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

Nerve Agentsthat hydroxamine reactivated organophosphorylinhibitedChE faster than water did, 185 and later reportedthat an oxime (pyridine-2-aldoxime methiodide[2-PAM I]) was far more effective than hydroxaminein reactivating the enzyme. 186The oximes differ in their required doses, their toxicity,and their effectiveness. For example, TMB4 is moreeffective against tabun poisoning than is 2-PAM Cl.After thoroughly studying many of these compounds,2-PAM Cl was chosen for use in the United States. 187The choice was made because of research in both thecivilian and military sectors experimentally demonstratedeffectiveness as a reactivator and also becauseof the demonstrated clinical efficacy of 2-PAM Cl intreating organophosphorus insecticide poisoning. 188–194At present, the only oxime approved by the FDA foruse in the United States is 2-PAM Cl. The methanesulfonatesalt of pralidoxime is the standard oxime inthe United Kingdom, whereas TMB4 and toxogonin(obidoxime) are used in other European countries.Japan uses pralidoxime iodide. Other oximes, not yetapproved, are of interest to several countries. HI-6 isadvocated by some in Canada, while newer oximesare under study in the United States.Because oximes reactivate the ChE inhibited by anerve agent, they might be expected to completelyreverse the effects caused by nerve agents. However,because it is possible that nerve agents produce biologicalactivity by mechanisms other than inhibition ofChE, or because of reasons not understood, oximes arerelatively ineffective in reversing effects in organs withmuscarinic receptor sites. Oximes are also quaternarydrugs and have limited penetration into the CNS. Forthese reasons, they are ineffective in reversing thecentral effects of nerve agent intoxication. They aremuch more effective in reversing nerve-agent–inducedchanges in organs with nicotinic receptor sites. In particular,when oximes are effective (ie, in the absence ofaging), they decrease dysfunction in skeletal muscle,improving strength and decreasing fasciculations.DosageThe therapeutic dosage of 2-PAM Cl has not beenestablished, but indirect evidence suggests that it is15 to 25 mg/kg. The effective dose depends on thenerve agent, the time between poisoning and oximeadministration, and other factors. An early study 195showed that a plasma concentration of about 4 µg/mLin blood reversed the sarin-induced neuromuscularblock in anesthetized cats; for years this concentrationwas generally accepted as being therapeutic for sarin.There is little data to support or disprove this contention.The 2-PAM Cl administered with the ComboPenor MARK 1 autoinjector (600 mg) produces a maximalplasma concentration of 6.5 µg/mL when injectedintramuscularly in the average soldier (8.9 mg/kg ina 70-kg male). 178Different doses of 2-PAM Cl were administered(with atropine) in several studies. In sarin-poisonedrabbits, the protective ratio (PR; the ratio of the LD 50with treatment to the LD 50without treatment) increasedfrom 25 to 90 when the IV dose of 2-PAM Clincreased from 5 to 10 mg/kg. 196 The PR increased from1.6 to 4.2 when the IM dose of 2-PAM Cl increased from30 to 120 mg/kg in sarin-poisoned rats, 160 and the PRincreased from 1.9 to 3.1 when the IM dose of 2-PAMCl increased from 11.2 to 22.5 mg/kg in VX-poisonedrabbits. 163 In the first two studies, the antidote wasgiven immediately after the nerve agent. In the third, itwas given at the onset of signs. No ventilatory supportwas used. When 2-PAM Cl was administered intravenouslyin humans 1 hour after sarin, a dose of 10 mg/kg reactivated 28% of the RBC-ChE, and doses of 15 or20 mg/kg reactivated 58% of the enzyme. When given3 hours after sarin, 5 mg/kg of 2-PAM Cl reactivatedonly 10% of the inhibited RBC-ChE, and 10 mg/kg ormore reactivated more than 50%. When 2-PAM Cl wasgiven at times from 0.5 to 24 hours after VX, doses of2.5 to 25 mg/kg were found to reactivate 50% or moreof the inhibited enzyme. 113For optimal therapy, 2-PAM Cl should be givenintravenously, but usually this is not possible in thefield. Even at small doses (2.5–5.0 mg/kg), the drug,when given intravenously in the absence of nerveagent poisoning, may cause transient effects, suchas dizziness and blurred vision, which increase asthe dose increases. Transient diplopia may occur atdoses higher than 10 mg/kg. These effects, if theyoccur, are insignificant in a casualty poisoned with aChE-inhibiting substance. Occasionally, nausea andvomiting may occur. The most serious side effect ishypertension, which is usually slight and transient atIV doses of 15 mg/kg or less, but may be marked andprolonged at higher doses. 197 2-PAM Cl is commerciallyavailable as the cryodesiccated form (Protopam Chloride,manufactured by Wyeth-Ayerst Laboratories,Philadelphia, Pa) in vials containing 1 g, or about 14mg/kg for a 70-kg person. Blood pressure elevationsgreater than 90 mm Hg systolic and 30 mm Hg diastolicmay occur after administration of 45 mg/kg, and theelevations may persist for several hours. 197 Givingthe oxime slowly (over 30–40 min) may minimizethe hypertensive effect, and the hypertension can bequickly but transiently reversed by phentolamine 5mg, administered intravenously (Figure 5-7).2-PAM Cl is rapidly and almost completely excretedunchanged by the kidneys: 80% to 90% of an IM or IV187