Toxicity muscarinic effects

Ophthalmic effects due to direct ocular exposure to OPs include optic neuropathy, retinal degeneration, defective vertical smooth pursuit, myopia, and miosis. Respiratory effects, including muscarinic, nicotinic, and central effects, contribute to respiratory distress in acute and delayed OP toxicity, Muscarinic effects, such as bronchospasm and laiyngeal spasm, can lead to airway obstruction. Nicotinic effects can lead to weakness and paralysis of respiratory oropharyngeal tiiuscles. Central effects can lead to cessation of respiration. 

Carbamates effect the reversible carbamylation of acetylcholinesterase, permitting accumulation of acetylcholine at cholinergic neuroeffector junctions (muscarinic effects), at the myoneural junctions of skeletal muscle, and in the autonomic ganglia (nicotinic effects). CNS function is also impaired. However the relatively large dissociation constant of the carbamyl-enzyme complex indicates that it dissociates more readily than does the organophosphate-enzyme complex, mitigating the toxicity of the carbamate pesticides. The reversibility of the carbamyl-enzyme complex affects (limits) the utility of blood enzyme measurements as a diagnostic tool. 

Although our military experience managing toxicity from nerve agent exposure is limited, exposures to related chemicals such as the OP class occur commonly each year in the USA. In 2006, there were a total of approximately 5,400 OP exposures across the USA (Bronstein et al, 2007). OPs, such as malathion, are commonly used as pesticides. OP toxicity manifests in a similar fashion as toxicity from nerve agents however, this chemical class is considerably less toxic. One case series of 16 children who experienced poisonings with OPs confirmed that pediatric patients present with toxicity differently than adults (Lifshitz et al, 1999). These children often did not manifest the classic muscarinic effects (such as salivary secretions and diarrhea) seen in adults. 

Toxic effects occur within seconds to 5 min of nerve agent vapor or aerosol inhalation. The muscarinic effects include ocular (miosis, conjunctival congestion, ciliary spasm), nasal discharge, respiratory (bronchoconstriction and increased bronchial secretion), gastrointestinal (anorexia, vomiting, abdominal cramps, and diarrhea), sweating, salivation, and cardiovascular (bradycardia and hypotension) effects. The nicotinic effects include muscular fa-sciculation and paralysis. CNS effects can include ataxia, confusion, loss of reflexes, slurred speech, coma, and paralysis. 

Atropine administered repeatedly as necessary and pralidoxime (2-PAM Cl) are antidotes for nerve agent toxicity. Although atropine has no effect on nicotinic receptors, and therefore will not reverse muscle weakness or paralysis, it can reduce morbidity and mortahty by reversing some of the muscarinic effects such as bron-chospasm, bradycardia, sahvation, diaphoresis, diarrhea, and vomiting (2). These antidotes may not be available in the field, especially in or near the site of attack. If mihtary Mark 1 kits are available, they provide autoinjectors that automatically dehver 2mg of atropine and 600mg pralidoxime (9). 

Organophosphates. The acute toxicity of organophosphate pesticides is basically derived from the anticholinesterase property of these chemicals. This property, which results in accumulation of acetylcholine at synapses and myoneural junctions, is responsible for both the insecticidal activity and mammalian toxicity. Early symptoms of organophosphate poisoning in humans include, among others, miosis (pinpoint pupils) and blurred vision, and a response known as the SLUD (salivation, lacrimation, urination, and diarrhea) syndrome all of these are the result of muscarinic effects (12-15). Clinical manifestations of more severe poisoning involve predominantly nicotinic and central effects which include convulsions, paralysis, depressed respiration and cardiovascular functions, and coma (12-15). Death is usually due to respiratory failure, accompanied by cardio-vascular failure (13). 

Neostigmine, which is unable to penetrate the blood-brain barrier, does not cause CNS toxicity. However, it may produce dose-dependent and full-range muscarinic effects, characterized by miosis, blurring of vision, lacrimation, salivation, sweating, increased bronchial secretion, bronchoconstriction, bradycardia, hypotension, and urinary incontinence. 

Pilocarpine is a tropane alkaloid. Toxic symptoms are characterized by muscarinic effects. Toxic effects include hypersecretion of saliva, sweat, and tears contraction of the pupils of the eyes and gastric pain accompanied with nausea, vomiting, and diarrhea. Other symptoms are excitability, twitching, and lowering of blood pressure. High doses may lead to death due to respiratory failure. A lethal dose in humans is estimated within the range of 150-200 mg. 

A. Oximes are used to treat poisoning caused by cholinesterase inhibitor insecticides and nerve agents, ie, organophosphates, mixtures of organophospho-ms and carbamate insecticides, or pure carbamate insecticide intoxication with nicotinic-associated symptoms. Because of its low toxicity, possible ineffectiveness if treatment is delayed until after the cholinesterase enzyme has aged, ability to reverse nicotinic as well as muscarinic effects, and ability to reduce atropine requirements, pralidoxime should be used early and empirically for suspected cholinesterase inhibitor poisoning. 

Well-known symptoms of sarin toxicity include miosis, hypersecretions, bradycardia, and fasciculations. However, the mechanism of organophosphate toxicity seems to involve conflicting actions. For example, mydriasis or miosis, and bradycardia or tachycardia may occur. Acute respiratory insufficiency is the most important cause of immediate death. Early symptoms include (i) tachypnea due to increased airway secretions and bronchospasm (a muscarinic effect), (ii) peripheral respiratory muscle paralysis (a nicotinic effect), and (iii) inhibition of respiratory centers (a CNS effect), all of which lead to severe respiratory deficiency. If left untreated at this stage, death will result. Cardiovascular symptoms may include hypertension or hypotension. Various arrhythmias can also occur, and caution is required when the QT interval is prolonged. In particular, if hypoxemia is present, fatal arrhythmias may occur with intravenous administration of atropine... 

Some features of the pulmonary toxicity of OPs have been discussed in section 10.3.1.1. Muscarinic effects cause bronchoconstriction and bronchor-rhoea, whilst nicotinic actions at the neuromuscular junction may cause paralysis of the muscles of respiration. Further, there may be effects on the respiratory centre. IMS (see section 10.3.1.2) commonly results in paralysis of the respiratory muscles. These effects or a combination of them may be fatal. The pulmonary toxicity of OPs has been reviewed by Hilmas and colleagues. 

It is known that human exposure to organophosphorus compounds can result in a variety of acute toxic effects. These arise primarily as a result of the inhibition of acetylcholinesterase. Signs of acute toxicity are due to effects on the central nervous system (anxiety, ataxia, hypotension), to muscarinic effects (wheezing, cough, rhinitis) and to nicotinic effects (muscle weakness, mydriasis and tachycardia). Other acute effects include chest tightness, abdominal cramps, confusion and convulsions. With some organophosphorus compounds, a specific syndrome may develop. This is delayed peripheral neuropathy or OP-induced delayed neuropathy (OPIDN). (For a more detailed discussion on the toxicity of organophosphorus compounds see Chapter 10.)... 

The adverse side-effects of the TCAs, coupled with their toxicity in overdose, provoked a search for compounds which retained their monoamine uptake blocking activity but which lacked the side-effects arising from interactions with Hj, aj-adreno-ceptors and muscarinic receptors. One of the first compounds to emerge from this effort was iprindole, which has an indole nucleus (Fig. 20.3). This turned out to be an interesting compound because it has no apparent effects on monoamine uptake and is not a MAO inhibitor. This, together with its relatively minor antimuscarinic effects, led to it commonly being described as an atypical antidepressant. Mechanisms that could underlie its therapeutic actions have still not been identified but, in any case, this drug has now been withdrawn in the UK. 

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