Paralysis acetylcholinesterase inhibition

Although OPPs and carbamates exhibit very similar modes of action in various animal species, i.e, acetylcholinesterase inhibition in the CNS with resulting paralysis—there is an important difference between the two classes of pesticides. Carbamates do not require metabolic conversion prior to exhibiting their toxicity. Furthermore the enzyme activity may at times be rapidly regenerated by reversal of inhibition. The kinetics of the inhibition (carbamoylation) reaction have been well studied in it electrophilic carbamoyl moieties form covalent bonds with enzyme esteratic sites. This is followed by carbamate transfer of an acidic group to the site to yield the acetylated enzyme complex (ref. 176). 

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. 

Bronchoconstriction and secretion, muscular weakness or paralysis, CNS depression, including respiratory centers Inhibition of acetylcholinesterase (reversible or irreversible)... 

Another important example is the nicotinic acetylcholine receptor, which is activated by the agonist nicotine causing muscular fibrillation and paralysis. Indirect effects can also occur. For example, organophosphates and other acetylcholinesterase inhibitors increase the amount of acetylcholine and thereby overstimulate the receptor, leading to effects in a number of sites (see chap. 7). Alternatively, botulinum toxin inhibits the release of acetylcholine and causes muscle paralysis because muscular contraction does not take place (see chap. 7). 

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. 

It is believed that metabolic products of TOCP inhibit acetylcholinesterase. Apparently other factors are involved in TOCP neurotoxicity. A study of tri-o-cresylphosphate poisoning in China has described a number of symptoms.4 Initial pain in the lower leg muscles was followed by paralysis and lower limb nerve injury. Patients with mild poisoning recovered after several months, but more severely poisoned ones suffered permanent effects. Despite the devastating effects of TOCP, the percentage of virtually complete recovery in healthy subjects is relatively high. 

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. 

Nerve agents are organophosphorus (OP) compounds that inhibit acetylcholinesterase (AChE) extremely rapidly, which results in an accumulation of acetylcholine (ACh), leads to muscle fasciculations and paralysis, and finally results in death (Dacre, 1984). There are several strategies available to verify an exposure to nerve agents. It is not... 

Tri-ort/io-cresyl phosphate, the contaminant in a homemade liquor called Ginger Jake , which is responsible for delayed neuropathy and paralysis of the legs, is bioactivated to a form that inhibits neuropathy target esterase but not acetylcholinesterase (Casida and Quistad, 2004 Glynn, 2006). Large structures with a 12-20 carbon alkyl chain on the phosphorus atom inhibit fatty acid amide hydrolase but not acetylcholinesterase (Casida and Quistad, 2004). These examples clearly show that OPs which do not affect... 

FIGURE 62.1. OPs bind to and inhibit acetylcholinesterase (AChE), the enzyme responsible for degrading the neurotrans-mitter, acetycholine (ACh), into choline and acetate. When AChE is inhibited by an organophosphate nerve agent, the subsequent reduced hydrolysis of ACh results in an accumulation of ACh within the synaptic cleft and overstimulation of the post-synaptic nerve. Seizures and possibly paralysis and/or death may occur. 

Unlike the nonspecific effects and uncommon occurrence of direct mortality observed in wildlife exposed to chlorinated hydrocarbon pesticides, several studies have documented direct mortality from exposure to OP and carbamate insecticides. The method by which the OPs and carbamate insecticides affect wildlife is quite different from the method by which the chlorinated hydrocarbon insecticides effect wildlife. The OPs and carbamates inhibit cholinesterase, primarily acetylcholinesterase (AChE), which is an enzyme that functions in the breakdown of the neurotransmitter acetylcholine. Acetylcholine functions in the transmission of nerve impulses. Therefore, when AChE is inhibited by an OP or carbamate insecticide, it can no longer breakdown acetylcholine and there is continued transmission of nerve impulses that eventually leads to nerve and muscle exhaustion. The respiratory muscles are a critical muscle group that is affected, often leading to respiratory paralysis as the immediate cause of death. A major difference in the mode of action between OPs and carbamates is that the inhibition of AChE by OPs is, from a biological standpoint, irreversible, while the inhibition from exposure to carbamates is reversible in a biologically relevant time frame. There... 

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. 

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