Interaction potential of Escitalopram/Lexapro??

[Abject]

I may be wrong but I think CFC was referring to the fact that doubling a dose of any drug won't create a linear doubling of effects.
Especially with multiple affinities: if dose x binds to [receptor a] at 80%, and dose y binds to [receptor a] at 100% and [receptor b] at 20%, dose z will produce no further increase in [receptor a] activitiy, but [receptor b] activity will be much higher.
Also, some things cap out far before 100% saturation, in that 80% will no be stronger than 50%.
This misunderstanding creates a lot of confusion in the average person imo.

 

[JohnBoy2000]

At 75 mg Venlafaxine in combination with Mianserin and Atomoxetine - there seemed to be, an increase in the presser effect.

My question would be - would this be due to additional noradrenergic activity of Venlafaxine - which is supposedly non-existent, or very modest at a dose of 75 mg.

Or due to amplification of noradrenergic post synaptic cascade - given and NA and SER share common immediate post synaptic effectors?

AS per Stephen Stahl - 50% NA occupancy yields NA correlated effects and outcomes - when used via SNRI's.
But NRI's in monotherapy - require 85-90% receptor occupancy for similar effects.

So, you see my inference.

Can anyone shed light on that?



Edit: I'm just reading in one paper now that, in contrast to Escitalopram's 100% AUC increase in desipramine concentrations - Citalopram results in 40% AUC increase.

Can that be right?

 

[clubcard]

I was scripted tramadol and with my epilepsy, I kept falling off my crutches. Has anyone got data on tapentadol analogues? I think the piperidine & (thio)morpholine might work. IF the piperidine works, adding a 4-aryl to it is VERY likely to yield what is more or less a perfect overlay of phenoperidine. You can even add the -OH which will be achiral. Maybe a methoxy? Maybe a 2,2-dimethyl on the piperidine ring? Just remember than phenol (or carboxamide or other bioisostere) lends antagonism. You will have to look VERY hard to find an antagonist that doesn't have said feature. The 2-Cl of Viminol is a bioisostere, BTW. 1) (3,4R)Picenidol, 2) (S)ethoheptazine and 3) alvimopan shows that alkyl chain-length mediates 1)agonism 2)partial agonism 3)antagonism. AFAIK this QSAR isn't taught anywhere in the world - so all of you BLs can think 'I have rare and precious knowledge'. I just let CHARMM do the work. I'm an idiot. If I can do this, a smart person can do amazing things.

 

[JohnBoy2000]

I was scripted tramadol and with my epilepsy, I kept falling off my crutches. Has anyone got data on tapentadol analogues? I think the piperidine & (thio)morpholine might work. IF the piperidine works, adding a 4-aryl to it is VERY likely to yield what is more or less a perfect overlay of phenoperidine. You can even add the -OH which will be achiral. Maybe a methoxy? Maybe a 2,2-dimethyl on the piperidine ring? Just remember than phenol (or carboxamide or other bioisostere) lends antagonism. You will have to look VERY hard to find an antagonist that doesn't have said feature. The 2-Cl of Viminol is a bioisostere, BTW. 1) (3,4R)Picenidol, 2) (S)ethoheptazine and 3) alvimopan shows that alkyl chain-length mediates 1)agonism 2)partial agonism 3)antagonism. AFAIK this QSAR isn't taught anywhere in the world - so all of you BLs can think 'I have rare and precious knowledge'. I just let CHARMM do the work. I'm an idiot. If I can do this, a smart person can do amazing things.

 

[JohnBoy2000]

Citalopram - according to the FDA website - produced 2x AUC increase for Metoprolol

Also produces 50% AUC increase for Desipramine.

Both via CYP2D6 inhibition.

Desipramine is more sensitive to CYP2D6 than Metoprolol.

Makes little sense to me....​

 

[JohnBoy2000]

To those who have ever taken Lexapro or Citalopram - can you comment on - did you find it fatigue inducing, did it make you tired?

When did you take it - morning or night?

Did it also interfere with your sleep?

 

[Abject]

Why on Earth are you overthinking this so much?
The healthcare professional will think about what they're prescribing you. This sort of this is trial and error.

 

[CFC]

Okay - that's the part I'm having difficulty understanding.

With drugs that have narrow therapeutic index - twice the bioavailability; first off, twice bioavailability - without the inhibitor combination drug causing the AUC increase, would that be the equivalent of taking twice the dose of the drug in question?

In other words - twice the bioavailability/exposure - but without twice the effects; how is that?​

Lots of reasons, some of which Abject mentioned in his post, and also because AUC isn't a measure of concentration. A drug can have sub-threshold/poor effects but attain a very good AUC if it's concentration in any particular relevant system is prolonged but never particularly high.

 

[CFC]

To those who have ever taken Lexapro or Citalopram - can you comment on - did you find it fatigue inducing, did it make you tired?

When did you take it - morning or night?

Did it also interfere with your sleep?

I disliked both and didn't find either much different. I felt lethargic and suffered insomnia and somewhat like a zombie. I've felt like that on most SSRIs though.

 

[JohnBoy2000]

Lots of reasons, some of which Abject mentioned in his post, and also because AUC isn't a measure of concentration. A drug can have sub-threshold/poor effects but attain a very good AUC if it's concentration in any particular relevant system is prolonged but never particularly high.

So - basically gonna repeat what you've outlined here but - in other words, one should take into account the Cmax as being at least, if not more important than the AUC - in perspective of the therapeutic effect of the drug?

 

[JohnBoy2000]

Why on Earth are you overthinking this so much?
The healthcare professional will think about what they're prescribing you. This sort of this is trial and error.

Actually - my experience with psychiatry is that they tell me it's trial and error, and basically don't seem aware of, or basically neglect the scientific particulars of drugs they're prescribing.

My local services ditched me a while ago; basically the treatment I required didn't fit their typical protocol so, they said basically, "look elsewhere".

Since then - I deduce my own treatment, and then set about the long arduous task of trying to find a doctor willing to accommodate me.

 

[CFC]

So - basically gonna repeat what you've outlined here but - in other words, one should take into account the Cmax as being at least, if not more important than the AUC - in perspective of the therapeutic effect of the drug?

Yes, it's very important for some drugs, but there isn't one binary yes/no answer here, and so many factors that can complicate things. Which is why researchers study the in vivo effects of drugs or drug combinations. Biological systems are (at present) too complex and unexpected (think how many different receptors we keep discovering, for example) for us to programme a theoretical analysis like that with any hope of accuracy.

 

[JohnBoy2000]

Just interpreting the Cmax and AUC increases:

Those values presumably corresponding to this table:

Am I missing something here?

The Cmax for escitalopram is 89% vs sertralines 39% - but the graphs don't seem to reflect that.

Also - the ultimate AUC doesn't really seem different for either...?

 

[JohnBoy2000]

From the same paper:

Again - Duloxetine is meant to give rise to elevated Metoprolol levels - but the graph doesn't suggest this?

 

[Coolwhip]

Yes it does, and that the effect is stronger at 2.5 weeks than at week 1...and for your earlier post, the chart's appear to be comparing levels between day 7 and day 17.

 

[JohnBoy2000]

Yes it does, and that the effect is stronger at 2.5 weeks than at week 1...and for your earlier post, the chart's appear to be comparing levels between day 7 and day 17.

Obviously - somehow I must be reading this backwards.

Which is quite possibly attributable to my brain being totally fried out on a highly unorthodox combination of medications - which I am attempting to make sense of via this thread.

So in light of that - the duloxetine graph delineating associated metoprolol levels - appears to me to have distinctly lower plasma concentration of Metoprolol, than the sertraline graph.
For the 17 day - not so much.

But for the 7 day - it looks distinctly lower.

This - to me - suggests lower inhibition of metoprolol metabolism by duloxetine than sertraline, for the 7 day period.

Where's in actual fact - duloxetine presents with significantly higher degree of CYP2d6 inhibition than sertraline...?

So - conflicting data?

Can anyone invalidate my brain fog with a more insightful explanation?

 

[Coolwhip]

Oh, I read that wrong as well. it is saying day -7, as in 7 days before co administration. Honestly, I would need to read the text to really see what is going on here, but regardless the cmax and AUC are much higher in the Sertraline group at day -7. But at day 17 both the cmax and AUC are largely in line with each other. Which doesn't make any sense intuitively(the levels before coadministration), but I suspect there is a lot more going on that only the text could elucidate. Although the fact that the levels increased much more for duloxetine than sertraline agrees with its higher level of inhibition.

 

[JohnBoy2000]

http://sci-hub.tw/https://journals....rison_of_Duloxetine,_Escitalopram,_and.5.aspx

That's the full text article but, yes - that makes sense now, as I didn't pick up on the -7 part.
That obviously being metoprolol levels pre introduction of sertraline, escitalopram etc.

60 mg/d for duloxetine, 20 mg/d forescitalopram, and 100 mg/d for sertraline

Are the doses - which would suggest sertraline may have greater inhibition at higher doses.

What further slightly confuses me is - the increase in Cmax for sertraline vs escitalpram is, 38% vs 88% but, again - the graphs seem to show only the most slight disparity within the actual graphs themselves.

The paper itself however does note that - differences of inhibition between sertraline and Lexapro, aren't "statistically significant".

A 50% difference in Cmax - I would have assumed would certainly yield a significant enough difference in therapeutic effect but - then I know less than squat about pharmacokinetics.

 

[JohnBoy2000]

I disliked both and didn't find either much different. I felt lethargic and suffered insomnia and somewhat like a zombie. I've felt like that on most SSRIs though.

When you say most SSRI's - do you include sertraline in that discussion?
As in - lethargic etc?

I'm getting the "zombie" feeling - and am weighing my options.

 

[JohnBoy2000]

The other thing I'd be curious about relative to the graphs - and this would be particularly important relative to dosing times:

Can drugs dosed say, 12 hours apart - exert lower incidence of enzymatic inhibition, than if they were dosed at the same time?

What I found with reboxetine and mianserin/mirtazapine - which interacted in terms of plasma protein binding displacement was that - times made no difference.
Together or 12 hours apart - the interaction was consistent.

Curious as to whether that may be the case for CYP enzymes also??