cholinesterase update
 

This article is so confusing it's funny, but I think they are answering my probing question about AD and PD taking cholinesterase inhibitors.
I think this article says that when anti-cholinesterase drugs [Aricept] are given to a person with a cholinesterase deficiency [polymorphism? gene?] it can cause it to overexpress the enzyme, resulting in pools of extra enzyme.

Researchers who are multi lingual and speak this language feel free to add.

http://hmg.oxfordjournals.org/cgi/content/full/9/9/1273

One of the last sentences says,

"To conclude, this polymorphism, identifies a new HNF3-binding enhancer domain important for AChE expression. Heterozygosity for the deletion is manifested as constitutive overproduction of AChE;

such overproduction, which increases the susceptibility to acute anti-AChE exposures in mice, [ surely this increases acetylcholine?] is likely to be the cause of the hypersensitivity of proband I to pyridostigmine.

pyridostigmine is anticholinesterase [like Aricept]

The proposed link between this mutation and the hypersensitivity points to carriers of this allele [gene?]as individuals at risk of developing adverse responses under treatment with or exposure to anti-AChEs, which is important in view of the increasing use of anti-AChEs as Alzheimer’s disease drugs (11).

Moreover, stress- or anti-AChE-induced increases in AChE levels (17) may cause acquired anti-AChE sensitivity, putting at risk a considerably wider group of individuals (7).

This type of chemical hypersensitivity therefore emerges from our study as a complex trait, perhaps involving both early modulators such as transcription factors and downstream responding genes."

So messing with the enzyme can ruin its function,which can cause permanent sensitivity problems and dysfunction. It's an overproduction of the enzyme, but rather than flowing freely it collects, but i'm left with the same question:

Is the result of this an increase in acetycholine? Is the bottom line still too much acetylcholine? or does the trouble stop at the pool of enzyme spillage? i doubt the latter. Does anyone know?


It isn't as cut and dry as i thought when starting this research but now i know more about what leads to a similar reaction as mine when trying aricept. From what I can tell, the results are delivering the same message. It's risky to take this type of drugs if you have alzheimers or pd. It interferes and interrupts the break down of acetylcholine, which is toxic if givven too large a quantity. These drugs whose purpose is to provide greater quantities of acetylcholine for cognition cause overexpression of the enzyme inhibitor AChE which collects in pools. Collecting in pools sounds ominous.

thanks!
paula

case report
 

pyridostigmine - cholinesterase iinhibitor like aricept.

Proband I, a 30-year-old woman of Ashkenazi Jewish origin and no significant history of adverse drug responses, received a single oral dose of 30 mg pyridostigmine, a dose considered safe, which is given prophylactically under anticipation of chemical warfare (12).

Within 1 h, peripheral blood AChE fell to an almost undetectable level, increasingly severe muscle fasciculations developed, accompanied by intense headache, rhinnorea, lacrimation and frequent urination. These acute symptoms continued for 3 days, and resolved into a 5-day period of extreme fatigue, muscle weakness and general malaise.

I hear ya!
Been there,
paula

http://hmg.oxfordjournals.org/cgi/content/full/9/9/1273

a lightbulb moment
 

ahhhha, It's stress triggerring changes in the epigenome which controls the expression of the gene which controls ACHe levels, resulting in increased ACHe levels....
I am certain the answer is not that linear...nonetheless

For what it's worth, we are very careful about any drug or supplement which impacts the acetylcholine system for my husband--he reacts in a definite adverse way.

trying to keep up.........
 

and wasn't able to manage it but found this site which might help some of the mind-boggled (like me) among us!! browsing around it helped a little.

http://www.brainexplorer.org/neurolo...smitters.shtml

Thanks for this Paula, I am dimly understanding some of what it is about, keep it coming ;)

Collecting in pools...
 

Paula,

Laughing at the ominous collecting in pools comment; you are funny. :) I think of a new sort of West Side Story with our neurotransmitters in primary roles!

Speaking of ominous...I ran across this disturbing, but highy detailed and nicely formatted governmental site that has multiple pages explaining the function of acetylcholine, the peptide (AcHe), and the main types of receptors: the nicitinic and the muscarinic. The CDC site on environmental toxins explores something called cholinergic toxicity and its symptoms, etc....interestingly enough this toxic buildup can result from toxic exposure to insecticides or chemical warfare nerve agents. Yikes, interesting to see a pesticide link though.

http://www.atsdr.cdc.gov/csem/cholin...nhibitors.html

What is more alarming, but not at all surprising, is that abrupt withdrawal from an anti-cholinergic can cause what is called "cholinergic rebound" with some serious symptoms. When we end up with too much acetylcholine we can get a "cholinergic toxidrome".

I find the research on how the receptors (muscarinic) are implicated in demential and that they are different again for PD and AD.

Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer's and Parkinson's diseases.
Aubert I, Araujo DM, Cécyre D, Robitaille Y, Gauthier S, Quirion R.

Department of Neurology, McGill University, Montreal, Quebec, Canada.

Interesting to pursue and may post more later...

Anyone know if too much a-choline causes a focal dystonia (like my darn foot) or a general dystonia?

Laura

If it doesn't get you one way it will get you another :(
 

Laura, thanks for this. I am on an anti-cholinergic patch which is working ok, except......I seem to have developed a rash, so need to change it. Trying to come off is not good, I'll need another clinic appointment to address this problem, I had no idea till I tried that it would be so bad.

Suppose that is one of the reasons I am following Paula's research, even though I am way in over my head with the science.

In the meantime I itch all over...........

About foot dystonia - While on the patch I have had nocturnal foot cramps ......and an increase in jaw dystonia when sinemet wears off......

Benadryl
 

Is Benadryl an anticholinergic?

It seems to help my dystonia.

Yep, it is considered in the same drug family as the anticholinergics. Benadryl was used early on in PD treatment before our standard drugs were in play.

i'm going to think out loud and lindy i don't have it down either. This is not to be taken as fact.

the article says they give it to people when a chemical weapon is expected for protection. they give them the enzyme inhibitor - which blocks the AChE - then- what right here is what i am trying to learn.

why would they want the enzyme to stop breaking down acetylcholine? They are giving people meds to stop cholinergic activity during chemical warfare.

we know that acetylcholine is used in chemical warfare, so would the enzyme prevent the acetylcholine from a chemical attack from getting processed? it is offering some kind of protection that we haven't learned about yet, it seems. This is a contradiction to me so I need help with it.

next, lindy says she is getting dystonia when off since she started taking an anticholinergic. So your patch's job is to assist in keeping acetylcholine regulated as the enzyme does that breaks it down - namely it helps AChE which is cholinesterase. Acetylcholine needs to be kept low.

So lindy's patch is causing dystonia when off. Did you not have dystonia before this lindy or did it get worse? my dystonia is quite bad when i'm off and it sounds like this could be the imbalance of acetylcholine and dopamine and i 'm wondering if the type of dystonia we are talking about is from acetylcholine levels being too high when we are off.

But the anti-cholinergic activity from the patch should keep you from getting dystonia because it should balance the transmitters. it should be enabling the enzyme to break it down and keep the levels low. Nortriptyline has reduced the length and severity of my morning dystonia.

Therefore, I don't understand why lindy would be getting increased dystonia with an anti-cholinergic patch. Were you on an anticholinergic pill before you started the patch? Did you have a reduction in the dosage by going on the patch? is this an experimental med?

exelon has the patch.but it is not anticholinergic. it's anti-acetylcholinesterase, a cholinesterase inhibitor, an alzheimer med. and if so it's raising your aceptylcholine and that causes cramping and i think it causes the dystonia. So if your patch is exelon or any cholinesterase inhibitor and it is giving you dystonia, you have proven my point. this is not for people with pd unless they have a deficiency like franny. But even with the psuedo AChE deficiency franny felt the best with nortriptyline, which is not a cholinesterase inhibitor- but rather an anti-cholinergic to help lower acetylcholine. if you are on exelon and getting more dystonia, you have validated what i'm thinking based on my own experience. if not, i'm still confused.

donw -Benadryl quite a few pwp take benadryl and say it helps. it helps to keep acetylcholine low [as it should be]

i asked my pharmacist about giving pwp alzheimers medicines and mentioned acetycholine- asked him if i was speaking his language. he said they wouldn't do that or shouldn't or who would do that? something like that. i told him it was FDA approved for pd and they gave it to me and it made me very sick. he thought i meant sick to my stomach but i was getting the feeling that he didn't want to go against my neuro as he changed and said, 'well i guess it's an individual thing...have to try it and see." he also added, well it makes sense to give it to pwp. i didn't walk away with the matter cleared up at all. There were two people waiting so i gave it up.

my question remains the same. is the problem with using cholinesterase inhibitors too much acetylcholine? This is a deadly poison in access.

thanks for helping with your comments. it's very important. i'm confused about whether the sensitivity and polymorphism talked about in this article which is soooo technical is the same genetic deficiency as the one franny has? pseudoAChE deficiency? yet it sounds like it can be a result of the alzheimer-like meds.

keep the info coming - lindy i'm very curious about your patch.

paula

Enzyme prevents breakdown
 

Paula,

From all I've read, a cholinisterase inhibitor is an enzyme which inhibits the breakdown of acetylcholine. In other words, our bodies naturally produce this enzyme and drugs like Aricept interfere with the enzyme either blocking it or dampening it, so acetylcholine does not break down. In PD, we already have too much of it, so in essence using something like Aricept leave us with even more which could result in more dystonia! Is this what you are wondering?

To your question...

we know that acetylcholine is used in chemical warfare, so would the enzyme prevent the acetylcholine from a chemical attack from getting processed? it is offering some kind of protection that we haven't learned about yet, it seems. This is a contradiction to me so I need help with it.

The drug or chemical warfare blocks the enzyme from breaking down acetylcholine; it does the opposite, it allows the acetyl-ch to proliferate unchecked. The enzyme is like a bouncer at a bar keeping things in check, by giving the bouncer the night off (the cholinesterase inhibitor), the bar is over run with too much drunken acetyl choline- I'm bad with analogies, but you get it. In war we end up with cholinergic toxidrome or toxicity (too much acetyl choline) which can result in death.

This info and research I put together is buried in another post; I am going to copy/paste it here. Also, the common sense idea about this aggravating our symptoms has been corraborated by a pharmacist and by research. Next, I ask, do our doctors have any common sense?

From my other post:

Fairly recently, it has become in vogue for neuros to prescribe cholinesterase inhibitors used routinely for Alzheimer's to treat cognitive impairment for PD. However, you should ask your neuro many questions before doing so because they directly counteract the effect of any other PD drugs we may take and further screw with what little neurotransmitters we have left. We have dissected this in another recent long thread, but this is the gist of it all:

-PD results in loss of dopamine and a subsequent increase in acetylcholine; the latter is what causes our motor symptoms: bradykinesia, tremor, and rigidity.

-Taking a cholinesterase inhibitor actually raises our levels of acetylcholine when we already have too much. Common sense would tell us that this will exacerbate our Parkinson's symptoms. Sure enough, there are studies to substantiate this:

From PubMed:

Cholinesterase inhibitors: tremor and exacerbation of Parkinson's disease.

[No authors listed] Prescrire Intl

(1) Three cholinesterase inhibitors are marketed in France for the treatment of Alzheimer's disease: donepezil, galantamine and rivastigmine. Tremor and dystonia are known adverse effects of cholinesterase inhibitors. (2) In patients with Parkinson's disease who have cognitive disorders, or in patients with Lewy body dementia, exacerbations of parkinsonism and tremor have been observed during treatment with cholinesterase inhibitors at normal doses. The disorders were reversible on withdrawal of the cholinesterase inhibitor. (3) Withdrawal of cholinesterase inhibitors should be considered if gait disorders, falls or parkinsonism occur or worsen during treatment.


-To further confound our treatment, neuros do this when we are already taking anticholinergics like Amantadine to lower the acetylcholine levels. Why would they give us another drug that then increases it? Doesn't this seem counterintuitive?

-Finally, from the DSM IV:

e. Mild cognitive impairment

The term "mild cognitive impairment" describes a heterogeneous group of individuals, with some patients in the earliest stages of Alzheimer's disease and others suffering from other conditions. There are no FDA-approved medications for the treatment of mild cognitive impairment at this time. Clinical trials of cholinesterase inhibitors for mild cognitive impairment have enrolled a narrower and better defined population of patients with mild cognitive impairment than most clinicians actually treat in practice, but even with these well-defined patients the evidence from clinical trials supporting use of cholinesterase inhibitors is weak (172, 173). Given the inconclusive data, the potential safety concerns that exist with this class of medications in this patient population, and the lack of FDA approval for this indication (reviewed in Sections V.B.1.a.4 and II.C.5.a.1.a), no specific recommendation can be made in favor of routine use of cholinesterase inhibitors in patients with mild cognitive impairment at this time. Nonetheless, individual patients may benefit from their use.

Not sure about Lindy' s patch; I'd like to know too. Hope I'm not thread-jacking...trying to help :)

Laura

it's not hijacking - it's interaction - how else to succeed?
 

It's discussion, learning, and so forth. please do so. Very helpful and now I can narrow down and hopefully soon pinpoint what the scenario actually is.

I hate having discussions with myself......don't you?

oops forgot the main thought - Given the inconclusive data, the potential safety concerns that exist with this class of medications in this patient population, and the lack of FDA approval for this indication (reviewed in Sections V.B.1.a.4 and II.C.5.a.1.a), no specific recommendation can be made in favor of routine use of cholinesterase inhibitors in patients with mild cognitive impairment at this time. Nonetheless, individual patients may benefit from their use.

What isn't clear about this? i didn't check the year of that artcle, but nothing has changed that I know of in the area of ACbE drug development and what follows.....it's all on cholinesterase inhibitors.



paula

patch
 

Paula and Laura,
My patch is called Kentera, and is one of a string of anti-cholinergic drugs I have tried for PD-related OAB. The others have all been tablets, some of them 3 a day, others 1 a day. The patch differs from this in that it is changed every 3-4 days. From the outset with all of these drugs there have been two main side effects. The most bothering has been brain fog and apathy. The other is increase in joint pain, something that I was prepared to live with if it improved OAB. From the outset my urologist has discussed with me that this class of drugs bring some improvement as a side-benefit for PD, and I would agree with this. These side-benefits are with mobility, smoother faster movement, and less wearing off in terms of mobility, though other wearing off signs are more sudden and acute. With all there was this trade off in terms of pain when sinemet wore off, to a degree that does not happen when I am on just the sinemet/entacapone PD regime I use. Taking the anti-ch pills in the night gave me dystonia so I took them in the morning instead, and it resolved. The difference between them and the patch is that it is active over a much longer period. I am now experiencing acute wearing off dystonia, expecially if I leave it too long between sinemet doses, as TMJ type pain, and nocturnal foot dystonias, and I would also correlate early morning lower back dystonia and internal dystonias with this. All resolve when sinemet kicks in. All I had to a degree BEFORE going on sinemet, i.e. when untreated. None were a problem last year when I spent nearly 4 months off anti-ch meds and only on sinemet. I went onto Kentera because the OAB became unbearable. So my conclusion from this was the same as yours Paula, that when sinemet is at it's lowest there is a corresponding increase in acetycholine DESPITE being on the patch. In other words an imbalance. And perhaps taking this medication means my body is no longer regulating acetycholine naturally?? I don't know how to wean myself off this patch, I cannot split it like a pill, leaving it on longer does not seem to work, by the 5th day I am in trouble, and leaving it off is giving me over heating, nausea, headaches, joint pain and a feeling of being very unwell, similar to flu, I have tried this 4 times, and each is pretty much the same. I did not have the same difficulty with oral anti'ch's, I just weaned myself off gradually over a couple of weeks. I had absolutely no idea that there would or could be an issue. So Laura's info made some kind of sense to me. By the third day of trying to get off I am desperate and whack another patch on because otherwise I am losing too many days not functioning, and to put it bluntly I do not have a practical support system other than my 18 yr old son. I am going out a lot less, because on the patch I have this apathy thing where I am rather unmotivated, and off it continence of both kinds as well as the other awfulness makes being away from home difficult. So until I can get advice from someone who knows I am stuck, i.e. waiting for a urology appointment to come through. I think that the patch must be hitting different receptors from the tablets taken previously, and of course the delivery method is different....

Sorry about the length of this, I have tried to include what I think might be useful. I am also not saying that everyone would feel this way on the same medication. It is my belief that the problems do not occur when there is more acetylcholine per se, but rather when the body is unable to balance it with other nt's,

Lindy

One step forward...
 

Lindy,

Blech, sorry you have to go through this. It seems with every drug it's one step forward, two steps back.

I found this at at the Net Doctor UK site where it explains how Kentera works:

Kentera patches contain the active ingredient oxybutynin hydrochloride, which is a type of medicine called an anticholinergic (or antimuscarinic) muscle relaxant. It works by relaxing the involuntary muscle that is found in the wall of the bladder.

The muscle in the wall of the bladder is called the detrusor muscle. It can sometimes contract in uncontrollable spasms, and this is often referred to as having an overactive or unstable bladder.

Oxybutynin works by relaxing the detrusor muscle in the wall of the bladder. It does this by blocking receptors called cholinergic (or muscarinic) receptors that are found on the surface of the muscle cells. This prevents a natural body chemical called acetylcholine from acting on these receptors.

Normally when acetylcholine acts on these receptors, it causes the detrusor muscle to contract and the bladder to empty. By blocking acetylcholine, oxybutynin helps the muscle in the bladder wall to relax. This reduces unstable, involuntary contractions of the bladder,

I am confused; however, as to why it would cause "more" dystonia or muscular problems. As an anticholinergic it is in the same league as Amantadine which helps lower our acetylcholine levels. This is why it is prescribed because it helps prevent the bladder from spasms which result in overactive bladder issues.

On the other hand, if your doctor also gave you Aricept for some reason, that is an cholinesterase inhibitor and this increases acetyl choline; thus, in essence canceling out effects of the patch.

So I guess I am in the dark as to how this would make your dystonia worse from a neurotransmitter perspective unless it somehow makes things more off balance. If anything, as you experience more mobility with Kentera, I would think that the anti-cholinergic aspect would play in your wearing off too, that you would have less acetyl choline, unless there is some sort of weird symptom rebound going on? I also don't see much out there on side effects...some do report muscle pain. I wonder if because it is fairly new how there may be some negatives that are relatively unknown. Have you asked your neurologist for feedback?

I'm stumped.

Laura

Thanks for reply Laura, like you I try and keep the equation in some kind of balance, and it does not work out - the only thing that made sense really was that you found some research that seems to indicate that an imbalance could give problems. Anecdotally my PD nurse said that very few are able to take this class of drugs for very long, the effects wear off and the side effects outweigh the benefits by a long way. She also said that we should not be taking these, we meaning PwP. BUT acknowledged that for OAB there is little choice, and that people keep stopping and starting them, because without them they are '-------' and with them they are ' ------'.

I wondered if this was another of those things that like dopamine, give problems both when there is too little and too much that have similarities symptomatically, when altered with medication.

Sorry Paula if this is confusing the issue more, though it seems there is more to this chemical than the empirical 'they' let on, some of the stuff you posted earlier is mind-boggling, why do people make some of these things, what do they eat for breakfast.......

...... another thing that I have wondered about is whether we are particularly susceptible as PwP because of the hit and miss nature of the other drugs we take, it seems like very far from exact science.... only a small percentage of levodopa crosses the BBB for instance, and the rest is floating around our system, giving us nausea dyskinesias, and other stuff, while acetylcholine can hook up almost anywhere, and we are trying to either limit it or increase it - how much levodopa and/or acetylcholine attaches to receptors here and there, hooks up in the wrong way, creates imbalances that our own little chemical sweatshops can't compete with, creating even more mess - and that goes for all the other stuff we have to take to make us feel human.....

Lindy

maybe write it down and keep track of dystonia
 

Here's a helpful site that explains how anticholinergic drugs work. They block acetylcholine receptors. Too much acetylcholine causes muscle contraction as we have learned. Our natural cholinesterase enzyme, cleans up the excess acetylcholine.

From webpage: here's what cholinesterase does naturally

"The transmitter is either broken down by enzymes (10%) and removed or taken back up again into the nerve ending (i.e. recycled) - a process known as re-uptake."

and

" the less dopamine activity you have in the extra-pyramidal system, the more acetylcholine is released in the muscles. Acetylcholine is the transmitter in the synapses of the muscles which make them contract. If you block dopamine in the extra-pyramidal system, you get more acetylcholine in the muscles, so they tighten up. Neuroleptics can thus block your ability to relax your muscles. So, your muscles can't relax and stiffen up and you get stiffness, tremor etc.

Anticholinergic drugs (such as procyclidine, benzhexol, benztropine, orphenadrine etc) block the acetylcholine receptors in the muscles, and reduce the effect of having too much acetylcholine, so your muscles are able to relax;"
------

Now i have to go look up the link again. I have heard that anti-cholinergic meds do not have bad side effects. But Cogentin gave me brain fog. Recently an article did come out saying something about anti-cholinergic drugs causing dementia or cognitive loss. They may know this, but i don't take an anticholinergic for any of the reasons talked about. It relieves my leg weakness that I wonder about coming from too much acetycholine. I was wrapping my legs in ace bandages to be able to hold myself up steady and walk. Nortriptyline takes it away, and other benefits are extra, including an antidepressant function and a nerve pain killer.

lindy your dystonia might be an excellent way of telling if the patch works or not. do you see any pattern to your dystonia? at certain points of your med cycle are you more cramped than others? med changes are very difficult. When merck [europe] began playing with sinemet availability, did anyone even think about how hard it is for pwp to quit or change anything? I am sorry to hear about the withdrawal.... Can you start another med at the same time as you titrate down? Maybe you could google that question.

Cogentin made me feel better than anything [took it before i got the muscle weakness]. I could actually relax [pre-sinemet - i was on eldepryl and maybe mirapex by then. I would take it again....the brain fog might be the lesser of the evils someday.

http://www.nmhct.nhs.uk/pharmacy/moa-proc.htm
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