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Dr. Bob is Robert Hsiung, MD,
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Posted by Lamdage22 on February 4, 2023, at 15:55:42
In reply to Are Neuroleptics brain specific anticholinergics?, posted by Lamdage22 on February 4, 2023, at 15:54:59
Damn it. I meant to say antihistaminergics in the subject line.
Posted by SLS on February 4, 2023, at 17:35:21
In reply to Re: Are Neuroleptics brain specific anticholinergics?, posted by Lamdage22 on February 4, 2023, at 15:55:42
> Damn it. I meant to say antihistaminergics in the subject line.
Yeah, but we all knew what you meant...
:-)
Usually, things in the blood stream are blocked from entering the brain by what's called the "blood brain barrier" - BBB. The barrier is actually a closely-packed layer of epithelial cells (flat and skin-like) coating both the inside and the outside of brain blood vessels. Unlike the peripheral circulatory vessels, the epithelial cells in the brain are packed tightly together. When cell membrane meet, they form "tight junctions". This barrier will allow some substances to pass through it and keep other substances out. Many substances cross the barrier passively by osmosis. Others are blocked from crossing passively and must be shepherded across the barrier by active transport. This takes energy, and the power generators in the cells are known as miitochondria. Lots of them cluster around the cell membranes to power the transporters.In order to "feel" the sedation that Seroquel (quetiapine) or Remeron (mirtazepine) produce, the drug molecules must first cross the BBB, after which they bind to histamine receptors and sedate you. Most medical uses for anticholinergic drugs are peripheral. You don't want them to get into your brain. They tend to make you "stupid" and impairs memory. It would be great if they could invent a drug that would block acetylcholine receptors throughout the body without affecting the brain. There are such drugs. The drug designers created anticholinergic drugs that treat bodily functions while sparing the brain from being exposed.
Somewhere in there, I hope you find the answer to your question - especially since I didn't understand what it is you wanted to know.
- Scott
Posted by Lamdage22 on February 5, 2023, at 2:31:40
In reply to Re: Are Neuroleptics brain specific anticholinergics? » Lamdage22, posted by SLS on February 4, 2023, at 17:35:21
I have many allergies and my tryptase blood test came in at 30 mcg/l. Thus I wonder if the reason why I need such high doses of my neuroleptics and struggle to reduce them is that I need the antihistaminergic activity...
Healthy tryptase is below 11.
Im thinking its a mast cell problem possibly.
So the question is if Seroquel and Zyprexa are anthihistaminergic in the whole body or just the CNS or just the brain?
Posted by undopaminergic on February 5, 2023, at 10:19:12
In reply to Re: Are Neuroleptics brain specific anticholinergics?, posted by Lamdage22 on February 5, 2023, at 2:31:40
>
> So the question is if Seroquel and Zyprexa are anthihistaminergic in the whole body or just the CNS or just the brain?
>Whole body. I'm not aware of *any* drug that is specific to the CNS.
-undopaminergic
Posted by SLS on February 5, 2023, at 11:17:10
In reply to Are Neuroleptics brain specific anticholinergics?, posted by Lamdage22 on February 4, 2023, at 15:54:59
Hi.
I agree with UD.I wonder, though, if the BBB barrier prevents some substances from exiting the brain that it had previously allowed to enter it. If this occurs, then I imagine the concentration of a drug in the brain becomes higher than that in the rest of the body. Could be.
* Lamdage - You are kicking *ss in your posts. I must say that I am truly impressed - and surprised - by you. I underestimated you.
- Scott
Posted by Lamdage22 on February 5, 2023, at 13:41:33
In reply to Re: Are Neuroleptics brain specific anticholinergics? » Lamdage22, posted by SLS on February 5, 2023, at 11:17:10
> * Lamdage - You are kicking *ss in your posts. I must say that I am truly impressed - and surprised - by you. I underestimated you.
> - ScottThanks guys and thanks SLS. It sounds like my theory is worth investigating.
Posted by Lamdage22 on February 5, 2023, at 14:14:31
In reply to Re: Are Neuroleptics brain specific anticholinergics?, posted by Lamdage22 on February 5, 2023, at 2:31:40
Next question: Do MAOI increase histamine?
Posted by NKP on February 5, 2023, at 14:22:26
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 5, 2023, at 14:14:31
Not quite what you were asking, but glycopyrrolate is an anticholinergic that acts on the peripheral, but not central, nervous system, it being unable to cross the blood-brain barrier.
Posted by Lamdage22 on February 5, 2023, at 14:26:49
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 5, 2023, at 14:14:31
> Next question: Do MAOI increase histamine?
Because it grossly destabilized me.
@ NKP I regret this typo. Lets keep it to the topic. We can open a new thread if you want to discuss anticholinergic. Thanks :)
Posted by undopaminergic on February 5, 2023, at 16:15:47
In reply to Re: Are Neuroleptics brain specific anticholinergics? » Lamdage22, posted by SLS on February 5, 2023, at 11:17:10
> Hi.
>
>
> I agree with UD.
>
> I wonder, though, if the BBB barrier prevents some substances from exiting the brain that it had previously allowed to enter it. If this occurs, then I imagine the concentration of a drug in the brain becomes higher than that in the rest of the body. Could be.
>I can't clarify your question about the BBB possibly retaining substances. However, another mechanism for accumulation of a substance in the brain is if the substance is lipophilic, in which case the concentrations will be higher in the brain (and other fatty tissues) than the bloodstream.
-undopaminergic
Posted by SLS on February 5, 2023, at 19:43:04
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 5, 2023, at 14:14:31
> Next question: Do MAOI increase histamine?
Like dopamine (DA), norepinephrine (NE), and serotonin (5-HT), the histamine molecule is a biogenic amine. Monoamine oxides type A (MAO-A) leaves histamine virtually untouched. MAO-B metabolizes (breaks-down) histamine, but to a very small degree. MAO exists *inside* the neuron, but not outside the neuron. Histamine is metabolized *outside* the neuron by an enzyme called diamine oxidase (DAO). Another enzyme located outside the neuron is catechol-O-methyltransferase (COMT). As with the MAO enzyme located inside the neuron, it metabolizes DA, NE, and 5-HT outside the neuron, but to a much smaller degree.I don't know very much about how histamine functions in the body.
- Scott
Posted by SLS on February 6, 2023, at 8:03:02
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by SLS on February 5, 2023, at 19:43:04
Hi.
In re: The Blood-Brain Barrier and anticholinergic drugs.
Anticholinergic drugs enter the brain at different rates.
Trospium (Sanctura) is an anticholinergic (muscarinic) drug used to treat overactive bladder, a peripheral function. However, it seems to be blocked from entering the brain almost entirely by the BBB. It can't even be detected in the cerebrospinal fluid (CSF). Trospium effectively treats a broad array of maladies like overactive bladder. It accomplishes this by reducing the tone of the muscles involved. Anticholinergics work by blocking the (muscranic) acetylcholine receptors that normally innervate muscles to contract. These are peripheral effects. However, when an anticholinergic drug makes its way into the brain / CNS, central side-effects can occur:
1. Short-term: Produces impairments in cognition and memory, confusion, impaired concentration, restlessness, agitation, and delirium.
2. Long-term: Increases risk for developing irreversible dementia.
Hopefully, the risk of contracting dementia when using trospium long-term will be much lower than for other anticholinergic drugs.
https://pubmed.ncbi.nlm.nih.gov/22390261/
- Scott
Posted by undopaminergic on February 6, 2023, at 12:45:07
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by SLS on February 5, 2023, at 19:43:04
> > Next question: Do MAOI increase histamine?
>
>
> Like dopamine (DA), norepinephrine (NE), and serotonin (5-HT), the histamine molecule is a biogenic amine. Monoamine oxides type A (MAO-A) leaves histamine virtually untouched. MAO-B metabolizes (breaks-down) histamine, but to a very small degree. MAO exists *inside* the neuron, but not outside the neuron. Histamine is metabolized *outside* the neuron by an enzyme called diamine oxidase (DAO). Another enzyme located outside the neuron is catechol-O-methyltransferase (COMT). As with the MAO enzyme located inside the neuron, it metabolizes DA, NE, and 5-HT outside the neuron, but to a much smaller degree.
>As the name implies, COMT breaks down catecholamines, but not serotonin.
> I don't know very much about how histamine functions in the body.
>I don't know much about histamine either, but I've read it is the neurotransmitter whose activity is most correlated with wakefulness (and inversely correlated with the lack of wakefulness). This is perhaps not so surprising given the sedative effects of antihistamine drugs.
-undopaminergic
Posted by undopaminergic on February 6, 2023, at 12:58:00
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by SLS on February 6, 2023, at 8:03:02
> Hi.
>
> In re: The Blood-Brain Barrier and anticholinergic drugs.
>
> Anticholinergic drugs enter the brain at different rates.
>
> Trospium (Sanctura) is an anticholinergic (muscarinic) drug used to treat overactive bladder, a peripheral function. However, it seems to be blocked from entering the brain almost entirely by the BBB. It can't even be detected in the cerebrospinal fluid (CSF). Trospium effectively treats a broad array of maladies like overactive bladder. It accomplishes this by reducing the tone of the muscles involved. Anticholinergics work by blocking the (muscranic) acetylcholine receptors that normally innervate muscles to contract. These are peripheral effects. However, when an anticholinergic drug makes its way into the brain / CNS, central side-effects can occur:
>
> 1. Short-term: Produces impairments in cognition and memory, confusion, impaired concentration, restlessness, agitation, and delirium.
>
> 2. Long-term: Increases risk for developing irreversible dementia.
>
> Hopefully, the risk of contracting dementia when using trospium long-term will be much lower than for other anticholinergic drugs.
>
> https://pubmed.ncbi.nlm.nih.gov/22390261/
>
>
> - ScottFor local (such as nasal mucosa) treatment ipratropium and tiotropium are other antimuscarinics that don't cross the blood-brain-barrier. I'm using the former to reduce night-time salivation.
-undopaminergic
Posted by Lamdage22 on February 6, 2023, at 14:15:59
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by undopaminergic on February 6, 2023, at 12:45:07
> I don't know much about histamine either, but I've read it is the neurotransmitter whose activity is most correlated with wakefulness (and inversely correlated with the lack of wakefulness). This is perhaps not so surprising given the sedative effects of antihistamine drugs.
>
> -undopaminergicSome psychiatrists describe psychosis as being 'too awake'.
Posted by Lamdage22 on February 6, 2023, at 14:18:00
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 6, 2023, at 14:15:59
Posted by Lamdage22 on February 6, 2023, at 14:50:44
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 6, 2023, at 14:18:00
It seems that Histamine is at least involved in Psychosis and Schizophrenia. https://www.hmpgloballearningnetwork.com/site/pcn/article/antihistamine-decreases-schizophrenia-symptoms
Maybe in a subset of patients? Im trying to get further testing in the histamine/mast cell direction asap. Im opting to go to a lab directly. I won't go around begging doctors.
Posted by undopaminergic on February 6, 2023, at 15:10:35
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 6, 2023, at 14:50:44
> It seems that Histamine is at least involved in Psychosis and Schizophrenia. https://www.hmpgloballearningnetwork.com/site/pcn/article/antihistamine-decreases-schizophrenia-symptoms
>Note that this study is about a histamine *H2*-receptor antagonist (famotidine). Ordinary antihistamines block the H1-receptor.
Trimipramine and clozapine do block histamine H2, though, in addition to H1.
-undopaminergic
Posted by SLS on February 6, 2023, at 19:11:09
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by undopaminergic on February 6, 2023, at 12:45:07
> > > Next question: Do MAOI increase histamine?
> >
> >
> > Like dopamine (DA), norepinephrine (NE), and serotonin (5-HT), the histamine molecule is a biogenic amine. Monoamine oxides type A (MAO-A) leaves histamine virtually untouched. MAO-B metabolizes (breaks-down) histamine, but to a very small degree. MAO exists *inside* the neuron, but not outside the neuron. Histamine is metabolized *outside* the neuron by an enzyme called diamine oxidase (DAO). Another enzyme located outside the neuron is catechol-O-methyltransferase (COMT). As with the MAO enzyme located inside the neuron, it metabolizes DA, NE, and 5-HT outside the neuron, but to a much smaller degree.
> As the name implies, COMT breaks down catecholamines, but not serotonin.
Good catch. Thanks.
> > I don't know very much about how histamine functions in the body.
> I don't know much about histamine either, but I've read it is the neurotransmitter whose activity is most correlated with wakefulness (and inversely correlated with the lack of wakefulness). This is perhaps not so surprising given the sedative effects of antihistamine drugs.I'm not sure how many pathways / neurotransmitters are involved with sleep. It's more than one, though. Hypocretin (orexin) is important in maintaining wakefulness. Hypocretin was first labeled as being a neuropeptide. Later, it was found in synaptic vesicles, so it is now often considered to be a neurotransmitter. Another substance that reduces wakefulness and promotes sleep is adenosine. Unlike hypocretin, it is not found in presynaptic vesicles, and is therefore considered a neuropeptide. Adenosine is liberated from the cell membrane along the neuron and into the fluid. There are several types of adenosine receptor. The major role of adenosine is to inhibit wakefulness and promote sleep. Caffeine produces its stimulatory behavioral effects by blocking adenosine receptors, and thus prevents adenosine from performing its role to oppose wakefulness.
Google and PubMed are fun to look through when we are discussing points of interest. I already knew some basics regarding hypocretin, adenosine, and caffeine, but I don't like to leave things that I am uncertain about go unchecked. I start out trying to fact-check what I'm writing, but this usually leads to expanding the scope of the discussion and adding details.
I didn't want to leave you with the impression that I was really that smart. <grin>.
- ScottP.S. I really should have double-checked COMT. <wink>
Posted by SLS on February 6, 2023, at 19:19:45
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 6, 2023, at 14:18:00
> https://pubmed.ncbi.nlm.nih.gov/17349864/
Thanks, Lamdage. I had no idea.
I found something that you might find useful:
https://pubmed.ncbi.nlm.nih.gov/20021346/
How does that blood test work?
- Scott
Posted by Lamdage22 on February 7, 2023, at 2:49:50
In reply to Re:Neuroleptics brain specific antihistaminergic? » Lamdage22, posted by SLS on February 6, 2023, at 19:19:45
You mean the test(s) I am contemplating? From what I have gathered thus far: There are urine tests for the following:
Histamin, N-Methylhistamin and Prostaglandin D2 11-β-PGF2α
Blood:
Serum-Tryptase.
Serum-Chromogranin A.
chilled plasma: Prostaglandin D2, und/oder 11-β-PGF2α.
chilled Plasma: Histamin
chilled Plasma: HeparinThese can give you a good idea if your mast cells are overactive. There are mast cell stabilizers, natural and pharmaceutical.
Posted by Lamdage22 on February 7, 2023, at 2:51:19
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by Lamdage22 on February 7, 2023, at 2:49:50
My apologies: 11-beta-PGF2alpha
Posted by undopaminergic on February 7, 2023, at 11:15:54
In reply to Re:Neuroleptics brain specific antihistaminergic?, posted by SLS on February 6, 2023, at 19:11:09
>
> I'm not sure how many pathways / neurotransmitters are involved with sleep. It's more than one, though.
>Dopamine too. I find it particularly interesting that dopamine neurons involved in wakefulness have been found in a region called the ventral periaqueductal gray (vPAG):
https://pubmed.ncbi.nlm.nih.gov/16399687/
"Identification of wake-active dopaminergic neurons in the ventral periaqueductal gray matter"> Hypocretin (orexin) is important in maintaining wakefulness. Hypocretin was first labeled as being a neuropeptide. Later, it was found in synaptic vesicles, so it is now often considered to be a neurotransmitter. Another substance that reduces wakefulness and promotes sleep is adenosine. Unlike hypocretin, it is not found in presynaptic vesicles, and is therefore considered a neuropeptide. Adenosine is liberated from the cell membrane along the neuron and into the fluid. There are several types of adenosine receptor. The major role of adenosine is to inhibit wakefulness and promote sleep. Caffeine produces its stimulatory behavioral effects by blocking adenosine receptors, and thus prevents adenosine from performing its role to oppose wakefulness.
>I think maybe what you mean by "neuropeptide" is "neurohormone" or "neuromodulator". A neuropeptide is a substance that (1) has a peptide structure, and that (2) is involved with the nervous system. Orexin does have a peptide structure, but adenosine does not.
-undopaminergic
Posted by undopaminergic on February 7, 2023, at 11:20:30
In reply to Re:Neuroleptics brain specific antihistaminergic? » Lamdage22, posted by SLS on February 6, 2023, at 19:19:45
>
> I found something that you might find useful:
>
> https://pubmed.ncbi.nlm.nih.gov/20021346/
>I'm very interested in trying a histamine H3-receptor antagonist (or inverse agonist), but none are clinically available.
-undopaminergic
Posted by SLS on February 8, 2023, at 6:02:51
In reply to Re:Neuroleptics brain specific antihistaminergic? » SLS, posted by undopaminergic on February 7, 2023, at 11:15:54
Hi, UD.
> I think maybe what you mean by "neuropeptide" is "neurohormone" or "neuromodulator". A neuropeptide is a substance that (1) has a peptide structure, and that (2) is involved with the nervous system. Orexin does have a peptide structure, but adenosine does not.
Another good catch. Thanks.
- Scott
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