Cholinesterase inhibitors (ChEIs), also known as anti-

cholinesterase The enzyme cholinesterase (EC 3.1.1.8, choline esterase; systematic name acylcholine acylhydrolase) catalyses the hydrolysis of choline-based esters: : an acylcholine + H2O = choline + a carboxylate Several of these serve as neurotransmitte ...

, are chemicals that prevent the breakdown of the neurotransmitter

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

butyrylcholine Butyrylcholine is a choline-based ester that can function as a neurotransmitter. It is similar to acetylcholine, with activation of some of the same receptors as acetylcholine. Butyrylcholine is a synthetic compound and does not occur in the body ...

. This increases the amount of the acetylcholine or butyrylcholine in the

synaptic cleft Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in neuromuscular junction, muscles or glands. Chemical synapses allow neurons to form biological neural ...

that can bind to

muscarinic receptors Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-recep ...

nicotinic receptors Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...

and others. This group of inhibitors is divided into two subgroups,

acetylcholinesterase inhibitor Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level an ...

s (AChEIs) and butyrylcholinesterase inhibitors (BChEIs). ChEIs may be used as drugs for

Alzheimer's Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

and

myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, ...

, and also as

chemical weapon A chemical weapon (CW) is a specialized munition that uses chemicals formulated to inflict death or harm on humans. According to the Organisation for the Prohibition of Chemical Weapons (OPCW), this can be any chemical compound intended as ...

s and

insecticide Insecticides are pesticides used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. The major use of insecticides is in agriculture, but they are also used in home and garden settings, i ...

s. Side effects when used as drugs may include

loss of appetite Anorexia is a medical term for a loss of appetite. While the term outside of the scientific literature is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while o ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

loose stools Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration due ...

, vivid dreams at night,

dehydration In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...

rash A rash is a change of the skin that affects its color, appearance, or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracke ...

bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...

peptic ulcer disease Peptic ulcer disease is when the inner part of the stomach's gastric mucosa (lining of the stomach), the first part of the small intestine, or sometimes the lower esophagus, gets damaged. An ulcer in the stomach is called a gastric ulcer, while ...

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

weight loss Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...

rhinorrhea Rhinorrhea (American English), also spelled rhinorrhoea or rhinorrhœa (British English), or informally runny nose is the free discharge of a thin mucus fluid from the nose; it is an extremely common condition. It is a common symptom of allergie ...

saliva Saliva (commonly referred as spit or drool) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which ...

tion,

muscle cramps A cramp is a sudden, involuntary, painful skeletal muscle contraction or overshortening associated with electrical activity. While generally temporary and non-damaging, they can cause significant pain and a paralysis-like immobility of the affe ...

, and

fasciculation A fasciculation, or muscle twitch, is a spontaneous, involuntary muscle contraction and relaxation, involving fine muscle fibers. They are common, with as many as 70% of people experiencing them. They can be benign, or associated with more seriou ...

s. ChEIs are indirect-acting

parasympathomimetic drug A parasympathomimetic drug, sometimes called a cholinomimetic drug or cholinergic receptor stimulating agent, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs becaus ...

s. ChEls are widely used as

s. Since November 2019 the group of ACheIs known as ''Novichoks'' have been banned as agents of warfare under the

Chemical Weapons Convention The Chemical Weapons Convention (CWC), officially the Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction, is an arms control treaty administered by the Organisation for ...

. Novichok agents are

neurotoxic Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

organophosphorus compounds Organophosphorus chemistry is the scientific study of the synthesis and properties of organophosphorus compounds, which are organic compounds containing phosphorus. They are used primarily in pest control as an alternative to chlorinated hydrocarbo ...

and are considered more potent than

VX gas VX is an extremely toxic synthetic chemical compound in the organophosphorus class, specifically, a thiophosphonate. In the class of nerve agents, it was developed for military use in chemical warfare after translation of earlier discoverie ...

, also a neurotoxic organophosphorus compound.

Medical use

While 4 ChEIs are approved in the US for the treatment of Alzheimer's Disease, only three of these are available commercially. The three available are

rivastigmine Rivastigmine, sold under the brand name Exelon among others, is an acetylcholinesterase inhibitor used for the treatment of dementia associated with Alzheimer's disease and with Parkinson's disease. Rivastigmine can be administered orally or v ...

donepezil Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, has not been shown to ...

, and

galantamine Galantamine is a type of acetylcholinesterase inhibitor. It is an alkaloid extracted from the bulbs and flowers of ''Galanthus nivalis'' (common snowdrop), '' Galanthus caucasicus'' (Caucasian snowdrop), '' Galanthus woronowii'' (Voronov's snow ...

, while

tacrine Tacrine is a centrally acting acetylcholinesterase inhibitor and indirect cholinergic agonist (parasympathomimetic). It was the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer's disease, and was marketed u ...

is not. They are generally used to treat

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

and

dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...

. If a benefit occurs, it is generally during the second or third month after starting. It is difficult to determine which ChEI has greater efficacy, due to

design flaw ''Design Flaw'' is the fifth studio album by Art Bergmann, released on the Other People's Music record label in 1998."Bergmann back to form". ''The Province'', November 6, 1998. The album featured acoustic recordings of songs, primarily from Ber ...

s in head-to-head comparison studies.

Pyridostigmine Pyridostigmine is a medication used to treat myasthenia gravis and underactive bladder. It is also used together with atropine to end the effects of neuromuscular blocking medication of the non-depolarizing type. It is also used off-label to t ...

is used in the treatment of

Neostigmine Neostigmine, sold under the brand name Bloxiverz, among others, is a medication used to treat myasthenia gravis, Ogilvie syndrome, and urinary retention without the presence of a blockage. It is also used in anaesthesia to end the effects of n ...

is used in combination with a

muscarinic antagonist A muscarinic acetylcholine receptor antagonist, also simply known as a muscarinic antagonist or as an antimuscarinic agent, is a type of anticholinergic drug that blocks the activity of the muscarinic acetylcholine receptors (mAChRs). The muscarin ...

to reverse the effects of non-depolarizing muscle relaxants e.g.

rocuronium bromide Rocuronium bromide (brand names Zemuron, Esmeron) is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia to facilitate tracheal intubation by providing skeletal muscle relaxation for surgery o ...

Cholinesterase inhibitor toxicity

Common side effects of one ChEI include

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

and

, accidental injury,

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...

ecchymosis A bruise, also known as a contusion, is a type of hematoma of tissue, the most common cause being capillaries damaged by trauma, causing localized bleeding that extravasates into the surrounding interstitial tissues. Most bruises occur clo ...

, and

sleep Sleep is a state of reduced mental and physical activity in which consciousness is altered and certain Sensory nervous system, sensory activity is inhibited. During sleep, there is a marked decrease in muscle activity and interactions with th ...

disturbance.

Binding affinity

Acetylcholinesterase inhibitors

Donepezil Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, has not been shown to ...

, phenserine,

huperzine A Huperzine A, a Lycopodium alkaloid, was first isolated in 1983 from ''Huperzia serrata'', a plant used in Chinese folk medicine. Huperzine A also exists in other Huperzia species, including ''H. elmeri'', ''H. carinat'', and ''H. aqualupian'' ...

, and BW284c51 are selective AChE inhibitors.

Butyrylcholinesterase inhibitor

Tetra (monoisopropyl) pyrophosphoramide ( Iso-OMPA) and ethopropazine are selective BChE inhibitors.

AChE and BChE inhibitor

Paraoxon Paraoxon is a parasympathomimetic drug which acts as an cholinesterase inhibitor. It is an organophosphate oxon, and the active metabolite of the insecticide parathion. It is also used as an ophthalmological drug against glaucoma. Paraoxon is o ...

and

are both acetylcholinesterase inhibitors and butyrylcholinesterase inhibitors. In 2015, the

United States Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

's Adverse Event Reporting System database compared rivastigmine to the other ChEI drugs

and

found that rivastigmine was associated with a higher frequency of reports of death as an adverse event.

Acetylcholinesterase inhibitors and nicotinic receptor modulator

Galantamine Galantamine is a type of acetylcholinesterase inhibitor. It is an alkaloid extracted from the bulbs and flowers of ''Galanthus nivalis'' (common snowdrop), '' Galanthus caucasicus'' (Caucasian snowdrop), '' Galanthus woronowii'' (Voronov's snow ...

might be less well tolerated than donepezil and rivastigmine.

Chemical weapons

Assassination Attempt

Cholinesterase inhibitors came to a public attention in 2020 when Russian opposition and dissent figure

Alexei Navalny Alexei Anatolyevich Navalny (, ; 4 June 197616 February 2024) was a Russian Opposition to Vladimir Putin in Russia, opposition leader, anti-corruption in Russia, corruption activist and political prisoner. He founded the Anti-Corruption Found ...

was treated in Berlin Charité hospital for

poisoning Poisoning is the harmful effect which occurs when Toxicity, toxic substances are introduced into the body. The term "poisoning" is a derivative of poison, a term describing any chemical substance that may harm or kill a living organism upon ...

by a Russian-made

nerve agent Nerve agents, sometimes also called nerve gases, are a class of organic chemistry, organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase (ACh ...

which is known since 2019 as belonging to the

Novichok agents Novichok () is a family of nerve agents, some of which are binary chemical weapons. The agents were developed at the GosNIIOKhT state chemical research institute by the Soviet Union and Russia between 1971 and 1993. Some Novichok agents are s ...

subgroup of ChEI.

References

{{Pharmacomodulation Neurophysiology Neurotoxins Hydrolase inhibitors Anticholinesterases Parasympathomimetics Organophosphates

Medical use

Cholinesterase inhibitor toxicity

Binding affinity

Acetylcholinesterase inhibitors

Butyrylcholinesterase inhibitor

AChE and BChE inhibitor

Acetylcholinesterase inhibitors and nicotinic receptor modulator

Chemical weapons

Assassination Attempt

See also

Further reading

References