Cholinesterase inhibitors metabolic effects

Many compounds have been tested simultaneously with (2-chloroethyl)tri-methylammonium chloride on Thatcher wheat, to ascertain, if possible, whether these chemicals were affecting a particular metabolic process. Other cholinesterase inhibitors such as eserine, diisopropyl fluorophosphate, and nitrogen mustard, neither negated the effect from (2-chloroethyl)trimethylammonium chloride nor altered the growth of the plant themselves. Many other substances were also without effect on the action of (2-chloroethyl)trimethylammonium chloride. A very slight reversal of the alteration by (2-chloroethyl)trimethylam-monium chloride was obtained by 10 2 and 10 3 M choline, betaine, and adenine. Only gibberellin completely and rapidly reversed the shorter growth pattern of a plant which had been treated with (2-chloroethyl)trimethylammonium chloride. 

Procaine, which has a pKa of 8.9, is highly ionized at physiological pH and has a short duration of action. Because it causes vasodilation, a vasoconstricting substance is added to the procaine solution to delay systemic absorption. Procaine may prolong the effect of succinylcholine because both drugs are metabolized by the same enzyme. Cholinesterase inhibitors alter metabolism of procaine. 

Benomyl is a synthetic, organic fungistat having little or no acute toxic effect in mammals. No systemic poisonings have been reported in humans. Although the molecule contains a carbamate grouping, benomyl is not a cholinesterase inhibitor. It is poorly absorbed across skin that which is absorbed is promptly metabolized and excreted. 

Its systemic effect is related to its metabolism. In plants it is converted to its sulfoxide (41), which is water soluble and therefore easily translocated in the transport system. The sulfoxide is a 10-20 times stronger cholinesterase inhibitor than aldicarb. However, when applied directly to insects it is less toxic because, due to its hydrophilic nature, it can hardly penetrate the insect cuticle. Presumably, a similar bioactivation takes place also in the insect organism. As metabolism proceeds, the sulfoxide derivative 41 is hydrolysed to 2-methyl-2-methylsulfinyl-propionaldehyde (42), which is partly converted by oxidation to 2-methyl-2-methysuffinylpropionic acid (43), and partly by reduction to the corresponding alcohol (44), as shown in Scheme 1.8. Part of the sulfoxide is converted to sulfon... 

There are many cholinesterase inhibitors diminishing both AChE and BuChE activities to a comparable extent. However, there are a number of important exceptions the selectivity of some OP and carbamates for BuChE has been described by Aldridge (A4). Carbamates belong to a group of insecticides having a large variation in their effectiveness. They are biologically active because of their structural complementarity to the active surface of AChE and their consequent reaction as substrates with very low turnover numbers (A4, B2). Some carbamates inhibit selectively either AChE or BuChE (Bll, B22). The toxicity of carbamates is dependent on their ability to carbamylate AChE in different tissues and on other factors such as distribution, detoxification, and metabolization. 

LD50 (oral, male rat) 80 mg/kg, (IP, mouse) 22 mg/kg, (subcut., mouse) 24 mg/kg, (skin, rabbit) 107 mg/kg poison by ing., inh., subcut., IV, IP routes toxic by skin absorption cholinesterase inhibitor very rapidly metabolized and excreted confirmed carcinogen tumorigen experimental teratogen, reproductive effects human mutagenic data TSCA listed... 

Natural (-)-cocaine (7.57, Fig. 7.8), which has the (2/ ,3S)-configuration, is a relatively poor substrate for hepatic carboxylesterases and plasma cholinesterase (EC 3.1.1.8), and also a potent competitive inhibitor of the latter enzyme [116][121], In contrast, the unnatural enantiomer, (+)-(2S,3/ )-cocaine, is a good substrate for carboxylesterases and cholinesterase. Because hydrolysis is a route of detoxification for cocaine and its stereoisomers, such metabolic differences have a major import on their monooxygenase-catalyzed toxification, a reaction of particular effectiveness for (-)-cocaine. 

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. 

Rivastigmine is a pseudo-irreversible inhibitor of both acetyl and butyryl cholinesterases. Thus although the drug initially blocks the enzymes, it is metabolized by them thereby giving the drug a relatively short half-life. The top dose is often necessary to achieve therapeutic efficacy, at which dose the central and peripheral cholinergic side effects become apparent. 

The organophosphorus insecticides are all structurally related and undergo similar reactions. The chemical classification of the most widely used compounds of this type is given in Table V. These compounds can also be differentiated on the basis of whether they are largely effective per se or undergo oxidative conversions in plants or animals. All are inhibitors of the enzyme, cholinesterase. Their potency depends not only upon their intrinsic enzyme affinity but also on anticholinesterase properties acquired through in vivo metabolism. 

Not fully understood. Aprotinin is only a very weak inhibitor of serum cholinesterase (100 000 KIU caused a maximd 16% inhibition in man) and on its own would have little effect on the metabolism of suxamethonium. However, it might tip the balance in those whose cholinesterase was already very depressed. 

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