Acetylcholinesterase inhibitor
Encyclopedia
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...
that inhibits the cholinesterase enzyme from breaking down acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
, increasing both the level and duration of action of the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
acetylcholine.
Uses
Acetylcholinesterase inhibitors:- Occur naturally as venoms and poisonPoisonIn the context of biology, poisons are substances that can cause disturbances to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism....
s - Are used as weapons in the form of nerve agentNerve agentNerve agents are a class of phosphorus-containing organic chemicals that disrupt the mechanism by which nerves transfer messages to organs...
s - Are used medicinally:
- To treat myasthenia gravisMyasthenia gravisMyasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
. In myasthenia gravis, they are used to increase neuromuscular transmission. - To treat GlaucomaGlaucomaGlaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye...
- To treat Alzheimer's diseaseAlzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
- To treat Lewy Body Dementia
- As an antidoteAntidoteAn antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....
to anticholinergicAnticholinergicAn anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
poisoning
- To treat myasthenia gravis
Reversible inhibitor
Compounds which function as reversibleReversible inhibitor
For acetylcholine esterase , reversible inhibitors are those that do not irreversibly bond to and decactivate AChE.Drugs that reversibly inhibit acetylcholine esterase are currently being explored as treatments for Alzheimer's disease and myasthenia gravis, among others. Examples include tacrine...
competitive or noncompetitive inhibitors of cholinesterase are those most likely to have therapeutic uses. These include:
- Some organophosphateOrganophosphateAn organophosphate is the general name for esters of phosphoric acid. Phosphates are probably the most pervasive organophosphorus compounds. Many of the most important biochemicals are organophosphates, including DNA and RNA as well as many cofactors that are essential for life...
s not listed under "Irreversible" below - Delta9-tetrahydrocannabinol (THC)
- CarbamateCarbamateCarbamates are organic compounds derived from carbamic acid . A carbamate group, carbamate ester, and carbamic acids are functional groups that are inter-related structurally and often are interconverted chemically. Carbamate esters are also called urethanes.-Synthesis:Carbamic acids are derived...
s- PhysostigminePhysostigminePhysostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean....
- NeostigmineNeostigmineNeostigmine is a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor.- Synthesis :Neostigmine was first synthesized by Aeschlimann and Reinert in 1931....
- PyridostigminePyridostigminePyridostigmine is a parasympathomimetic and a reversible cholinesterase inhibitor. Since it is a quaternary amine, it is poorly absorbed in the gut and does not cross the blood-brain barrier, except possibly in stressful conditions.-Mode of action:...
- Ambenonium
- Demarcarium
- RivastigmineRivastigmineRivastigmine is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects, which...
- Physostigmine
- PhenanthrenePhenanthrenePhenanthrene is a polycyclic aromatic hydrocarbon composed of three fused benzene rings. The name phenanthrene is a composite of phenyl and anthracene. In its pure form, it is found in cigarette smoke and is a known irritant, photosensitizing skin to light...
derivatives- GalantamineGalantamineGalantamine is used for the treatment of mild to moderate Alzheimer’s disease and various other memory impairments, in particular those of vascular origin...
- Galantamine
- PiperidinePiperidinePiperidine is an organic compound with the molecular formula 5NH. This heterocyclic amine consists of a six-membered ring containing five methylene units and one nitrogen atom...
s- DonepezilDonepezilDonepezil, marketed under the trade name Aricept by its developer Eisai and partner Pfizer, is a centrally acting reversible acetylcholinesterase inhibitor. Its main therapeutic use is in the palliative treatment of mild to moderate Alzheimer's disease. Common side effects include...
, also known as E2020
- Donepezil
- TacrineTacrineTacrine is a centrally acting anticholinesterase and indirect cholinergic agonist . It was the first centrally-acting cholinesterase inhibitor approved for the treatment of Alzheimer's disease, and was marketed under the trade name Cognex. Tacrine was first synthesised by Adrien Albert at the...
, also known as tetrahydroaminoacridine (THA') - EdrophoniumEdrophoniumEdrophonium 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...
- Huperzine AHuperzine AHuperzine A is a naturally occurring sesquiterpene alkaloid compound found in the plant firmoss Huperzia serrata. and in varying quantities in other Husperzia spp.including H. elmeri, H. carinat, H. aqualupian,...
- LadostigilLadostigilLadostigil is a novel neuroprotective agent being investigated for the treatment of neurodegenerative disorders like Alzheimer's disease, Lewy body disease, and Parkinson's disease...
- Ungeremine
Comparison table
| Inhibitor | Duration | Main site of action | Clinical use | Adverse effects |
|---|---|---|---|---|
| Edrophonium 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... |
short (10 min.) | neuromuscular junction Neuromuscular junction A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract... |
diagnosis of myasthenia gravis Myasthenia gravis Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability... |
|
| Neostigmine Neostigmine Neostigmine is a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor.- Synthesis :Neostigmine was first synthesized by Aeschlimann and Reinert in 1931.... |
medium (1-2 hrs.) | neuromuscular junction Neuromuscular junction A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract... |
|
visceral |
| Physostigmine Physostigmine Physostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean.... |
medium (0.5-5 hrs.) | postganglionic parasympathetic | treat glaucoma Glaucoma Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye... (eye drops Eye Drops Eye Drops was a television program on TechTV that showcased short computer animation movies and clips made using off the shelf 3D animation software. The show claimed to showcase all different types of animation, but only a very small number of shorts featured non-CG animation... ) |
|
| Pyridostigmine Pyridostigmine Pyridostigmine is a parasympathomimetic and a reversible cholinesterase inhibitor. Since it is a quaternary amine, it is poorly absorbed in the gut and does not cross the blood-brain barrier, except possibly in stressful conditions.-Mode of action:... |
medium (2-3 hrs.) | neuromuscular junction Neuromuscular junction A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract... |
Myasthenia gravis Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability... (orally Mouth The mouth is the first portion of the alimentary canal that receives food andsaliva. The oral mucosa is the mucous membrane epithelium lining the inside of the mouth.... ) |
|
| Dyflos | long | postganglionic parasympathetic | historically to treat glaucoma Glaucoma Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye... (eye drops Eye Drops Eye Drops was a television program on TechTV that showcased short computer animation movies and clips made using off the shelf 3D animation software. The show claimed to showcase all different types of animation, but only a very small number of shorts featured non-CG animation... ) |
toxic |
| Ecothiopate | long | postganglionic parasympathetic | treat glaucoma Glaucoma Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye... (eye drops Eye Drops Eye Drops was a television program on TechTV that showcased short computer animation movies and clips made using off the shelf 3D animation software. The show claimed to showcase all different types of animation, but only a very small number of shorts featured non-CG animation... ) |
systemic effects |
| Parathion Parathion Parathion, also called parathion-ethyl or diethyl parathion, is an organophosphate compound. It is a potent insecticide and acaricide. It was originally developed by IG Farben in the 1940s. It is highly toxic to non-target organisms, including humans. Its use is banned or restricted in many... (irreversible) |
long | none | toxic |
Quasi-irreversible inhibitor
Compounds which function as quasi-irreversible inhibitorQuasi-irreversible inhibitor
For acetylcholine esterase , 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 formation...
s of cholinesterase are those most likely to have use as chemical weapons or pesticide
Pesticide
Pesticides are substances or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.A pesticide may be a chemical unicycle, biological agent , antimicrobial, disinfectant or device used against any pest...
s. These include:
- OrganophosphateOrganophosphateAn organophosphate is the general name for esters of phosphoric acid. Phosphates are probably the most pervasive organophosphorus compounds. Many of the most important biochemicals are organophosphates, including DNA and RNA as well as many cofactors that are essential for life...
s- EchothiophateEchothiophateEchothiophate is a parasympathomimetic and a phosphorothioate. It is an acetylcholinesterase inhibitor.- Uses :It is used as an ocular antihypertensive in the treatment of chronic glaucoma and, in some cases, accommodative esotropia...
- Diisopropyl fluorophosphate
- Cadusafos
- CyclosarinCyclosarinCyclosarin or GF 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 team led by Dr. Gerhard Schrader. The major nerve gases are the G agents, sarin , soman, tabun, and...
- DichlorvosDichlorvosDichlorvos or 2,2-dichlorovinyl dimethyl phosphate is a highly volatile organophosphate, widely used as a insecticide to control household pests, in public health, and protecting stored product from insects. It is effective against mushroom flies, aphids, spider mites, caterpillars, thrips, and...
- DimethoateDimethoateDimethoate is a widely used organophosphate insecticide used to kill insects on contact. It was patented and introduced in the 1950s by American Cyanamid. Like other organophosphates, dimethoate is an anticholinesterase which disables cholinesterase, an enzyme essential for central nervous system...
- MetrifonateMetrifonateMetrifonate or trichlorfon is an irreversible organophosphate acetylcholinesterase inhibitor.it is a prodrug which is activated non-enzymatically into 2,2-dichlorovinyl dimethyl phosphate ....
(irreversible) - SarinSarinSarin, or GB, is an organophosphorus compound with the formula [2CHO]CH3PF. It is a colorless, odorless liquid, which is used as a chemical weapon. It has been classified as a weapon of mass destruction in UN Resolution 687...
- SomanSomanSoman, or GD , is an extremely toxic chemical substance. It is a nerve agent, interfering with normal functioning of the mammalian nervous system by inhibiting the cholinesterase enzyme. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations according to UN...
- TabunTabun (nerve agent)Tabun or GA is an extremely toxic chemical substance. It is a clear, colorless, and tasteless liquid with a faint fruity odor. It is classified as a nerve agent because it fatally interferes with normal functioning of the mammalian nervous system...
- VXVX (nerve agent)VX, IUPAC name O-ethyl S-[2-ethyl] methylphosphonothioate, is an extremely toxic substance whose only application is in chemical warfare as a nerve agent. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations in UN Resolution 687...
- VEVE (nerve agent)VE is a "V-series" nerve agent closely related to the better-known VX nerve agent.Like most of the agents in the V-series , VE has not been extensively studied outside of military science...
- VGVG (nerve agent)VG is a "V-series" nerve agent chemically similar to the better-known VX nerve agent. Tetram is the common Russian name for the substance...
- VMVM (nerve agent)VM is a "V-series" nerve agent closely related to the better-known VX nerve agent.Like most of the agents in the V-series , VM has not been extensively studied outside of military science...
- DiazinonDiazinonDiazinon , a colorless to dark brown liquid, is a thiophosphoric acid ester developed in 1952 by Ciba-Geigy, a Swiss chemical company...
- MalathionMalathionMalathion is an organophosphate parasympathomimetic which binds irreversibly to cholinesterase. Malathion is an insecticide of relatively low human toxicity, however one recent study has shown that children with higher levels of organophosphate pesticide metabolites in their urine are more likely...
- ParathionParathionParathion, also called parathion-ethyl or diethyl parathion, is an organophosphate compound. It is a potent insecticide and acaricide. It was originally developed by IG Farben in the 1940s. It is highly toxic to non-target organisms, including humans. Its use is banned or restricted in many...
- Echothiophate
- CarbamateCarbamateCarbamates are organic compounds derived from carbamic acid . A carbamate group, carbamate ester, and carbamic acids are functional groups that are inter-related structurally and often are interconverted chemically. Carbamate esters are also called urethanes.-Synthesis:Carbamic acids are derived...
s- AldicarbAldicarbAldicarb is a carbamate insecticide which is the active substance in the pesticide Temik. It is effective against thrips, aphids, spider mites, lygus, fleahoppers, and leafminers, but is primarily used as a nematicide. Aldicarb is a cholinesterase inhibitor which prevents the breakdown of...
- BendiocarbBendiocarbBendiocarb 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...
- Bufencarb
- CarbarylCarbarylCarbaryl is a chemical in the carbamate family used chiefly as an insecticide. It is a white crystalline solid commonly sold under the brand name Sevin, a trademark of the Bayer Company. Union Carbide discovered carbaryl and introduced it commercially in 1958...
- CarbendazimCarbendazimCarbendazim is a widely used broad-spectrum benzimidazole fungicide. A 4.7% solution of carbendazim hydrochloride is sold as Eertavas, an effective treatment for Dutch elm disease....
- Carbetamide
- CarbofuranCarbofuranCarbofuran is one of the most toxic carbamate pesticides. It is marketed under the trade names Furadan, by FMC Corporation and Curater, among several others. It is used to control insects in a wide variety of field crops, including potatoes, corn and soybeans...
- CarbosulfanCarbosulfanCarbosulfan is an organic compound adherent to the carbamate class. At normal conditions, it is brown viscose liquid. It is not very stable; it decomposes slowly at room temperature. Its solubility in water is low but it is miscible with xylene, hexane, chloroform, dichloromethane, methanol and...
- Chlorbufam
- Chloropropham
- Ethiofencarb
- Formetanate
- MethiocarbMethiocarbMethiocarb is a chemical mainly used as a bird repellent, as a insecticide and as molluscicide. It is toxic to humans, not listed as a carcinogen, is toxic to reproductive organs, and a potent neurotoxin. Methiocarb can also cause acute toxicity in humans if anyone is exposed to it for long periods...
- MethomylMethomylMethomyl is a carbamate insecticide. It was introduced in 1966, but its use is restricted because of its high toxicity to humans. Its current primary use is on alfalfa for forage....
- Oxamyl
- Phenmedipham
- Pinmicarb
- PirimicarbPirimicarbPirimicarb is a carbamate insecticide used to control aphids on vegetable, cereal and orchard crops by inhibiting acetylcholinesterase activity. It was originally developed by Imperial Chemical Industries Ltd., now Syngenta, in 1970....
- Propamocarb
- Propham
- PropoxurPropoxurPropoxur is a carbamate insecticide and was introduced in 1959. Propoxur is a non-systemic insecticide with a fast knockdown and long residual effect used against turf, forestry, and household pests and fleas. It is also used in pest control for other domestic animals, Anopheles mosquitoes, ants,...
- Aldicarb
Effects
Some major effects of cholinesterase inhibitors:- Actions on the autonomic nervous system, that is parasympathetic nervous system will cause bradycardia, hypotension, hypersecretion, bronchoconstriction, GI tract hypermotility, and decrease intraocular pressure.
- SLUDGE syndrome.
- Actions on the neuromuscular junction will result in prolonged muscle contraction.
Administration of reversible cholinoesterase inhibitors is contraindicated with those that have urinary retention due to obstruction.
Titration phase
When used in the central nervous system to alleviate neurological symptoms, such as rivastigmineRivastigmine
Rivastigmine is a parasympathomimetic or cholinergic agent for the treatment of mild to moderate dementia of the Alzheimer’s type and dementia due to Parkinson's disease. The drug can be administered orally or via a transdermal patch; the latter form reduces the prevalence of side effects, which...
in Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, all cholinesterase inhibitors require doses to be increased gradually over several weeks, and this is usually referred to as the titration phase.
External links
- ATSDR Case Studies in Environmental Medicine: Cholinesterase Inhibitors, Including Insecticides and Chemical Warfare Nerve Agents U.S. Department of Health and Human Services