Chemicals which prevent breakdown of acetylcholine and butyrylcholine
Acetylcholine
Sarin molecule, C4H10FO2P
Tetraethyl pyrophosphate molecule, C8H20O7P2
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
synaptic cleft that can bind to
muscarinic receptors ,
nicotinic receptors and others. This group of inhibitors is divided into two subgroups,
acetylcholinesterase inhibitors (AChEIs) and
butyrylcholinesterase inhibitors (BChEIs).
[1]
[2]
[3]
ChEIs may be used as drugs for
Alzheimer's and
myasthenia gravis , and also as
chemical weapons and
insecticides .
[4]
[5] Side effects when used as drugs may include
loss of appetite ,
nausea ,
vomiting ,
loose stools ,
vivid dreams at night,
dehydration ,
rash ,
bradycardia ,
peptic ulcer disease ,
seizures ,
weight loss ,
rhinorrhea ,
salivation ,
muscle cramps , and
fasciculations .
[6]
[7]
ChEIs are indirect-acting
parasympathomimetic drugs .
[8]
ChEls are widely used as
chemical weapons . Since November 2019 the group of ACheIs known as Novichoks have been banned as agents of warfare under the
Chemical Weapons Convention .
[9] Novichok agents are
neurotoxic
organophosphorus compounds and are considered more potent than
VX gas , also a neurotoxic organophosphorus compound.
[10]
Medical use
While 4 ChEIs are approved in the US for the treatment of Alzheimer's Disease, only three of these are available commercially.
[6] The three available are
rivastigmine ,
donepezil , and
galantamine , while
tacrine is not.
[6] They are generally used to treat
Alzheimer's disease and
dementia .
[6] If a benefit occurs, it is generally during the second or third month after starting.
[6]
It is difficult to determine which ChEI has greater efficacy, due to
design flaws in head-to-head comparison studies.
[11]
Pyridostigmine is used in the treatment of
myasthenia gravis .
[12]
Neostigmine is used in combination with a
muscarinic antagonist to reverse the effects of non-depolarizing muscle relaxants e.g.
rocuronium bromide
Cholinesterase inhibitor toxicity
Common side effects of one ChEI include
insomnia ,
nausea and
vomiting , accidental injury,
headache ,
dizziness ,
bradycardia ,
hypotension ,
ecchymosis , and
sleep disturbance.
[13]
Binding affinity
Acetylcholinesterase inhibitors
Donepezil ,
phenserine ,
huperzine A , and
BW284c51 are selective AChE inhibitors.
[14]
[11]
Butyrylcholinesterase inhibitor
Tetra (monoisopropyl)
pyrophosphoramide (
Iso-OMPA ) and
ethopropazine are selective BChE inhibitors.
[14]
AChE and BChE inhibitor
Paraoxon and
rivastigmine are both acetylcholinesterase inhibitors and butyrylcholinesterase inhibitors.
[14]
[11]
[7]
In 2015, the
United States Food and Drug Administration 's Adverse Event Reporting System database compared rivastigmine to the other ChEI drugs
donepezil and
galantamine found that rivastigmine was associated with a higher frequency of reports of death as an adverse event.
[15]
Acetylcholinesterase inhibitors and nicotinic receptor modulator
Galantamine might be less well tolerated than donepezil and rivastigmine.
[11]
Chemical weapons
Assassination Attempt
Cholinesterase inhibitors came to a public attention in 2020 when Russian opposition and dissent figure
Alexei Navalny was treated in
Berlin Charité hospital for
poisoning by a Russian-made
nerve agent which is known since 2019 as belonging to the
Novichok agents subgroup of ChEI.
[16]
See also
Further reading
Institute, National; (UK), Care Excellence (2019-12-27).
Cholinesterase inhibitors and memantine for dementia . Retrieved 2019-12-27 .
Parsons, Chris G.; Danysz, Wojciech; Dekundy, Andrzej; Pulte, Irena (2013-05-09).
"Memantine and Cholinesterase Inhibitors: Complementary Mechanisms in the Treatment of Alzheimer's Disease" . Neurotoxicity Research . 24 (3). Springer Science and Business Media LLC: 358–369.
doi :
10.1007/s12640-013-9398-z .
ISSN
1029-8428 .
PMC
3753463 .
PMID
23657927 .
Meng, Yan‑Hong; Wang, Pan‑Pan; Song, Ya‑Xue; Wang, Jian‑Hua (2019-03-01).
"Cholinesterase inhibitors and memantine for Parkinson's disease dementia and Lewy body dementia: A meta‑analysis" . Experimental and Therapeutic Medicine . 17 (3): 1611–1624.
doi :
10.3892/etm.2018.7129 .
ISSN
1792-0981 .
PMC
6364145 .
PMID
30783428 . Retrieved 2019-12-27 .
References
^ English, Brett A.; Webster, Andrew A. (2012). "Acetylcholinesterase and its Inhibitors". Primer on the Autonomic Nervous System . Elsevier. pp. 631–633.
doi :
10.1016/b978-0-12-386525-0.00132-3 .
ISBN
978-0-12-386525-0 .
^ Deutch, Ariel Y.; Roth, Robert H. (2014). "Pharmacology and Biochemistry of Synaptic Transmission". From Molecules to Networks . Elsevier. pp. 207–237.
doi :
10.1016/b978-0-12-397179-1.00007-5 .
ISBN
978-0-12-397179-1 .
^ Colovic, Mirjana B.; Krstic, Danijela Z.; Lazarevic-Pasti, Tamara D.; Bondzic, Aleksandra M.; Vasic, Vesna M. (2013-04-01).
"Acetylcholinesterase Inhibitors: Pharmacology and Toxicology" . Current Neuropharmacology . 11 (3). Bentham Science Publishers Ltd.: 315–335.
doi :
10.2174/1570159x11311030006 .
ISSN
1570-159X .
PMC
3648782 .
PMID
24179466 .
^
"Cholinesterase Inhibitors (Medical Use & WMD)" . PharmWiki .
Tulane University School of Medicine . Retrieved 24 August 2020 .
^ Mandour, Raafat (2013).
"Environmental Risks of Insecticides Cholinesterase Inhibitors" . Toxicology International . 20 (1).
United States National Library of Medicine : 30–34.
doi :
10.4103/0971-6580.111556 .
PMC
3702124 .
PMID
23833435 .
^
a
b
c
d
e Budson, Andrew E.; Solomon, Paul R. (2016). "Cholinesterase Inhibitors". Memory Loss, Alzheimer's Disease, and Dementia . Elsevier. pp. 160–173.
doi :
10.1016/b978-0-323-28661-9.00016-0 .
ISBN
978-0-323-28661-9 .
^
a
b Khoury, Rita; Rajamanickam, Jayashree; Grossberg, George T. (2018-01-08).
"An update on the safety of current therapies for Alzheimer's disease: focus on rivastigmine" . Therapeutic Advances in Drug Safety . 9 (3). SAGE Publications: 171–178.
doi :
10.1177/2042098617750555 .
ISSN
2042-0986 .
PMC
5810854 .
PMID
29492246 .
^ Forrester, John V.; Dick, Andrew D.; McMenamin, Paul G.; Roberts, Fiona; Pearlman, Eric (2016). "General and ocular pharmacology". The Eye . Elsevier. pp. 338–369.e1.
doi :
10.1016/b978-0-7020-5554-6.00006-x .
ISBN
978-0-7020-5554-6 . Parasympathomimetics are a group of drugs that act either by directly stimulating the muscarinic receptor, for example pilocarpine, or by inhibiting the enzyme
acetylcholinesterase , which hydrolyses the acetylcholine in the synapse.
^ Castelvecchi, Davide (2019). "Novichok nerve agents banned by chemical-weapons treaty". Nature .
doi :
10.1038/d41586-019-03686-y .
PMID
33244185 .
^ Chai, Peter R.; Hayes, Bryan D.; Erickson, Timothy B.; Boyer, Edward W. (2018).
"Novichok agents: A historical, current, and toxicological perspective" . Toxicology Communications . 2 (1): 45–48.
doi :
10.1080/24734306.2018.1475151 .
PMC
6039123 .
PMID
30003185 .
^
a
b
c
d Hersen, Michel (2006).
Comprehensive handbook of personality and psychopathology (
Tertiary source ). Hoboken, New Jersey: John Wiley. p.
514 .
ISBN
978-0-471-75725-2 .
OCLC
63041762 .
^
World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008 . World Health Organization. p. 429.
hdl :
10665/44053 .
ISBN
9789241547659 .
^
"Prescribing information : Aricept" (PDF) . FDA access data . Eisai Inc. and Pfizer Inc. 2012.
Archived (PDF) from the original on 2016-02-21. Retrieved 6 May 2021 .
^
a
b
c Waiskopf, Nir; Soreq, Hermona (2015). "Cholinesterase Inhibitors". Handbook of Toxicology of Chemical Warfare Agents . Elsevier. pp. 761–778.
doi :
10.1016/b978-0-12-800159-2.00052-x .
ISBN
978-0-12-800159-2 .
^ Ali TB, Schleret TR, Reilly BM, Chen WY, Abagyan R (2015).
"Adverse Effects of Cholinesterase Inhibitors in Dementia, According to the Pharmacovigilance Databases of the United-States and Canada" . PLOS ONE . 10 (12): e0144337.
Bibcode :
2015PLoSO..1044337A .
doi :
10.1371/journal.pone.0144337 .
PMC
4671709 .
PMID
26642212 .
^
"Alexei Navalny was poisoned 'using Novichok' nerve agent, say German government" . Telegraph Media Group Limited. 2 September 2020.