Cholinesterase Inhibitors

Do We Get Them from Dementia Drugs or Nerve Agents?

Strange things happen in nowadays strange times. Surprisingly, all these events seem to accumulate…  Currently new words are used in news headlines across the globe – cholinesterase inhibitors – but what is the story behind this new (old) term?

In order to understand it, we need to go back in time, back to Germany during the World War II.

Historical background of cholinesterase inhibitors

In 1943, the German Army recruited Nobel Prize winner (1938) biochemist Richard Kuhn to determine the nerve agent damage cause mechanism.

Kuhn and his research team discovered the nerve agent blocking enzyme – cholinesterase – and its mechanism.  They discovered that nerve agents interfered with the normal functioning of the mammalian nervous system, by inhibiting the cholinesterase enzyme. It is an inhibitor of both acetylcholinesterase and butyrylcholinesterase.  

A nerve uses chemical signals to transmit messages to organs and tissues in the body. Nerve agents block the normal functioning of these chemicals at nerve endings, and the nerve ends up sending too many signals. This constant signaling of the nerve can cause overload in some parts of the body.

As part of their research in 1944, Kuhn and colleagues synthesised a new insection: the nerve agent, Soman. This nerve agent is two times stronger than Sarin at inhibiting cholinesterase.

Medical use

In later medical research, it was also found a “healing approach” for using this blocking mechanism. The cholinesterase inhibitors – aka acetylcholinesterase inhibitors – are drugs that prevent the breakdown of acetylcholine in the body, and cholinesterase inhibitors block the action of acetylcholinesterase.

Being acetylcholinesterase an enzyme that breaks down acetylcholine to an inactive form, this reduces nerve cell communications that use acetylcholine to help transmit cell to cell messages. Acetylcholine is one of the chemicals that nerve cells use to communicate with one another in the brain, the central nervous system, and other areas of the body.

Studies prove that acetycholine affects learning, memory, and other cognitive function(s). Scientists think that reduced levels of acetylcholine in the brain cause some of the symptoms of Alzheimer’s disease. Therefore, blocking the enzyme that destroys acetylcholine with a cholinesterase inhibitor (anticholinesterase) increases the concentration of acetylcholine in the brain, and this increase may improve memory and cognitive function.

In normal civilian use, medical doctors prescribe these cholinesterase inhibitors to control Alzheimer’s disease and dementia.

Side effects and poisoning symptoms

Cholinterase inhibitors’ side effects are almost the same as nerve agent poisoning symptoms. 

Some common side effects or adverse events of cholinesterase inhibitors are: nausea, vomiting, diarrhoea, muscle cramps, headache, abnormal dreams, hallucinations, confusion, fainting, fatigue, hypertension, frequent urination.. and for nerve gas poisoning, even death.

However, you may also die if you ingest an unprescribed overdosage of these inhibitors, let’s say with tea, or use perfume.

Like above descripted, these cholinterase inhibitors can commonly be found in dementia and Alzheimer drugs like, Donepezil, Rivastigme and Galantamine. Its effecting components can also be found in pesticides and in chemical warfare agents nerve agents. As you remember, almost all nerve agents were originally developed as pesticides, like Tabun, Sarin, Soman and Cyclosarin. VX and Novichock were directly developed as nerve agents.

About nerve agents

Nerve agents are chemicals that affect the nervous system. These agents are man-made and have been manufactured for use in chemical warfare.

Nerve agents are known to be present in military stockpiles of several nations and do not occur naturally. Novichoks are Soviet and later Russian develop A-Agents which included at least 5 types of binary nerve agents. This development project code name was NOVICHOK (“newbie”).

Cholinterase inhibitors “misusage”

Past events where cholinterase inhibitors have been found in abnormal circumstances:

• Matsumoto Japan on 27^th 1994. Over 500 affected and 2 persons overdosed by cholinterase inhibitors via home-made Sarin.
• Tokyo Metro on 20^th March 1994. Around 6200 affected and 12 persons overdosed by cholinterase inhibitors via home-made Sarin.
• Kuala Lumpur airport 13^th February 2017. North-Korean president half-brother overdosed by cholinterase inhibitors sniffing hand towel with VX.
• Khan Sheikhoun Syria on 4^th April 2017. More than 80 persons overdosed by cholinterase inhibitors via government delivered Sarin.
• Salisbury UK on 4^th March 2018. Former KGB spy and his daughter affected by cholinterase inhibitors via Russian agents delivered Novichok.
• Amesbury UK on 30 June 2018. One overdosed and one affected by cholinterase inhibitors via perfume bottle (related to Salisbury) filled by Novichok.
• Tomsk Russia on 20^th August 2020. Russian opposition leader potentially affected by cholinterase inhibitors via tea? Alzheimer drug or something else?

As we have learned, this type of accident of affecting or even getting overdosed by cholinterase inhibitors can be possible, since these can be found at home in pesticides, in special medicines, or even in perfumes, and teas…?

Sources:
MedicineNet
National Center for Biotechnology Information
World of Chemicals
ScienceDirect
OPCW – Organisation for the Prohibition of Chemical Weapons
BBC
Yle

Solutions for Chemical Detection