Nicotinic receptors, acetylcholinesterase inhibition

Figure 6.2 Diagrammatic representation of a cholinergic synapse. Some 80% of neuronal acetylcholine (ACh) is found in the nerve terminal or synaptosome and the remainder in the cell body or axon. Within the synaptosome it is almost equally divided between two pools, as shown. ACh is synthesised from choline, which has been taken up into the nerve terminal, and to which it is broken down again, after release, by acetylcholinesterase. Postsynaptically the nicotinic receptor is directly linked to the opening of Na+ channels and can be blocked by compounds like dihydro-jS-erythroidine (DH/IE). Muscarinic receptors appear to inhibit K+ efflux to increase cell activity. For full details see text...

Woodruff-Pak DS, Vogel RW 3rd, Wenk GL. (2001) Galantamine Effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning. Proc Natl Acad Sci USA 98 2089-2094. 

Diazinon, an anticholinesterase organophosphate, inhibits acetylcholinesterase in the central and peripheral nervous system. Inhibition of acetylcholinesterase results in accumulation of acetylcholine at muscarinic and nicotinic receptors leading to peripheral and central nervous system effects. These effects... 

The OPPs inhibit acetylcholinesterase (AChE) by phosphorylating the esteratic site of the enzyme. As a result of AChE inhibition, ACh accumulates and binds to muscarinic and nicotinic receptors throughout the nervous system. Transformation of OPPs in the organisms takes place by conversion of the phosphorothioate (P=S) group to oxon (P=0) analogs. These oxo compounds are of concern because they are the activated forms of the OPPs, with a considerably stronger inhibition of acetylcholinesterase activity (27). 

These compounds inhibit the hydrolysis of the neurotransmitter acetylcholine by the enzyme acetylcholinesterase within the mammalian nervous system (Zwiener and Ginsburg, 1988). This inhibition causes acetylcholine levels to rise, thus causing cholinergic hyperstimulation at muscarinic and nicotinic receptors. There are important differences in the way carbamates and OPs bind to acetylcholinesterase as well as their abililty to affect the CNS. Carbamates are reversible inhibitors of cholinesterase enzymes. Carbamates create a reversible bond to the cholinesterase enzyme through carbamylation which can spontaneously hydrolyze, reversing toxicity. Carbamate poisoning produces toxicity similar to that of OPs however, the toxicity is usually of a shorter duration and less severe in nature (Lifshitz et al, 1994). In contrast, OPs inhibit cholinesterase via an irreversible bond of phosphate radicals... 

The main use of drugs at the neuromuscular junction is to relax muscle in anaesthesia, or to inhibit acetylcholinesterase in diseases where nicotinic receptor activation is reduced.e.g. myasthenia gravis. 

The recommended treatment in cases of acute poisoning is symptomatic. It is important to monitor and support breathing if signs of respiratory paralysis appear and to monitor blood pressure and pulse rate, since bradycardia and hypotonia may occur. Since imidacloprid does not inhibit acetylcholinesterase activity, treatment with a reactivating oxime (e.g., pralidoxime) is not indicated. Furthermore, treatment with a nicotinic antagonist may be ineffective or potentially harmful since symptoms of poisoning may be mediated by stimulation or inhibition of various nicotinic receptor subtypes or by other possible mechanisms. 

Reversible and competitive acetylcholinesterase inhibition leading to an increased concentration of acetylcholine at cholinergic synapses modulates nicotinic acetylcholine receptor may increase glutamate and serotonin levels APOE, APP... 

TABLE 10—11. Effects of Acetylcholinesterase Inhibition at Muscarinic, Nicotinic, and CNS Receptors... 

Symptoms (a) are due to the excess acetylcholine at muscarinic receptors. Symptoms (b) are due to excess acetylcholine at nicotinic receptors. Symptoms (c) are due to the accumulation of acetylcholine in the central nervous system. Acetylcholine accumulates because the organophosphates inhibit the enzyme acetylcholinesterase which normally removes the neurotransmitter substance. 

A) Both are hydrolyzed by acetylcholinesterase Both inhibit nicotinic receptors Both may decrease sweating Both may increase gastrointestinal motility Neither causes tachycardia Actions of chohnoceptor agonists and their clinical uses include which one of the following (A) Bronchodilation (asthma)... 

A. Organophosphorus (OP) compounds inhibit the enzyme acetylcholinesterase (AChE), allowing the accumulation of excessive acetylcholine at muscarinic receptors (cholinergic effector cells), at nicotinic receptors (skeletal neuromuscular junctions and autonomic ganglia), and in the central nervous system. 

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