Remember what your drug is competing with...

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aim-agm

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(If I made a mistake with the below, please let me know. I'm noticing this sort of miscalculation in all sorts of places.)

I was reading Stahl's paper on trazodone, and he theorizes a great deal based on trazodone's predicted receptor occupancy. For example, that 5-HT2a antagonism cannot solely explain trazodone's hypnotic effect, because it is 50% occupied with 1 mg but hypnotic dose is 25+ mg. That surprised me, so I did some digging.
Some background and other numbers:
- Kd of trazodone for 5HT2a receptor is ~35 nM
- 1 mg of trazodone PO achieves 37 nM serum Cmax, and dose:concentration is linear (i.e. 25 mg = 925 nM)
- Also, reported serum level for antidepressant effect is 1.75 uM

At Cmax, the occupancy of 5-HT2A by trazodone by itself is:
1 mg: ~50%
25 mg: ~96%
1.75 uM: ~98%
600 mg: ~99.8%

That all checks out until you factor in that trazodone is competing with serotonin, which has a Kd of ~1 nM for 5-HT2a and a CSF concentration of at least tens of nM, and an intrasynaptic concentration when released in the mM range.

When you factor in that it is competing with basal serotonin (let's say 50 nM to be conservative), the occupancy is instead:
1 mg: ~2%
25 mg: ~31%
1.75 uM: ~50%
600 mg: ~91%

When competing with serotonin released into the synapse the occupancy at all doses is negligible.


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Haha uhhh that’s a lot of stuff to totally ignore that….

Trazodone is an H1 antagonist. Mayhaps that’s why it’s sedating?

I mean he even basically says in the paper that’s why you don’t get the hypnotic effects until those doses.
 
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Haha uhhh that’s a lot of stuff to totally ignore that….

Trazodone is an H1 antagonist. Mayhaps that’s why it’s sedating?

I mean he even basically says in the paper that’s why you don’t get the hypnotic effects until those doses.

Well, trazodone has a Kd for H1 of ~200-300 nM. Histamine's Kd is ~5-10 nM or so. Not saying that's not how it works, but it's not so simple to come to a conclusion.

More to the point, does trazodone do anything significant in patients on mirtazapine/doxepin/hydroxyzine/olanzapine/etc.? Because in those patients H1 receptors are already antagonized with ~100-1000x as much affinity as trazodone.
 
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Well, trazodone has a Kd for H1 of ~200-300 nM. Histamine's Kd is ~5-10 nM or so. Not saying that's not how it works, but it's not so simple to come to a conclusion.

More to the point, does trazodone do anything significant in patients on mirtazapine/doxepin/hydroxyzine/olanzapine/etc.? Because in those patients H1 receptors are already antagonized with ~100-1000x as much affinity as trazodone.

All these Kd's may or may not mean anything in real life. There are a lot more parameters to evaluate anyway besides the dissociation constant and you can't discount the fact that even if the dissociation constants are markedly different that doesn't mean Histamine is knocking Trazodone off the receptor 100% of the time.

I mean I don't put people on Remeron, Doxepin or Hydroxyzine and Trazodone at the same time because yes, you're already using another drug that's utilizing a similar mechanism of action for sedation and has a theoretically higher affinity so whats the point.

You can use Zyprexa and Trazodone for completely different reasons.
 
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I mean I don't put people on Remeron, Doxepin or Hydroxyzine and Trazodone at the same time because yes, you're already using another drug that's utilizing a similar mechanism of action for sedation and has a theoretically higher affinity so whats the point.

I had one guy at my last CMHC job who was on doxepin and trazodone together. Primary psychosis (+/- alcohol) on an injectable. He was convinced this was what he needed to fall asleep and staying asleep and was extremely hostile a lot of the time. I felt goofy continuing it but it was not the hill I wanted to die on if it meant he would keep coming back for his Sustenna.
 
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