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 duration of action of acetylcholine in the central nervous system, autonomic ganglia and neuromuscular junctions, which are rich in acetylcholine receptors. Acetylcholinesterase inhibitors are one of two types of cholinesterase inhibitors; the other being butyryl-cholinesterase inhibitors.
Acetylcholinesterase 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 and sarin inhibit cholinesterases, enzymes that hydrolyze the neurotransmitter acetylcholine.
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.
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. 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
<chem>E + PX <=> E-PX ->[k_3] EP + X </chem>
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.
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:
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:
Administration of reversible cholinoesterase inhibitors is contraindicated with those that have urinary retention due to urethral obstruction.
Examples.
Reversible inhibitor.
Compounds which function as reversible competitive or noncompetitive inhibitors of cholinesterase are those most likely to have therapeutic uses. These include:
Quasi-irreversible inhibitor.
Compounds which function as quasi-irreversible inhibitors of cholinesterase are those most likely to have use as chemical weapons or pesticides.