Cholinesterase inhibitors tolerance

Oxime carbamates are generally applied either directly to the tilled soil or sprayed on crops. One of the advantages of oxime carbamates is their short persistence on plants. They are readily degraded into their metabolites shortly after application. However, some of these metabolites have insecticidal properties even more potent than those of the parent compound. For example, the oxidative product of aldicarb is aldicarb sulfoxide, which is observed to be 10-20 times more active as a cholinesterase inhibitor than aldicarb. Other oxime carbamates (e.g., methomyl) have degradates which show no insecticidal activity, have low to negligible ecotoxicity and mammalian toxicity relative to the parent, and are normally nondetectable in crops. Therefore, the residue definition may include the parent oxime carbamate (e.g., methomyl) or parent and metabolites (e.g., aldicarb and its sulfoxide and sulfone metabolites). The tolerance or maximum residue limit (MRL) of pesticides on any food commodity is based on the highest residue concentration detected on mature crops at harvest or the LOQ of the method submitted for enforcement purposes if no detectable residues are found. For example, the tolerances of methomyl in US food commodities range from 0.1 to 6 mg kg for food items and up to 40 mg kg for feed items. ... 

Tacrine was the first cholinesterase inhibitor approved for the treatment of AD, but it has been replaced by safer drugs which are better tolerated. 

Nordberg, A., Svensson, A.L. (1998) Cholinesterase inhibitors in the treatment of Alzheimer s disease a comparison of tolerability and pharmacology. Drug Saf., 19, 465-480. 

If muscarinic effects of such therapy are prominent, they can be controlled by the administration of antimuscarinic drugs such as atropine. Frequently, tolerance to the muscarinic effects of the cholinesterase inhibitors develops, so atropine treatment is not required. 

Excitotoxic activation of glutamate transmission via NMDA receptors has been postulated to contribute to the pathophysiology of Alzheimer s disease. Memantine binds to NMDA receptor channels in a use-dependent manner and produces a noncompetitive blockade. This drug appears to be better tolerated and less toxic than the cholinesterase inhibitors. Memantine is available as Namenda in 5 and 10 mg oral tablets. 

Rivasrigmine Transdermal (Exelon Patch) [Cholinesterase Inhibitor/Anri-Alzheimer Agent] Uses Mild/mod Alzheimer and Parkinson Dz dementia Action Acetylcholinesterase inhibitor Dose Initial 4.6-mg patch/d applied to back, chest, upper arm, T 9.5 mg after 4 wk if tolerated Caution [ ] Sick sinus synd, conduction defects, asthma, COPD, urinary obst, Sz Contra Hypersensitivity to rivastigmine, other carbamates Disp Transdermal patch 5 cm2 (4.6 mg/24 h), 10 cm2 (9.5 mg/24 h) SE N/V/D EMS See Rivastigmine OD See Rivastigmine... 

In 1952, Rider, Ellinwood, and Coon (7) demonstrated that rats can become tolerant to octamethyl pyrophosphoramide (OMPA). Since then it has been shown that rats can acquire tolerance to a variety of organophosphorus cholinesterase inhibitors. Typical of such reports is that of Bombinski and DuBois (2), who administered 0,0-diethyl S-2-ethyl-2-mercaptoethyl phosphorodithioate (Di-Syston) to rats each day for periods as long as 60 days. Signs of poisoning appeared after 2 days, but began to subside after 7-10 days, even though the activity of brain cholinesterase remained at or about 20% of its normal value from the 5th day onward. 

Hoskins, B. and I.K. Ho. 1992. Tolerance to organophosphate cholinesterase inhibitors. In Organophosphates Chemistry, Fate and Effects, J.E. Chambers and P.E. Levi, eds. Academic Press, New York, pp. 285-297. 

May work in some patients who do not tolerate other cholinesterase inhibitors... 

Fonnum, F., Sterri, S.H. (2006). Tolerance development to toxicity of cholinesterase inhibitors. In Toxicology of Organ-ophosphate and Carbamate Compounds (R.C. Gupta, ed.), pp. lSl-61. Elsevier Academic Press, San Diego, CA. 

Phenothiazine cholinesterase inhibitors. Synthetic derivatives of phe-nothiazine are well-tolerated drugs against a variety of human ailments from psychosis to cancer. A number of synthetic N-10-carbonyl phenothiazine derivatives, with cholinesterase inhibitory activity, were tested for interaction with a variety of neurotransmitter receptor systems. Phenothiazines can be prepared without significant neurotransmitter receptor interactions while retaining high potency as cholinesterase ligands for treatment of AD [165],... 

Donepezil was the second cholinesterase inhibitor approved in the US [6]. It is currently the only acetylchohnesterase approved by the FDA for the treatment of severe Alzheimer s disease. Donepezil is a reversible, noncompetitive chohnesterase inhibitor. It has a high binding specificity for brain acetylcholinesterase, with httle to no affinity for butylchohnesterase. Compared with the other cholinesterase inhibitors in this class, donepezil may be better tolerated, with less gastrointestinal side effects. The long half-life of this medication allows once a day dosing (See Table 3). 

Several cholinesterase inhibitors are now available, raising the question of whether it is appropriate to switch a patient from one to another if the first is not considered effective. Theoretical differences exist in their mechanisms of action, but some clinicians feel that these differences will not be clinically meaningful therefore switching is not helpful. Switching is recommended if a patient is not tolerating the initial treatment. Most clinicians probably switch to another agent, and initial data seem to indicate that some patients do respond to an alternative cholinesterase inhibitor. 

Cholinesterase inhibitors should be used throughout the course of illness because of the cognitive benefits, possible treatment of behavioral symptoms, and economic factors. Additionally, vitamin E should be used adjunctively with the chohnesterase inhibitors throughout treatment. Vitamin E is recommended solely based on the results of one smdy that showed no cognitive benefit, but a delayed requirement for nursing home placement with vitamin E. Figure 63-3 shows pharmacotherapeutic treatment algorithms for AD. These recommendations are made based on available efficacy, safety, and tolerability data. 

Donepezil should be initiated at a 5-mg/day dose in the morning and titrated to 10 mg/day after 4 to 6 weeks if it is well tolerated. Table 63-6 summarizes cholinesterase inhibitor dosing recommendations. The most common donepezil side effects are nausea, vomiting. 

Cholinesterase inhibitors are the primary treatment for patients with AD. Early and continued use seem to offer patients the optimal benefit. While no differences in effectiveness have been demonstrated to date, tolerability, dosing frequency, and ease of titration may be used for selection of the initial agent. The MMSE may be helpful as a monitoring tool for changes in severity of illness. Unless patients are not tolerating the initial medication, it is recommended to continue for at least a year before considering an alternative agent. 

Overall, memantine has been well tolerated in clinical trials. The most frequent adverse events associated with memantine include constipation, confusion, dizziness, headache, coughing, and hypertension. As some of these side effects are also reported with cholinesterase inhibitors, caution should be used when administering memantine with this class of medications. ... 

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