Nerve Agents Chapter 5 NERVE AGENTS FREDERICK R. SIDELL, M.D.* INTRODUCTION HISTORY PHARMACOLOGY OF CHOLINESTERASE INHIBITORS Cholinesterase in Tissue Blood Cholinesterases Nerve Agents EXPOSURE ROUTES Inhalational Exposure to Vapor Dermal Exposure to Liquid EFFECTS ON ORGANS AND ORGAN SYSTEMS The Eye The Nose Pulmonary System Skeletal Musculature Central Nervous System and Behavior Cardiovascular System GENERAL TREATMENT PRINCIPLES Terminating the Exposure Ventilatory Support Atropine Therapy Oxime Therapy Anticonvulsive Therapy Therapy for Cardiac Arrhythmias SPECIFIC TREATMENT BY EXPOSURE CATEGORY Suspected Exposure Minimal Exposure Mild Exposure Moderate Exposure Moderately Severe Exposure Severe Exposure RETURN TO DUTY SUMMARY *Formerly, Chief, Chemical Casualty Care Office, and Director, Medical Management of Chemical Casualties Course, U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010-5425; currently, Chemical Casualty Consultant, 14 Brooks Road, Bel Air, Maryland 21014 129 Medical Aspects of Chemical and Biological Warfare INTRODUCTION Nerve agents are extremely toxic chemicals that The military stockpiles of several major powers were first developed in secrecy before and during are known to include nerve agents, and the arma- World War II primarily for military use. Related mentaria of other countries are thought to contain substances are used in medicine, in pharmacology, them as well (see Chapter 4, The Chemical War- and for other purposes, such as insecticides, but fare Threat and the Military Healthcare Provider). they lack the potency of the military agents. Much Because of the possibility of nerve agent use in of the basic knowledge about the clinical effects of future conflicts, military medical personnel should nerve agents comes from research performed in the have some knowledge of these agents, their effects, decades immediately following World War II. and the proper therapy for treating casualties. HISTORY Possibly the earliest recorded use of a substance in Germany; the “V” allegedly stands for venom- that works, like nerve agents, by inhibiting cho- ous. GF is an old agent, previously discarded by linesterase (ChE) is by native tribesmen of western the United States as being of no interest. During the Africa who used the Calabar bean as an “ordeal Persian Gulf War, it was believed that Iraq might poison” in witchcraft trials.1,2 An extract, “the elixir have GF in its arsenal; however, interest has waned of the Calabar bean,” was later used medicinally, 3 again and GF has retreated to obscurity. and in 1864, the active principle was isolated by Lange and Krueger reported on the marked po- Jobst and Hesse and called physostigmine.1 Vee and tency of organophosphorus compounds in 1932 af- Leven independently isolated this same substance ter noting the effects of the vapors of dimethyl and in 1865 and named it eserine,1 hence its dual nomen- diethyl phosphorofluoridate on themselves.1,4 clature. Shortly thereafter, the German company I. G. The first organophosphorus ChE inhibitor was Farbenindustrie developed an interest in organo- probably tetraethyl pyrophosphate (TEPP), synthe- phosphorus compounds as insecticides. On 23 De- sized by Wurtz and tasted (with no ill results) by cember 1936, Gerhard Schrader, who headed the Clermont in 1854.4 During the next 80 years, chem- company’s research effort, synthesized what today ists (such as Michaelis, Arbusow, and Nylen) made is known as tabun.5,6 Like Lange and Krueger, he numerous advances in organophosphorus chemis- noted the toxicity (miosis and discomfort) of the try, but generally they did not realize the toxicity vapors of the substance in himself. of the substances with which they were working.4 Over a year later, Schrader synthesized a second In the early 1930s, interest in both physostigmine- organophosphorus compound and named it sarin type (reversible) and organophosphorus-type (irre- in honor of those who were instrumental in its de- versible) ChE inhibitors increased. (The terms “re- velopment and production: Schrader, Ambros, versible” and “irreversible” refer to the duration of Rudriger, and van der Linde.5 Because the German binding of the compound with the enzyme ChE; see Ministry of Defense required that substances pass- the Mechanism of Action section below.) The revers- ing certain toxicity tests be submitted to the gov- ible type, most of which are carbamates, were de- ernment for further investigation, these compounds veloped for treating conditions such as intestinal were examined for possible military use. atony, myasthenia gravis, and glaucoma; for ex- The potential of tabun and sarin as weapons ample, treating gastric atony with neostigmine was was soon realized. A large production facility was described in 1931.1 built in Dyhernfurth and production of tabun was Five organophosphorus compounds are gener- begun in 1942.5,6 Sarin was also produced in ally regarded as nerve agents. They are commonly Dyhernfurth and possibly at another plant in known as tabun (North Atlantic Treaty Organiza- Falkenhagen.6 Late in World War II, Soviet troops tion [NATO] military designation, GA), sarin (GB), captured the Dyhernfurth facility (then in Germany, and soman (GD); and GF and VX (also NATO mili- now in Poland), dismantled it, and moved it, along tary designations; these compounds have no com- with key personnel, to the former Soviet Union, mon names). The agents in the “G” series allegedly where production of the agents commenced in were given the code letter G because they originated 1946.6 130 Nerve Agents About 10,000 to 30,000 tons of tabun and smaller example, GF, which may have been first synthesized quantities of sarin were produced and put into about 1949 by a chemist in another country in the munitions by the Germans during World War II, but search for other nerve agents, was studied in both these weapons were never used.6 Why they were the United States and the United Kingdom. It was not remains a matter of conjecture. then discarded for reasons that are not entirely clear. In the waning days of World War II, troops of Possible explanations are that it was too expensive the United States and the United Kingdom captured to manufacture or that there was no perceived need some of these munitions, which were being stored for an agent with its properties. The manufactur- at Raubkammer, a German testing facility. The mu- ing process for GF is apparently similar to that for nitions, which contained an agent unknown to sci- GB. During the Persian Gulf War (1990–1991), Iraq entists in the United Kingdom and the United was believed to have switched from the manufac- States, were taken to the two countries for exami- ture of GB to the manufacture of GF when the pre- nation. Over a single weekend, a small group of cursors of GB, but not those of GF, were embargoed. scientists at the U.K. Chemical Defence Establish- The United States began to produce sarin in the ment, working despite miosis caused by accidental early 1950s, and VX in the early 1960s, for potential exposure to the agent vapor, elucidated the phar- military use; production continued for about a de- macology and toxicity of tabun and documented the cade.6 The U.S. munitions inventory today contains antidotal activity of atropine.7 these two nerve agents in 30- to 45-year-old M55 Thus, during the latter part of World War II, Ger- rockets; land mines; 105-mm, 155-mm, and 8-in. many possessed chemical weapons against which projectiles; 500-lb and 750-lb bombs; wet-eye bombs its foes had little protection and no antidotes. (one of a family of “eye” bombs, which has liquid Use of these weapons probably would have been chemical [wet] contents); spray tanks; and bulk con- devastating and might have altered the outcome of tainers.9 These munitions are stored at six depots that conflict. The Germans had tested nerve agents within the continental United States (CONUS) and on inmates of concentration camps, not only to in- one outside the continent; the locations of these vestigate their intoxicating effects but also to de- depots are public knowledge.10 The six CONUS velop antidotes.8 Many casualties, including some depots are near Tooelle, Utah; Umatilla, Oregon; fatalities, were reported among the plant work- Anniston, Alabama; Pine Bluff, Arkansas; Newport, ers at Dyhernfurth; the medical staff there eventu- Indiana; and Richmond, Kentucky; the seventh de- ally developed antidotal compounds.5 The Allies pot is on Johnston Island in the Pacific Ocean. were unaware of these German experiments until Sarin has also been used in terrorist attacks. In the close of the war, months after the initial U.K. June 1994, members of a Japanese cult released sarin studies.7 in an apartment complex in Matsumoto, Japan. Al- Soman was synthesized in 1944 by Richard Kuhn though there were almost 300 casualties, including of Germany, again in a search for insecticides. 6 Small 7 dead, this event was not well publicized. On 20 amounts were produced, but development had not March 1995, sarin was released on Tokyo subways. proceeded far by the end of the war. The nerve agent More than 5,500 people sought medical care; about VX was first synthesized by an industrial concern 4,000 had no effects from the agent but 12 casual- in the United Kingdom in the early 1950s6 and was ties died. This incident required a major expendi- given to the United States for military development. ture of medical resources to triage and care for the Other potential nerve agents were synthesized casualties. (Also see Chapter 1, Overview: Defense by scientists in the United States and United King- Against the Effects of Chemical and Biological War- dom but were not developed for military use. For fare Agents). PHARMACOLOGY OF CHOLINESTERASE INHIBITORS Cholinesterase in Tissue nism and, in a broad sense, can also be considered nerve agents.