Why do anticholinergics cause sedation?

[fiznat]

I was doing some light research the other day after assisting my medic 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).

What I dont understand is why inhibition of the cholinergic (parasympathetic) response through acetylcholine reduction 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?

RE:

diphenhydramine: http://en.wikipedia.org/wiki/Diphenhydramine

anticholinergic: http://en.wikipedia.org/wiki/Anticholinergic

[Ace844]

"Fiznat,"

Here is some information related to your request.

Antihistamines and anticholinergics (agents that block the action of acetylcholine) may be effective in the treatment of motion sickness as the result of a similar action: the ability to block the transmission of information from the vestibular apparatus (the part of the middle ear that is involved in balance) to the emetic center in the medulla oblongata, which is a part of the brain involved in coordinating various reflexes (e.g., swallowing, vomiting).

Why is drowsiness a usual side effect?

Histamine, acting via H1 receptors in the central nervous system, increases wakefulness. Therefore, antihistamines that block the binding of histamine to H1 receptors and which enter the central nervous system cause drowsiness. In addition, anticholinergic agents cause drowsiness and, thus, antihistamines which possess anticholinergic activity also produce drowsiness via this action. Thus, older agents, such as diphenhydramine, which enter the central nervous system, cause sedation, while newer antihistamines, such as astemizole (HISMANAL) and loratadine (CLARITIN), which poorly penetrate into the CNS, are nonsedating. Patients vary in their susceptibility to the sedative effects of antihistamines.

HTH,

ACE844

[fiznat]

The bit about H1 receptors causing "wakefulness" is interesting, I didnt know that. Hmm.

Still,

In addition, anticholinergic agents cause drowsiness and, thus, antihistamines which possess anticholinergic activity also produce drowsiness via this action.

This is the mechanism that I am specifically asking about. It seems like it should go the other way, doesnt it? I mean- if parasympathetic tone causes the "feed and breed" (and sedate?) response, why wouldnt antagonising that system cause the opposite (or, at least, less sedation- not more)?

[Ace844]

The bit about H1 receptors causing "wakefulness" is interesting, I didnt know that. Hmm.

Still,

This is the mechanism that I am specifically asking about. It seems like it should go the other way, doesnt it? I mean- if parasympathetic tone causes the "feed and breed" (and sedate?) response, why wouldnt antagonising that system cause the opposite (or, at least, less sedation- not more)?

Most antihistamines cross the blood-brain barrier and produce sedation due to inhibition of histamine N -methyltransferase and blockage of central histaminergic receptors. Antagonism of other central nervous system receptor sites, such as those for serotonin, acetylcholine, and alpha-adrenergic stimulation, may also be involved . Phenothiazines are thought to cause indirect reduction of stimuli to the brain stem reticular system.

Now to break this down into some easily understood english.

1.) The basic ethylamine group common to antihistamines (Read molecular structure) is also common to anticholinergics, ganglionic- and adrenergic-blocking agents, local anesthetics, and antispasmodics, some antihistamines may exhibit some of the activities of these other classes of drugs. They do so by competively binding, in some cases blocking, and or activating these receptor sites.

2.) The 1st generation of H1 Blockers like dyphenhydramine are able to croos the blood brain barrier due to their lipophylicity. (READ THEIR ATTRACTION TO THE FAT IN THE CELLULAR MEMBRANES WHICH ALLOW IT TO CROSS THE BLOOD BRAIN BARRIER)

3.) Because some of dyphenhydramines action is in the 'higher brain centers it's neurotransmitter effects this is how you get soem of the sedative properties.

HTH, ACE844

Here's a link to a study describing the pharm dynamics: http://dmd.aspetjournals.org/cgi/content/full/34/6/955

[Just Plain Ruff]

HEY ACE!!!!!!!!!!!! YO MAMMA

But to get back to the thread, the info posted by Ace is spot on. Great research.

[Ace844]

HEY ACE!!!!!!!!!!!! YO MAMMA

But to get back to the thread, the info posted by Ace is spot on. Great research.

Your papa....

[Ridryder 911]

That is why Benadryl can have opposite effects... some it might cause sedation and others it might produce anxiety. Question of the day.. What is the symptoms of a major Benadryl O.D. ( i.e. 500 t0 1000mg) ... I had one last night..

R/r 911

[chbare]

Ridryder911, some of the problems I have seen with a major Benadryl overdose included,seizures, altered mental status, and ECG changes. I have heard that hyperpyrexia can occur as well. Benadryl can have class Ia cardiac activities so, you may see BBB, QT prolongation, other associated ECG changes. These would be in addition the the other Atropine like effects of Benadryl.

Take care,

chbare.

[Ace844]

"ChBare,"

Now I may be recalling incorrectly, but isn't there some kind of mechanisim or clinical pearl which says not to use valium for this?{the seizures}

ACE844

[chbare]

Ace844, I am not sure. I have not heard that Valium is specifically contraindicated. However, in very severe cases benzos may not work and the use of Physostigmine may be required. Here is a good article covering toxicity of antihistamines.

http://www.emedicine.com/EMERG/topic38.htm

Take care,

chbare.