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No, not so. Dextro *is* the correct answer here. From the choices given, dextro is the least likely to cause constipation since its main mechanism of action is NMDA antagonism w/ *some* opioid activity -- it can cause constipation but the other choices are MUCH MORE likely to. As for diphenhydramine = it is not appropriate for elderly patients and it isn’t an antitussive.
Agreed with @rockediny. Dextro would be the best to prescribe because it has the least amount of constipation out of the drugs that you could prescribe + Anti-cholinergics in the elderly have much more morbidity and risk of mortality.
The only way to wrap your head around this is to conclude that Dextro is the "least wrong". I thought a lot about this, and I can't think of any drugs that can suppress cough without also causing constipation, so it makes sense that Dextro is the answer because it is the "least likely" to cause significant constipation. This is probably just a clinical correlate that will be learned during rotations/years in practice.
Tiotropium would cause constipation bc it’s an anticholinergic. Don’t have any insight into why dextromethorphan is the right answer though, other than process of elimination and diphenhydramine wouldn’t treat his symptoms.
I thought it was dextromethorphan because it would bind NMDA receptors and have weaker opioid effect = less constipation? Idk though :/
I agree. I mainly went by way of elimination but even DXM made me think of opiod-induced constipation. Though, all the other answer choices had obvious anticholinergic effects. At least, that was my reasoning for picking dxm.
Thank you for your explanation!
One question: How about the serine phosphorylation? Is it answered by pure memorization that the FOXO TF is serine phosphorylated, or is it a general fact that all TF's are serine-threonine phosphorylated?
I'm not sure, but it may be as simple as this: ubiquitin-mediated proteolysis is irreversible, but both N/C shuttling and phosphorylation are generally reversible processes.
I also guessed that FOXO must be a part of the PI3K pathway, since insulin regulates metabolism through PI3K and the question stem specifically mentions that. Phosphorylation is a major part of that pathway, so even indirectly phosphorylation would regulate FOXO. Frustrating question.
According to wikipedia (https://en.wikipedia.org/wiki/FOXO1) phosphorylation of FOXO1 is irreversible. This is referring to phosphorylation of serine residues on FOXO by Akt, which occurs in response to insulin. But the NBME answer suggests it's reversible. What's up?
could wiki be wrong on phosphorylation being irreversible? according to this article, it is a reversible process: regulation of FoxO transcription factors by reversible phosphorylation and acetylation (https://www.sciencedirect.com/science/article/pii/S0167488911000735#s0010)
some wiki info, however, is helpful : In its un-phosphorylated state, FOXO1 is localized to the nucleus, where it binds to the insulin response sequence located in the promoter for glucose 6-phosphatase and increases its rate of transcription. FOXO1, through increasing transcription of glucose-6-phosphatase, indirectly increases the rate of hepatic glucose production. However, when FOXO1 is phosphorylated by Akt on Thr-24, Ser-256, and Ser-319, it is excluded from the nucleus, where it is then ubiquitinated and degraded. The phosphorylation of FOXO1 by Akt subsequently decreases the hepatic glucose production through a decrease in transcription of glucose 6-phosphatase.
It seems like the phosphorylation from Akt leads to destruction, but maybe the assumption is that that phosphorylation step (excluding every other step of ubiquitin-proteosome pathway) is reversible, where proteolysis is final.
@niboonsh video is good but doesn't split this one.