Nicotinic effects nerve agents

AH of the nerve agents under consideration are anticholinesterase compounds and induce accumulation of the neurotransmitter acetylcholine (ACh) at neural synapses and neuromuscular junctions by phosphorylating acetylcholinesterase (AChE). Depending on the route of exposure and amount absorbed, the PNS and/or CNS can be affected and muscarinic and/or nicotinic receptors may be stimulated. Interaction with other esterases may also occur, and direct effects to the nervous system have been observed. 

Anticholinesterase effects of nerve agent exposure can be characterized as muscarinic, nicotinic, or CNS. Muscarinic effects occur in the parasympathetic system and, depending on the amount absorbed, can be expressed as conjunctival congestion, miosis, ciliary spasm, nasal discharge, increased bronchial secretion, bronchoconstriction, anorexia, emesis, abdominal cramps, sweating, diarrhea, salivation, bradycardia, and hypotension. Nicotinic effects are those that... 

Nerve agents are OP compounds, which irreversibly inhibit AChE, leading to ACh accumulation, and cause over-stimulation of muscarinic and nicotinic ACh receptors. The effect at the SA node, the primary heart control site, is inhibitory and bradycardia results. VX primarily affects neurotransmitter receptors, those of norepinephrine, and also affects the central nervous system (CNS) not related to AChE inhibition. 

The standard treatment of nerve agent-induced muscle toxicity calls for (1) reactivation of the phosphorylated AChE with an oxime, and (2) blockage of the nicotinic ACh receptor sites from the stimulating action of ACh with fii-tubocurarine. Oximes such as obidoxime, pralidoxime (2-pyridine aldoxime methochloride, 2-PAM) and a few others have been found very effective when given in combination with other drugs such as atropine, pretreatment with oximes varies with the ehemieal structures of the nerve agents and depends on the time after exposure. For example, it has been... 

Atropine is an antidotal treatment. It is used to reverse the muscarinic signs, but it will not reverse the nicotinic effects (muscular weakness, diaphragmatic weakness, etc.). Atropine blocks the effects of accumulated acetylcholine (ACh) at the synapse and should be continued until the nerve agent is metabohzed (Midthng et al, 1985). Over-atropinization can cause hyperthermia, tachycardia, agitation, mydriasis, and ileus, which can be life threatening in the horse (Meerstadt, 1982). 

Pyridostigmine bromide studies have been performed in dogs, guinea pigs, monkeys, rabbits, rats, and mice. Diarrhea, salivation, tremors, and respiratory failure were seen prior to death. Side effects of the drug are related to muscarinic and nicotinic effects. Toxicity is also related to cholinergic stimulation. Effectiveness of pretreatment to reduce lethality after exposure to nerve agents (in particular, soman) is dependent on the administration of atropine and pralidoxime, postexposure. 

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). 

Miosis may also occur as a systemic feature, although more usually it follows direct exposure. This explains why, for example, modest dermal exposure may produce systemic features but not miosis. Abdominal pain, nausea and vomiting, involuntary micturition and defecation, muscle weakness and fasciculation, tremor, restlessness, ataxia and convulsions may follow dermal exposure, inhalation or ingestion of a nerve agent. Bradycardia, tachycardia and hypertension may occur, dependent on whether muscarinic or nicotinic effects predominate. If exposure is substantial, death may occur from respiratory failure within minutes, whereas mild or moderately exposed individuals usually recover completely, although EEG abnormalities have been reported in those severely exposed to sarin in Japan (Murata etal., 1997 Sekijima et al., 1997). 

---