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pre-med student with a question about antihistamines

Discussion in 'Medical Students - MD' started by evoviiigsr, May 6, 2007.

  1. evoviiigsr

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    First off, I'm just a pre-med student with a question that I thought you guys could easily answer:

    I know that antihistamines like diphenhydramine are CNS depressants. This would mean it decreases heart rate. BUT, I've taken it before and had an increase in heart rate. I did some reading and found out that antihistamines have anti-muscarinic effects, which I presume will only affect the parasympathetic nervous system. Since HR is controlled by the vagus nerve, a decrease in parasymp. activity should increase HR.

    I've tried researching it, but I'm having trouble. SO my question is, why is diphenhydramine supposed to decrease heart rate but can sometimes increase it?

    My second question is: what part of the CNS is specifically depressed and what is the general mechanism
     
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  3. colbgw02

    colbgw02 Delightfully Tacky
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    Okay, so I did a brain dump of most of the crap you just said about 3 years ago, but...

    Apart from their anti-histamine effects, they also have anti-cholinergic effects, which can cause tachycardia. As to why it affects some people more severely, or in some cases causes an opposite reaction, I always thought it was just idiosyncratic.
     
  4. Tired

    Tired Fading away
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    The brain part.
     
  5. tulane06

    tulane06 Private Joker
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    Scratch that
     
  6. evoviiigsr

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    Thanks for you reply

    I've read that tachycardia and excitatory symptoms occur in an "overdose", which I guess could happen at normal doses for some people. So, my question is: is it safe to say that if your HR decreases, antihistamine effects>anticholinergic effects and vice versa? This would imply that antihistamine effects are more common and occur before anticholinergic effects, correct?

    OK one last question: diphenhydramine decreases ventilation rate, and I was kind of confused on how this occurs. I'm assuming that action potentials to the diaphragm and external intercostals are reduced? Is the phrenic nerve responsible for this? How exactly so, I don't really understand what the phrenic nerve actually is (parasymp or symph) and how it works. ahhh, I'm just trying to link the effects of the drug on HR and VR together and my lack of knowledge is hindering my progress, and researching is yielding me too complicated results.
     
  7. DoctorFunk

    DoctorFunk Get down with the boogie
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    Better not to think too hard on these things. The control of ventilation becomes a really fuzzy brainstem-controlled issue--much more complex than simple sympathetic vs. parasympathetic reasoning methinks.

    If it's really bugging you that much write the question down and come back to it after you take med school physiology. Or go ask a pharmacist.
     
  8. SeventhSon

    SeventhSon SIMMER DOWN
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    there are many pathways that control outflow of the autonomic nervous system. H1 receptors control alertness, so anti-histamine effects will cause sedation through that pathway. That tends to cause a decrease in central sympathetic flow.

    antihistamines, as you point out, can have anti-muscarinic effects as well. However, mAchR aren't really involved with sympathetic and parasympathetic outflow in the CNS... they are involved in things like balance, memory, emotion, and coordination. So really, the anti-muscarinic effects only contribute periperhally, which tends to cause an increase in heart rate.

    I think anti-histamines often have anti alpha1-adr effects as well. This can cause a BP drop, and reflex tachycadia.

    It is imaginable that people with a SNP affecting one of these receptors, or as part of a degradation pathway, that could make people more or less susceptible to one of these effects.
     
  9. SeventhSon

    SeventhSon SIMMER DOWN
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    also, your vagus nerve can fire all you want but if there are anti-muscarinics blocking your SA node, it doesn't matter. The increased parasympathetic outflow (manifested as ACh in the neuroeffector junction) never reaches the heart
     
  10. evoviiigsr

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    Right. Since the effectiveness of the vagus nerve is reduced by anti-muscarinics, that would explain the tachycardia?

    I figured that there is an abundance of these receptors, so a higher than normal amount of the antagonist drug would be required for tachycardia to be observed. What I am trying to figure out is, does diphen. have a higher affinity for H1 receptors than muscarinic, since bradycardia is more common than tachycardia? Or are H1 receptors more sensitive, explaining why it takes higher dosages for tachycardia to occur.
     
  11. megadon

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    Uhmm, this premed know more that me after my entire first year. Is he available to take my tests?
     
  12. cfdavid

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    While I haven't had pharm yet, we're doing neuroscience/neuroanatomy right now. So, I can add a bit to this.

    You may know that most OTC sleep aids are antihistamines.
    When it comes to higher cognitive function, things get a little gray (pun intended). But, the thalamus plays a role in determining if the cortex receives sensory information (It's a major pass through center of information going to the cortex). Thus, the thalamus is important in the sleep/wake cycle (if the thalamus relays the info you are awake or in REM, but if not then you are in non-REM sleep), depending on inputs it receives from different nuclei (that secrete different neurotransmitters), and in what ratios of those NT's. So, as the different NTs are secreted to the thalamus in different quantities/ratios throughout the day, this contributes to our circadian rhythm, and thus our sleep/wake cycle.

    Histamine secreted by the posterior hypothalamus is released to the thalamus. It's part of what is known as the Reticular Activating System (other neurotransmitters released as inputs to the thalamus are dopamine, NE, serotonin, and Ach). And, again, depending on the time of the day, the different ratios will dictate whether we are in wake "mode", non-REM sleep, or REM sleep.

    Histamine has been proven to be stimulatory to the thalamus (along with other combo's/ratios of other NT's) in terms of stimulating thalamic relay cells to allow for information flow to pass through the thalamus and enter various areas of the cortex. This allows for consciousness, versus an unconscious state (non-REM sleep) such as if the thalamic relay cells were inhibited from relaying sensory information to the cortex.

    Thus, inhibit Histamine and this will take away that stimulating effect on thalamic relay cells. And this will make you tired. As for why the tachycardia, I'm just not sure. I'm not there yet. But, thought you may appreciate the mechanism behind Histamine being stimulatory to the CNS.

    Also, needless to say (but I'll say it anyway), if anyone can add to this or clarify it, please do. I paraphrased this from our notes, which I found to be mediocre at best.
     
  13. evoviiigsr

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    Thanks!

    So I'm assuming that these receptors in the thalamus are the H1 receptors.

    So diphenhydramine binds to these H1 receptors and doesn't allow histamine to bind, therefore depressing the CNS. And decreased heart rate and ventilation rate are caused by this depression. Does the decreased thalamus activity directly cause a decrease in activity of the respiratory control center and cardiovascular control center in the medulla?
     
  14. SeventhSon

    SeventhSon SIMMER DOWN
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    i think that for the first-generation antihistamines, the anti-muscarinic potency is on the same order of magnitude as the anti-H1. Overall the anti-muscarinic probably "wins out" more because it is last point of extracellular body regulation... every signal influencing HR converges on beta-1/M2 activation, so a disturbance at this point in the pathway is more important. I'm not sure whether the "spare receptor effect" applies to muscR on the heart.
     
  15. cfdavid

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    Not sure about this. I haven't had pharm yet, and it would be speculation on my part.

    Regarding the H1 receptors, obviously they are present elsewhere in the body other than the thalamus. Hence the more commonly known use of antihistamines in prohibiting the effects of histamine release in the case of allergies (mast cells dumping histamine and haparin peripherally).
     
  16. evoviiigsr

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    After some reading and your help, this is what I've come up with:

    Diphenhydramine is a 1st gen antihistamine that exhibits both anti-histamine and anti-muscarinic effects, by binding to H1 and muscarinic receptors respectively. When it binds to H1 receptors in the thalamus, stimulatory input to the cortex is removed, which causes CNS depression, namely decreased HR and possibly decreased VR. The drug is lipophilic, so it can cross the BBB and exhibit effects in the brain. Most of the decrease in VR is due to the bronchiodilation effects of the drug, which reduces the amount of breathing work. When diphen. binds to the muscarinic receptors, the amount of ACh that can bind to the SA node decreases, so tonic control of the HR is removed and HR increases.

    2nd generation antihistamines like celebrex have just anti-muscarinic effects, but no anti-histamine effects in the CNS since they are lipophobic and can't cross the BBB.
     

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