Cholinesterases quaternary

Based on features of their interaction with ChE, anti-cholinesterase substances are classified as reversible and irreversible inhibitors. Referred to the reversible anti-cholinesterase substances are quaternary ammonium compounds and aminoformic acid esters OPC are referred to the irreversible anti-cholinesterase substances. 

We may now consider in a little more detail the interaction of true (or a-) cholinesterase with acetylcholine. Wilson and Berg mann1 suggest that there are two active sites in the enzyme, known as anionic site and esteratic site respectively. These sites (represented diagrammatically in fig. II)2 are not to be considered independent. The mode of attachment will be seen to depend upon (a) the quaternary nitrogen atom (N+< ) and... 

Acetylcholinesterase can be inhibited by two general mechanisms. In the first mechanism, positively charged quaternary ammonium compounds bind to the anionic site and prevent ACh from binding—a simple competitive inhibition. In the second mechanism, the agents act either as a false substrate for the cholinesterase or directly attack the esteratic site in both cases they covalently modify the esteratic site and non-competitively prevent further hydrolytic activity. Either mechanism can be effective in preventing the hydroly-... 

Pyridostigmine (Mestinon) is a quaternary ammonium carbamate. Neostigmine and pyridostigmine also have direct agonist activity at nicotinic receptors on skeletal muscle. Rivastigmine (Exelon) is a carbamate cholinesterase inhibitor with good penetration into the brain. 

Metabolites of the cholinesterase inhibitors and in some instances significant amounts of the parent compound are eliminated in the urine. Renal excretion is very important in the clearance of agents such as neostigmine, pyridostigmine, and edrophonium. This is demonstrated by a twofold to threefold increase in elimination half-lives for these drugs in anephric patients. Renal elimination is largely the result of glomerular filtration but probably also involves, at least in the case of quaternary amines, secretion via the renal cationic transport system. 

Anticholinesterase agents of all classes can initiate antidromic firing of action potentials in motor neurons, possibly due to an activation of prejunctional ACh receptors that are activated by the elevated synaptic ACh. Quaternary ammonium inhibitors can also act as agonists at these receptors. The initiation of antidromic firing may be a mechanism by which cholinesterase inhibitors produce fasciculation of skeletal muscle. 

If the poisoning is due to an organophosphate, prompt administration of pralidoxime chloride will result in dephosphorylation of cholinesterases in the periphery and a decrease in the degree of the blockade at the skeletal neuromuscular junction. Since pralidoxime is a quaternary amine, it will not enter the CNS and therefore cannot reactivate central cholinesterases. In addition, pralidoxime is effective only if there has been no aging of the phosphorylated enzyme. Pralidoxime has a greater effect at the skeletal neuromuscular junction than at autonomic effector sites. 

Chemical Class Cholinesterase inhibitor quaternary ammonium compound Ciinicai Pharmacology ... 

Some cholinesterase inhibitors also inhibit butyrylcholinesterase (pseudocholinesterase). Flowever, inhibition of butyrylcholinesterase plays little role in the action of indirect-acting cholinomimetic drugs because this enzyme is not important in the physiologic termination of synaptic acetylcholine action. Some quaternary cholinesterase inhibitors also have a modest direct action as well, eg, neostigmine, which activates neuromuscular nicotinic cholinoceptors directly in addition to blocking cholinesterase. 

Absorption of the quaternary carbamates from the conjunctiva, skin, and lungs is predictably poor, since their permanent charge renders them relatively insoluble in lipids. Thus, much larger doses are required for oral administration than for parenteral injection. Distribution into the central nervous system is negligible. Physostigmine, in contrast, is well absorbed from all sites and can be used topically in the eye (Table 7-4). It is distributed into the central nervous system and is more toxic than the more polar quaternary carbamates. The carbamates are relatively stable in aqueous solution but can be metabolized by nonspecific esterases in the body as well as by cholinesterase. However, the duration of their effect is determined chiefly by the stability of the inhibitor-enzyme complex (see Mechanism of Action, below), not by metabolism or excretion. 

Cholinesterase inhibitors have minimal effects by direct action on vascular smooth muscle because most vascular beds lack cholinergic innervation (coronary vasculature is an exception). At moderate doses, cholinesterase inhibitors cause an increase in systemic vascular resistance and blood pressure that is initiated at sympathetic ganglia in the case of quaternary nitrogen compounds and also at central sympathetic centers in the case of lipid-soluble agents. Atropine, acting in the central and peripheral nervous systems, can prevent the increase of blood pressure and the increased plasma norepinephrine. 

Some quaternary carbamate cholinesterase inhibitors, eg, neostigmine, have an additional direct nicotinic agonist effect at the neuromuscular junction. This may contribute to the effectiveness of these agents as therapy for myasthenia. 

Both the nicotinic and the muscarinic effects of the cholinesterase inhibitors can be life-threatening. Unfortunately, there is no effective method for directly blocking the nicotinic effects of cholinesterase inhibition, because nicotinic agonists and antagonists cause blockade of transmission (see Chapter 27). To reverse the muscarinic effects, a tertiary (not quaternary) amine drug must be used (preferably... 

The enzyme choline esterase has been shown to have two binding points on its protein surface for these substances—one site for the quaternary ammonium group and one for X. This enzyme catalyzes the hydrolysis of an ester at the X position. From a consideration of the structure of the (2-chloroethyl)trimethylammonium chloride derivatives which were active as plant growth substances, a similar protein-binding site in the plant has been postulated. This site would have a point of attachment for both the ammonium cation and the X constituent of the molecule. This postulated site in the plant is thus similar, but not identical, to cholinesterase, which is an enzyme not known to occur in plants. There is no direct proof for this hypothetical site in the plant. 

On the Forces Acting Between Quaternary Ammonium Ions and the Anionic Sites of Cholinesterases... 

The Inhibitory Activity of Quaternary Ammonium Ions of the Structure RtN against True Cholinesterase of Electric Eel... 

Ashani, Y., Bhattacharjee, A.K., Leader, H., Saxena, A., Doctor, B.P. (2003). Inhibition of cholinesterases with cationic phos-phonyl oximes highlights distinctive properties of the charged pyridine groups of quaternary oxime reactivators. Biochem. Pharmacol. 66 191-202. 

It was at one time generally assumed chat physostigmlne, neostigmine, and related Inhibitors that possess a carbamyl ester linkage or urethane structure, in addition to a tertiary amino or quaternary ammonium group, inhibit Che enzyme in the same reversible fashion. However, careful kinetic studies showed chat physostigmlne and neostigmine are hydrolyzed by cholinesterase (11 14). 

Carbachol is a quaternary ammonium compound that shares both the muscarinic and nicotinic actions of acetylcholine but is much more slowly deactivated. Carbachol has been used topically in ophthalmology and systemically (subcutaneously, for example in doses of 2 mg/day) for urinary retention. Severe cholinergic effects can result. In one instance they primarily involved the gastrointestinal tract and the patient died of esophageal rupture (1). In other cases patients have experienced extreme bradycardia with hypotension, requiring treatment with intravenous atropine. As carbachol is not destroyed by cholinesterase, a cumulative effect is possible in patients who receive regular doses at short intervals in one case, hypotension only developed on the third treatment day (2). 

Echothiophate iodide is a long-lasting cholinesterase inhibitor of the irreversible type, as is isofluorphate. Unlike the latter, however, it is a quaternary salt, and when applied locally, its distribution in tissues is limited, which can be very de.sirablc. It is used as a long-acting anticholinesterase agent in the treatment of glaucoma. 

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