Medical Aspects of Chemical Warfare (2008) - The Black Vault
Share Embed Flag
Download ePaper

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

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

documents.blackvault.com
from documents.blackvault.com More from this publisher
13.07.2015 Views

Nerve AgentsFig. 5-2. This schematic ribbon diagram shows the structureof Torpedo californica acetylcholinesterase. The diagram iscolor-coded; green: the 537-amino acid polypeptide of theenzyme monomer; pink: the 14 aromatic residues that linethe deep aromatic gorge leading to the active site; and goldand blue: a model of the natural substrate for acetylcholinesterase,the neurotransmitter acetylcholine, docked in theactive site.Reproduced with permission from: Sussman JL, SilmanI. Acetylcholinesterase: Structure and use as a model forspecific cation-protein interactions. Curr Opin Struct Biol.1992;2:724.produce biological activity by disabling (or inhibiting)AChE, an action that leads to an accumulation of ACh.The biological activity, or toxicity, of ChE inhibitorsis due to this excess endogenous ACh, which is nothydrolyzed. The resulting toxidrome is referred to ascholinergic crisis.The compounds in the two major categories ofAChE inhibitors, carbamates and organophosphoruscompounds, also attach to the ChE enzyme. Thereare some differences, however, between them and thenatural substrate ACh. Carbamates attach to both theesteratic and the anionic sites. A moiety of the carbamateis immediately split off, leaving the enzymecarbamoylated at the esteratic site. Instead of hydrolysisoccurring at this site within microseconds, as itdoes with the acetylated enzyme, hydrolysis does notoccur for minutes to hours, and the enzyme remainsinactive or inhibited for about an hour after reactingwith physostigmine and for 4 to 6 hours after reactingwith pyridostigmine.Most organophosphorus compounds combinewith the ChE enzyme only at the esteratic site, andthe stability of the bond (ie, the interval during whichthe organophosphorus compound remains attached)depends on the structure of the compound. Hydrolyticcleavage of the compound from the enzyme may oc-cur in several hours if the alkyl groups of the organophosphoruscompound are methyl or ethyl, but if thealkyl groups are larger, cleavage may not occur. Thus,the phosphorylated form of the enzyme may remainindefinitely. In that case, enzymatic activity returnsonly with the synthesis of new enzyme. Functionallythen, organophosphorus compounds may be said tobe irreversible inhibitors of ChE, whereas the carbamatescause only temporary inhibition and are thereforereferred to as reversible inhibitors.Because most of these compounds attach to theesteratic site on AChE, a second binding compoundcannot attach on that site if the site is already occupiedby a molecule. A previously administered ChEinhibitor will, in a manner of speaking, protect theenzyme from a second one. 16,17 This activity forms thepharmacological basis for administering a carbamate(pyridostigmine) before expected exposure to somenerve agents to provide partial protection (lasting 6–8h) against the more permanently bound nerve agents(see below).After inhibition by irreversibly bound inhibitors,recovery of the enzymatic activity in the brain seemsto occur more slowly than that in the blood ChE. 18,19An individual severely exposed to soman, however,was alert and functioning reasonably well for severaldays while ChE activity in his blood was undetectable(Exhibit 5-1). 20 This case study and other data suggestthat tissue function is restored at least partially whenChE activity is still quite low.Blood CholinesterasesIndividuals occupationally exposed to ChEinhibitingsubstances are periodically monitored forasymptomatic exposure by assays of blood-ChE activity.Those at risk include crop sprayers and orchardworkers who handle ChE-inhibiting insecticides, andchemical agent depot workers or laboratory scientistswho handle nerve agents. To be meaningful, suchmonitoring must include knowledge of physiologicalvariation in the blood enzymes.Individuals who work with or around nerveagents must have their RBC-ChE activity monitoredperiodically. Before the individuals begin work, twomeasures of RBC-ChE, drawn within 14 days butnot within 24 hours of each other, are averaged as abaseline. At periodic intervals, the frequency of whichdepends on the individuals’ jobs, blood is drawn formeasuring ChE activity. If the activity is 90% or moreof the worker ’ s baseline, no action is taken. If theactivity is below 90% of the baseline, the sample isrerun. If the second test also indicates activity below90% of baseline, the individual is referred to the oc-161

Medical Aspects of Chemical WarfareEXHIBIT 5-1CASE REPORT: ACCIDENTAL EXPOSURE OF A MAN TO LIQUID SOMANThis 33-year-old man [who worked at Edgewood Arsenal, Edgewood, Maryland] had been working with small amounts of somanin solution [25% (V/V) concentration, total volume

<strong>Medical</strong> <strong>Aspects</strong> <strong>of</strong> <strong>Chemical</strong> <strong>Warfare</strong>EXHIBIT 5-1CASE REPORT: ACCIDENTAL EXPOSURE OF A MAN TO LIQUID SOMANThis 33-year-old man [who worked at Edgewood Arsenal, Edgewood, Maryland] had been working with small amounts <strong>of</strong> somanin solution [25% (V/V) concentration, total volume

logo

products

Resources

Company

Terms of service
Privacy policy
Cookie policy
Cookie settings
Imprint
Change language
Made with love in Switzerland
© 2024 Yumpu.com all rights reserved

Hooray! Your file is uploaded and ready to be published.

Saved successfully!

Ooh no, something went wrong!