Cholinergic overstimulation

The acute effects of aldicarb exposure are due to cholinergic overstimulation and may include the SLUDGE syndrome (salivation, lacrimation, urination, diarrhea, gastrointestinal cramping, and emesis), respiratory depression, bronchospasms, increased bronchial secretions, pulmonary edema, blurred vision, miosis, headache, tremors, muscle fasciculations, convulsions, mental confusion, coma, and death due to respiratory failure. Recovery from nonlethal exposures occurs very rapidly, usually within a few hours. 

The acute effects of exposure are due to cholinergic overstimulation and may include the SLUDGE (salivation, lacrimation, urination, diarrhea. 

Acetylcholinesterase is a component of the postsynaptic membrane of cholinergic synapses of the nervous system in both vertebrates and invertebrates. Its structure and function has been described in Chapter 10, Section 10.2.4. Its essential role in the postsynaptic membrane is hydrolysis of the neurotransmitter acetylcholine in order to terminate the stimulation of nicotinic and muscarinic receptors (Figure 16.2). Thus, inhibitors of the enzyme cause a buildup of acetylcholine in the synaptic cleft and consequent overstimulation of the receptors, leading to depolarization of the postsynaptic membrane and synaptic block. 

Respiratory Effects. Information on respiratory effects due to exposure to disulfoton is very limited. Exposure to disulfoton causes overstimulation of the muscarinic cholinergic receptors in the respiratory tract (Murphy 1986). This usually results in excessive bronchial secretions, bronchoconstriction, and eventually respiratory failure. Pulmonary edema and hemoptysis were recognized as probable causes of death in a man who ingested an unknown amount of disulfoton (Hattori et al. 1982). Studies regarding inhalation exposure were concerned primarily with lethality or cholinesterase inhibition. However, in intermediate-duration inhalation studies in rats, inflammation... 

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. 

It is expected that severe exposure would produce a broad spectrum of clinical effects indicative of massive overstimulation of the cholinergic system including headache, weakness, dizziness, blurred vision, respiratory difficulty, paralysis, convulsions, and coma. 

Two reviews (2,3) of the use of metrifonate in Alzheimer s disease have been published. Both reported a positive effect of metrifonate, with generally mild and usually transient adverse effects, consisting of gastrointestinal symptoms (such as abdominal pain, diarrhea, flatulence, and nausea, probably reflecting cholinergic overactivation) and leg cramps, possibly caused by the overstimulation of nicotinic receptors at the neuromuscular junction. No laboratory abnormalities were reported. 

A similar plant is water hemlock, which contains a different toxin, called cicutoxin. This is very potent and exposure to it is often fatal. One study of poisonings with this plant found that 30 per cent of victims died. It affects primarily the brain and the spinal cord, causing seizures and epileptic fits, possibly by overstimulating certain nerves (cholinergic pathways). 

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. 

These include the effects of nerve agents on y-amino-butyric acid neurons and cyclic nucleotides. In addition, changes in brain neurotransmitters, such as dopamine, serotonin, noradrenaline, as well as acetylcholine, following inhibition of brain cholinesterase activity, have been reported. These changes may be due in part to a compensatory mechanism in response to overstimulation of the cholinergic system or could result from direct action of nerve agent on the enzymes responsible for noncholinergic neurotransmission. 

The mechanism of toxicity for parathion is similar to that of chlorpyrifos. Following activation to the potent anticholinesterase paraoxon, acetylcholinesterase is inhibited within synapses and acetylcholine levels accumulate. This leads to overstimulation of cholinergic receptors of neurons, muscle cells, and end-organs culminating in cholinergic toxicity. 

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