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

Medical Aspects of Chemical Warfarean improvised explosive device. 13 There have beenreports that Iran may have developed nerve agentsand used them against Iraq, but these reports havenever been confirmed.Sarin has also been used in terrorist attacks. In June1994 members of a Japanese cult released sarin fromthe rear of a van in Matsumoto, Japan. Although therewere almost 300 casualties, including 7 deaths, thisevent was not well publicized. On March 20, 1995, thesame group broke open plastic containers of sarin onseveral Tokyo trains during the morning commute. Thecontainers held a 30% solution of liquid sarin, whichthe cult members synchronously ripped open on threesubway trains and allowed to spill onto the seats andfloors. More than 5,500 people sought medical care;about 4,000 had no effects from the agent but 12 casualtiesdied. This incident required a major commitmentof medical resources to triage and care for the casualties.(For more information on the Aum attacks, seeChapter 2, History of Chemical Warfare and Chapter4, History of the Chemical Threat, Chemical Terrorism,and Its Implications for Military Medicine).PHARMACOLOGY OF CHOLINESTERASE INHIBITORSCholinesterase in TissueAccording to the current, widely accepted explanation,nerve agents are compounds that exert theirbiological effects by inhibiting the enzyme acetylcholinesterase(AChE). The cholinergic system is the onlyneurotransmitter system known in which the actionof the neurotransmitter is terminated by an enzyme,AChE.AChE belongs to the class of enzymes called esterases,which catalyze the hydrolysis of esters. ChEs,the class of esterases to which AChE belongs, have highaffinities for the esters of choline. Although there areseveral types of choline esters, ACh, the neurotransmitterof the cholinergic portion of the nervous system, ismost relevant to nerve agent activity.AChE, found at the receptor sites of tissue innervatedby the cholinergic nervous system, hydrolyzesACh rapidly. It has one of the highest known enzymeturnover numbers (number of molecules of substratethat it turns over per unit time). 14 A similar enzymewith ACh as its preferred substrate is found in or onerythrocytes (red blood cells) and is known as redblood cell, or true, cholinesterase (RBC-ChE). Butyrylcholinesterase(BuChE, also known as serum orplasma cholinesterase and as pseudocholinesterase),another enzyme of the ChE family, uses butyrylcholineas its preferred substrate. Butyrylcholine is present inplasma or serum and in some tissues.BuChE and RBC-ChE are the two forms of ChE inthe blood. While there is a single gene for each formof ChE, the active sites are identical regardless of thephysical form. However, because blood is easy to draw,the activities of each of these enzymes can be assayedby standard, relatively simple laboratory techniques,whereas tissue enzyme is unavailable for assay. Themeasurements obtained from the blood assay can beused as an approximation of tissue enzyme activityin the event of a known or possible exposure to anAChE inhibitor.Cholinesterase-Inhibiting CompoundsMost ChE-inhibiting compounds are either carbamatesor organophosphorus compounds. The best knownamong the carbamates is physostigmine (eserine, elixirof the Calabar bean), which has been used in medicinefor more than a century. 3 Neostigmine (Prostigmin,manufactured by ICN Pharmaceuticals, Costa Mesa,Calif) was developed in the early 1930s to manage myastheniagravis; ambenonium was developed later forthe same purpose. Pyridostigmine bromide (Mestinon,manufactured by ICN Pharmaceuticals, Costa Mesa,Calif) has been used for decades to manage myastheniagravis. On any given day, an estimated 16,000 patientsin the United States take pyridostigmine bromidemedication to treat myasthenia gravis. The US militaryand several other nations also field pyridostigminebromide (manufactured by Phillips Duphar, Holland),known as PB or NAPP (nerve agent pyridostigminepretreatment), as a pretreatment or antidote-enhancingsubstance to be used before exposure to certain nerveagents (see below). Today these carbamates are mainlyused for treating glaucoma and myasthenia gravis.Other carbamates, such as carbaryl (Sevin, manufacturedby Bayer, Leverkusen, North Rhine-Westphalia,Germany), are used as insecticides.Recently, several anticholinesterase drugs have beenused to treat Alzheimer ’ s disease, in which cholinergictransmission is faulty. In the past few years, these havebecome the basis of treatment of early stages of thisdisease. Three are approved for this indication by theUS Food and Drug Administration (FDA): donepezil,rivastigmine, and galanthamine. Rivastigmine is acarbamate, donepezil is a piperidine compound, andgalanthamine is a tertiary alkaloid. All inhibit ChEs.Most commonly used insecticides contain either acarbamate or an organophosphorus compound. Theorganophosphorus insecticide malathion has replacedparathion, which was first synthesized in the 1940s.The organophosphorus compound diisopropyl phos-158