Why would one drug work when another very closely related drug had no effect? For example, why would nortriptyline be effective in treating one of its indications when amitriptyline wasn't? The only difference between the two is a missing carbon at the end of the nitrogen.
It's not like enantiomers where one might be more active because of its completely reversed structure.
The missing carbon makes the molecule bind to its receptor more/less
???
Hudson Morgan
but in this case, the nortriptyline is the active metabolite of the amitriptyline. why would a purer form of the active metabolite have an effect when the prodrug did not?
Jason Jackson
bump
Easton Kelly
Because it binds to receptors differently, so with nor you only get nor effects byt with ami you get ami + nor effects.
It literally says this on wikipedia.
Levi Ortiz
doesn't make any sense.
James Allen
>specific receptor doesn't bind to everything equally Gee I wonder why it doesn't make sense
Chase Robinson
Because nortryptyline is a metabolite of amitriptyline, you first have amitriptyline acting on the brain, then as its metabolized you have nortryptyline created, so now you have decreasing levels of amitriptyline and increasing nortryptaline, but you have both because metabolism isnt instant.
When you only take nortryptyline you dont get the effects of amitriptyline.
Wikipedia states this AND has the binding affinities/action on transporters of both drugs, compared
Austin Jenkins
That doesn't answer my question on why the metabolite would be effective when the prodrug that metabolizes into the metabolite doesn't work.
I understand that they bind differently, but unless amitriptylene interferes deconstructively with nortriptylene then I don't understand why nortriptylene on it's own would work when amitriptylene doesn't.
Nathan Nguyen
Someone already explained this in the thread, different steric interactions with the receptor protein = different magnitude of effects, and sometimes even different effects altogether like in the case of functional selectivity.
Brody Bailey
still doesn't make any sense. at some point all of drug 1 will be metabolized into drug 2. drug 1 was not effective at any point, so pure drug 2 shouldn't be either.
Alexander Cruz
>fires eventually burn out and ash doesn't produce heat so therefore fires do not produce heat Dude what the fuck.
Nathan Rogers
comparison would be more apt if the first fire didn't produce heat at all for someone, but somehow i am expected to believe that the ash will.
Camden Reyes
Why are you asking this question? Is there a case report of this actually happening? Has this happened to you?
Ami is a prodrug of nor, and its metabolism into nor is mediated by highly polymorphic CYP enzymes like 2D6 and 2C19 i.e. if you are a poor 2D6 metaboliser it might take longer to get therapeutic drug concentrations. Nor by itself might have a different therapeutic effect by that reason alone.
I could come up with a convoluted pharmacodynamic explanation because of the differing effects on serotonin and norepinephrine transporters between the two drugs, but who the fuck knows? Some people have weird physiology for whatever reason.
Gavin Hughes
QSAR and ADME considerations
Chase Johnson
>Why are you asking this question? I don't know why it matters, but because I have taken amitriptylene for tension headache purposes before at different dosages without effect. I was taking cyclobenzaprine for them at one point, but I do not see that doctor anymore. I recently started taking modafinil for another issue, and it increases muscle tension which obviously makes the headaches worse. I went to see a different doctor that lied to me about how her "literature did not indicate muscle relaxers for the maintenance of tension headaches at all," and put me on nortriptylene despite my objections to it. If I was put on modafinil, why the fuck would I want to take something that is notorious for causing lethargy?
Luke Collins
Bbecause they are different drugs with different effects on the brain. How is this difficult
One produces the other. What are you not understanding?
Parker Baker
Muscle relaxants have not shown any benefit in clinical trials in the treatment of tension-type headaches, which is why they are not generally used for that purpose. But that's beside the point.
I can't find much record of nortriptyline causing sedation/lethargy, and it's not listed in the drug references I'm looking at. I would think it's uncommon if anything, since nor tends to be more stimulating than ami.
>Muscle relaxants have not shown any benefit in clinical trials in the treatment of tension-type headaches Doesn't match my experience of relief with a muscle relaxant, but here's a real source: ncbi.nlm.nih.gov/books/NBK10693/ >Common musculoskeletal conditions causing tenderness and muscle spasms include fibromyalgia, tension headaches > Skeletal muscle relaxants are one of several classes of medications (including antidepressants, neuroleptics, anti-inflammatory agents, and opioids) frequently used to treat these conditions mayoclinic.org/diseases-conditions/tension-headache/diagnosis-treatment/treatment/txc-20211544
So clearly there is disagreement about how this should be treated.
Andrew Morales
Fair enough, but again, nor is more stimulating than ami so it's at least worth a try. Worst case it doesn't work, and you get to try something else.
I mean if they worked for you, then they worked for you. If your doctor's not as flexible, I don't know what to say.
Isaiah Barnes
>If your doctor's not as flexible, I don't know what to say. I am asking for an answer to the question in the OP so I know whether or not to even pick up the nortriptylene prescription, or if I should just go find another doctor.
Logan Davis
Then you have your answer: nor and ami have different pharmacological properties. The fact that one is a prodrug of the other has little bearing on that.
Owen Parker
an extra carbon can have massive effects on both binding and absorption. All these effects are extremely subtle, and differ person to person in ways we still can't begin to understand.
Oliver Turner
They have different mechanisms of action.
Do you think drugs are metabolized instantly?
Samuel Reed
Yes, you've said that, and it still doesn't make any sense. There should have been some response the differing dosages of amitriptylene, but there were not. It's like saying that if adrafinil was completely ineffective, you shouldn't expect the same or similar results from its active metabolites.
Juan Adams
>There should have been some response the differing dosages of amitriptylene, but there were not
Maybe, maybe not. Just because amitriptyline-derived nortriptyline was in your system doesn't mean you're getting the same effects you would have from pure nortriptyline. Say you take codeine for pain and it isn't effective. That doesn't mean you should rule out oral morphine as another option.