausea overlap substantially. That is why the ceiling of this drug class is where it is, and it is…
The label says four weeks. The clinic says whatever holds.
Deviation from the printed ladder is not non-compliance. In this class it is the modal behaviour of competent prescribing.
The interventions with trial support, and the much longer list without
The intervention with the clearest evidence is the one nobody frames as an intervention: adjusting the dose.