Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme

acetylcholinesterase Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme Enzymes () are proteins that a ...

from breaking down the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...

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 ...

into choline and

acetate An acetate is a salt (chemistry), salt formed by the combination of acetic acid with a base (e.g. Alkali metal, alkaline, Alkaline earth metal, earthy, Transition metal, metallic, nonmetallic or radical Radical (chemistry), base). "Acetate" als ...

, thereby increasing both the level and duration of action of acetylcholine in the central nervous system,

autonomic ganglia An autonomic ganglion is a cluster of nerve cell bodies (a ganglion) in the autonomic nervous system The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the peripheral nervous system that s ...

and

neuromuscular junction A neuromuscular junction (or myoneural junction) is a chemical synapse between a motor neuron and a muscle fiber. It allows the motor neuron to transmit a signal to the muscle fiber, causing muscle contraction. Muscles require innervation to ...

s, which are rich in acetylcholine receptors. Acetylcholinesterase inhibitors are one of two types of

cholinesterase inhibitor Cholinesterase inhibitors (ChEIs), also known as anti-cholinesterase, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine. This increases the amount of the acetylcholine or butyrylcholine in the syn ...

s; the other being butyryl-cholinesterase inhibitors.

Acetylcholinesterase Acetylcholinesterase (HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme Enzymes () are proteins that a ...

is the primary member of the cholinesterase enzyme family. Acetylcholinesterase inhibitors are classified as reversible, irreversible, or quasi-irreversible (also called pseudo-irreversible).

Mechanism of action

Organophosphates

Organophosphates like

TEPP Tetraethyl pyrophosphate, abbreviated TEPP, is an organophosphate compound with the formula . It is the tetraethyl derivative of pyrophosphate (P2O74-). It is a colorless oil that solidifies near room temperature. It is used as an insecticide. Th ...

and

sarin Sarin (NATO designation GB G-series, "B"">Nerve_agent#G-series.html" ;"title="hort for Nerve agent#G-series">G-series, "B" is an extremely toxic synthetic organophosphorus compound.cholinesterases, enzymes that hydrolyze the neurotransmitter

. The active centre of cholinesterases feature two important sites, namely the anionic site and the esteratic site. After the binding of acetylcholine to the anionic site of the cholinesterase, the acetyl group of acetylcholine can bind to the esteratic site. Important amino acid residues in the esteratic site are a glutamate, a histidine, and a serine. These residues mediate the hydrolysis of the acetylcholine. Hydrolysis of acetylcholine

At the esteratic site the acetylcholine is cleaved, which results in a free choline moiety and an acetylated cholinesterase. This acetylated state requires hydrolysis to regenerate itself. Inhibitors like TEPP modify the serine residue in the esteratic site of the cholinesterase. Inhibition mechanism

This

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...

inhibits the binding of the acetyl group of the acetylcholine to the esteratic site of the cholinesterase. Because the acetyl group can't bind the cholinesterase, the acetylcholine can't be cleaved. Therefore, the acetylcholine will remain intact and will accumulate in the synapses. This results in continuous activation of acetylcholine receptors, which leads to the acute symptoms of TEPP poisoning. The phosphorylation of cholinesterase by TEPP (or any other organophosphate) is irreversible. This makes the inhibition of the cholinesterase permanent. The cholinesterase gets irreversible phosphorylated according to the following reaction scheme E + PX <=> E-PX -> _3EP + X In this reaction scheme the E indicates the cholinesterase, PX the TEPP molecule, E–PX the reversible phosphorylated cholinesterase, ''k''₃ the reaction rate of the second step, EP the phosphorylated cholinesterase and X the leaving group of the TEPP. The irreversible phosphorylation of the cholinesterase occurs in two steps. In the first step the cholinesterase gets reversibly phosphorylated. This reaction is very fast. Then the second step takes place. The cholinesterase forms a very stable complex with TEPP, in which TEPP is covalently bound to the cholinesterase. This is a slow reaction. But after this step the cholinesterase is irreversibly inhibited. The time dependent irreversible inhibition of the cholinesterase can be described by the following equation. :

\ln \frac E  = \frac

In this formula, ''E'' is the remaining enzyme activity, ''E''₀ is the initial enzyme activity, ''t'' is the time interval after mixing of the cholinesterase and the TEPP, ''K''_''I'' is the dissociation constant for cholinesterase-TEPP complex (E–PX) and I is the TEPP concentration. The reaction mechanism and the formula above are both also compatible for other organophosphates. The process occurs in the same way. Furthermore, certain organophosphates can cause OPIDN, organophosphate-induced delayed polyneuropathy. This is a disease, which is characterized by degeneration of axons in the peripheral and central nervous system. This disease will show a few weeks after contamination with the organophosphate. It is believed that the neuropathy target esterase (NTE) is affected by the organophosphate which induces the disease. However, there are no references found, which indicate that TEPP is one of the organophosphates that can cause OPIDN.

Uses

Acetylcholinesterase inhibitors: * Occur naturally as venoms and

poison Poison is a chemical substance that has a detrimental effect to life. The term is used in a wide range of scientific fields and industries, where it is often specifically defined. It may also be applied colloquially or figuratively, with a broa ...

s (e.g.

onchidal Onchidal is a naturally occurring neurotoxin produced as a defensive secretion by the mollusc '' Onchidella binneyi'' and several other related species in ''Onchidella'', a genus of small, air-breathing sea slugs. It acts as an irreversible acet ...

) * Are used as weapons ( nerve agents) * Are used medicinally: ** To treat

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 ...

. In myasthenia gravis, they are used to increase neuromuscular transmission. ** To treat glaucoma ** To treat

postural tachycardia syndrome Postural orthostatic tachycardia syndrome (POTS) is a condition characterized by an abnormally large increase in heart rate upon standing. Symptoms may include lightheadedness, brain fog, blurred vision, weakness, fatigue, headaches, heart pa ...

** As an antidote to anticholinergic poisoning ** To reverse the effect of non-depolarising muscle relaxants ** To treat neuropsychiatric symptoms of diseases such as

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 ...

, particularly apathy ** To increase chances of

lucid dreaming A lucid dream is a type of dream in which the dreamer becomes aware that they are dreaming while dreaming. During a lucid dream, the dreamer may gain some amount of control over the dream characters, narrative, or environment; however, this is n ...

(by prolonging

REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the sleeper to dream viv ...

) ** To treat Alzheimer's disease, the Lewy body dementias and Parkinson's disease. In these neurodegenerative conditions AChEIs are primarily used to treat the cognitive (memory and learning deficits mostly) symptoms of dementia. These symptoms are attenuated due to the role of acetylcholine in cognition in the CNS. There is some evidence to suggest that AChEIs may attenuate psychotic symptoms (especially visual hallucinations) in Parkinson's disease. ** To treat cognitive impairments in patients with schizophrenia. There is some evidence to suggest efficacy in treating positive, negative and affective symptoms. ** As a treatment for autism and to increase the percentage of rapid eye movement sleep in autistic children, in line with the mechanism by which they encourage lucid dreaming. * Are used as (e.g.

malathion Malathion is an organophosphate insecticide which acts as an acetylcholinesterase inhibitor. In the USSR, it was known as carbophos, in New Zealand and Australia as maldison and in South Africa as mercaptothion. Pesticide use Malathion is a pesti ...

): ** : The hunt for resistance genes in ''

Rhipicephalus microplus The Asian blue tick (''Rhipicephalus'' (''Boophilus'') ''microplus'', ''Rhipicephalus microplus'', or ''Boophilus microplus'') is an economically important tick that parasitises a variety of livestock species especially cattle, on which it is th ...

'' has been hampered by high copy number in the three

AChEs Patrick Price (born July 18, 1994) known by his video game moniker ACHES, is an American professional esports player. Price is best known for playing '' Call of Duty''. Career Price won the Call of Duty Championship 2014 with compLexity Gaming ...

involved. Bellgard et al. 2012, Temeyer et al. 2012, and Bendele et al. 2015 all investigate such populations and encounter difficulty confirming the involvement of these three due to copy number.

Guideline recommendations

The clinical guidelines for medication management in people with dementia recommend trialing an AChE inhibitor for people with early to mid stage dementia. These guidelines, known as the Medication Appropriateness Tool for Comorbid Health conditions in Dementia (MATCH-D), suggest that these medicines are at least considered.

Side effects

Some major effects of cholinesterase inhibitors: * Actions on the

parasympathetic nervous system The parasympathetic nervous system (PSNS) is one of the three divisions of the autonomic nervous system, the others being the sympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of ...

, (the parasympathetic branch of the

autonomic nervous system The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the peripheral nervous system that supplies viscera, internal organs, smooth muscle and glands. The autonomic nervous system is a control ...

) may cause

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 ...

, hypotension,

hypersecretion 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical ...

, bronchoconstriction, GI tract hypermotility, and decrease intraocular pressure, increase lower esophageal sphincter (LES) tone * Cholinergic crisis. * Actions on the neuromuscular junction may result in prolonged muscle contraction. * The effects of neostigmine on postoperative nausea and vomiting are controversial and there is not a clear linkage in clinical practice, however, there is good evidence to support the reduction in risk when anticholinergic agents are administered. Administration of reversible cholinesterase inhibitors is contraindicated with those that have urinary retention due to urethral obstruction.

Overdose

Hyperstimulation of nicotinic and muscarinic receptors.

Titration phase

When used in the central nervous system to alleviate neurological symptoms, such as rivastigmine in

, all cholinesterase inhibitors require doses to be increased gradually over several weeks, and this is usually referred to as the ''titration phase''. Many other types of drug treatments may require a titration or stepping up phase. This strategy is used to build tolerance to adverse events or to reach a desired clinical effect. This also prevents accidental overdose and is therefore recommended when initiating treatment with drugs that are extremely potent and/or toxic (drugs with a low therapeutic index).

Examples

Reversible inhibitor

Compounds which function as reversible competitive or noncompetitive inhibitors of cholinesterase are those most likely to have therapeutic uses. These include: * Some

organophosphate In organic chemistry, organophosphates (also known as phosphate esters, or OPEs) are a class of organophosphorus compounds with the general structure , a central phosphate molecule with alkyl or aromatic substituents. They can be considered a ...

s not listed under "Irreversible" below *

Carbamate In organic chemistry, a carbamate is a category of organic compounds with the general formula and structure , which are formally derived from carbamic acid (). The term includes organic compounds (e.g., the ester ethyl carbamate), formally o ...

s ** Physostigmine ** Neostigmine ** Pyridostigmine **

Ambenonium Ambenonium (as ambenonium dichloride, trade name Mytelase) is a cholinesterase inhibitor Cholinesterase inhibitors (ChEIs), also known as anti-cholinesterase, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or b ...

Demecarium Demecarium bromide, trade name Humorsol, is a carbamate parasympathomimetic drug that acts as an acetylcholinesterase inhibitor, and is used as a glaucoma medication. It is applied directly to the eye in order to reduce elevated intraocular pre ...

** Rivastigmine *

Phenanthrene Phenanthrene is a polycyclic aromatic hydrocarbon (PAH) with formula C14H10, consisting of three fused benzene rings. It is a colorless, crystal-like solid, but can also appear yellow. Phenanthrene is used to make dyes, plastics and pesticides, e ...

derivatives ** Galantamine * Caffeine – noncompetitive (also an

adenosine Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...

receptor antagonist) * Rosmarinic acid – ester of caffeic acid. Found in plants species of family

Lamiaceae The Lamiaceae ( ) or Labiatae are a family of flowering plants commonly known as the mint, deadnettle or sage family. Many of the plants are aromatic in all parts and include widely used culinary herbs like basil, mint, rosemary, sage, savory ...

. * Alpha-pinene – noncompetitive reversible * Piperidines ** Donepezil * Tacrine, also known as tetrahydroaminoacridine (THA') *

Edrophonium Edrophonium is a readily reversible acetylcholinesterase inhibitor. It prevents breakdown of the neurotransmitter acetylcholine and acts by competitively inhibiting the enzyme acetylcholinesterase, mainly at the neuromuscular junction. It is so ...

* Huperzine A *

Ladostigil Ladostigil (TV-3,326) is a novel neuroprotective agent being investigated for the treatment of neurodegenerative disorders like Alzheimer's disease, Lewy body disease, and Parkinson's disease. It acts as a reversible acetylcholinesterase and but ...

Ungeremine Ungeremine is a betaine-type alkaloid isolated from ''Nerine bowdenii'' and related plants such as ''Pancratium maritimum''. Pharmacologically, it is of interest as an acetylcholinesterase inhibitor and accordingly as possibly relevant to Alzheim ...

* Lactucopicrin *

Acotiamide Acotiamide, sold under the brand name Acofide, is a medication manufactured and approved in Japan for the treatment of postprandial fullness, upper abdominal bloating, and early satiation due to functional dyspepsia. It acts as an acetylcholinest ...

* Hybrid/bitopic ligands

Comparison table

Quasi-irreversible inhibitor

Compounds which function as

quasi-irreversible inhibitor For acetylcholinesterase (AChE), quasi-irreversible inhibitors are those that rapidly phosphorylate AChE. A subsequent internal dealkylation reaction may then occur, which, according to X-ray crystallography data, is suggestive of covalent bond form ...

s of cholinesterase are those most likely to have use as chemical weapons or

pesticide Pesticides are substances that are meant to control pests. This includes herbicide, insecticide, nematicide, molluscicide, piscicide, avicide, rodenticide, bactericide, insect repellent, animal repellent, microbicide, fungicide, and lampri ...

s. *

Organophosphates In organic chemistry, organophosphates (also known as phosphate esters, or OPEs) are a class of organophosphorus compounds with the general structure , a central phosphate molecule with alkyl or aromatic substituents. They can be considered ...

Echothiophate Echothiophate (Phospholine) is an irreversible acetylcholinesterase inhibitor. Uses It is used as an ocular antihypertensive in the treatment of chronic glaucoma and, in some cases, accommodative esotropia. It is available under several trade ...

** Diisopropyl fluorophosphate **

Cadusafos Cadusafos (2- utan-2-ylsulfanyl(ethoxy)phosphorylulfanylbutane) is a chemical insecticide and nematicide often used against parasitic nematode populations. The compound acts as a acetylcholinesterase inhibitor. It belongs the chemical class of s ...

** Chlorpyrifos **

Cyclosarin Cyclosarin or GF (cyclohexyl methylphosphonofluoridate) is an extremely toxic substance used as a chemical weapon. It is a member of the '' G-series'' family of nerve agents, a group of chemical weapons discovered and synthesized by a German te ...

Dichlorvos Dichlorvos (2,2-dichlorovinyl dimethyl phosphate, commonly abbreviated as an DDVP) is an organophosphate widely used as an insecticide to control household pests, in public health, and protecting stored products from insects. The compound has bee ...

** Dimethoate **

Metrifonate Metrifonate (INN) or trichlorfon (USAN) is an irreversible organophosphate acetylcholinesterase inhibitor. It is a prodrug which is activated non-enzymatically into the active agent dichlorvos. It is used as an insecticide. According to the US ...

(irreversible) **

Sarin Sarin (NATO designation GB G-series, "B"">Nerve_agent#G-series.html" ;"title="hort for Nerve agent#G-series">G-series, "B" is an extremely toxic synthetic organophosphorus compound.Soman ** Tabun ** VX ** VE ** VG ** VM ** Diazinon **

Malathion Malathion is an organophosphate insecticide which acts as an acetylcholinesterase inhibitor. In the USSR, it was known as carbophos, in New Zealand and Australia as maldison and in South Africa as mercaptothion. Pesticide use Malathion is a pesti ...

Parathion Parathion, also called parathion-ethyl or diethyl parathion and locally known as "Folidol", is an organophosphate insecticide and acaricide. It was originally developed by IG Farben in the 1940s. It is highly toxic to non-target organisms, incl ...

s ** Aldicarb **

Bendiocarb Bendiocarb is an acutely toxic carbamate insecticide used in public health and agriculture and is effective against a wide range of nuisance and disease vector insects. Many bendiocarb products are or were sold under the tradenames "Ficam" and "T ...

** Bufencarb ** Carbaryl **

Carbendazim Carbendazim is a widely used, systemic, broad-spectrum benzimidazole fungicide and a metabolite of benomyl. It is also employed as a casting worm control agent in amenity turf situations such as golf greens, tennis courts etc. and in some countr ...

** Carbetamide **

Carbofuran Carbofuran is a carbamate pesticide, widely used around the world to control insects on a wide variety of field crops, including potatoes, corn and soybeans. It is a systemic insecticide, which means that the plant absorbs it through the r ...

Carbosulfan Carbosulfan is an organic compound adherent to the carbamate class. At normal conditions, it is brown viscous liquid. It is not very stable; it decomposes slowly at room temperature. Its solubility in water is low but it imisciblewith xylene, hex ...

** Chlorbufam ** Chloropropham ** Ethiofencarb **

Formetanate Formetanate is an insecticide and acaricide. It is used on alfalfa grown for seed and on some fruits, including citrus, pome, and stone fruit In botany, a drupe (or stone fruit) is an indehiscent fruit in which an outer fleshy part ( exo ...

** Methiocarb ** Methomyl ** Oxamyl ** Phenmedipham ** Pinmicarb ** Pirimicarb **

Propamocarb Propamocarb is a systemic fungicide used for control of soil, root and leaf disease caused by oomycetes. It is used by watering or spraying. Propamocarb is absorbed and distributed through the plant's tissue. Use Propamocarb has fungicidal activi ...

** Propham ** Propoxur * Atypical inhibitors **

Onchidal Onchidal is a naturally occurring neurotoxin produced as a defensive secretion by the mollusc '' Onchidella binneyi'' and several other related species in ''Onchidella'', a genus of small, air-breathing sea slugs. It acts as an irreversible acet ...

** Coumarins

References

External links

*
Acetylcholinesterase: A gorge-ous enzyme
QUite Interesting PDB Structure article a
PDBe
{{Acetylcholine metabolism and transport modulators