Possible Long-Term Health Effects of Short-Term Exposure To Chemical Agents, Volume 2 Cholinesterase Reactivators, Psychochemicals and Irritants and Vesicants (1984) / Chapter Skim
Currently Skimming:
2. Cholinesterase Reactivators
2. Cholinesterase Reactivators
Pages 3-46
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 3... ...
The research was followed by the development of treatment methods, and prominent among these was the use of cholinesterase Deactivators to reverse the lethal ef fec ts of anticholinesterase nerve gases . Rapid advances in chemistry during centuries, coupled with the success of in Wnrl r1 War T attracted attention to The terminal ion of World War II brought to light the highly potent chemical-warfare agents of the organophosphorus ester class that had been synthesized by both sides during the conflict.
|
From page 4... ...
5 Additional studies demonstrated that the most effective treatment of organophosphonus ester-poisoned animates was to use oximes concomi tantly wi th atropine . The general conclusions were that atropine minimizes or abolishes the toxic actions of AChEinhibi tiny compounds on mu scarinic and central chorine rgic si tea and the pyridini''m and other quater~ary hydroxamic acids and oxides reverse the toxic ef fects of the organophosphorus esters by react ivating the inhibited AChE.
|
From page 5... ...
ether dichloride FIGURE 2-1 Structural formulas of cholinesterase Deactivators tested at Edgewood
|
From page 6... ...
TABLE 2-l Subjects Tested with Cholinesterase Reactivators at Edgewood No .
|
From page 7... ...
P reacti~ration by oximes and hydroxamic acids of cholinesterase inhibi~ced by organophosphorus compounds.
|
From page 8... ...
XTII. Reactivation of alkyl phosphate-inhibited enzyme.
|
From page 9... ...
, [C14Hl6Cl2N4O3] , is a grayishwhi te powder that exists as ache chloride with a molecular weight of 359.
|
From page 10... ...
values are about 0.2 mM. 7616 Whatever the source, the enzyme is sub ject to inhibition by the same reversible and irreversible inhibitors.
|
From page 11... ...
Because a hydroxyl group in an alcohol is a weak nucleophile at neutral pH, the capacity of choline to function as a Deactivator must be a consequence of its molecular complementarily with the enzyme and the increased acidity of the alcohol. The idea arose of f inding a rigid structure that would include a quaternary ammonium group and an acidic nucleophile that would be complementary with the phosphorylated enzyme ire such a way that the nucleophilic oxygen would be positioned close to the elec trophilic phosphorus atom.
|
From page 12... ...
|
From page 13... ...
SIDE ~ ;~'d-~_O~P-(08) 2 cE3I inhibited enzyme Deactivator active enzyme phosphorylated oxime The reactivation is an equilibria reaction.
|
From page 14... ...
underwent a stoichiometric reaction with sarin.4i Additional studies confirmed that 2-PAM, 4-PAM, and probably TMB-4 were converted to potent inhibitora of AChE when they reacted with sarin in vitro.45 That TMB-4 was converted to a potent anticholinest erase agent when it reacted with satin in vitro was confirmed in studies that suggested that this bis-quaternary oxime could exist either as a mono~hosphonylated or as a diphosphonylated compound (Figure 2_3~.6 Zech et al. demonstrated that 2-PAM, 4-PAM, and TMB-4 were more potent inhibitors of cholinesterases after incubation with dimethoate (O,O-dimethyl S-methylcarbamoylmethyl phosphorodithioate)
|
From page 15... ...
In brief an alkyd group is cleaved from the phosphorylated enzyme, leaving an "aged" enzyme that is resistant to reactivation by the oxime. The rate at which a phosphorylated enzyme "ages" is determined by the alkyl groups on the organophosphate, as described in Volume ~ .
|
From page 16... ...
Hence, blood concentrations are always low after oral administration, arid substantial blood concentrations are dif ficult to produce or maintain when the drug is given by this route. 28~99 Marked gastrointestinal distress is produced by oral 1 y given oximes, particularly if therapy is continued.99 2-PAM may ef fective 1 y be given either intravenously or intramuscularly, although the latter route is more erratic and sl ower in producing high blood concentrations and may in~rol~re some local pain.
|
From page 17... ...
. They imply dif ferent mechanisms of renal handling.
|
From page 18... ...
when giver as tablets coated with dimethylaminoethyl methacrylate, each containing 400 mg of the drug and 71 mg of excipierlt.~°° Local pain and increased creative phosphokinase in the blood follow intramuscular injection. Using 2-PAM chloride and saline, Sidell_ al.95 showed that the degree of tissue in Jury was directly related to the osmolarity of the injected solutions when the volume was kept constant and directly related to the volume when the osmolarity was constant .
|
From page 19... ...
Gastrointestinal distress Paresthesia and/or anesthesia Rash Bleeding Hypertension (moderate systolic and diastolic with increased pulse pressure and tachycardia) Initial hypertension followed by hypotension ECG changes Icterus and/or clinical test implicating liver Other biochemical changes Loss of consciousness Convulsions b ~5 g, pa &1 a, iv, NEG ~1 g, iv ~1 g, iv '1 g, iv b b b 61 56 56 56 ~6 b b '10 g, pa, NEG 61 &1 g, iv, NEG S6 b b ~1 g, iv, NEG 56 b b .
|
From page 20... ...
2 g, iv 20 1 g, iv, NEG 20 ^2 g, po, qid, 3 d, NEG 20 2 g, po, bid, 180 d, NEG 20 0.35 g, iv, NEG 108 Ini t ial hypertens ion b followed by hypotension ECG changes 3 g, iv 20 2 g, po, bid, 180 d Icterus and/or clinical 2 g, po, bid, 180 d 20 ' tes t impl icat ing ~ iver Other biochemical .3 g, iv, NEG 20 changes '2 g, po, q id, 3 d, NEG 20 Loss of consciousness b Convul ~ ions b a in = intramuscular; iv = intravenous; po = oral; q id ~ 4 t imes a day; bid = 2 times a day; NEG s administration failed to produce effect indicated. b Ef feet looked for, but not observed at any dose or by anY route .
|
From page 21... ...
Gastroin~cestinal distress &2. 5 Pare~ thesia and/or anesthes ia Ra sh Bleed ing Hypertens ion (moderate systolic and diastolic with increased pulse pressure and tachycardia, Initial hypertension followed by hypotension ECG changes Icterus and/or clinical test implicating liver Other biochemical changes Loss of consciousnese Convulsions Dose and Routea References &0.
|
From page 22... ...
g, po, 70 d 20 Pares tines ia and /or anes tines ia &1 g, po, 70 d 20 Rash &1 g, po, 70 d 20 Bleeding * t g, po, 70 d 20 Hypertens ion (moderate ~ys eol ic b and d ias tol ic wi th increased pulse pressure and tachycard ia ~ Initial hypertension 4 8, P° 20 fol lowed by hypotens ion 2 g, iv ECG changes 4 g, po, NEG 20 2 g, iv Icterus and/or clinical ~1 g, po, 70 d 20 tes impl icating liver Other biochemical changes b Loss of consciousness b Convulsions b a po = oral; iv s intravenou produce e f feet indicated .
|
From page 23... ...
&3 g, po 98 ~1.84 g, po 102 Iodism b Local irritation ~0.175 g, im 97 0.25 g, im 33 Headache ~2.76 g, po 102 Dizziness and nausea, po~sibly 7 g, po 98 progres ~ ing to vomi t ing Blurred vis ion, impaired b accononodat ion Muscular weakness and/or malaise, fatigue, etc. Gastrointestinal distress Pares tines ia and /or anes tines ia '2.76 g, po b 0.175 g, im &3 g, po 0.25 g, im &2.76 g, po b b Ra sh B1 eed ing Hypertension (moderate systolic 0.175 g, im and diastol ic with increased &4 .6 g, po, NEG pulse pressure and tachycard ia ~ Init ial hypereension followed by hypotens ion ECG changes Icterus and/or cl~nical tes t impl icating 1 iver Other b iochemical changes Loss of consciousness Convul ~ ions a im ~ intramuscular; po ~ ore to prociuce ef feet indicated.
|
From page 24... ...
lad ism Local irritation Headache Dizziness and nausea, possibly progress ing to vomi t ing Blurred vis ion, impaired acco~ranodat ion Muscular weakness and/or malaise, fatigue, eec. Gastrointestinal distress Paresthesia and/or anesthesia Rash Bleeding Hypertension (moderate systolic and diastolic with increased pulse pressure and tachycardia)
|
From page 25... ...
20 GASTROINTESTINAL EFFECTS Direct ef fects of oximes on ache gastrointestinal tract are related entirely to the route of admir~istration -- they are seen only after oral administration. Ingestion of tablets of 2-PAM or related salts is often accompanied by transient diarrhea and cramps.
|
From page 26... ...
At least three classes of action have been attributed to the effects of altered calcium metabolism on autonomic ganglia. A sympathomimetic action of 2-P~ was postulated to explain the increase in blood pressure and the augmented myocardial contractility by one or more of the following mechanisms: 2-PAM may not be ock the release of the endogenous compounds, but may prevent the uptake of catecholamine; ~ O it may stimul ate the release of norepinephrine;l8 it increases m;}ocardial contractility by directly stimulating beta receptors ;3 and it increases blood pressure by directly stimulating alpha receptors.85 2-PAM increased the contracti~ e force of stimulated rabbit atria that did not result from an increase in the frequency response.
|
From page 27... ...
It has been postulated that 2-PAM exerts its cardiac action in rabbit atria through its alteration of calcium metabolism. The relaxation phase of skeletal muscle contraction seems to be directly affected by the sarcoplasmic reticulum because of its ability to sequester calcium actively.29~46 A similar role has been su,gested for the sarcoplasmic reticulum in cardiac muscle.
|
From page 28... ...
from the nerve terminal. ~ Effects of Oximes on AChE Activity ACh contrac Lion of frog rectus abdominis muscle was potent fat ed by 2-PAM, and progressive AChE inhibition was seen with increasing concentrations of 2-PAM.
|
From page 29... ...
There was transient hypotension due to block of ganglionic tranamission.9~63~7 Presynaptic Effects of Oximes Concentration-dependent presynaptic effects of 2-PAM on the release of acetylcholine from terminals of nerves innervating the rat diaphragm muscle were seen; at concentrations of 10-4-10-3 M 2-PAM stimulated the release of acetylcholine; higher concentrations led to a total block of the evoked release of acetylcholine .30 ,40 MUTAGENIC, REPRODUCTIVE, AND CARCINOGENIC EFFECTS No information on mutagenic, carcinogenic, reproduct ive , or teratogenic effects of any of the compounds in question is available. None of the compounds or their in viva intermediates is likely to bind covalently with DNA and other macromolecules.
|
From page 30... ...
were administered during the first day of illness and somewhat small er doses later. 5 DELAYED AND LONG-TERM EFFECTS Appendix B reviews some important animal studies of cholinesterase Deactivator chemicals.- The extensive literature reviewed offers little definitive information with which to project possible long-term effects or delayed sequelae in hen subjects tested at Edgewoode These compounds have a short biologic half-life of 1 to 3 h.
|
From page 31... ...
Oral administration of cholinest erase reactlvators for up to 17 wk produced erosion of the mucosa along ridges of the rugae in the fundus of the stomach and fibrosis in vicinities of the cardiac and pyloric sphincters . ~ The finding that an azotemic sub ject had markedly decreased clearance from blood56 is of interest, although probably not pertinent to the Edgewood studies on hen subjects, because the volunteers were in good physical condition when tested.
|
From page 32... ...
to 79 Subjectsa Manifestationab None Dry mouthb Diz z ines s Diplopia Eye discomfort Blurred vi sion Mood e' evasion Voiding dif ficulty Nausea Vomi tiny Uric acid increase Faintness Claustrophobia Abdominal cramps Diarrhea Muscle pain Tachycard lab Grand mal seiz urea Intravenous, 5 mg/kg, to total of 500 ma, N = 29 o 2 23 8 12 9 1 2 6 l 1 1 1 __ Oral, 5-7 g total, N - 13 6 1 Intramuscular, 2.5 mg/kg, to total of 600 ma, N ~ 37c o __ __ 37 1 1 a Task plan: absorption efficacy of 2-PAN (chloride form) as function of pH (intramuscular studies)
|
From page 33... ...
5-~. 0 ,ug/kg, 60-128 me infused, Manifestations N ~ 11 None Hot, cold, numb, tingling sensation Eye discomfort Dizzinen ~ Dry mouth Local pain Peculiar taste Drowsines ~ Blurred vision Headache Nausea Vomiting o 10 1 l Oral, 1-9 g total, N ~ 20 3 9 2 2 10 51 3 1 a Records on all 41 subjects tested were summarized.
|
From page 34... ...
Records on 75 of 95 subjects tested were summarized; each subject was tested once with P2S. b Subject 2307 (see text)
|
From page 35... ...
a Records on 24 of 34 subjects tested were summarized; clinical data available on 11, only laboratory data on eight, and no data (except RBC cholinest erase content) on five.
|
From page 36... ...
He was transferred to Walter Reed Hospital. His Multiphasic Multiple Personali ty Inventory (MMPI)
|
From page 37... ...
Barr, A.M. Further experience in the treatment of severe organic phosphate poisoning.
|
From page 38... ...
cardiac action in rabbit atria.
|
From page 39... ...
Calcium ion and muscle contraction.
|
From page 40... ...
., ed. Chol inesterases and Anticholinesterase Agents .
|
From page 41... ...
S Army Chemical Center, Md., 1959.
|
From page 42... ...
S Army Chemical Warfare Laboratories, Army Chemical Center, Md., 1959.
|
From page 43... ...
lathe metabolism of C14 2-PAM in the isolated perfused rat liver.
|
From page 44... ...
Tozogonin : Oral administration to man.
|
From page 45... ...
F.~., Groff, W.A., and Kaminakis, A Pralidoxime methanesulfona'ce: plasma levele and pharmacokinetics af ter oral administration to man.
|
From page 46... ...
The compounds are eliminated very rapidly from the body, but they produce a variety of acute effects that are shortlived a~ re~rersible, such as gastrointestinal distress following oral administration, pain at ar~ injection site, dizzir~ese, headache, a~ ocular discomfort. The Committee found no data on the basis of which to deter~ine or rule out carcinogenicity, mutagenicity, teratogenici~cy, or reproductive ef fects of the four oximes and therefore did not reach a conclusion in this area.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.