A friend with an interest in cholinesterase inhibitors like insecticides and nerve agents asked me about cholinesterase enzymes. I had already been researching anticholinergic medications a little bit, so this struck my fancy. My preliminary response to them is reproduced below. I'll probably update it as I learn more about anticholinergic medications that aren't as intimately related to treatment of poisoning by AchE inhibitors and as they present follow-up questions.
The cholinesterase that I know about is acetylcholinesterase. It breaks down acetylcholine into acetic acid and choline. Acetylcholine is the neurotransmitter used throughout your parasympathetic nervous system (the one conventionally glossed as "rest and digest", in contrast with the sympathetic nervous system, which is "fight or flight"), and if the acetylcholinesterase enzyme is inhibited by a drug or pesticide, then your parasympathetic nervous system sees too much acetylcholine and starts being too parasympathetic.
The parasympathetic nervous system has multiple kinds of acetylcholine receptors in different parts of the body, all with different functions, but some of the things that the PSNS does are the promotion of digestion and secretion of fluids, e.g. urination, salivation, and lacrimation. It also constricts the pupils, decreases heart rate and blood pressure, tightens the smooth bronchial muscles, and increases bronchial vasodilation.
If you come into contact with a strong cholinesterase inhibitor, you get cholinergic syndrome, which is basically just all of those parasympathetic functions: diarrhea, slow heart rate, salivation, lacrimation, bronchoconstriction, et cetera. Eventually you get symptoms that aren't even dialed up version of normal results of the functioning of the parasympathetic nervous system, like muscle weakness and seizures.
When the acetylcholinesterase enzyme tries to metabolize an acetylcholinesterase inhibitor, the inhibitor leaves behind some garbage, like a phosphoryl group, in a fold of the enzyme. Different inhibitors leave behind different garbage in different ways: some like the medication donepezil leave garbage that the body can remove in seconds to minutes. Some like the medication physostigmine leave garbage that the body can hydrolyze in hours, and some organophosphates leave garbage residues that can last for days in the folds of acetylcholinesterase before being hydrolyzed by phosphatase enzymes, if you don't die first.
If you've been exposed to a long-acting "irreversible" acetylcholinesterase inhibitor, there are a few treatments available:
I said before that there are lots of types of acetylcholine receptors in different tissues with different functions: they're a principally and perfectly divided into muscarinic receptors (which were first known to respond to the mushroom alkaloid muscarine, found in poisonous fly agaric mushrooms) and nicotinic receptors (which were first known to respond to nicotine).
One antagonist of muscarinic acetylcholinesterase receptors is a plant alkaloid called atropine, found in several nightshade plants. It blocks muscarine receptors non-selectively - all the sub-types - and is often used to treat the symptoms of cholinergic syndrome. There are other non-selective anti-muscarinics, like scopolamine, diphenhydramine, doxylamine, glycopyrrolate, and ipratropium. I'm not sure yet why those aren't used for symptomatic relief of organophosphate poisoning. Still reading. I'm also not sure why nicotinic acetylcholine receptor antagonists aren't used therapeutically.
Edit: Scopolamine has some therapeutic use, and since it crosses the blood-brain barrier, it might be better than atropine at treating acetylcholinesterase inhibition in the central nervous system system, rather than the parasympathetic nervous system [1], [2], [3]. Diphenhydramine and doxylamine are antihistamines first and antimuscarinics second, and it's probably good to avoid messing with other systems while trying to treat poisoning. Which is too damn bad really, because they're available over-the-counter, and wouldn't it be great if you could get organophosphate antidote for 5 cents per tablet? Ipratropium is a derivative of atropine that crosses the blood-brain barrier even less well than atropine, so probably not good for treating CNS effects. Glycopyrrolate still kinds of looks interesting to me after reading further.
If the long-acting acetylcholinesterase inhibitor that you've been exposed to is of the organophosphate type, and not the carbamate type, then there's another great therapy available for use in conjunction with atropine: cholinesterase reactivators. In practice the reactivators are all chemicals from one structural class, called oximes. They include Pralidoxime, Trimedoxime, Obidoxime, Methoxime, H-oxime HI-6 (a.k.a. Asoxime chloride). Oximes can remove inhibitory phosphoryl groups that organophosphates leave behind in acetylcholinesterase molecules. If we ever get lab-grown phosphoryl-phosphatase enzymes into production and use, those will also be worth calling cholinesterase reactivators.
Diazepam is also used to treat acetylcholinesterase inhibitor poisoning. I'm not sure if it's specifically for organophosphates or also for carbamates, and I don't know how it helps. It treats seizures And there are few other seldom-used treatment options that I don't know much about. The end.
Wait, no! One more thing I think you'll enjoy: If someone takes too much of an anticholinergic medication like atropine, one of the treatments is a cholinesterase inhibitor, physostigmine, which leaves garbage in the enzyme molecule for just a few hours. Physostigmine is a plant alkaloid derived from the African Calabar bean, and it has a carbamate group! Too much nerve agent or pesticide? Take atropine. Too much atropine? Take a natural nerve agent pesticide. Cool beans.
And actually, there's evidence that you can take physostigmine or the related pyridostigmine prophylactically to prevent or reduce the severity of acetylcholinesterase inhibitor poisoning. My guess is that physostigmine leaves garbage in the enzyme molecule (that the body can remove within hours), and that means that the irreversible inhibitors don't have a place to leave their own garbage. But I just made that up.
Next up: Acetylcholine in neuromuscular junctions, the sympathetic nervous system, and the central nervous system. Also, and highly related: classes of cholinergic and anticholinergic drugs that have effects you wouldn't predict if you'd only read the stuff above about the parasympathetic nervous system.
....
Some papers I want to read about diphenhydramine use to counter OP poisoning:
https://onlinelibrary.wiley.com/doi/pdf/10.1197/aemj.9.12.1369
https://www.mmsl.cz/pdfs/mms/2014/03/02.pdf
https://pubmed.ncbi.nlm.nih.gov/6497117/
https://pubmed.ncbi.nlm.nih.gov/18167037/
...
It looks like diphenhydramine is pretty great for combating nerve agents? In mice. And by injection. And really crazy doses, like 30 mg per kg, which would be like 2300 mg for a 77 kg human, whereas you buy 25 mg tablets in stores. I'm sure they're just using high doses of diphenhydramine and high doses of nerve agents to more easily test effects, like "can we keep the subject from dying within 24 hours". I've read that the fatal dose of diphenhydramine for humans not on nerve agents is 20 to 40 mg / kg. If we assume the lethal human dose is at the low end, 20 mg / kg, and hope that a quart of that will be both safe and therapeutic against nerve agents, then we're looking at a 385 mg therapeutic dose, or 15.4 tablets of 25 mg diphenhydramine, for a 77 kg human. That's hoping that oral tablets provide relief in a way comparable to injection. I think, if I suspected exposure to a nerve agent and I didn't have any other anticholinergic available, like a duodote pen, I'd start with maybe 7 tablets of diphenhydramine while rushing to a hospital, and see how things go from there. None of this is medical advice. Please be smarter than me. Do not take weird quantities of antihistamines because of an internet weirdo's blog. "FDA warns about serious problems with high doses of the allergy medicine diphenhydramine (Benadryl)", "can lead to serious heart problems, seizures, coma, or even death", "he consumed over a dozen Benadryl tablets; he then immediately began seizing, and upon admission to intensive care, it was found that he had suffered critical brain damage, and he died following six days of mechanical ventilation".
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