Receptor activity across drugs

[Psychferlyfe3000]

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Hi all,

I was trying to figure out today at what dose quetiapine and hydroxyzine have equivalent antihistaminergic activity and I could not find a good answer to this question. More broadly, however, I began wondering: is there a reliable way to calculate CNS receptor activity comparisons between drugs in general? The answer seems to be no for most comparisons and equivalent receptor activity is usually just estimated by clinical response. Is this correct?

 

[romanticscience]

This site is good:

Quetiapine: Uses, Interactions, Mechanism of Action | DrugBank Online

Quetiapine is an atypical antipsychotic agent used for the management of bipolar disorder, schizophrenia, and major depressive disorder.

go.drugbank.com

Have fun!

 

[wolfvgang22]

Hi all,

I was trying to figure out today at what dose quetiapine and hydroxyzine have equivalent antihistaminergic activity and I could not find a good answer to this question. More broadly, however, I began wondering: is there a reliable way to calculate CNS receptor activity comparisons between drugs in general? The answer seems to be no for most comparisons and equivalent receptor activity is usually just estimated by clinical response. Is this correct?

Generally, yes that's correct. Keep in mind different patients are going to metabolize drugs at different rates based on their health, genetics, and the polypharmacy primary care and other specialists already has them taking.

 

[aim-agm]

Hi all,

I was trying to figure out today at what dose quetiapine and hydroxyzine have equivalent antihistaminergic activity and I could not find a good answer to this question. More broadly, however, I began wondering: is there a reliable way to calculate CNS receptor activity comparisons between drugs in general? The answer seems to be no for most comparisons and equivalent receptor activity is usually just estimated by clinical response. Is this correct?

I happened to look this up specifically because I was trying to titrate a patient off an antihistaminergic dose of quetiapine, and the molar masses, oral bioavialabilitys, half-lives, protein binding, Ki for H1 and a bunch of other chemical properties are very similar and based on those you could substitute quetipaine and hydroxyzine on an approximately 1mg:1mg basis..,.in theory. In reality there's a lot more to it, and actually in theory there's a lot more to it too.

My fairly amateur take:

Pharmicokinetic information is relatively easy to find but as @wolfvgang22 points out are highly individually and situationally variable.

Pharmicodynamics are much more complicated.
Affinity (Ki/Kd) is a big part and there are good resources (Ki database is great https://pdsp.unc.edu/databases/pdsp.php) but remember only values against human receptors is useful for our purposes, and Ki values can vary by up to a factor of 10 between labs, and vary quite a bit between people.
PET studies are pretty good for directly measuring receptor occupancy, but there aren't tons of them. But receptor occupancy and affinity are only part of the story, e.g. buprenorphine and morphine have about the same affinity for mu-OR but very difficult effects because they have different intrinsic activities.

Intrinsic activity I haven't found a good resource for, although I'm not sure where to look. You can find some indirect measures, such as TYR30 for NRIs, platelet function measures for SRIs. Not sure what you would use for H1antagonism.

Also remember that you aren dealing with metabolites as well in many cases, although with quetiapine it's not as complicated because norquetiapine's highest affinity is for H1 too.

tl;dr-To my (limited) knowledge, no.

 

[birchswing]

I am not a medical professional, not a healthcare provider, nor a medical student. And not seeking medical advice in writing this.

A long time ago, I read the now famous "Last Psychiatrist" article on quetiapine. I came away from it thinking that low dosage of quetiapine were exclusively antihistamine in their effect.

But then I started noting in online forums how people mentioned low dose quetiapine had helped immensely with OCD/intrusive thoughts. And it made me curious. Why would an anthistamine at such low doses (25-50 mg) work in this way? On drugs.com you can search for reviews of drugs by use, and under OCD it was rated highly by many for that purpose.

At the same time I came across an article stating that low dose quetiapine (around the same dosages) could *induce* mania, which is quite paradoxical, given that higher dosages are used to treat mania.

This raised my curiosity even more about its 5HT2A properties. I searched and searched and asked psychiatrists: At what dosage does quetiapine become a 5HT2A antagonist? The people I asked thought it was at much higher dosages.

I finally came upon the answer here:

Quetiapine is not a sleeping pill

16.09.2019: Perspectives - Use of the antipsychotic drug quetiapine to treat sleep disorders has become widespread, also in Norway.

tidsskriftet.no

"
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 (12). In other words, there is evidence that quetiapine exerts an effect on several receptor systems even in low doses.
"

The source they use (which I don't have access to is a pharmacology book by Stahl.

I was shocked that such a low dose, which for years I had been told both in articles I had read and doctors I consulted, was only an antihistamine had such potency at the 5HT2A receptor.

It's unfortunately a nasty drug for me. I only realized its mental benefit after discontinuing it. But the side effects (particularly inducing SVT) were too terrible. And I've been searching for something that could similarly target 5HT2A. And I, as a patient, have come across the same difficulty in doing such research. I went through Wikipedia's entire listing of 5HT2A antagonists.

Anyhow, I guess the answer to the question from my experience is that you have to extensively research each particular drug.

Also, I would have never even gone down the rabbit hole of trying to discover its other properties had I not read from so many other people who found benefit at low dosages for OCD, which speaks to what others have said about individual experiences. Their experiences with benefit for OCD at low dosages seems to counter the prevailing common wisdom that it's merely an antihistamine at low dosages. Is Stahl right? I don't know. I don't agree with him on a lot. But what is quoted there seems to jibe with experiences I have read.

 

[aim-agm]

"
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 (12). In other words, there is evidence that quetiapine exerts an effect on several receptor systems even in low doses.
"

The source they use (which I don't have access to is a pharmacology book by Stahl.

I was shocked that such a low dose, which for years I had been told both in articles I had read and doctors I consulted, was only an antihistamine had such potency at the 5HT2A receptor.

You were right to be shocked. The quote is wrong. I don't have Essential Pharmacology either, but perhaps they misunderstood him or his estimate is simply just an estimate...or he is showing his industry bias. Even theoretically 50% occupancy of both receptors at a given dose doesn't make sense, as quetiapine and norquetiapine have ~4x as much affinity for 5-HT2A as D2. There is another variable of significant interindividual variability, for example Patient 3 in bottom graph had 19% 5HT2A occupancy at 17.2 ng/ml and Patient 10 had 49% occupancy at 12.7 ng/ml

D2 and 5HT2A receptor occupancy of different doses of quetiapine in schizophrenia: a PET study

Objective: Quetiapine is a novel antipsychotic agent with many atypical features, including low D2 and higher 5HT2A affinity in vitro, low propensity …

www.sciencedirect.com

A Positron Emission Tomography Study of Quetiapine in Schizophrenia

Background Quetiapine is a new atypical antipsychotic medication. As such, relatively little has been published regarding its in vivo effects at the dopamine type 2 (D2) and serotonin type 2a (5-HT2a) receptor systems. The following study was undertaken to explore these effects across the...

jamanetwork.com

 

[Taddy Mason]

Quetiapine is not a sleeping pill

16.09.2019: Perspectives - Use of the antipsychotic drug quetiapine to treat sleep disorders has become widespread, also in Norway.

tidsskriftet.no

"
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 (12). In other words, there is evidence that quetiapine exerts an effect on several receptor systems even in low doses.
"

The source they use (which I don't have access to is a pharmacology book by Stahl.

I was shocked that such a low dose, which for years I had been told both in articles I had read and doctors I consulted, was only an antihistamine had such potency at the 5HT2A receptor.

They're referring to a chart in Stahl's out of context, particularly in regard to what he states in the actual text (as well as what the chart is conveying), and broadly extrapolating beyond that about vague implications. Also, the chart in Stahl's is of estimates of receptor occupancy over time at varying doses without clearly cited sources, thus I'd take it with a large grain of salt, particularly given the problems surrounding this issue mentioned in previous posts.

However, I don't disagree with their opinion that quetiapine is overprescribed and there are much better alternatives for insomnia.

 

[FlowRate]

You were right to be shocked. The quote is wrong. I don't have Essential Pharmacology either, but perhaps they misunderstood him or his estimate is simply just an estimate...or he is showing his industry bias. Even theoretically 50% occupancy of both receptors at a given dose doesn't make sense, as quetiapine and norquetiapine have ~4x as much affinity for 5-HT2A as D2. There is another variable of significant interindividual variability, for example Patient 3 in bottom graph had 19% 5HT2A occupancy at 17.2 ng/ml and Patient 10 had 49% occupancy at 12.7 ng/ml

D2 and 5HT2A receptor occupancy of different doses of quetiapine in schizophrenia: a PET study

Objective: Quetiapine is a novel antipsychotic agent with many atypical features, including low D2 and higher 5HT2A affinity in vitro, low propensity …

www.sciencedirect.com

View attachment 342457

D(2) and 5HT(2A) receptor occupancy of different doses of quetiapine in schizophrenia: a PET study - PubMed

In clinically effective doses, quetiapine induced low occupancy at D(2) receptors, which is consistent with atypical antipsychotics such as clozapine, and probably explains the lack of EPS observed in this trial. Correlations between receptor occupancy and plasma concentrations of quetiapine...

pubmed.ncbi.nlm.nih.gov

View attachment 342458

I'll try to pull the full article later but why are there negative occupancy values?

 

[aim-agm]

"Twelve hours after the last dose, quetiapine had a weak effect on D2 occupancy (Figure 1). Two subjects (Table 1) exhibited negative occupancies (ie, the D2BP on quetiapine was higher than that expected from naive patients at that age) of −24% and −29%, a finding that probably reflects baseline variance and/or receptor upregulation from previous treatments."
From the second paper

I need to read more on PET I think though.