Effects of Cholinesterases

Cholinesterases hydrolyze a wide variety of substrates, but differ from 

The catalytic action of ChE s is, however, not limited to ester hydrolysis. Thus, these enzymes catalyze also the reverse reaction, i.e., esterification of acids with choline (14). They promote transesterification 15) and the condensation of hydroxylamine with acids 14) or esters 15). Anhydrides of carboxylic acids are also substrates of ChE s 16, 17) and can undergo all the reactions, mentioned with esters, i.e., hydrolysis, esterification, and hydroxamation. 

After Augustinsson (17a). ----- true ChE from electric eel. H-------1- pseudo- 

ChE from human plasma. Ordinate b30 = microliters carbon dioxide, evolved in 30 min. Abscissa pS = — log substrate concentration. 

Behavior of Cholinesterases towards Homologous Choline Esters 

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Sideroff, S.I. and Santoluc, J.A. (1972). Behavioral and physiological effects of cholinesterase inhibitor carbaryl (1-naphthyl methylcarbamate). Physiology and Behavior 9, 459 62. 

The initial enthusiasm for tacrine and velnacrine, which are the anticholinesterases most studied clinically, has been tempered by the fact that not all patients respond. Most show the peripheral parasympathomimetic effects of cholinesterase inhibition, e.g. dyspepsia and diarrhoea, as well as nausea and vomiting, and about half of the patients develop hepatotoxicity with elevated levels of plasma alanine transaminase. While some peripheral effects can be attenuated with antimuscarinics that do not enter the brain, these add further side-effects and the drop-out rate from such trials is high (<75%) in most long-term studies. Donepezil appears to show less hepatotoxicity but its long-term value remains to be determined. 

Giacobini, E. (2006) Cholinesterases in human brain the effect of cholinesterase inhibitors on Alzheimer s disease and related disorders. In The brain cholinergic system in health and disease. Giacobini, E., Pepeu, G. (eds.), Informa Healthcare, Oxon, pp. 235-264. 

Sano, M. (2004) Economic effect of cholinesterase inhibitor therapy imphcations for managed care. Manag. Care Interface, 17, 44 9. 

The adverse effects of cholinesterase reactivating chemicals on the human cardiovascular system are shown in Tables 2-2 through 2-7. These effects may be classified as hypertension characterized by moderate Increased systolic and diastolic pressure with hypertension followed by hypotension, and ECG changes.20,61,97,102,107 The... 

Although there are only few published data with antidementia drugs, the effects of cholinesterase inhibitors in healthy awake volunteers appear to be unspecific. In contrast, the REM-sleep facilitating effect of these compounds appears to be a property not shared by other psychotropic drugs. 

The most prominent pharmacologic effects of cholinesterase inhibitors are on the cardiovascular and gastrointestinal systems, the eye, and the skeletal muscle neuromuscular junction (as described in the Case Study). Because the primary action is to amplify the actions of endogenous acetylcholine, the effects are similar (but not always identical) to the effects of the direct-acting cholinomimetic agonists. 

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... 

In California, mixer-loaders and spray applicators who work with toxicity category I and II organophosphates or N-methyl carbamates more than 30 hours per 30-day period are required to have medical supervision. Supervision consists of an interview and a medical examination to determine if a medical condition exists which would make the worker unusually susceptible to poisoning due to cholinesterase inhibition, and to caution the individual about the use of certain drugs such as the pheno-thiazine tranquilizers vdtich potentiate the effects of cholinesterase (ChE) inhibition. Two blood samples, taken several days apart, are analyzed to determine the individual s preexposure plasma and red blood cell (RBC) ChE activity (baseline value). The physician arranges a routine ChE testing program and provides for extra ChE tests should the worker be accidently exposed to OP s. If ChE activity is depressed to 50 percent of the baseline value, the physician may ask the employer to place the worker on... 

A review of the literature disclosed no long-term effects of cholinesterase reactivators (Appendix A). They are eliminated rapidly and produce a variety of short-term, reversible acute effects. These short-term effects might explain in part the slightly increased (nonsignificant) rates of admission to Army hospitals during the first 5 years after testing (Table 12). However, there was no evidence of a difference in current health status between these subjects and the other subjects. Nor was there evidence of differences in the current social functioning of these subjects, e.g., In employment, marital status, and family life. 

Cholinesterase inhibitors have been evaluated in schizophrenia as adjunctive treatments to ameliorate cognitive deficits as well as negative symptoms. O Table 1.2-2 summarizes studies on the adjunctive use of cholinesterase inhibitors for the treatment of schizophrenia. Overall, the effects of cholinesterase inhibitors on cognitive function in schizophrenia are modest (Ferreri et al., 2006). Beyond cognition, cholinesterase inhibitors also have modest effects on tardive dyskinesia (Tammenmaa et al., 2004). 

Moser, V.C. (1995). Comparisons of the acute effects of cholinesterase inhibitors using a neurobehavioral screening battery in rats. Neurotoxicol. Teratol. 17 617-25. 

Disagreement exists about how to determine effectiveness of cholinesterase inhibitors. Selection of qualitative versus quantitative assessment may bias a clinician s impression of response. Subtle changes are often detected only by psychometric testing rather than with routine questioning. No standard has been suggested to define the effectiveness of these medications therefore great variation exists between clinicians, and the duration of treatment ranges from months to years. 

Because the effects of cholinesterase inhibitors are modest, there is great interest in developing alternative or additional treatments for AD. Most of these alternatives have shown promise in epidemiologic studies however, benefit in prospective clinical trials has been limited or insufficiently stndied. Memantine is the first non-cholinesterase inhibitor approved for AD treatment. Its role in treatment will become more clearly defined in the next several years. 

Cerebrum structure Average effect of cholinesterase % Delayed lethality % ... 

Somani, S.M., Babu, S.R., Americ, S.P., and Dube, S.N., Effect of cholinesterase inhibitor and exercise on choline acetyltransferase and acetylcholinesterase activities in rat brain regions, Pharmacol. Biochem. Behav., 39, 337, 1991. 

Lojkowska, W Ryglcwicz, D, Jedrzejezak, T., Mine, S, Jakubowska, T.. Jarosz, H., and Bochynska, A. (2003). The effect of cholinesterase inhibitors on the regional blood fiow in patients with Alzheimer s disease and vascular dementia. J. Neuroi. Sci. 216, 119-126. 

Recovery from behavioral effects of cholinesterase inhibitors ks somewhat similar between the young and adult animals, which in both cases occurs much more rapidly... 

Ehrich. M., Shell, L., Rozum, M and Jortner, B. S, (1993). Shortterm clinical and neuropathologic effects of cholinesterase inhibitors in rats. J. Aw. Coll. To.xicol. 12,5S--68. 

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