I had a pharmacist as my professor for psychopharm, and I wish he had presented his teaching in this manner. I work in a large hospital system on a psych consult team where I am consulted by medical teams. I use psychopharmacology for multiple reasons, other than psychosis--- such as sedation and agitation, especially in cases of delirium, where narcotics and anticholinergics are contraindicated. Thank you!
As a psychiatric NP, this is going to be soooo helpful when prescribing. The fountain analogy is amazing and way better than what we encounter in textbooks. Thank you!
Wow! I'm a psychiatrist in Viet Nam and i've never heard an explanation like this video. It blows my mine! Hopefully you keep do more videos like that. We really need it
I like this video but I think it is also important to include a footnote about how differences in individual metabolism or receptor density can affect response to a given dose, i.e. not all dose ranges will have the same effect in all individuals.
So incredibly helpful. Thank you! I also feel like this is a more clear explanation than other prominent teachers of psychopharm principles typically offer.
With drug combination say between diphenhydramine and quetiapine would it be which compound is used first and would the histamine receptors being saturated cause the diphenhydramine to go straight to the next receptor site? Would this be the danger of mixing substances like antipsychotics and antihistamines with the increased activity at acetylcholine receptor sites? Or is it more complicated when it comes to drug combinations? Would they both fight for a place?
This is an excellent question. A universal answer couldn't be given for different drug combinations, because it would depend on whether the drugs were full/partial agonists or antagonists (ie a high affinity antagonist would negate the effects of an agonist fe narcan would negate an opioid). It also would depend on whether the drugs were competitive or non-competitive. So now thinking of the example you provide specifically, I don't know the answer. I would think some sort of equilibrium is reached between seroquel/bendryl binding, but don't know the specifics (see derangedphysiology.com/main/cicm-primary-exam/required-reading/pharmacodynamics/Chapter%20121/affinity-association-constant-and-dissociation-constant).
@@PsychoFarm @suitswonderland I have a follow up question here. in this video, what isn't clear to me is if each drug profile (with its dozens of receptor binding actions/affinities that are sequential), might have a mix of agonists, and antagonists? or is it just the principle to know, that is, that it occurs in a sequence whereby the highest affinity wins first no matter if acting as an agonist, antagonist, partial agonist, etc at that receptor? in this example, of course the H1 is an antagonist, we know this as we know the antihistaminic effects of Seroquel at low doses. we also know the d2 is antagonism as we use Seroquel to lower dopamine in various dopamine pathways. but, when I saw so many different 5HT receptors, as I know these are sometimes antagonists and sometimes agonists. maybe it isn't important to know this or spend time on this, but just wondering if this concept of sequential binding is particular to antagonism?
@@PsychoFarm okay, I'm going to study the PD and PK sections of this guy's work. looks really helpful, especially the section in PD on "receptor theory of drug action."
Spoke with someone with decades of experience prescribing venlafaxine, and he said that no matter what the books say, you get a lot if spillover even at very low doses.
Venlafaxine is one of my least favorite drugs to prescribe. Although it is effective-- patients get side effects even have a few hours of being off timing in their daily dose, and it has to be tapered slowly if they want off of it. Patients are miserable. It doesn't foster trust in psychiatry or medication compliance among patients.
Venlafaxine was horrible for me. I have bipolar (at the time my psychiatrist didn't listen to me when I described mania in response to SSRIs) and I had severe anorexia where I could only have a few bites of food a day before feeling sick and my depression worsened to a point I was a danger to myself. I had to phone my psychiatrist after a few weeks to stop it. I'm a small person so losing any weight is really bad for me, let alone losing 4kg in one month.
This is excellent it's criminal you don't have millions of views you've made a whole bunch of experiences I've had on seroquel make sense for the first time, I can't thank you enough.
At what dosage does Cymbalta hit the NET receptors? Curious as someone that tried 30mg at two different points of my life and just, couldn't. I think I've also noticed norepinephrine receptor meds just NOT work for me; from what I know, Wellbutrin (Buproprion) is an NDRI : and I reacted very similarly, if not worse on Cymbalta. Meds are meds and drugs are drugs, with my individual chemical makeup and reactions who knows of course but also curious on any kind of input from anyone
I have this question as well, or something similar. we know that another SNRI, venlafaxine, has different actions at different dosages. for example, venlafaxine behaves differently at 225 mg versus 75 mg, having more NE action in the former. I would like to know @PsychoFarm if the concept of the sequential binding/fountain would apply here as well, basically it applies to every drug really. that is, unless a drug was highly specific for a specific receptor only (which most molecules do not, they are "promiscuous" as they say, just like neurotransmitters are with similar chemical structures), then the concept of the sequential binding/fountain most likely applies. this, then, begs my next question. are receptor binding profile affinities available for all drugs? or only the ones who have had binding affinity assays done in vivo? I'd like to learn about the signature binding affinities on a handful of meds. thank you so much, your channel is my favorite.
You mention that its not possible to predict the efficacy of higher doses by the effectiveness of lower doses. What about the other way around? If I'm using it for depression, does that mean I'll be also sedated? I guess yes, since the H1 receptors are already fully occupied. Does that make sense? Should we expect that this drug will also work as sedatives for patients with depression and psychosis?
This series is exactly what I was looking for. I plan to be in a Psych NP program; n the fall. I know enough to understand that drugs hot multiple receptors. I need to start to unravel the differences in receptor profiles. As a floor nurse, my work life is full of case studies to observe. THANKS! Will definitely recommend.
Interesting...I was wondering how people tolerate such high doses where I struggled at 25mg and 50mg. I'm wondering if individual differences in people can affect the therapeutic dose. My psychiatrist thought it wasn't doing anything other than helping with sleep so he weaned me off it a few months ago and my anxiety returned as bad as it was prior to starting Quetiapine in 2021, my short seasonal depression I get every year lasted 5 months until I started Quetiapine again (just went up to 50mg) and during this depression, a stressful event which triggered my PTSD resulted in a severe psychotic episode that almost had me hospitalised and my entire social support network gone either by me shutting them out or them backing off to recover from me themselves. I've been back on seoquel for about a week, thinking I'd have to wait to see any mood improvements but I've been able to leave my apartment without panic attacks again and my depression has started easing up, even though I have no friends after this psychotic episode. I don't know how else to explain it other than Quetiapine is helping.
Binding affinities are based on a fundamentally statistical/thermodynamic principle, so "one molecule of quetiapine" could definitely bind to a D2r, it just almost certainly wouldn't. The pharmacological/therapeutic/clinical conclusion is the same, and it's exactly as true as you say that different doses of an agent don't just scale up all the same effects.
"Sequential Binding" is a useful oversimplification for thinking about receptor targets at specific doses, but in it's literal / strong form "Sequential Binding" can't be true, otherwise if you would add a drug with higher affinity for D2 - say 15mg of Olanzapine to your 800mg Quetiapine, Quetiapine would then move on and occupy the next receptor in line (which it has lower affinity for) hence you could knock Quetiapine down to receptors which it has lower affinity for. It would also imply that any ligand no matter how low it's affinity would bind to all receptors of a specific type that it has the highest affinity for, even at low concentrations. If you want to know the receptor occupation you can just look at "receptor occupation - concentration curves", but I agree that with many drugs the affinity for different receptors varies to such a large degree that the fountain analogy is useful.
does affinity imply a certain occupancy rate? is receptor occupancy tied to potency? is receptor affinity linked to the transiency or permanency at the receptor? (which I think is related to occupancy)? @PsychoFarm
Hey, wait.... It's not that the drug is magically attracted to a given receptor,.... it's that it tends to stick there longer, right? The drug can't 'know' where the receptors are, and go there... it's all just stochastic stickiness. I'm almost sure someone has already brought this up, though, since it's so obvious. It's still an acceptable heuristic, of course.
do you have any good sources for understanding the "stickiness"? it isn't just about the initial affinity of a molecule for a receptor, but how long it occupies, right?
The principle is sound, but the numbers and the emphasis that it's a "different drug on different doses" doesn't seem the most accurate. It's true it's being used as a sleeping pill on low doses by many doctors, but such use is not recommended because quetiapine will still retain some of its anti-psychotic properties that you claim only happens at 300 mg. "It is assumed that central histamine H1 receptor blockade, and to a lesser extent alpha-1-antiadrenergic and antimuscarinergic properties, play an important part in the sedative effect of quetiapine. It is estimated that almost 100 % of the H1 receptors and over 50 % of serotonin 5HT2a and dopamine D2 receptors are blocked by use of 50 mg quetiapine. In other words, there is evidence that quetiapine exerts an effect on several receptor systems even in low doses." Quoted text: tidsskriftet.no/en/2019/09/kronikk/quetiapine-not-sleeping-pill
I skimmed the article you linked. maybe it isn't quite as linear as the sequential or fountain ideas lead you to believe. with 80% occupancy of d2 needed to obtain the antipsychotic effects typically needed, maybe the spectrum between 50 mg and 300 mg of Seroquel, for example, is not linear either. like, as doses approach 300 mg, occupancy on d2 spikes. I think perhaps @psychofarm edited the video. see at 7:59
I had a pharmacist as my professor for psychopharm, and I wish he had presented his teaching in this manner. I work in a large hospital system on a psych consult team where I am consulted by medical teams. I use psychopharmacology for multiple reasons, other than psychosis--- such as sedation and agitation, especially in cases of delirium, where narcotics and anticholinergics are contraindicated. Thank you!
As a psychiatric NP, this is going to be soooo helpful when prescribing. The fountain analogy is amazing and way better than what we encounter in textbooks. Thank you!
Wow! I'm a psychiatrist in Viet Nam and i've never heard an explanation like this video. It blows my mine! Hopefully you keep do more videos like that. We really need it
I agree. Please make more, they are so relevant.
Do you still practice in Vietnam??
@@LynaNguyen-rf5te yeah! I’m still in VN and follow this channel 😅
Wow an educated psychiatrist that doesn't know how to spell mind. It blows my mine? Lol
I like this video but I think it is also important to include a footnote about how differences in individual metabolism or receptor density can affect response to a given dose, i.e. not all dose ranges will have the same effect in all individuals.
I just want to say how much I love your content. And, as others have said - fabulous, quirky keyboard version of the intro - my favorite band.
Much appreciated!
such a good explanation, well done
So incredibly helpful. Thank you! I also feel like this is a more clear explanation than other prominent teachers of psychopharm principles typically offer.
With drug combination say between diphenhydramine and quetiapine would it be which compound is used first and would the histamine receptors being saturated cause the diphenhydramine to go straight to the next receptor site? Would this be the danger of mixing substances like antipsychotics and antihistamines with the increased activity at acetylcholine receptor sites? Or is it more complicated when it comes to drug combinations? Would they both fight for a place?
This is an excellent question. A universal answer couldn't be given for different drug combinations, because it would depend on whether the drugs were full/partial agonists or antagonists (ie a high affinity antagonist would negate the effects of an agonist fe narcan would negate an opioid). It also would depend on whether the drugs were competitive or non-competitive. So now thinking of the example you provide specifically, I don't know the answer. I would think some sort of equilibrium is reached between seroquel/bendryl binding, but don't know the specifics (see derangedphysiology.com/main/cicm-primary-exam/required-reading/pharmacodynamics/Chapter%20121/affinity-association-constant-and-dissociation-constant).
That is an excellent question. Huh
@@PsychoFarm @suitswonderland I have a follow up question here. in this video, what isn't clear to me is if each drug profile (with its dozens of receptor binding actions/affinities that are sequential), might have a mix of agonists, and antagonists? or is it just the principle to know, that is, that it occurs in a sequence whereby the highest affinity wins first no matter if acting as an agonist, antagonist, partial agonist, etc at that receptor? in this example, of course the H1 is an antagonist, we know this as we know the antihistaminic effects of Seroquel at low doses. we also know the d2 is antagonism as we use Seroquel to lower dopamine in various dopamine pathways. but, when I saw so many different 5HT receptors, as I know these are sometimes antagonists and sometimes agonists. maybe it isn't important to know this or spend time on this, but just wondering if this concept of sequential binding is particular to antagonism?
@@PsychoFarm okay, I'm going to study the PD and PK sections of this guy's work. looks really helpful, especially the section in PD on "receptor theory of drug action."
This is incredibly helpful, thank you very much
This was incredibly helpful. Thank you so much. Keep up the great work, brother!
Spoke with someone with decades of experience prescribing venlafaxine, and he said that no matter what the books say, you get a lot if spillover even at very low doses.
Venlafaxine is one of my least favorite drugs to prescribe. Although it is effective-- patients get side effects even have a few hours of being off timing in their daily dose, and it has to be tapered slowly if they want off of it. Patients are miserable. It doesn't foster trust in psychiatry or medication compliance among patients.
Venlafaxine was horrible for me. I have bipolar (at the time my psychiatrist didn't listen to me when I described mania in response to SSRIs) and I had severe anorexia where I could only have a few bites of food a day before feeling sick and my depression worsened to a point I was a danger to myself. I had to phone my psychiatrist after a few weeks to stop it. I'm a small person so losing any weight is really bad for me, let alone losing 4kg in one month.
This is excellent it's criminal you don't have millions of views you've made a whole bunch of experiences I've had on seroquel make sense for the first time, I can't thank you enough.
Glad it helpful ☺️
@@PsychoFarm -- This seems to be a very foundational concept. How is it that it doesn't seem to be a major part of psychiatric education?
Thanks
Much appreciated!!
You are a phenomenal teacher
Thank you!
Great video! I like the different section titles haha :)
At what dosage does Cymbalta hit the NET receptors? Curious as someone that tried 30mg at two different points of my life and just, couldn't. I think I've also noticed norepinephrine receptor meds just NOT work for me; from what I know, Wellbutrin (Buproprion) is an NDRI : and I reacted very similarly, if not worse on Cymbalta.
Meds are meds and drugs are drugs, with my individual chemical makeup and reactions who knows of course but also curious on any kind of input from anyone
I have this question as well, or something similar. we know that another SNRI, venlafaxine, has different actions at different dosages. for example, venlafaxine behaves differently at 225 mg versus 75 mg, having more NE action in the former. I would like to know @PsychoFarm if the concept of the sequential binding/fountain would apply here as well, basically it applies to every drug really. that is, unless a drug was highly specific for a specific receptor only (which most molecules do not, they are "promiscuous" as they say, just like neurotransmitters are with similar chemical structures), then the concept of the sequential binding/fountain most likely applies. this, then, begs my next question. are receptor binding profile affinities available for all drugs? or only the ones who have had binding affinity assays done in vivo? I'd like to learn about the signature binding affinities on a handful of meds. thank you so much, your channel is my favorite.
Wow what a great way to explain! Thank you!
excellent explanation of drug dosages. I like the receptors profile part. can you produce more about other drugs receptors profile? Thank you so much.
You mention that its not possible to predict the efficacy of higher doses by the effectiveness of lower doses. What about the other way around? If I'm using it for depression, does that mean I'll be also sedated? I guess yes, since the H1 receptors are already fully occupied. Does that make sense? Should we expect that this drug will also work as sedatives for patients with depression and psychosis?
wow this really helps me understand why it's important I stay on my meds being bipolar.
Outstanding explanation! what other drugs does this principal apply for? thanks!
Thanks! Antipsychotics, SNRIs, newer antidepressants, anti-histamines/muscarinics (sometimes)
This series is exactly what I was looking for. I plan to be in a Psych NP program; n the fall. I know enough to understand that drugs hot multiple receptors. I need to start to unravel the differences in receptor profiles. As a floor nurse, my work life is full of case studies to observe. THANKS! Will definitely recommend.
Good luck on the path!
Thank you for the explanation.
You are welcome!
Great video!
What's a good reference to find these sequential binding pattern charts?
Helpful, simple but effective! Thanks
What receptor would be for heavy OCD, ruminating and intrusive thoughts?
Interesting...I was wondering how people tolerate such high doses where I struggled at 25mg and 50mg. I'm wondering if individual differences in people can affect the therapeutic dose. My psychiatrist thought it wasn't doing anything other than helping with sleep so he weaned me off it a few months ago and my anxiety returned as bad as it was prior to starting Quetiapine in 2021, my short seasonal depression I get every year lasted 5 months until I started Quetiapine again (just went up to 50mg) and during this depression, a stressful event which triggered my PTSD resulted in a severe psychotic episode that almost had me hospitalised and my entire social support network gone either by me shutting them out or them backing off to recover from me themselves.
I've been back on seoquel for about a week, thinking I'd have to wait to see any mood improvements but I've been able to leave my apartment without panic attacks again and my depression has started easing up, even though I have no friends after this psychotic episode. I don't know how else to explain it other than Quetiapine is helping.
I really love you channel and all the informative videos, the only thing that bugs me is that I couldn't find any info about you..
thanks anyways!
Binding affinities are based on a fundamentally statistical/thermodynamic principle, so "one molecule of quetiapine" could definitely bind to a D2r, it just almost certainly wouldn't. The pharmacological/therapeutic/clinical conclusion is the same, and it's exactly as true as you say that different doses of an agent don't just scale up all the same effects.
Could you cover more in-depth on RIMA Moclobomide please.
Thank you so much!
A cool explenation thank you!
You’re welcome!
"Sequential Binding" is a useful oversimplification for thinking about receptor targets at specific doses, but in it's literal / strong form "Sequential Binding" can't be true, otherwise if you would add a drug with higher affinity for D2 - say 15mg of Olanzapine to your 800mg Quetiapine, Quetiapine would then move on and occupy the next receptor in line (which it has lower affinity for) hence you could knock Quetiapine down to receptors which it has lower affinity for. It would also imply that any ligand no matter how low it's affinity would bind to all receptors of a specific type that it has the highest affinity for, even at low concentrations. If you want to know the receptor occupation you can just look at "receptor occupation - concentration curves", but I agree that with many drugs the affinity for different receptors varies to such a large degree that the fountain analogy is useful.
does affinity imply a certain occupancy rate? is receptor occupancy tied to potency? is receptor affinity linked to the transiency or permanency at the receptor? (which I think is related to occupancy)? @PsychoFarm
Where is My Mind intro, great
agree!
Hey, wait.... It's not that the drug is magically attracted to a given receptor,.... it's that it tends to stick there longer, right? The drug can't 'know' where the receptors are, and go there... it's all just stochastic stickiness. I'm almost sure someone has already brought this up, though, since it's so obvious. It's still an acceptable heuristic, of course.
do you have any good sources for understanding the "stickiness"? it isn't just about the initial affinity of a molecule for a receptor, but how long it occupies, right?
too bad the earlier receptors cant be pre-saturated with an inert.
…😊
Video on dmt
crazy…😅😮good information🧘додлвэшшхиахаха😊willuse
Do you think Blake Shelton understands sequential binding?
The principle is sound, but the numbers and the emphasis that it's a "different drug on different doses" doesn't seem the most accurate. It's true it's being used as a sleeping pill on low doses by many doctors, but such use is not recommended because quetiapine will still retain some of its anti-psychotic properties that you claim only happens at 300 mg.
"It is assumed that central histamine H1 receptor blockade, and to a lesser extent alpha-1-antiadrenergic and antimuscarinergic properties, play an important part in the sedative effect of quetiapine. It is estimated that almost 100 % of the H1 receptors and over 50 % of serotonin 5HT2a and dopamine D2 receptors are blocked by use of 50 mg quetiapine. In other words, there is evidence that quetiapine exerts an effect on several receptor systems even in low doses."
Quoted text: tidsskriftet.no/en/2019/09/kronikk/quetiapine-not-sleeping-pill
I skimmed the article you linked. maybe it isn't quite as linear as the sequential or fountain ideas lead you to believe. with 80% occupancy of d2 needed to obtain the antipsychotic effects typically needed, maybe the spectrum between 50 mg and 300 mg of Seroquel, for example, is not linear either. like, as doses approach 300 mg, occupancy on d2 spikes. I think perhaps @psychofarm edited the video. see at 7:59