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 neurotransmitters ...

, are chemicals that prevent the breakdown of the neurotransmitter

acetylcholine Acetylcholine (ACh) is an organic chemical 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. Part ...

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 muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous syste ...

that can bind to

muscarinic receptor Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several r ...

s, nicotinic receptors 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 and ...

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

Alzheimer's Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...

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, dro ...

, and also as

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

and

insecticide Insecticides are substances used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Insecticides are used in agriculture, medicine, industry and by consumers. Insecticides are claimed to b ...

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 in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while others i ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...

loose stool Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

vivid dream A dream is a succession of images, ideas, emotions, and sensations that usually occur involuntarily in the mind during certain stages of sleep. Humans spend about two hours dreaming per night, and each dream lasts around 5 to 20 minutes, althou ...

s at night,

dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...

rash A rash is a change of the human skin which 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, cr ...

bradycardia Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...

peptic ulcer disease Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines i ...

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...

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, rhinorrhoea, or informally runny nose is the free discharge of a thin mucus fluid from the nose; it is a common condition. It is a common symptom of allergies ( hay fever) or certain viral infections, such as the common cold or COVID- ...

salivation Saliva (commonly referred to as spit) 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 DNA can be e ...

muscle cramp 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 aff ...

s, 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 serio ...

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 because ace ...

s. ChEls are widely used 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 a ...

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 – specificall ...

organophosphorus compounds Organophosphorus compounds are organic compounds containing phosphorus. They are used primarily in pest control as an alternative to chlorinated hydrocarbons that persist in the environment. Some organophosphorus compounds are highly effective ins ...

and are considered more potent than

VX gas VX is an extremely toxic chemical synthesis, synthetic chemical compound in the organophosphorus compound, organophosphorus class, specifically, a phosphonate, thiophosphonate. In the class of nerve agents, it was developed for military use i ...

, 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 trade name Exelon among others) is a cholinesterase inhibitor used for the treatment of mild to moderate Alzheimer's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces t ...

donepezil Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's disease, Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, ha ...

, and

galantamine Galantamine is used for the treatment of cognitive decline in mild to moderate Alzheimer's disease and various other memory impairments. It is an alkaloid that has been isolated from the bulbs and flowers of ''Galanthus nivalis'' (Common snowdro ...

, 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 un ...

is not. They are generally used to treat

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

and

dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...

. 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 A product defect is any characteristic of a product which hinders its usability for the purpose for which it was designed and manufactured. Product defects arise most prominently in legal contexts regarding product safety, where the term is appl ...

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 typically given by mouth ...

is used in the treatment of

Cholinesterase inhibitor toxicity

Common side effects of one ChEI include

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

and

, accidental injury,

headache Headache 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 in those with severe headaches. Headaches can occur as a result ...

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

hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...

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 close e ...

, and

sleep Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefulness by a de ...

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 disease, Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, ha ...

, phenserine,

huperzine A Huperzine A is a naturally occurring sesquiterpene alkaloid compound found in the firmoss ''Huperzia serrata'' and in varying quantities in other food ''Huperzia'' species, including ''H. elmeri'', ''H. carinat'', and ''H. aqualupian''. Huperz ...

, 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 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 one 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 federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

'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 used for the treatment of cognitive decline in mild to moderate Alzheimer's disease and various other memory impairments. It is an alkaloid that has been isolated from the bulbs and flowers of ''Galanthus nivalis'' (Common snowdro ...

might be less well tolerated than donepezil and rivastigmine.

Chemical weapons

Alleged Assassination Attempt

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

Alexei Navalny Alexei Anatolievich Navalny ( rus, links=no, Алексей Анатольевич Навальный, , ɐlʲɪkˈsʲej ɐnɐˈtolʲjɪvʲɪtɕ nɐˈvalʲnɨj; born 4 June 1976) is a Opposition to Vladimir Putin in Russia, Russian opposition ...

was treated in Berlin Charité hospital for alleged poisoning by a Russian-made

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

which is known since 2019 as belonging to the

Novichok agents Novichok (russian: Новичо́к, lit=newcomer, novice, newbie) is a group 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 Ru ...

subgroup of ChEI.

References

{{Pharmacomodulation Neurophysiology Neurotoxins Hydrolase inhibitors Anticholinesterases Parasympathomimetics Organophosphates