Medical Aspects of Chemical Warfare (2008) - The Black Vault

Nerve Agentsphorofluoridate (DFP) was synthesized before WorldWar II and studied by Allied scientists before and duringthe war, but was rejected for use as a military agent.For a period of time, this compound was used topicallyto treat glaucoma, but later was deemed unsuitablebecause it produced cataracts. It has been widely usedin pharmacology as an investigational agent.Mechanism of ActionNerve agents inhibit ChE, which then cannot hydrolyzeACh. This classic explanation of nerve agentpoisoning holds that the intoxicating effects are dueto the excess endogenous ACh; nerve agents disablethe off switch for cholinergic transmission, producingcholinergic overactivity or cholinergic crisis. A detaileddiscussion of the chemistry of ChE inhibition is beyondthe scope of this chapter and can be found in mosttextbooks of pharmacology, 14,15 though the relevantaspects are summarized here.The human nervous system is made up of conductingcells, or neurons, whose primary mission is to conveyinformation from place to place via efficient electricsignals or action potentials. When a signal reaches theend of a neuron, it can only continue as a chemicalsignal, the secretion of a packet of neurotransmittermolecules and its diffusion across the space or synapticcleft separating its parent neuron from the next cell inseries. When the neurotransmitter molecule reachesthe target cell, it interacts with specific postsynapticreceptors on the receiving cell ’ s surface membrane,giving rise to a miniature endplate potential. Oncesufficient numbers of these are generated, they summateand a new action potential is created, allowinginformation transmission to proceed. Each neuron inthe nervous system uses only one neurotransmitter forthis purpose. The neuroanatomy of each neurotransmittersystem is specific; neurons in particular tractsor regions use specific neurotransmitters. Approximately20 neurotransmitters have been identified inneurobiology. The portion of the nervous system thatuses ACh as its neurotransmitter is referred to as thecholinergic system. It is the most widely distributedand best studied in neurobiology.Cholinergic tracts are found in almost every partof the brain within the central nervous system (CNS).Within the peripheral nervous system, however, thecholinergic system is found only in very specific fibertracts. Clinically, the most important of these are thesympathetic and parasympathetic divisions of theautonomic nervous system.The cholinergic nervous system can be furtherdivided into the muscarinic and nicotinic systems,because the structures that are innervated have receptorsthat recognize two false experimental transmitters,alkaloids muscarine and nicotine, and can be stimulatedby these compounds. In the periphery, wherecholinergic input is primarily autonomic, muscarinicsites are innervated by postganglionic parasympatheticfibers. In the periphery, these sites includeglands (eg, those of the mouth and the respiratoryand gastrointestinal systems), the musculature of thepulmonary and gastrointestinal systems, the efferentorgans of the cranial nerves (including the heart viathe vagus nerve), and other structures. Nicotinic sitesare predominantly found at the autonomic gangliaand skeletal muscles.The brain contains a high number of cholinergicneurons. Both muscarinic and nicotinic receptors areactive in the central cholinergic system, with muscarinicreceptors predominating in a ratio of roughly 9 to1. Clinically, the most important characteristic of thecentral cholinergic system is that it is the most anatomicallywidespread of any known neurotransmittersystem in human brain. Consequently, a chemical, suchas nerve agent, that affects the cholinergic system as awhole will affect all parts of the brain rather than onlya few, as in more restricted neurotransmitter systemssuch as the dopaminergic or serotoninergic systems.When an action potential in a cholinergic neuronreaches the terminal bouton, ACh packets are released,cross the synaptic cleft, interact with postsynapticcholinergic receptors, and cause a new action potentialto be generated. The cycle continues until ACh is hydrolyzedby AChE, a membrane-bound protein. Thisis the mechanism that prevents cholinergic stimulationfrom getting out of hand (Figure 5-1).In the cholinergic nervous system, ChE hydrolyzesthe neurotransmitter ACh to terminate its activity atthe receptor site (Figure 5-2). The catalytic mechanismof AChE involves first an acylation step, in which serine203 reacts with ACh to displace the choline moietyand forming an acylated serine (the choline, havingbeen displaced, diffuses away). This reaction is greatlyfacilitated by other strategically placed residues inthe active site that orient the ACh to the appropriateangle for serine to displace the choline and stabilize thetransition state by a three-pronged hydrogen bond (the“oxyanion hole“). In a second step, a water moleculebound to, and polarized by, another key amino acidresidue, histidine 447, attacks the acyl group, displacingit from the serine to form acetic acid, which diffusesaway and leaves a regenerated or reactivated enzymethat can repeat the operation.If AChE is absent from the site, or if it is unable tofunction, ACh accumulates and continues to producepostsynaptic action potentials and activity in the organ.The nerve agents and other ChE-inhibiting substances159