Cholinesterases peripheral

There is a second type of cholinesterase called butyrylcholinesterase, pseudocholinesterase, or cholinesterase. This enzyme is present in some nonneural cells in the central and peripheral nervous systems as well as in plasma and serum, the liver, and other organs. Its physiologic function is not known, but is hypothesized to be the hydrolysis of esters ingested from plants (Lefkowitz et al. 1996). Plasma cholinesterases are also inhibited by organophosphate compounds through irreversible binding this binding can act as a detoxification mechanism as it affords some protection to acetylcholinesterase in the nervous system (Parkinson 1996 Taylor 1996). 

Some agonists, such as methacholine, carbachol and bethanecol are structurally very similar to ACh (Fig. 6.6). They are all more resistant to attack by cholinesterase than ACh and so longer acting, especially the non-acetylated carbamyl derivatives carbachol and bethanecol. Carbachol retains both nicotinic and muscarinic effects but the presence of a methyl (CH3) group on the p carbon of choline, as in methacholine and bethanecol, restricts activity to muscarinic receptors. Being charged lipophobic compounds they do not enter the CNS but produce powerful peripheral parasympathetic effects which are occasionally used clinically, i.e. to stimulate the gut or bladder. 

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. 

Donepezil is a piperidine cholinesterase inhibitor, which reversibly and non-competitively inhibits centrally active acetylcholinesterase 34 This specificity is claimed to result in fewer peripheral side effects as compared to the other ChE inhibitors. 

As an inhibitor of plasma (pseudo) cholinesterase, DFP produced only minimal reversal of scopolamine-induced incapacitation. Note the very low plasma ChE levels, with only minor decreases in RBC ChE (Fig. 71). DFP does improve near vision when applied to the eye (David Flarper, unpublished data) suggesting that paralysis of the muscles of visual accommodation is probably peripheral in origin. Persistence of pupillary enlargement (in the face of systemic treatment with physostigmine) may be due to physiological or pK factors, causing limited access to the iris. 

It is effective orally and resistant to pseudo-cholinesterase and possesses longer duration of action. Its nicotinic action is less than acetylcholine and actions are more marked on CVS as compared to GIT and urinary system. Earlier it was used for CVS disorders such as peripheral vascular disease and paroxysmal supraventricular tachycardia. But now, it is rarely used in therapeutics. 

In addition to battlefield trauma, there is also the risk of exposure to chemical weapons such as the nerve agents, notably the organophosphorus gases (soman, sarin, VX, tabun) [6]. Organophosphorus toxicity arises largely from their ability to irreversibly inhibit acetyl-cholinesterases, leading to effects associated with peripheral acetyl-choline accumulation (muscarinic syndrome) such as meiosis, profuse sweating, bradychardia, bronchioconstriction, hypotension, and diarrhoea. Central nervous system effects include anxiety, restlessness, confusion, ataxia, tremors. 

Metoclopramide is structurally related to orthoclopramide, a procaine derivative, and it can prolong the action of suxamethonium because of competition for cholinesterase. However, its common side effects are similar to those seen with phenothiazine derivatives. In high doses, a range of extrapyramidal symptoms may develop. The anti-emetic effects of metoclopramide are due to two main actions. Centrally, it blocks dopamine in the CTZ and peripherally, it hastens gastric emptying, abolishes irregular intestinal contractions, and increases... 

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. 

The cholinesterase inhibitors cause significant adverse effects, including nausea and vomiting, and other peripheral cholinomimetic effects. These drugs should be used with caution in patients receiving other drugs that inhibit cytochrome P450 enzymes (eg, ketoconazole, quinidine see Chapter 4). Preparations available are listed in Chapter 7. 

W.O. Cook, V.R. Beasley, R.A. Lovell, A.M. Dahlem, S.B. Hooser, N.A. Mahmood and W.W. Carmichael, Consistent inhibition of peripheral cholinesterases by neurotoxins from the freshwater cyanobacterium... 

Among the agents cited, only d-tubocurarine is useful as a drug (skeletal muscle relaxant) the rest are useful only as research tools. Cholinesterase, found in liver and plasma, can hydrolyze other esters such as succinylcholine (a skeletal muscle relaxant). Cholinergic peripheral receptors are located on (1) postganglionic parasympathetic fibers, (2) postganglionic sympathetic fibers, (3) all autonomic ganglia, and (4) skeletal end plates. 

Several centers have been collecting human samples, including urine, breast milk, peripheral blood, cord blood, meconium, vernix, saliva, hair, and placental tissue (Eskenazi et al. 2005). The samples have been analyzed for the presence of numerous substances, such as mercury, lead, cotinine, pesticides, phthalates, PAHs, PAH-DNA adducts, allergens, endotoxin, antioxidant micronutrients, cytokines, immunoglobulin E, cholinesterase, and thyroid hormones. The centers have also been storing samples for future research purposes (Eskenazi et al. 2005). 

Monitoring the effect of muscle relaxants during surgery (and recovery following the use of cholinesterase inhibitors) typically involves the use of a device that produces transdermal electrical stimulation of one of the peripheral nerves to the hand and recording of the evoked contractions (twitches Figure 27-6). The motor responses to different patterns of peripheral nerve stimulation are measured. The three most commonly used patterns of include (1) single-twitch stimulation, (2) train-of-four (TOF) stimulation, and (3) tetanic stimulation. Two newer modalities are also available to monitor neuromuscular transmission double-burst stimulation and posttetanic count. 

Insecticides fall largely into three main chemical groups 1) the organochlorines whose action is primarily on the peripheral nervous system 2) organophosphates, and 3) carbamates. The latter two classes are cholinesterase inhibitors. 

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. 

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