What is the strongest sedative of the antihistamines?

[llamer]

I can't tell if the sedative properties of certain antihistamines results from their H1 antagonism or if it's because of their cross effect with antagonizing the adrenergic receptors. Are all H1 antagonists innately sedating or is it just the first generation ones? Anyway I'd like to know which of them (regardless as their branding as 'antihistamines') has the strongest affiliations with these receptors known for producing hypnotic properties.

From what I can tell I think the list beginning with the strongest goes something like this:
Quetiapine (seroquel)
Mirtazipine (remeron)
(from experience)
Hydrazine
Promethazine
(from inference from the internet's experience)

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Anything else I'm missing here?
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IMHO dipenhydramine, trazadone and haldol are not even worthy of placing on this list, unless you like restless leg syndrome and feeling like a mental ward patient. Even seroquel at tolerance-level dosing gave me very uncomfortable nightmarish RLS/insomnial hellacious torture that I would never wish to endure ever again. My only interest here is to know what works acutely and is not going to pussyfoot around. I've taken both remeron and seroquel but I can't for the life of me determine which of them is technically the stronger sedative (aside from relative dose) because the time between taking them has been too long to compare.

Just wondering if someone could supply some binding affinity charts to this thread. Thanks.

 

[Swimmingdancer]

Histamine antagonism in the brain is inherently sedating, but apparently many of the 2nd-gen antihistamines are poor at crossing the blood brain barrier, and therefore less sedating, (it depends on which one though, some 2nd-gen ones are still sedating). Adrenergic antagonism helps with sedation/anxiolysis too.

A few antihistamines can have additional mechanisms of action that may add to anxiolysis/relaxation/sedation. Most antihistamines also have additional mechanisms of action that can counteract the sedation. Dose is very important, because an antihistamine is not just an antihistamine, it will have varying binding affinities for other receptors and you want a dose that gives you a decent amount of histamine antagonism yet little activation of other receptors that are stimulating. Most people's problem with antihistamines for sleep is they take too high a dose, assuming more is better. Less is better with most of them. And when tolerance builds, taking more is not going to help because then you get more of the other stuff like anticholinergic effects. Tolerance to sedation from antihistamines can build very rapidly. One study on diphenhydramine for example found sedation to be equal to placebo after just 4 days of daily use.

Binding affinity chart for diphenhydramine:

I wish I could find graphs like this for each drug, that would be a lot easier to compare. I am too lazy to make them myself.

I do have the binding affinities for the other drugs you mentioned, but I will have to post them later as I have to get off the internet for a while.

 

[Cloroxtastebad]

Typically doxylamine is found to be the most sedating. Unfortunately for me antihistamines cause aksthesia.

 

[Swimmingdancer]

Did you mean hydroxyzine, not hydrazine? Hydrazine is a toxic chemical or an old group of MAOIs which are rarely ever used anymore due to toxicity.

Hydroxyzine is good option for sedation/anxiolysis. Unlike most other first-generation antihistamines, it has negligible affinity for the mACh receptors and therefore does not produce clinically significant anticholinergic effects.

Just wondering if someone could supply some binding affinity charts to this thread.

Here is info on the binding affinities (it would be nicer if they were bar graphs like the one I posted for diphenhydramine).
*Note: some of the ones listed as antagonists might possibly be inverse agonists.

Hydroxyzine - antagonist at the following receptors:
α1-adrenergic (Ki = ~300 nM)
H1 (Ki = 2 nM)
5-HT2A (Ki = ~50 nM)
D2 (Ki = 378 nM)
mACh (Ki = >10,000 nM)

Promethazine - antagonist at the following receptors: (*I'll try to find exact numbers)
α1-adrenergic (weak to moderate)
D2 (weak to moderate)
H1 (strong)
5-HT2A (weak to moderate)
5-HT2C (weak to moderate)
mACh (moderate)

Doxylamine - I can't find the info on right now, I'll try to find it and add it.

Quetiapine - antagonist at the following receptors:

α1-adrenergic (IC50 = 94nM)
α2-adrenergic (IC50 = 271nM)
D1 (IC50 = 1268nM)
D2 (IC50 = 329nM)
D3 (unspecified)
D4 (unspecified)
H1 (IC50 = 30nM)
5-HT1A (IC50 = 717nM)
5-HT2A (IC50 = 148nM)
5-HT2C (unspecified)
5-HT7 (unspecified)
mACh receptor (IC50 = >5000nM) antagonist

Mirtazepine - antagonist at the following receptors:
α1-adrenergic (Ki = 608 nM?)
α2C-adrenergic (Ki = 18 nM)
α2A-adrenergic (Ki = 20 nM)
α2B-adrenergic (unspecified, likely similar to α2A/α2B-adrenergic)
D1 (Ki = 4,167nM)
D2 (Ki = 1,460nM)
D3 (Ki = 5,723nM)
D4 (Ki = 25nM)
H1 (Ki = 5.1 nM)
5-HT1A (Ki=18nM; IC50=1,000nM)
5-HT2A (Ki = 69 nM)
5-HT2B (unspecified, ~20-fold lower than for 5-HT2A/2C)
5-HT2C (Ki = 39 nM)
5-HT3 (unspecified, likely similar to 5-HT2A/2C)
5-HT7 (Ki = 265 nM)
mACh receptors (Ki = 794 nM?)
Also shown affinity towards: (I'm not sure what the action on these is though?)
Serotonin transporter (IC50 = 100nM)
Norepinephrine transporter (IC50 = 260nM)
Dopamine transporter (IC50 = 1,000nM)

Haloperidol - antagonist at the following receptors:
α1-adrenergic (Ki = 12nM)
Alpha Adrenergic 2a (Ki = 1130nM)
Alpha Adrenergic 2b (Ki = 480nM)
Alpha Adrenergic 2c (Ki = 550nM)
D1 (Ki = 10-15nM)
D5 (Ki = 15-17nM)
D2 (Ki = 1.55nM)
D3 (Ki = 0.74nM)
H1 (Ki = 1800nM)
5HT2A (Ki = 53nM)
5HT2C (Ki = 10,000nM)
5HT6 (Ki = 3666nM)
5HT7 (Ki = 377.2nM)
M1 (Ki = 10,000nM)
NR1\NR2B Subunit containing NMDA receptor antagonist Ifenprodil site (IC50 = 2mM)
And also acts on the following:
D4 inverse agonist (Ki = 5-9nM)
5HT1A agonist (Ki = 1927nM)
Sigma 1 Irreversible inactivation by HPP+ (Ki = 3nM)
Sigma 2 agonist (Ki = 54nM)

Trazodone - antagonist at the following receptors:
α1-adrenergic (Kd = 39 nM)
α2-adrenergic (Kd = 405 nM)
H1 (Kd = 725 nM)
5-HT2A (Ki = 13 nM)
5-HT2B (Ki = 74 nM)
5-HT2C (Ki = 192 nM)
Also has the following actions:
5-HT1A receptor partial agonist (Kd = 78 nM)
SERT transporter inhibitor (Kd = 160 nM)

So, if one is able to understand these, you can see from the numbers why some are more effective than others for sedation, likelihood of unwanted side effects, and why dose is so important.

. . . . . . . . . .

Moving this to Other Drugs
BDD -> OD

 

[NeighborhoodThreat]

Quetiapine and promethazine are pretty damn sedating. I mean, they're antipsychotic drugs. The sedating effects of these drugs does not only stem from their antihistamine activity.

 

[Tussmann]

Doxylmine without doubt.

 

[Swimmingdancer]

Quetiapine and promethazine are pretty damn sedating. I mean, they're antipsychotic drugs. The sedating effects of these drugs does not only stem from their antihistamine activity.

Yep, as I said in my first post some antihistamines have additional mechanisms of action that may add to the sedation. I think dopamine blockade increases melatonin production or something?

I'm not psyched about the propensity for both antihistamine and antidopamine actions to cause/exacerbate RLS and other movement disorders though. Ugh, I really need to find something for sleep that doesn't have a lot of unwanted side effects or cause rapid dependence. Or a couple with different mechanisms to alternate in order to reduce possibility of dependence.

 

[BIGsherm7272]

I have tried diphenhydramine, promethazine, and seroquel. Out of those, seroquel was by far the most sedating, with promethazine coming in second. Diphenhydramine is a good and cheap option, but you gain a tolerance to it extremely fast, so everyday use is not really beneficial.

 

[sekio]

Doxylamine has been shown to be a more effective sedative than babiturates.

I don't doubt that Seroquel etc are just as good though. Generally the broader action that these compounds have at blocking receptors, the more sedatibg they will be.

 

[Fire&Water]

Typically doxylamine is found to be the most sedating. Unfortunately for me antihistamines cause aksthesia.

Could you please explain "aksthesia" ?

 

[tomatalli]

Could you please explain "aksthesia" ?

Akathisia not aksthesia and its a medical term for restless leg syndrome

 

[Lightning-Nl]

I know this thread is a little old, but I thought I'd chime in anyways. You can't compare all of these because they all have very different effects around the body. Sure, they may all antagonize H1, but antagonization of H1 is not the only thing that produces sedation!

Quetiapine (seroquel)
Mirtazipine (remeron)
(from experience)
Hydrazine
Promethazine
(from inference from the internet's experience)

---------
Anything else I'm missing here?
---------

Yes, you're assuming that sedation only comes from H1 antagonism. Lets compare Diphenhydramine and Quetiapine for instance.

Diphenhydramine has potent antagonization effects on Histamine H1 receptors, and Muscarinic acetylcholine receptors (all subtypes). Where as Quetiapine has potent antagonizing effects on Histamine H1, but also possesses antimuscarinic actions at M1 and M3. On top of that, it antagonizes Dopamine, Serotonin and Epinephrine. Because those are nearly all the main neurotransmitters that are responsible for excitation in the frontal lobe of the brain, it stands to reason that if these neurotransmitters can't produce there necessary function, you're going to be very tired and not able to think.

I've taken both remeron and seroquel but I can't for the life of me determine which of the

Again, these aren't comparable. Sure, you can compare how much sedation they provide, but not based on just histaminergic activity.

 

[bunge]

Mirtazapines sedation ime is not just H1 antagonism.
Ive taken many of the drugs mentioned (havent tried the anti-psychs) and mirtazapine has a much more relaxing enjoyable sedation then say, hydroxyzine.
Ive discussed this with a doctor and he said that the sedation has alot to do with antagonism of other receptors like the adrenergic receptors, which lends mirtazapine its hypnotic-like feeling.

 

[dopemegently]

Absolutely right; the antihistamine in mirtazipine is the only effective one I've used-others like dipenhydramine do not sedate me at, quite the opposite, in fact. When I take mirt, I feel very very tired, and I never get a hangover. If it wasn't for its appetite enhancement, I'd call mirt the perfect AD for my needs. (Until I took it, I had clinical depression and struggled to sleep).

Is it possible to buy the antihistamine in mirt alone? I have to say, if you could buy it, it would really clear up the sleep-aid market for sure-it's an excellent antihistamine/sedative imo

 

[bennyZA]

I recently noticed that unisom, tylenol pm, and nyquil - amongst others - have all switched from doxylamine to diphenhydramine. Anyone know why? Dox is by far the best OTC sleep aid, I don't understand why most meds would switch active ingredients.

 

[dopemegently]

Yeah? I wasn't sure doxylamine was ever available-the only ones here are nytol with dph or herbal nytol. It's annoying because I personally consider dph to be a terrible sedative. Maybe doxylamine was made a 'script item, or maybe the profit margins are higher with dph? I struggle to understand why a superior sleep-aid would be pulled. It just doesn't make sense, at least from a business poin of view.

 

[QUARE]

Personally, I find Diphenhydramine is more sedating then Quetiapine. I have to boost my Quetiapine script with DPH because my insomnia is too severe. Quetiapine only makes me tired, DPH makes me fall asleep.

 

[paranoid android]

I recently noticed that unisom, tylenol pm, and nyquil - amongst others - have all switched from doxylamine to diphenhydramine. Anyone know why? Dox is by far the best OTC sleep aid, I don't understand why most meds would switch active ingredients.

Well for some reason diphenhydramine has always been the most popular OTC sleep aid. I always got the Unisom-2 when i could but it's not in any of the stores here anymore so i get the NyQuil with the doxylamine and DXM in it. That's still around in every drugstore here. It's the yummy tasting red stuff. Pheniramine which is a anti-histamine found in combination products such as neo-citron up here in Canada is a pretty damn good sleep aid too and also good for mixing with opiates pretty good too.

Methotrimeprazine (trade name Nozinan) aka Levomepromazine is a old typical low potency anti-psychotic that is closely related to and about half as potent as Chlorpromazine (Largactil, Thorazine). It is a H1 antagonist and a very potent anti-cholinergic. Despite it being a less potent anti-psychotic then Thorazine methotripeprazine is far more sedating then Thorazine or any other anti-psychotic i have taken. 15mg's will usually have me knocked out for about half the day. It is so sedating that it literally makes Quetiapine look like dextroamphetamine. Largactil also has H1 antagonist properties and is a pretty good sleep aid and opiate potentiator in it's own right. It's probably abit too dangerous to use in even low doses of around 25mg's for sleep though.

 

[Psychedelic Jay]

Doxylamine is plentiful just like Diphenhydramine as generic OTC medications...

Doxylamine is strictly a sleep aid over the counter and not for allergies anymore...

 

[bennyZA]

yea, I have insomnia and dox has always worked really well. I've always bought the same unisom or nyquil for the dox, but in SF all that shit has been replaced with dph, even though on the internet the standard formulation says dox instead of dph. Perhaps there are certain restrictions in certain places and therefore they make two formulations, idk. Either way, dox is as powerful of a hypnotic I'll ever need. It doesn't "force" me to go to sleep like those z-drugs, but if I do get in bed it's lights out.