Acetylcholinesterase inhibitors cholinesterase inhibition

Inhibition of the two principal human cholinesterases, acetylcholinesterase and pseudocholinesterase, may not always result in visible neurological effects (Sundlof et al. 1984). Acetylcholinesterase, also referred to as true cholinesterase, red blood cell cholinesterase, or erythrocyte cholinesterase is found in erythrocytes, lymphocytes, and at nerve synapses (Goldfrank et al. 1990). Inhibition of erythrocyte or lymphocyte acetylcholinesterase is theoretically a reflection of the degree of synaptic cholinesterase inhibition in nervous tissue, and therefore a more accurate indicator than pseudocholinesterase activity of inhibited nervous tissue acetylcholinesterase (Fitzgerald and Costa 1993 Sundlof et al. 1984). Pseudocholinesterase (also referred to as cholinesterase, butyrylcholinesterase, serum cholinesterase, or plasma cholinesterase) is found in the plasma, serum, pancreas, brain, and liver and is an indicator of exposure to a cholinesterase inhibitor. 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

Mechanism of Action A cholinesterase inhibitor that inhibits the enzyme acetylcholinesterase, thus increasing the concentration of acetylcholine at cholinergic synapses and enhancing cholinergic function in the CNS. Therapeutic Effect Slows the progression of Alzheimer s disease. 

Exposure to some organophosphate cholinesterase inhibitors results in a delayed neuropathy characterized by degeneration of axons and myelin. This effect is not associated with the inhibition of acetylcholinesterase, but rather with the inhibition of an enzyme described as neuropathy target esterase (NTE) however, the exact mechanism of toxicity is not yet fully understood (Munro et al., 1994). For some organophosphate compounds, delayed neuropathy can be induced in experimental animals at relatively low exposure levels, whereas for others the effect is only seen following exposure to supralethal doses when the animal is protected from the acute toxic effects caused by cholinesterase inhibition. 

There are no effective therapies for Alzheimer s disease and no cure. Treatment aims to enhance cholinergic transmission. The most useful drugs are central acetylcholinesterase inhibitors, for example donepezil. Acetylcholinesterase is the enzyme that normally breaks down acetylcholine after it has interacted with its receptors at the synapse. Inhibition of this enzyme in the brain increases the amount of acetylcholine available and prolongs its action. These drugs produce a modest improvement in memory or slow progression of symptoms in some patients. The response to anti-cholinesterase drugs may take several weeks. Their use is limited by side effects, which can be severe. 

Succinylcholine produces a depolarizing blockade in skeletal muscle. The increased amount of acetylcholine produced by the administration of an inhibitor of acetylcholinesterase increases this blockade. Thus, circulatory and respiratory collapse may ensue. In addition, succinylcholine is metabolized by cholinesterases that may be inhibited by acetylcholinesterase inhibitors, causing the activity and duration of action of the drug to increase. 

A review of the literature of the distribution, function and structure of acetylcholinesterase is too voluminous for the scope of this article, and the reader is referred elsewhere [1]. Cholinesterase enzyme is a protein, and a dietary deficiency of protein can result in lower cholinesterase activity in liver microsomes and serum of rats. Cholinesterase inhibition by parathion and by Banol (6-chloro-3,4-xylyl methylcarbamate) (Upjohn) is more at lower dietary levels of casein than at higher levels, thus confirming that the toxicity of these enzyme inhibitors is greater at lower dietary protein levels [13]. This observation indicates that a causal relationship exists between amino-acid intake and cholinesterase activity. 

Donepezil is a piperidine cholinesterase inhibitor, which reversibly and non-competitively inhibits centrally active acetylcholinesterase 34 This specificity is claimed to result in fewer peripheral side effects as compared to the other ChE inhibitors. 

Anticholinesterase A drug that inhibits the enzyme acetylcholinesterase, which normally inactivates acetylcholine at the synapse. The effect of an anticholinesterase (or cholinesterase inhibitor) is thus to prolong the duration of action of the neurotransmitter. An example is rivastigmine, used in the treatment of Alzheimer s disease. 

Although bicyclophosphates do not inhibit acetylcholinesterase, they exhibit a synergistic toxic effect with materials that do. Individuals who have had previous exposure to cholinesterase inhibitors such as nerve agents and commercial organophosphate or carbamate pesticides may be at a greater risk from exposure to bicyclophosphates. 

Schaumann OO found that pretreatment of mice with 2-PAM 1 reduced inhibition of acetylcholinesterase in brain by paraoxon much more effectively than those by DFP and 217-A0. The finding of some protection against all three OP compounds could depend on direct reaction between the last two inhibitors and the oxime, with a reduction in inhibition of the enzyme. A similar consideration applies to the report by Bisa et al. that IV protected serum and brain cholinesterase from inhibition by paraoxon administered later at twice the LD5O. Although the same intraperitoneal dose of IV (7 mg) was found to protect the cholinesterase of rat serum and brain only incompletely from inhibition by DFP at 5 times the LD50, that of serum recovered its normal activity by 20 h after the dose of DFP, whereas that of brain required 26 h for recovery. 

Individual cholinesterase inhibitors differ in their selectivity, mechanism of inhibition of acetylcholinesterase (Schneider 2001), and pharmacokinetic properties (outlined in Table 7-2). 

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