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

Nerve AgentsOral administration may be considered preferable (althoughless reliable) to administration through a parenteralroute because tablets can be self-administeredand taking tablets avoids the pain of an injection.IM administration of 2-PAM Cl with automaticinjectors results in a plasma concentration of 4 µg/kg at 7 minutes, versus 10 minutes for conventionalneedle-and-syringe injection. 178 (A maximum plasmaconcentration of 6.9 µg/kg occurs at 19 min, versus 6.5µg/kg at 22 min for the needle-and-syringe method.)About 80% to 90% of the intact drug is excreted unmetabolizedin the urine; the half-life is about 90 minutes.When a 30% solution of 2-PAM Cl was injectedintramuscularly at doses ranging from 2.5 to 30 mg/kg, the drug caused no change in heart rate or anysigns or symptoms (except for pain at the injection site,as expected after an injection of 2 mL of a hypertonicsolution). 198,199 When given intramuscularly, 30 mg/kg caused an elevation in blood pressure and minimalECG changes, but no change in heart rate. 198Because of the rapid aging of the soman–AChEcomplex, oximes are often said to be ineffective intreating soman poisoning. Experimental studies inanimals have shown that oximes are not as effective intreating soman intoxication as in sarin intoxication, butthey do provide some therapeutic benefit (a 5%–10%reactivation of the inhibited enzyme). 209,210 Suggestedreasons for this benefit are that an oxime acts as a cholinergicblocking drug at the nicotinic sites, analogousto atropine at the muscarinic sites, 209 or that it causesthe circulation to improve, possibly by stimulating therelease of catecholamines. 210Because of the hypertensive effect of 2-PAM Cl, USmilitary doctrine states that no more than 2000 mg IVor three autoinjectors (600 mg each) should be givenin 1 hour. If patients require additional treatment inthe interim, atropine alone is used. Thus, as the AT-NAA combined autoinjector replaces the MARK 1 set,atropine-only autoinjectors should also be available foruse so that the 2-PAM Cl dosage limits are not exceededduring the treatment of a severe casualty.Laboratory studies indicate that the convulsiveperiod lasts much longer (hours) in animals, eventhose given therapy, than in humans. The antidotesare given in a standard dose to experimental animalsrather than titrated to a therapeutic effect as they arein human patients; this difference may account forthe greater duration of convulsions in animal studiesbecause the animals are protected from the immediatelethal effects of exposure but not the convulsanteffects.TherapyDiazepam, an anticonvulsant of the benzodiazepinefamily, has been shown to control nerve-agent–inducedseizures/convulsions in rats, guinea pigs, rabbits, andmonkeys. 128,211–215 It is commonly used to stop acuteseizures (eg, status epilepticus) that may result fromother etiologies, 141 including those produced by otheranticholinesterases. Experimental studies also haveshown that diazepam reduces or prevents nerveagent–inducedbrain lesions due to this anticonvulsantactivity. 128,129,131,132,135,211 Because of these properties andbecause diazepam is approved by the FDA for treatmentof status epilepticus seizures by the IM route,diazepam was adopted by the US military as the drugfor immediate anticonvulsant treatment of nerve agentcasualties in the field.During the Persian Gulf War, the US military issuedan autoinjector containing 10 mg of diazepam(Convulsive Antidote, Nerve Agent, or CANA) toall military personnel (Figure 5-8). The ConvulsiveAntidote, Nerve Agent injector was not intended forself-use, but rather for use by a buddy when a soldierexhibited severe effects from a nerve agent. TheAnticonvulsive TherapyConvulsions occur after severe nerve agent exposure.In reports 20,66,104 of severe cases, convulsions(or what were described as “convulsive jerks” or“spasms”) started within seconds after the casualty collapsedand lost consciousness, and persisted for severalminutes until the individual became apneic and flaccid.The convulsions did not recur after atropine and oximetherapy and ventilatory support were administered.In these instances, no specific anticonvulsive therapywas needed nor given.Fig. 5-8. The convulsive antidote nerve agent autoinjector(CANA) contains 10 mg of diazepam. The distinctive flared“wings” on each side make the shape of the injector uniqueand provide visual and tactual cues to indicate it is differentfrom either the 2-pyridine aldoxime methyl chloride (2-PAMCl) ComboPen or the antidote treatment nerve agent autoinjector(ATNAA).Reproduced with permission from: Meridian Medical TechnologiesInc, Bristol, Tenn.189