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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 20 of 20. This is the beginning of the thread.
Posted by Janelle on March 23, 2002, at 1:09:47
Fachad wrote in a thread further up that an anticholinergic drug, for example a TCA, binds to cholinergic receptors and keeps acetylcholine from acting there. Okay, so far, so good, I get this!
However, if acetylcholine is a *good* thing, why would a TCA be designed to block it, or is it an unwanted thing that a TCA blocks acetylcholine? I other words is the acetylcholine blockade an unwanted side effect of a TCA?
And this leads me to ask, just what are TCA's targeted to in the brain? (SSRI's prevent serotonin reuptake, what do TCA's do?)
And one other thing - I'm not sure I'm getting the concept of the receptor - from the spelling of the word I associate it with *receiving*, so I come away with the idea that receptors receive things. Yet, when I read various threads on here explaining things, it sounds like receptors RELEASE things? What do receptors do? Ack ... I'm confused.
Posted by IsoM on March 23, 2002, at 3:28:01
In reply to Fachad, others: question about TCA's and receptors, posted by Janelle on March 23, 2002, at 1:09:47
First, the link I'm giving may be too much to understand. If it is, I apologise. But even if you don't understand it all, you may be surprised how much you do. It's about synapses, receptors & neurotransmitters. It's very well explained & it may not be easy reading for you, I think you'll find it interesting to learn.
If you do think it understandable enough, you might want to book mark the site. It comes with a diagram to help understand it better.
http://www.ultranet.com/~jkimball/BiologyPages/S/Synapses.html#neurotransmittersTCAs increase the level of norepinephrine & serotonin in the brain by inhibiting its uptake. As fachad mentioned earlier, neurotransmitters aren't just used in our brain but throughout are body for our entire nervous system moderating digestion, blood flow, heartrate, motor function, etc. So affecting these neurotransmitters in the brain often affects other system. Side-effects in other systems are therefore unavoidable.
Posted by fachad on March 23, 2002, at 11:03:20
In reply to Fachad, others: question about TCA's and receptors, posted by Janelle on March 23, 2002, at 1:09:47
Janelle,
First let me say that I am not really a neuropsychopharmacologist, I just play one on PSB!
You asked, "However, if acetylcholine is a *good* thing, why would a TCA be DESIGNED to block it, or is it an unwanted thing that a TCA blocks acetylcholine? I other words is the acetylcholine blockade an unwanted side effect of a TCA?"
TCAs were not designed - they were discovered. It was a serendipitous scientific discovery that these chemicals could relieve depression.
So if you are treating depression with a TCA, the anticholinergic properties are unwanted, unneeded side effects.
However if you are treating something else with a TCA, going "off-label" with the drug, the anticholinergic effects might be very useful.
My wife has a stomach condition called "IBS" and although all the tests show nothing wrong, she has terrible stomach pain, cramping, and diarrhea.
We went through months of trying different pills to stop the pain and diarrhea. We had to go to the ER every 3rd day for her to get IV fluids. She was even taking lots of Percocet, which usually kills any pain and causes terrible constipation, and it did not help.
Finally her GI doc suggested Elavil, a TCA. It worked almost immediately. The anticholinergic properties stopped the spasming of her intestines, which meant less pain, and Elavil also blocks serotonin.
Besides modulating mood in the brain, it turns out that serotonin modulates pain in the GI tract. So properties of Elavil that have nothing to do with its AD effects made it very useful for her IBS.
Take a look at this link:
http://www.preskorn.com/columns/9803.html
If fact, if you have time, Dr. Preskorn's entire site if just chock full of the stuff that you are asking so many questions about.
Here's the main link to Dr. Preskorn's site
http://www.preskorn.com/columns.html
> Fachad wrote in a thread further up that an anticholinergic drug, for example a TCA, binds to cholinergic receptors and keeps acetylcholine from acting there. Okay, so far, so good, I get this!
>
> However, if acetylcholine is a *good* thing, why would a TCA be designed to block it, or is it an unwanted thing that a TCA blocks acetylcholine? I other words is the acetylcholine blockade an unwanted side effect of a TCA?
>
> And this leads me to ask, just what are TCA's targeted to in the brain? (SSRI's prevent serotonin reuptake, what do TCA's do?)
>
> And one other thing - I'm not sure I'm getting the concept of the receptor - from the spelling of the word I associate it with *receiving*, so I come away with the idea that receptors receive things. Yet, when I read various threads on here explaining things, it sounds like receptors RELEASE things? What do receptors do? Ack ... I'm confused.
Posted by IsoM on March 23, 2002, at 13:22:44
In reply to Anticholinergic as Side Effect vs. Healing Effect » Janelle, posted by fachad on March 23, 2002, at 11:03:20
It's interesting that your wife has found that Elavil (amitriptyline) helps her IBS. My oldest son has IBS too. Now that he's in his latter 20s, the frequency of attacks have gone way done, but so has his stress level.
When he was in his late teens, early 20s, he took a new med at the time, called Dicetel. He had been on clomipramine for his depression. It worked better than any other TCA for him. Dicetel is a selective calcium-channel blocker & it nicely blocked the wayward nerve impulses just enough that his digestive system resumed its normalacy. It's a prophylatic med but now that his cases are so infrequent, he no longer takes it. I don't know if it's available in the States. For him, it was a life saver. I'm sure you know how *severe* it can get & how unbearable the pain & nausea.
Posted by SLS on March 23, 2002, at 14:07:17
In reply to Fachad, others: question about TCA's and receptors, posted by Janelle on March 23, 2002, at 1:09:47
Hi Janelle.
> However, if acetylcholine is a *good* thing, why would a TCA be designed to block it, or is it an unwanted thing that a TCA blocks acetylcholine? I other words is the acetylcholine blockade an unwanted side effect of a TCA?
...just to make things more interesting...
At this point, I'm not sure that the anticholinergic properties of TCAs can be ruled out as playing a role in their therapeutic effects. I don't have any compelling reason to think they do, but...
One of the older theories proposed for the etiology of depression involved the balance between opposing cholinergic and dopaminergic pathways - too much acetylcholine and too little dopamine.
I like following the threads that you start. I learn so much. There are a lot of very smart people here, including those who ask smart questions!
Take care.
- Scott
Posted by Ritch on March 23, 2002, at 14:26:23
In reply to IBS and Elavil » fachad, posted by IsoM on March 23, 2002, at 13:22:44
> It's interesting that your wife has found that Elavil (amitriptyline) helps her IBS. My oldest son has IBS too. Now that he's in his latter 20s, the frequency of attacks have gone way done, but so has his stress level.
>
> When he was in his late teens, early 20s, he took a new med at the time, called Dicetel. He had been on clomipramine for his depression. It worked better than any other TCA for him. Dicetel is a selective calcium-channel blocker & it nicely blocked the wayward nerve impulses just enough that his digestive system resumed its normalacy. It's a prophylatic med but now that his cases are so infrequent, he no longer takes it. I don't know if it's available in the States. For him, it was a life saver. I'm sure you know how *severe* it can get & how unbearable the pain & nausea.
IsoM,That is interesting. I found that higher doses of Neurontin (if I could tolerate them) improved my IBS symptoms. It is supposed to be a selective calcium channel blocker as well.
Mitch
Posted by Janelle on March 23, 2002, at 20:40:50
In reply to Anticholinergic as Side Effect vs. Healing Effect » Janelle, posted by fachad on March 23, 2002, at 11:03:20
Fachad,
Just a coincidence but the first AD I was on was Elavil, and it got me to sleep like a baby the first week or so I was on it, then that sedating side effect wore off, as did the anticholinergic ones.
Now, you wrote in another thread somewhere that serotonin occurs in the synapses of the intestines (or someplace within the digestive system), but look what I found in the link that Iso posted:
"Serotonin (also known as 5-hydroxytryptamine or 5HT). Synthesized from tryptophan (Trp).
Histamine
Both of these neurotransmitters are confined to synapses in the brain"Based on this, there is NOT serotonin anywhere in the body but the synapses of the brain. But you said there's serotonin in the digestive system .... hmmmm ... I'm now confused again!!
What do you think of this?
-Janelle
Posted by Janelle on March 23, 2002, at 20:55:21
In reply to Anticholinergic as Side Effect vs. Healing Effect » Janelle, posted by fachad on March 23, 2002, at 11:03:20
Fachad,
You said "TCAs were not designed - they were discovered. It was a serendipitous scientific discovery that these chemicals could relieve depression."
Okay, so if TCA's were NOT originally designed for depression but it was a serendiptious discovery that they could relieve depression, WHAT were they originally designed for??!!??
Also, you wrote: "if you are treating something else with a TCA, going "off-label" with the drug, the anticholinergic effects might be very useful.
If TCA's were not originally designed for depression, then why would using them for something OTHER than depression be considered "off label"??
Thanks!
-Janelle
Posted by Janelle on March 23, 2002, at 21:11:00
In reply to FACHAD again! Quick question 4 U: » fachad, posted by Janelle on March 23, 2002, at 20:55:21
I'm copying/pasting something from the link provided by Fachad (great stuff there, btw!) and would appreciate it if someone could verify if I'm understanding it properly:
for TCA's it says "Serotonin and norepinephrine reuptake inhibition plus effects on multiple receptors and fast sodium channels (e.g., amitriptyline, imipramine)"
Based on this, my conclusion is that SSRI's and AD's such as Effexor which works on both Serotonin and Norepinephrine are SPECIFICALLY targeted to these neurotransmitters, whereas TCA's act on these neuros plus OTHER ones and it is their action on OTHER ones which may cause the anticholinergic side effects?
Posted by IsoM on March 23, 2002, at 21:52:18
In reply to Re: IBS and Elavil » IsoM, posted by Ritch on March 23, 2002, at 14:26:23
Posted by IsoM on March 23, 2002, at 22:04:36
In reply to FACHAD: re Serotonin and TCA's » fachad, posted by Janelle on March 23, 2002, at 20:40:50
Sorry, Janelle. This can be awfully confusing when you first learn but I've got to explain the context of "these neurotransmitters are confined to synapses in the brain". This is just talking about the context of the BRAIN only, & IN THE BRAIN, the only place serotonin is, is in the neural synapses.
When serotonin is found in other places in the body, it's not just confined to the synapses of nerves. I hope you can see this difference.
I hope this will help & not confuse you more. And when a person studies these things in university, remember, it's taken slow & easy with simple biology first & slowly becomes more complicated - building on a previous foundation of knowledge. Jumping in to learn just about brain biochemistry is going to make you feel like you're floundering at times. Don't give up! you're doing wonderfully, Janelle, & it'll all come together yet.
"The greatest concentration of 5HT (90%) is found in the enterochromaffin cells of the gastrointestinal tract. Most of the remainder of the body's 5HT is found in platelets and the CNS. The effects of 5HT are felt most prominently in the cardiovascular system, with additional effects in the respiratory system and the intestines. Vasoconstriction is a classic response to the administration of 5HT.
Neurons that secrete 5HT are termed serotonergic. Following the release of 5HT, a portion is taken back up by the presynaptic serotonergic neuron in a manner similar to that of the reuptake of norepinephrine.
The function of serotonin is exerted upon its interaction with specific receptors. Several serotonin receptors have been cloned and are identified as 5HT1, 5HT2, 5HT3, 5HT4, 5HT5, 5HT6, and 5HT7. Within the 5HT1 group there are subtypes 5HT1A, 5HT1B, 5HT1D, 5HT1E, and 5HT1F. There are three 5HT2 subtypes, 5HT2A, 5HT2B, and 5HT2C as well as two 5HT5 subtypes, 5HT5a and 5HT5B. Most of these receptors are coupled to G-proteins that affect the activities of either adenylate cyclase or phospholipase Cg. The 5HT3 class of receptors are ion channels.
Some serotonin receptors are presynaptic and others postsynaptic. The 5HT2A receptors mediate platelet aggregation and smooth muscle contraction. The 5HT2C receptors are suspected in control of food intake as mice lacking this gene become obese fromincreased food intake and are also subject to fatal seizures. The 5HT3 receptors are present in the gastrointestinal tract and are related to vomiting. Also present in the gastrointestinal tract are 5HT4 receptors where they function in secretion and peristalsis. The 5HT6 and 5HT7 receptors are distributed throughout the limbic system of the brain and the 5HT6 receptors have high affinity for antidepressant drugs."
Posted by IsoM on March 23, 2002, at 22:10:41
In reply to FACHAD again! Quick question 4 U: » fachad, posted by Janelle on March 23, 2002, at 20:55:21
Posted by Janelle on March 23, 2002, at 22:13:29
In reply to Serotonin and Where found » Janelle, posted by IsoM on March 23, 2002, at 22:04:36
Iso,
Thanks ever so much for clarifying where serotonin is found! I did understand what you said, but as far as the material you quoted - OHMIGOSH I could follow maybe one or two sentences!
I get the impression from reading the material, that there is actually MORE serotonin secreted in the digestive system than in the brain??? Is this right? It sounded like there are more 5HT receptors in the digestive area than in the brain?
Also, I gotta know - WHAT IS YOUR BACKGROUND???!! Are you a nurse, doctor or have some kind of degree/job in the medical profession? Or are you a scientist? Your knowledge and the links you provide are SO chock full of very technical information that YOU apparently understand and can follow that I am dying to know what your background is.
I feel SO dumb.
Posted by IsoM on March 23, 2002, at 22:41:52
In reply to ISO - Re: Serotonin and Where found » IsoM, posted by Janelle on March 23, 2002, at 22:13:29
What a sweetheart you are for saying that. I'm nothing much, just working part-time with plants & gardening which I love & will say I'm good at.
I've taken some university, but never finished. But I just love learning - almost like an insatiable hunger for learning & understanding.
Yes, far more serotonin (same thing as 5HT) receptors in the lining of the gut & stomach. And I'm ordering you NOT to feel dumb. Everybody has diff strengths in diff areas & nobody should think their area of expertise is better than another's.
P.S. It's funny but even some doctors have thought I have a background in some medical field. The thing is the more I learn, the more I realise how little I do know. Absolutely serious.
Posted by fachad on March 23, 2002, at 23:22:55
In reply to FACHAD again! Quick question 4 U: » fachad, posted by Janelle on March 23, 2002, at 20:55:21
Janelle, you'll have to cut me some slack if my writing is not up to par as I had some wine with dinner and my writing skills are suffering! Here's the story with drug discovery, development and marketing.
Chlorpromazine, the first anti-psychotic, was accidentally discovered. They were working on developing anti-histamines.
Imipramine, the first TCA, was accidentally discovered while trying to find other anti-psychotics that could be derived from anti-histamines.
They noticed that psychotic patients got better on chlorpromazine, and the depressed patients got better on imipramine.
They discovered that chlorpromazine blocked dopamine and the imipramine blocked serotonin and noreprenephrine reuptake.
So they postulated that psychosis was from excess dopamine, and depression was from deficient serotonin and norephinephrine. The drugs came first, then the theory as to how they worked.
Later on they saw that there was big $$ in psych drugs, so they set chemists to work on designing ones that would do what they thought would theoretically relive depression, while trying to avoid all the other receptors and side effects. That's how SSRIs were developed.
"Off-Label" is a legal term, not a medical term. In the US, the FDA requires drug companies to do trials that prove the drug is effective for the condition it is marketed for. An example is Paxil for depression.
SKB, the company that makes Paxil, did trials and showed that Paxil was more effective than placebo for depression. Then Paxil was released onto the market, with a "label indication" for depression.
Pdocs noticed that Paxil also helped their patients who had OCD or anxiety. If a pdoc gave an anxiety patient Paxil, that was considered "off label". You are not using the pill for it's official indication. That does not mean in any way that it is less effective. It is just not what the official FDA indication says.
Anyway, SKB went ahead and did trials to get Paxil labeled for anxiety, so now if a pdoc gives a patient Paxil for anxiety it is not off label.
Your original question was about TCAs and off label use. Well, because SSRIs seem more tolerable most people don't use TCAs for depression anymore.
But docs, not just pdocs, have found that TCAs work miracles for many conditions other than depression. TCAs are very effective in the prevention of migraine headaches, treatment of IBS, insomnia, chronic pain, fybromyalgia, anorexia, bed wetting in children, and on and on. But all of these uses are off label because there have not been any FDA supervised trials proving that they work. But docs do know that they work.
> Fachad,
>
> You said "TCAs were not designed - they were discovered. It was a serendipitous scientific discovery that these chemicals could relieve depression."
>
> Okay, so if TCA's were NOT originally designed for depression but it was a serendiptious discovery that they could relieve depression, WHAT were they originally designed for??!!??
>
> Also, you wrote: "if you are treating something else with a TCA, going "off-label" with the drug, the anticholinergic effects might be very useful.
>
> If TCA's were not originally designed for depression, then why would using them for something OTHER than depression be considered "off label"??
>
> Thanks!
> -Janelle
Posted by fachad on March 23, 2002, at 23:47:57
In reply to FACHAD: re Serotonin and TCA's » fachad, posted by Janelle on March 23, 2002, at 20:40:50
I don't know where you read that statement, but histamine and serotonin are massively distributed all thought the entire human body.
When you rub up against a bush that you are allergic to, the "weal" or hives is from histamine flare up.
SSRIs cause abdominal distress by affecting the serotonin in the GI tract.
Ondansetron, the most potent anti-nausea drug ever, works by blocking serotonin in the GI tract.
> Fachad,
>
> Just a coincidence but the first AD I was on was Elavil, and it got me to sleep like a baby the first week or so I was on it, then that sedating side effect wore off, as did the anticholinergic ones.
>
> Now, you wrote in another thread somewhere that serotonin occurs in the synapses of the intestines (or someplace within the digestive system), but look what I found in the link that Iso posted:
>
> "Serotonin (also known as 5-hydroxytryptamine or 5HT). Synthesized from tryptophan (Trp).
> Histamine
> Both of these neurotransmitters are confined to synapses in the brain"
>
> Based on this, there is NOT serotonin anywhere in the body but the synapses of the brain. But you said there's serotonin in the digestive system .... hmmmm ... I'm now confused again!!
>
> What do you think of this?
> -Janelle
Posted by Ritch on March 24, 2002, at 1:07:21
In reply to Is Dicetel not available in the States? (nm) » Ritch, posted by IsoM on March 23, 2002, at 21:52:18
I never heard of it before, but evidently it has been around for a long time. It isn't available here in the US, only in Canada-wonder why? Here is a link to Solvay's page on it:
http://www.solvaypharmaceuticals.com/html/products/Gastroenterology/dicetel.htmlMitch
Posted by fachad on March 24, 2002, at 3:58:11
In reply to IBS and Elavil » fachad, posted by IsoM on March 23, 2002, at 13:22:44
Yes, my wife's IBS was very severe. She did not have any IBS until one day in Nov 1992. She woke up with a stomachache, vomiting, and diarrhea.
Despite many visits to her doc and trials of different meds her symptoms never abated and continuously got worse. The pain was so bad she could not sleep. She vomited 5 or 6 times a day and had diarrhea 5 or 6 times a day. The pain and diarrhea were not even slowed down by huge doses of Percocet and Imodium. The vomiting would abate a little with composine suppositories. We would have to go to the ER, with her holding a trash bag for the drive, every 2 or 3 days so they could give her IV fluids for the dehydration.
Of course all the tests, which were a major hassle to get the HMO to consent to, showed NOTHING. Upper and Lower GI, nothing. Gallbladder, nothing. This went on from that day in November 92 when it started until March 93, almost 5 months of daily and nightly pain, vomiting and diarrhea. She was just crying all the time and we did not know what to do. Finally the greedy HMO authorized a visit to a GI doc (we would have self paid anyway, but they finally came thru) and he was the one that put her on Elavil.
He said that most people with IBS responded to 25 mg of Elavil, but let her titrate up the dose until her symptoms were gone. She ended up at 225 mg/day.
A few years later she was able to get down to 150 mg/day, but anytime we have tried to go lower, she ends up in the ER. Once we tried to switch to doxepin, and she ended up in the ER.
So she's resigned to taking 150mg Elavil every day for the rest of her life, and despite the unpleasant side effects, we are both so thankful that it worked so well.
> It's interesting that your wife has found that Elavil (amitriptyline) helps her IBS. My oldest son has IBS too. Now that he's in his latter 20s, the frequency of attacks have gone way done, but so has his stress level.
>
> When he was in his late teens, early 20s, he took a new med at the time, called Dicetel. He had been on clomipramine for his depression. It worked better than any other TCA for him. Dicetel is a selective calcium-channel blocker & it nicely blocked the wayward nerve impulses just enough that his digestive system resumed its normalacy. It's a prophylatic med but now that his cases are so infrequent, he no longer takes it. I don't know if it's available in the States. For him, it was a life saver. I'm sure you know how *severe* it can get & how unbearable the pain & nausea.
Posted by fachad on March 24, 2002, at 4:09:05
In reply to ANYONE: Y R TCA's but not SSRI's anticholinergic?, posted by Janelle on March 23, 2002, at 21:11:00
That's EXACTLY right - you're getting it, and it's only been a few weeks. Think where you'll be after you've been at this for a while!
What you just wrote: "Based on this, my conclusion is that SSRIs and ADs such as Effexor which works on both Serotonin and Norepinephrine are SPECIFICALLY targeted to these neurotransmitters, whereas TCAs act on these neuros plus OTHER ones and it is their action on OTHER ones which may cause the anticholinergic side effects?"
This is a key thing. SSRI are SPECIFIC Serotonin Reuptake Inhibitors. They are clean in that they do what they are supposed to do, and nothing else. Effexor is an SSNIR; it is SPECIFIC, but it blocks both NE and 5HT uptake.The whole quest for new drugs is to find ones that will affect the target receptors and have the desired actions without affecting other receptors and causing side effects.
> I'm copying/pasting something from the link provided by Fachad (great stuff there, btw!) and would appreciate it if someone could verify if I'm understanding it properly:
>
> for TCA's it says "Serotonin and norepinephrine reuptake inhibition plus effects on multiple receptors and fast sodium channels (e.g., amitriptyline, imipramine)"
>
> Based on this, my conclusion is that SSRI's and AD's such as Effexor which works on both Serotonin and Norepinephrine are SPECIFICALLY targeted to these neurotransmitters, whereas TCA's act on these neuros plus OTHER ones and it is their action on OTHER ones which may cause the anticholinergic side effects?
Posted by IsoM on March 24, 2002, at 13:46:16
In reply to Re: IBS and Elavil » IsoM, posted by fachad on March 24, 2002, at 3:58:11
And I thought my son's IBS was bad. Your wife has an unusually bad case!
My son's symptoms came on very suddenly too & I took him to ER. They ran a number of tests & strangely his amylase levels were sky-high. They thought he had pancreatitis, but there was no cause for it. He stayed in the hospital for a few days till the symptoms left & they ran test after test on him too. As you know, these tests are awful. He particularily "liked" the part where they clean out your lower tract & blow it up with air to stick a scope up it.
IBS is ususually diagnosed by all other tests coming back negative. They did EVERY test there was on him except they couldn't get a scope down his throat - his gag reflexes were so strong they still worked even when he was put out.
He had recurrent attacks despite our best efforts to control all conditions & his diet. When Dicetel came out, our doctor told us about it & he went on it. He used it for about three years straight (no longer needs it) & now has IBS attacks infrequently & much milder & shorter than before.
My sympathies for your wife. Perhaps you could inquire whether she could also take Dicetel & it might enable the Elavil to be evern further lowered, even if it can't be discontinued.
This is the end of the thread.
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