Neuromuscular junction acetylcholinesterase inhibition

Azinphos-methyl requires bioactivation for its action. The parent compound is activated to the potent oxon by microsomal mixed-function oxidase enzymes, which in turn elicits toxicity by inhibiting acetylcholinesterase in synapse and neuromuscular junctions. AChE inhibition leads to overstimulation of cholinergic receptors on postsynaptic neurons, muscle cells, and/or end-organs and consequent signs and symptoms of cholinergic toxicity. 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

We noted above that too much acetylcholine in the synapse or at a neuromuscular junction can be a problem black widow spider venom works that way by causing massive release of this neurotransmitter. There is another way to accomplish the same thing inhibit the normal route by which acetylcholine once released is subsequently removed. That route is degradation by acetylcholinesterase, an enzyme that catalyzes... 

Diazinon toxicity results predominantly from the inhibition of acetylcholinesterase in the central and peripheral nervous system. The enzyme is responsible for terminating the action of the neurotransmitter, acetylcholine, in the synapse of the pre- and post-synaptic nerve endings or in the neuromuscular junction. However, the action of acetylcholine does not persist long as it is hydrolyzed by the enzyme, acetylcholinesterase, and rapidly removed. As an anticholinesterase organophosphate, diazinon inhibits acetylcholinesterase by reacting with the active site to form a stable phosphorylated complex which is incapable of destroying acetylcholine at the synaptic gutter between the pre- and post-synaptic nerve... 

ACh, cholinomimetics and acetylcholinesterase inhibitors have been shown to inhibit the movement of flatworms and to cause flaccid paralysis (for reviews, see Fbx et a/., 1996 Halton et a/., 1997 Halton and Maule, 2004 Ribeiro et a/., 2005). This is in contrast to the mainly myoexcitatory effects of ACh at the vertebrate neuromuscular junction and in many other invertebrates including nematodes. Although ACh has predominantly inhibitory actions on flatworm muscle it has been shown to have inconsistent effects on the muscle of the monogenean, Diclidophora merlangi (Maule et a/., 1989), to induce the contraction of muscle fibres dispersed from planarians (Blair and Anderson, 1994 Moneypenny eta/., 2001) and, to cause increased muscle activity... 

Acetylcholine is a neurotransmitter, a key substance involved with transmission of nerve impulses in the brain, skeletal muscles, and other areas where nerve impulses occur. An essential step in the proper function of any nerve impulse is its cessation (see Figure 6.9), which requires hydrolysis of acetylcholine as shown by Reaction 6.10.1. Some xenobiotics, such as organophosphate compounds (see Chapter 18) and carbamates (see Chapter 15) inhibit acetylcholinesterase, with the result that acetylcholine accumulates and nerves are overstimulated. Adverse effects may occur in the central nervous system, in the autonomic nervous system, and at neuromuscular junctions. Convulsions, paralysis, and finally death may result. 

Adverse effects The effects of physostigmine on the CNS may lead to convulsions when high doses are used. Bradycardia may also occur. Inhibition of acetylcholinesterase at the skeletal neuromuscular junction causes the accumulation of acetylcholine and ultimately results in paralysis of skeletal muscle. However, these effects are rarely seen with therapeutic doses. 

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. 

Acephate exerts its toxicity by inhibiting the enzyme acetylcholinesterase in the synapse and neuromuscular junctions, which leads to accumulation of the neurotransmitter acetylcholine and overstimulation of postsynaptic receptors. 

IMS is clearly a separate clinical entity from acute cholinergic crisis and delayed neuropathy. The acute cholinergic crisis usually emerges within a few minutes to a few hours and is due to acetylcholinesterase (AChE) inhibition resulting in acetylcholine accumulation at the synapses in the nervous system and at the neuromuscular junctions. Patients acutely poisoned with OPs exhibit muscle fasciculations. 

The answer is e. (Murray, pp 505-626. Scriver, pp 4029-4240. Sack, pp 121-138. Wilson, pp 287-320.) The major problem in myasthenia gravis is a marked reduction of acetylcholine receptors on the motor endplate where cranial nerves form a neuromuscular junction with muscles. In these patients, autoantibodies against the acetylcholine receptors effectively reduce receptor numbers. Normally, acetylcholine molecules released by the nerve terminal bind to receptors on the muscle endplate, resulting in a stimulation of contraction by depolarizing the muscle membrane. The condition is improved with drugs that inhibit acetylcholinesterase. 

Acetylcholine levels in the neuromuscular junction are rapidly reduced by the enzyme acetylcholinesterase. A number of nerve gas poisons act to inhibit acetylcholinesterase (such as sarin and VX), such that muscles are continuously stimulated to contract. This leads to blurred vision, bronchoconstriction, seizures, respiratory arrest, and death. The poisons are covalent modifiers of acetylcholinesterase therefore, recovery from exposure to such poisons requires the synthesis of new enzyme. A new generation of acetylcholinesterase inhibitors, which act reversibly (i.e., they do not form covalent bonds with the enzyme), are now being used to treat dementia, in particular dementia as brought about by Alzheimer s disease. 

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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