Drug Receptor binding resource

[Scorcher31]

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In the past few months, I've been working at a state hospital and have been seeing a lot of antipsychotic regimens that involved multiple antipsychotics where I would have assumed D2 binding would have been maxed out with 1 drug. I've also seen super high doses of meds like Zyprexa 30 mg BID. It sounds more like desperation, but I want to try and understand if there is any science behind this.

Do you guys know where I can get a resource whether online chart, graph, table or actual text that would list specific receptor saturations for different doses of medications? I'll take whatever I can get, but it would be even better if it had Saphris, Latuda, and Fanapt for comparison. I know which meds have more eps, sedation, weight gain etc., but I'm sick of not knowing actual doses where each receptor is fully saturated. I know for example that seroquel's antihistaminic properties cap around 200 mg, but I'd love to be able to a reference text for this sort of thing. Thanks for any recommendations you can offer!

 

[firedoor]

I know exactly what you mean. Aside from individual kinetics, I don't understand the rationale behind dosing beyond maximum receptor/transporter occupancy.

 

[whopper]

Stahl is your best bet. I wish there were head-to-head charts for things like this. It's hard enough just to find one chart for one med.

As for the crazy dosages, many medications actually do well at dosages higher than the manufacturer's maximum recommended dosage. In fact Zyprexa was given out in the CATIE trial (if I remember correctly) at up to 30 mg a day on the recommendation of the manufacturer despite that the company, on their package inserts, write to only give up to 20 mg.

The only time I've had to place patients on polypharmacy more than rarely has been with psychotic patients on involuntary units. I've had several cases where the guy's on Zyprexa 20 mg QHS, but when the dosage is raised to 30 mg a day, the person does significantly better. At one of the institutions I work at, the pharmacy dept. has approved up to 40 mg a day and has several journal articles backing this practice as safe.

Why this is happening is not known in terms of receptor function and there are several theories. Remember, antipsychotics bind onto several receptors and do so with differing affinities. E.g. Seroquel binds onto histamine receptors more preferentially than D2 receptors. It could be that on some people the meds don't bind well on some receptors vs others, leading to differing dosages having differing effects. Perhaps for most people Zyprexa at 20 mg a day blocks the D2 receptor well, but others need higher dosage because their D2 receptor is of a slightly different shape that doesn't bind as well to the medication.

Another explanation is that D2 blockage only is the tip of the iceberg in terms of explaining psychosis. The binding onto other receptors likely does contribute something, in some manner, and perhaps the interaction of several receptors could lead to a sweet spot so to speak.


This all goes to show you how little we know.

 

[kugel]

Why this is happening is not known in terms of receptor function and there are several theories. Remember, antipsychotics bind onto several receptors and do so with differing affinities. E.g. Seroquel binds onto histamine receptors more preferentially than D2 receptors. It could be that on some people the meds don't bind well on some receptors vs others, leading to differing dosages having differing effects. Perhaps for most people Zyprexa at 20 mg a day blocks the D2 receptor well, but others need higher dosage because their D2 receptor is of a slightly different shape that doesn't bind as well to the medication.

Another explanation is that D2 blockage only is the tip of the iceberg in terms of explaining psychosis. The binding onto other receptors likely does contribute something, in some manner, and perhaps the interaction of several receptors could lead to a sweet spot so to speak.


This all goes to show you how little we know.

Exactly right!
Receptor binding is not only the tip of the iceberg, it might not even be the right iceberg.

Why is it that every time I get a bronchitis or pneumonia (I've had lots), it ALWAYS responds to a macrolide and rarely responds to a cephalosporin or tetracycline? You could come up with a number of theories, but we don't really know. But it is true.

What we know BEST is two things:
A) Real people aren't textbook cases, and rarely react like them, even in regards to max. dosages.
B) What works is what works. We might be able to fine-tune it to improve function or reaction or to reduce side-effects, but we can't ignore what works for any particular patient. Doesn't mean we have to cater to whatever the patient wants, but we need to keep in mind what has worked.
When it comes to antidepressants, what is the best possible information about what will work for a patient? What's worked before for that patient!
A) and B) are NOT limited to psychiatry.

 

[whopper]

I got a guy in the hospital on Zyprexa 20 mg QBID, Haldol 20 mg Qdaily and Depakote 1500 mg QHS.

With each increase in dosage (I did it step-wise), he did show marked improvement. I wouldn't have kept him at these high dosages unless I saw improvement every step of the way.

There was a recent article in the AJP showing that polypharm with psychosis could yield benefits, but that a large minority didn't need them. IMHO, you only give a med if it causes a benefit. If it doesn't, you stop it and try something else. With antidepressants, I push them to at least moderate dosages without waiting a week because studies have showed that lower dosages barely do anything, but from there I'd wait the full month before increasing again unless the the patient wanted me to increase faster.

With antipsychotics, I give it a few days. No improvement, I raise the dosage until I have reason to believe it's not going to work at all, then I try a different antipsychotic. (e.g. risperdal at 12 mg a day with no benefit, I'm not going to increase it to 16 mg a day).

Receptor binding is not only the tip of the iceberg,

Correct. Given that glutamate's involved, and the way that pathway works, I've thought that our current theories are nowhere adequate to what's going on, and that the antipsychotics working are the result of something just on the order of slightly better than accidental. Per some sources, several meds cause D2 blockage but never showed any antipsychotic benefit. Don't make sense why some of these D2 blockers work and others don't.

 

[Scorcher31]

True, but I guess I'm kind of working in reverse here. I clinically understand when certain antipsychotics are used, when doses are to be slightly exceeded, etc., but I was looking for some baseline pharmacolgical knowledge to back up most of the hearsay. I guess I'll see if Stahl's has a new edition and just buy that.

I have no problem with Zyprexa 30 mg daily, but I'm seeing doses like Zyprexa 30 mg BID. I'm also seeing odd combinations like Latuda 60 mg PO daily with food started on a patient and after a day or two of little improvement them starting risperdal which is titrated up to 3 mg BID after about 1 day. (which to me is a complicated regimen for a pt to follow and if they are good enough to be that compliant why not use clozaril). I've also seen abilify 10 mg daily seroquel 150 mg QHS for schizophrenia for which I ask why not just give benadryl instead of seroquel and up the abilify, stop the abilify and up the seroquel, or just use something different. Note, I'm not at my main academic facility now, and this is not reflective of the normal prescribing habits I see at my program.

 

[Scorcher31]

I got a guy in the hospital on Zyprexa 20 mg QBID, Haldol 20 mg Qdaily and Depakote 1500 mg QHS.

With each increase in dosage (I did it step-wise), he did show marked improvement. I wouldn't have kept him at these high dosages unless I saw improvement every step of the way.

There was a recent article in the AJP showing that polypharm with psychosis could yield benefits, but that a large minority didn't need them. IMHO, you only give a med if it causes a benefit. If it doesn't, you stop it and try something else. With antidepressants, I push them to at least moderate dosages without waiting a week because studies have showed that lower dosages barely do anything, but from there I'd wait the full month before increasing again unless the the patient wanted me to increase faster.

With antipsychotics, I give it a few days. No improvement, I raise the dosage until I have reason to believe it's not going to work at all, then I try a different antipsychotic. (e.g. risperdal at 12 mg a day with no benefit, I'm not going to increase it to 16 mg a day).



Correct. Given that glutamate's involved, and the way that pathway works, I've thought that our current theories are nowhere adequate to what's going on, and that the antipsychotics working are the result of something just on the order of slightly better than accidental. Per some sources, several meds cause D2 blockage but never showed any antipsychotic benefit. Don't make sense why some of these D2 blockers work and others don't.

Good point about the D2 blockers whooper. BTW have you heard anything about FDA approval or progress on the new antipsychotics that work on glutamate? Have you noticed benefit for using risperdal at that high of dosages ? I always used to hear that >4 mg per day was rarely more effective but has significantly higher risks of EPS. I guess since I'm new I'm just extra cautious. I'll go maybe 30%-50% over reccomended doses if I'm seeing a difference but at somepoint I'll stop for fear of increased risk of adverse effects.

 

[Sneezing]

Don't forget to look at the confounding varibles on hepatic inducers/inhibitors.

 

[whopper]

I push them to at least moderate dosages without waiting a week because studies have showed that lower dosages barely do anything,

Edit, meant to write without waiting a month.

E.g. I often give Citalopram at 20 mg Qdaily, then immediately afterwards recommend the patient to up it to 40 mg a day.

I don't do this without telling the patient my logic and reasoning, and give them the option to stay at 20 mg Q daily as long as they want.

but I'm seeing doses like Zyprexa 30 mg BID.

And I don't understand that dosage either. Like I said, one of my places of employment allows for up to 40 mg a day and has the allowed this only after a committee of several doctors (psychiatrists, an IM, and pharmacologists) reviewed the available data. 30 mg QBID? Well maybe there's something out there that supports this but unless the dosage actually showed some real superior benefit at that high a dosage vs a lower dosage, in fact even with that, I'd be highly suspicious of this dosage.

I've seen some doctors forget the dosage guidelines and give out meds, while not double checking their PDRs. I don't know what's going on with that doctor's recommendations. I've often ranted about this but I see other attending psychiatrists not following several guidelines that residents get their ass whooped over---daily.

Something to worry about with benzo-derived antipsychotics (and Remeron), especially at high dosages is it can cut neutrophil count. Most people only worry about this with Clozaril, but I've seen it happen several times. Add Depakote, and the problem can be greatly exacerbated. Further, African-American males have lower absolute neutrophil counts vs the rest of the population (it's called benign ethnic neutropenia).

Anyone on a high dosage of a benzo derived antipsychotic and/or Depakote should have their ANCs checked. I also sometimes am hesitant to give benzo-derived antipsychotics to people with HIV for the above reasons.