Why do anticholinergics cause sedation?

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I was doing some light research the other day after assisting my (paramedic) partner in giving diphenhydramine (benadryl) and hearing his warnings about the potential side effects of the drug, one of which is sedation. I understand that the drug works primairly as a H1 receptor antagonist, but also that it is quite non-selective and has some potent anticholinergic effects as well. Supposedly it is this effect that is the cause of the sedation (and many of the drug's other side effects also). Same is the case for Promethazine/Phenergan, another anticholinergic/sedative.

What I dont understand is why inhibition of the cholinergic (parasympathetic) response through reduction of acetylcholine produces sedative effects. It is my understanding that the parasympathetic response IS the relaxed, "feed and breed" sedate kind of response. It seems to me that inhibition of this system would serve to rather excite the patient, not sedate. (...Like Atropine will cause an increased heart rate, not decrease it.) Can anyone explain to me what mechanism is working here? I know there are some tox people in here, and many others much more knowledgable than myself: please help me understand!

RE:
diphenhydramine: http://en.wikipedia.org/wiki/Diphenhydramine
promethazine: http://en.wikipedia.org/wiki/Phenergan
anticholinergic: http://en.wikipedia.org/wiki/Anticholinergic

Sedation is due to blockade of histamine (H1) receptors centrally.

acetylcholine isn't just parasympathetic system. It is involved in higher functions of CNS (memory,thinking, learning), neuro-muscular transmitting and also the first neuron in sympathetic chain comunicates inpuls via ACH and CNS is the site being affected by sedation. That same fact contributes to sedation caused by certain groups of antidepressants for instance.

Originally Posted by fiznat

I understand that the drug works primairly as a H1 receptor antagonist, but also that it is quite non-selective and has some potent anticholinergic effects as well. Supposedly it is this effect that is the cause of the sedation (and many of the drug's other side effects also). Same is the case for Promethazine/Phenergan, another anticholinergic/sedative.

H1 antagonism is the cause of the sleepiness with antihistamines. There may also be an additional affect with anticholinergics if they are acting at specific cholinergic receptors in certain areas of the brain which are responsible for wakefulness. ACh can cause both wakefulness and sleepfulness depending on where it is being secreted and under surrounding conditions. Most of the neuroscience research into this stuff is still theoretical but it is interesting to some people. There is a flip-flop/mutually inhibitory theory about how the brain switches between wakefulness and drowsiness, and I bet you could find links if you Googled for it.

.... I just looked up some more about it - it is kind of hard to find if you want to be thorough, but anyway here's what I have: besides central H1 blockage (brain) sedation is also enhanced by cortical Na-channel blocking (not further specified - too tired to look that up) and the anti-cholinerg. effect is mental state alterating (obviously) + there were some studies discussing muscarinic receptors in reticular activating system and their effect on frontal cortex that were suggesting ACHergic regulation to have a role in initiating and maintaining a state of arousal as well as REM part of sleep....have a good night

Isn't diminished acetylcholine production in the brain associated with alzheimer's disease? Outside of H1 function, it is associated with all sorts of higher memory functions through an alphabet soup of receptors I believe.

Hm... Maybe it could be largely peripheral. ACh is used in neuromuscular junctions, so... If you inhibit ACh in some systemic way that affects neuromuscular transmission, you could end up feeling weak and tired in addition to the sleepiness from the histhamine suppression. In terms of what the patient feels, it would add up to a stronger sedative side effect...

Originally Posted by kate_g

Hm... Maybe it could be largely peripheral. ACh is used in neuromuscular junctions, so... If you inhibit ACh in some systemic way that affects neuromuscular transmission, you could end up feeling weak and tired in addition to the sleepiness from the histhamine suppression. In terms of what the patient feels, it would add up to a stronger sedative side effect...

Neuromuscular block or other kind of neu-musc. affection has nothing to do with sedation. For example people with botox poisoning, myasthenia gravis aren't considered sedated or less mentally allert (in fact people with botox poisoning suffocate while fully alert).

The actual mechanism by which histamine-1 antagonists cause sedation is complex & not fully understood.

Histamine itself is a neurotransmitter which is involved in wakefulness & sleep. H-1 antagonists are presumed to either inhibit histamine release in the brain or block histamine from activating neuroreceptors - still unclear. There is also evidence that histamine is involved in the GABA receptor complex binding & noradrenaline & 5HT uptake. Again...the direct mechanism is not understood.

Memory is yet another function which is inhibited to some degree by diphenhydramine & independent of the sedation side effect.

We also know there is yet another histamine receptor H-3 which is in the brain. The role of this receptor & how the "older" antihistamines such as diphenhydramine interact with it are not clear either, however, it is not presumed to be involved in the wakefulness/sleep cycle rather regulation of obesity.

In short - there is not simple pharmacologic explanation for your observation because its still not clearly understood.

An interesting experience with an antihistamine...

Over the past few days I have been sick with the flu. Yes, the flu. Yes, I did receive a vaccination this year, and yes it is rather late in the flue season. Alas, ye ole nasal swab done by the PMD says it's flu (flu B to be exact).

The good part is that it seems to be going away rather quickly.

During my worst day of the runny nose, I decided to take a cold and flu medicine to help dry up some secretions. I decided on the night-time formula because I thought it would make me sleep better. I looked at the ingredients to find that it contained doxalamine, an antihistaminergic known for its sedative properties.

So there I go... I mix it up with warm water and drink 'er down. Thirty minutes later I'm feeling groggy. So I head to bed. The next six hours were "interesting" to say the least. I had some of the most vivid dreams in my life. One of the dreams was of me and fellow friends hunting a lemur in Africa. Of course I miss the shot at the lemur, and my friend's gun jams, so the pissed off lemur starts to chase us trying to kill us. The next hour or so of my dream was spent with me and my friends hiding from a lemur trying to kill us. The funny part is that we were hiding in trees thinking it couldn't get to us.

The really funny part is that I've never seen a lemur in my life.

Oh well, I'm just way too drug naive.

Originally Posted by southerndoc

The really funny part is that I've never seen a lemur in my life.

Behold, the fearsome lemur...




Sounds like some good drugs.

Hope you're feeling better soon.

Originally Posted by southerndoc

An interesting experience with an antihistamine...

Over the past few days I have been sick with the flu. Yes, the flu. Yes, I did receive a vaccination this year, and yes it is rather late in the flue season. Alas, ye ole nasal swab done by the PMD says it's flu (flu B to be exact).

The good part is that it seems to be going away rather quickly.

During my worst day of the runny nose, I decided to take a cold and flu medicine to help dry up some secretions. I decided on the night-time formula because I thought it would make me sleep better. I looked at the ingredients to find that it contained doxalamine, an antihistaminergic known for its sedative properties.

So there I go... I mix it up with warm water and drink 'er down. Thirty minutes later I'm feeling groggy. So I head to bed. The next six hours were "interesting" to say the least. I had some of the most vivid dreams in my life. One of the dreams was of me and fellow friends hunting a lemur in Africa. Of course I miss the shot at the lemur, and my friend's gun jams, so the pissed off lemur starts to chase us trying to kill us. The next hour or so of my dream was spent with me and my friends hiding from a lemur trying to kill us. The funny part is that we were hiding in trees thinking it couldn't get to us.

The really funny part is that I've never seen a lemur in my life.

Oh well, I'm just way too drug naive.

this "trip report" gave me quite a good laugh.

get better soon,
stoic

Originally Posted by rayoflite

Neuromuscular block or other kind of neu-musc. affection has nothing to do with sedation.

Sure, but it might give the perception of a stronger "drowsiness" side effect, from the patient's point of view. Might even get things like decreased sleep latency and impaired performance on cognitive tests (compared to just the effect of histhamine block). Anyway, I just thought it was a cute idea, I don't have any good reason to argue for it.

Although not as vivid as Marvin the Martian's story, 2 years ago I had an allergic reaction. I went to the fire station on the corner where I was formerly a FF/paramedic. I got a shot of Benadryl IV. I don't recall if it was 25 or 50mg.

I went home, and laid down. What was weird was that it certainly made me drowsy (that's an understatement), but I could NOT fall asleep.

As I understand it, there is a basal level of histamine irritation - more than that, you get the hives, sneezing, rhinorrhea, etc. Less than that (as when a nonspecific or H1 blocker is used), that basal level of irritation is not there, and that is where the "sedation" comes from. However, since my RAS wasn't at the point for sleep, I think it was competitive inhibition.

After about 5 or 6 hours, my allergic s/s (mostly swollen tongue) had resolved, and I was awake and not drowsy.

Originally Posted by kate_g

Sure, but it might give the perception of a stronger "drowsiness" side effect, from the patient's point of view. Might even get things like decreased sleep latency and impaired performance on cognitive tests (compared to just the effect of histhamine block). Anyway, I just thought it was a cute idea, I don't have any good reason to argue for it.

I apologize, kate. I didn't mean to sound like an ...hole. That idea definetly comes to mind and I had played with it too.

Originally Posted by kate_g

Sure, but it might give the perception of a stronger "drowsiness" side effect, from the patient's point of view. Might even get things like decreased sleep latency and impaired performance on cognitive tests (compared to just the effect of histhamine block). Anyway, I just thought it was a cute idea, I don't have any good reason to argue for it.

Ultimately sedation is a perceptual experience determined by more factors than what can be drawn down to a simple neurotransmitter. One time I had a massive headache and could not sleep, but as soon as I took an ibuprofen and the pain began to subside I became very sleepy. Obvioulsy it was because the pain receded, but I hope you get my drift.

Originally Posted by leviathan

One time I had a massive headache and could not sleep, but as soon as I took an ibuprofen and the pain began to subside I became very sleepy. Obvioulsy it was because the pain receded, but I hope you get my drift.

Actually, you were sleepy before you took the ibuprofen. You just had distracting pain.

Originally Posted by leviathan

Ultimately sedation is a perceptual experience determined by more factors than what can be drawn down to a simple neurotransmitter. One time I had a massive headache and could not sleep, but as soon as I took an ibuprofen and the pain began to subside I became very sleepy. Obvioulsy it was because the pain receded, but I hope you get my drift.

Perhaps that is your perception....however, when testing drugs...there is a standard which must be reproducible. Currently, the standard for sleepiness is the Stanford Sleep Scale & the multiple sleep latency test (MSLT). We use these scales, in conjunction with EEGs, blood & CSF draws to determine if what the pt experiences is actually a neurotransmitter effect or due to what your own testimonial was of decreased sensory input. It takes hundreds of pts to acquire data which will be significantly significant & evidence does indeed suggest that histamine is acting as a neurotransmitter.

Originally Posted by southerndoc

The next hour or so of my dream was spent with me and my friends hiding from a lemur trying to kill us.

Man, I have EXACTLY the same dream from time to time.

The sad thing is I know what lemurs look like and still manage to have nightmares about them.

Fearsome indeed.

Take care,
Jeff

Originally Posted by southerndoc

An interesting experience with an antihistamine...

Over the past few days I have been sick with the flu. Yes, the flu. Yes, I did receive a vaccination this year, and yes it is rather late in the flue season. Alas, ye ole nasal swab done by the PMD says it's flu (flu B to be exact).

The good part is that it seems to be going away rather quickly.

During my worst day of the runny nose, I decided to take a cold and flu medicine to help dry up some secretions. I decided on the night-time formula because I thought it would make me sleep better. I looked at the ingredients to find that it contained doxalamine, an antihistaminergic known for its sedative properties.

So there I go... I mix it up with warm water and drink 'er down. Thirty minutes later I'm feeling groggy. So I head to bed. The next six hours were "interesting" to say the least. I had some of the most vivid dreams in my life. One of the dreams was of me and fellow friends hunting a lemur in Africa. Of course I miss the shot at the lemur, and my friend's gun jams, so the pissed off lemur starts to chase us trying to kill us. The next hour or so of my dream was spent with me and my friends hiding from a lemur trying to kill us. The funny part is that we were hiding in trees thinking it couldn't get to us.

The really funny part is that I've never seen a lemur in my life.

Oh well, I'm just way too drug naive.

haha.. i have a similar dream from time to time. My friends/family members are hunting monkeys, something goes wrong, and then they end up chasing us.

Originally Posted by IbnSina

Actually, you were sleepy before you took the ibuprofen. You just had distracting pain.

Yes, exactly what I just said.