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.
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.[6][7]
Inhibitors like TEPP modify the serine residue in the esteratic site of the cholinesterase.
This
phosphorylation 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.[8] The phosphorylation of cholinesterase by TEPP (or any other organophosphate) is irreversible. This makes the inhibition of the cholinesterase permanent.[6][7]
The cholinesterase gets irreversible phosphorylated according to the following reaction scheme
In this reaction scheme the E indicates the cholinesterase, PX the TEPP molecule, E–PX the reversible phosphorylated cholinesterase, k3 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.[6]
The time dependent irreversible inhibition of the cholinesterase can be described by the following equation.[6]
In this formula, E is the remaining enzyme activity, E0 is the initial enzyme activity, t is the time interval after mixing of the cholinesterase and the TEPP, KI 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.[9]
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.[11]
To treat cognitive impairments in patients with
schizophrenia. There is some evidence to suggest efficacy in treating positive, negative and affective symptoms.[12][13][14]
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.[15][16]
Resistance: The hunt for
resistance genes in Rhipicephalus microplus has been hampered by
high copy number in the three
AChEs involved.[17] 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.[17]
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.[22]
When used in the central nervous system to alleviate neurological symptoms, such as
rivastigmine in
Alzheimer's disease, 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.[20] 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).
^Seth (2009-11-18). "23". Textbook Of Pharmacology. Elsevier India. p. III.87.
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^Ribeiz SR, Bassitt DP, Arrais JA, Avila R, Steffens DC, Bottino CM (April 2010). "Cholinesterase inhibitors as adjunctive therapy in patients with schizophrenia and schizoaffective disorder: a review and meta-analysis of the literature". CNS Drugs. 24 (4): 303–17.
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abInglis F (June 2002). "The tolerability and safety of cholinesterase inhibitors in the treatment of dementia". International Journal of Clinical Practice. Supplement (127): 45–63.
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^Singh, Ravneet; Sadiq, Nazia M. (2020),
"Cholinesterase Inhibitors", StatPearls, Treasure Island (FL): StatPearls Publishing,
PMID31335056, retrieved 2020-10-12
^Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC (15 April 2013). Clinical Anesthesia (7th ed.). Lippincott Williams & Wilkins. pp. 552–554.
ISBN978-1-4511-4419-2.
^Karadsheh N, Kussie P, Linthicum DS (March 1991). "Inhibition of acetylcholinesterase by caffeine, anabasine, methyl pyrrolidine and their derivatives". Toxicology Letters. 55 (3): 335–42.
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10.1016/0378-4274(91)90015-X.
PMID2003276.
^Miyazawa M, Yamafuji C (March 2005). "Inhibition of acetylcholinesterase activity by bicyclic monoterpenoids". Journal of Agricultural and Food Chemistry. 53 (5): 1765–8.
doi:
10.1021/jf040019b.
PMID15740071.
^Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ (April 2009). "Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis". Journal of Neural Transmission. 116 (4): 457–65.
doi:
10.1007/s00702-009-0189-x.
PMID19221692.
S2CID8655284.