Nerve agents, nervous system effects caused

The initial effects of nerve agents depend on the dose and route of exposure. A small inhalation exposure from nerve agent vapor causes a response in the eyes, nose and airway, such as miosis, conjunctival injection, eye pain, rhinorrhea, bron-choconstriction, excessive bronchial secretions, and mild to moderate dyspnea (9,13,18). Larger exposures cause central nervous system effects within seconds to minutes, including loss of consciousness, seizures, and central apnea. Death can occur within 5-lOmin of a lethal dose, usually due to respiratory failure from the combined effects of respiratory muscle paralysis, loss of airway control and profuse bronchorrhea (13,14). 

The endogenous release of the potent vasoconstrictor neuropeptide Y (NPY) is increased during sepsis and the highest levels are detected in patients with shock (A8). NPY is a 36-amino-acid peptide belonging to the pancreatic polypeptide family of neuroendocrine peptides (T2). It is one of the most abundant peptides present in the brain and is widely expressed by neurons in the central and peripheral nervous systems as well as the adrenal medulla (A3). NPY coexists with norepinephrine in peripheral sympathetic nerves and is released together with norepinephrine (LI9, W14). NPY causes direct vasoconstriction of cerebral, coronary, and mesenteric arteries and also potentiates norepinephrine-induced vasoconstriction in these arterial beds (T8). It appears that vasoconstriction caused by NPY does not counterbalance the vasodilatator effects of substance P in patients with sepsis. The properties of vasodilatation and smooth muscle contraction of substance P are well known (14), but because of the morphological distribution and the neuroendocrine effects a possible stress hormone function for substance P was also advocated (J7). Substance P, which is a potent vasodilatator agent and has an innervation pathway similar to that of NPY, shows a low plasma concentration in septic patients with and without shock (A8). 

Toxins present a variety of both incapacitating and lethal effect. Most toxins of military significance can be broadly classified in one of two ways. Neurotoxins disrupt the nervous system and interfere with nerve impulse transmission similar to nerve agents (Chapter 1). However, all neurotoxins do not operate through the same mechanism of action or do they produce the same symptoms. Cytotoxins are poisons that destroy cells or impair cellular activities. Symptoms may resemble those of vesicants (Chapter 3) or they may resemble food poisoning or other diseases. Toxins may also produce effects that are a combination of these general categories. The consequences of intoxication from any individual toxin can vary widely with route of exposure and dose. In addition, some toxins act as biomediators and cause the body to release excessive, and therefore harmful, amounts of chemicals that are normally produced by the body. 

Target Organ Toxicity. -Hexane exposure is documented to cause toxicity in peripheral nerves of humans (both sensory and motor). In rats, -hexane exposure causes toxicity in the peripheral and central nervous system and in male reproductive tissues. Effects on respiratory tissue have been observed in mice and rabbits. The toxic agent in nervous system and reproductive tissues is believed to be the -hexane metabolite 2,5-hexanedione (Graham et al. 1995). 

Although there is the potential for nerve agents to have direct toxic effects on the nervous system, there is no evidence that such effects occur in humans at doses lower than those causing cholinesterase inhibition. For the purpose of evaluating potential health effects, inhibition of blood cholinesterase is generally considered the most useful biological endpoint. 

The toxins that inhibit the AChE are called anticholinesterase (anti-ChE) agents. They cause acetylcholine to accumulate in the vicinity of cholinergic nerve terminals, and thus are potentially capable of producing effects equivalent to excessive stimulation of cholinergic receptors throughout the central and peripheral nervous systems (Long, 1963). Nevertheless, several members of this class of compounds are widely used as therapeutics agents others that cross the blood-brain barrier have been approved or are in clinical trial for the treatment of Alzheimer s disease. 

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 binding of the nerve agent to the enzyme is considered irreversible unless removed by therapy. The accumulation of acetylcholine in the peripheral nervous system and central nervous system (CNS) leads to depression of the respiratory center in the brain, followed by peripheral neuromuscular blockade causing respiratory depression and death. The pharmacologic and toxicologic effects of the nerve agents are dependent on their stability, rates of absorption by the various routes of exposure, distribution, ability to cross the blood-brain barrier, rate of reaction and selectivity with the enzyme at specific foci, and their behavior at the active site on the enzyme. 

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