Anticholinesterases acetylcholinesterase inhibition

Diazinon, an anticholinesterase organophosphate, inhibits acetylcholinesterase in the central and peripheral nervous system. Inhibition of acetylcholinesterase results in accumulation of acetylcholine at muscarinic and nicotinic receptors leading to peripheral and central nervous system effects. These effects... 

Coudray-Luca.s, C., Prioux-Guyonneau. M., Tas.sel, A., Coq, H, M., Cohen. Y and Wepienc, J, (1981), Influence of intoxication by anticholinesterase agems on core teinpcraiure in rats Relationship between hypothennia and acetylcholinesterase inhibition in different brain areas, Acta Pharmacol. Toxicol 49, 215-222. 

One non-anticholinesterase effect of OPs has been discussed in section 10.3.1.3, namely OPIDP. The degree to which non-acetylcholinesterase inhibition effects contribute to acute OP toxicity continues to be a matter of interest and has been reviewed. Thus, Chambers " noted a poor correlation between rat oral LD50 values of various phosphorothionate insecticides and inhibition potency of corresponding oxons for brain acetylcholinesterase. However, there are a number of possible explanations for this, other than differences in target molecule notably, differences in site and magnitude of desulfuration of the thionate to the active oxon may be important. Studies by Duysen and colleagues with acetylcholinesterase knockout mice suggested that non-acetylcholinesterase inhibitory effects must contribute to the acute toxicity of VX. Maxwell et... 

Carbamates - Structure activity relationships have been studied with respect to toxicity and anticholinesterase activity. 9 The mechanism of acetylcholinesterase inhibition by the carbamates is not entirely clear. 

ACh is metabolised extraneuronally by the enzyme acetylcholinesterase, to reform precursor choline and acetate. Blocking its activity with various anticholinesterases has been widely investigated and some improvement in memory noted. Such studies have invariably used reversible inhibition because of the toxicity associated with long-term irreversible inhibition of the enzyme. Physostigmine was the pilot drug. It is known to improve memory in animals and some small effects have been seen in humans (reduces number of mistakes in word-recall tests rather than number of words recalled), but it really needs to be given intravenously and has a very short half-life (30 min). 

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. 

Presently available methods to diagnose and biomonitor exposure to anticholinesterases, e.g., nerve agents, rely mostly on measurement of residual enzyme activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in blood. More specific methods involve analysis of the intact poison or its degradation products in blood and/or urine. These approaches have serious drawbacks. Measurement of cholinesterase inhibition in blood does not identify the anticholinesterase and does not provide reliable evidence for exposure at inhibition levels less than 20 %. The intact poison and its degradation products can only be measured shortly after exposure. Moreover, the degradation products of pesticides may enter the body as such upon ingestion of food products containing these products. 

Mechanism of Action A parasympathetic, anticholinesterase agent that inhibits destruction of acetylcholine by acetylcholinesterase, thus causing accumulation of acetylcholine at cholinergic synapses. Results in an increase in cholinergic responses such as miosis, increased tonus of intestinal and skeletal muscles, bronchial and ureteral constriction, bradycardia, and increased salivary and sweat gland secretions. Therapeutic Effect Diagnosis of myasthenia gravis. 

Pralidoxime is administered by intravenous infusion, 1-2 g given over 15-30 minutes. In spite of the likelihood of aging of the phosphate-enzyme complex, recent reports suggest that administration of multiple doses of pralidoxime over several days may be useful in severe poisoning. In excessive doses, pralidoxime can induce neuromuscular weakness and other adverse effects. Pralidoxime is not recommended for the reversal of inhibition of acetylcholinesterase by carbamate inhibitors. Further details of treatment of anticholinesterase toxicity are given in Chapter 58. 

Treatment of test animals with anticholinesterase agents such as atropine and 2-PAM significantly reduced the acute lethality of diazinon in rats indicating that acute diazinon lethality is primarily attributable to the inhibition of acetylcholinesterase. Administration of 16 mg/kg atropine intramuscularly, with or without 30 mg/kg pyridine 2-aldoxime methochloride (2-PAM) given either orally or intravenously or both, to female albino rats 10 minutes before diazinon exposure increased the LD50 value (294 mg/kg) for diazinon for this species by a factor of 3.2 (with 2-PAM) or 1.7 (without 2-PAM) (Harris et al. 1969). 

Diazinon toxicity results predominantly from the inhibition of acetylcholinesterase in the central and peripheral nervous system. The enzyme is responsible for terminating the action of the neurotransmitter, acetylcholine, in the synapse of the pre- and post-synaptic nerve endings or in the neuromuscular junction. However, the action of acetylcholine does not persist long as it is hydrolyzed by the enzyme, acetylcholinesterase, and rapidly removed. As an anticholinesterase organophosphate, diazinon inhibits acetylcholinesterase by reacting with the active site to form a stable phosphorylated complex which is incapable of destroying acetylcholine at the synaptic gutter between the pre- and post-synaptic nerve... 

The major action resulting from human exposure to diazinon is the inhibition of cholinesterase activity (refer to Section 2.4 for discussion). Two pools of cholinesterases are present in human blood acetylcholinesterase in erythrocytes and serum cholinesterase (sometimes referred to as pseudocholinesterase or butyrlcholinesterase) in plasma. Acetylcholinesterase, present in human erythrocytes, is identical to the enzyme present in neural tissue (the target of diazinon action) while serum cholinesterase has no known physiological function. Inhibition of both forms of cholinesterase have been associated with exposure to diazinon in humans and animals (Coye et al. 1987 Edson and Noakes 1960 Soliman et al. 1982). Inhibition of erythrocyte, serum, or whole blood cholinesterase may be used as a marker of exposure to diazinon. However, cholinesterase inhibition is a common action of anticholinesterase compounds such as organophosphates (which include diazinon) and carbamates. In addition, a wide variation in normal cholinesterase values exists in the general population, and there are no studies which report a quantitative... 

The toxicity of organophosphoric esters for insects and mammals is associated with inhibition of cholinesterases. Investigations on the relation between chemical structure of organophosphoric esters and the inactivation of acetylcholinesterase (AChE) have revealed that anticholinesterase activity depends to a large extent on the chemical reactivity of the esters. As a rule, the chemical reactivity of the phosphorus atom is the single most important property which determines the anticholinesterase activity of an organophosphoric ester. 

Anticholinesterases are drugs that inhibit or inactivate acetylcholinesterase, causing the accumulation of acetylcholine at the cholinergic receptors. 

The clinically useful anticholinesterase agents diisopropyl fluorophosphate (DFP, Floropryl) and echothiophate iodide (Phospholine Iodide [PI]) demonstrate an indirect-acting mechanism resulting in increased levels of acetylcholine at the cholinergic receptor sites. The inhibition of acetylcholinesterase produces a relatively long-lasting and irreversible effect of maintaining active levels of acetylcholine at the parasympathetic synapses. 

TABLE 17-6 Inhibition Constants for Anticholinesterase Potency of Acetylcholinesterase Inhibitors ... 

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