Possible Long-Term Health Effects of Short-Term Exposure to Chemical Agents Volume 1 (1982) / Chapter Skim
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Anticholinesterases
Anticholinesterases
Pages 5-50
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From page 5... ...
cause ACh to accumulate at cholinocepeive sites and thus produce effects equivalent to continuous stimulation cuff cholinergic nerve fibers. Before World War ~ I, only "reversible" antl-ChE agents were generally known, of which physostigmine (eserine)
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From page 6... ...
Retention of the dimethy~carbamate side chain in the mete position, but with incorporation of the quaternary nitrogen atom Into the ring to fore a pyrityl nucleus, results in compounds with anti-ChE and other pharmacologic properties similar to those of neostigmine. Pyridostlgmine is a drug of this clasaO Although the carbamates are the most familiar and the most commonly encountered anei-ChEs, members of other chemical classes are also capable of inhibiting AChE.
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From page 7... ...
It undergoes hydrolytic cleavage at the ester linkage by cholinesterases, renal excretion plays only a minor role in its disposal. In man, a Beg dose of physostigmi-ne injected subcutaneously is largely destroyed in 2 h.
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· Arc #ma I ~~ Cx ACHED '0~ '0; I' · 1 ~ it_ Cow Cal ~~ ~ f cat I~Y_ S - ~~ ~ h - ~~ Iel ll.
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It was at one -time generally assumed that physostig~ine, neostigmine, and related inhibitors that possess a carbamyl ester linkage or urethane structure, in addition to a tertiary amino or quaternary ammonium group, inhibit the enzyme in the same reversible fashion. However, careful kinetic studies showed that physostigaine and neostigmine are hydrolyzed by cholinesterase ~ Il-14 ~ O Initially, inhibitors of this class form complexes in which the inhibitor is attached to the enzyme at both anionic and esteratic sites; subsequently, hydrolysis proceeds in a manner analogous to that of ACh, and the alcoholic moiety is split off, leaving a carbamylated ant inhibited enzyme.
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From page 10... ...
When the quaternary ammonium group of pralitoxime is attracted electrostatically to the anionic site of the enzyme, the oxime group of the former is oriented optimally to exert nucleophillc attack on the electrophilic phosphorus atom of the phosphorylatet esteratic site; the oxime-phospho~ate is then split off, leaving the enzyme (21,22~. Although the oximes reactivate phoaphorylatet cholinestereae in vitro and increase recovery from intoxication produced in vivo by some organophosphates, they are not panaceas for the treatment of pig by anti-ChEs.
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Pralidoxlme (lower reaction) combines with the anionic site by electrostatic attraction of ita qua ternary nitrogen atom, Which orients the nucleophlllc oxide group to react with the electrophilic phosphorus atom; the oxime-phoaphonate is split off, leaving the regenerated enzyme.
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From page 12... ...
pointed out that the difference in reactivatability may be associated with the relative reactivity of secondary and tertiary phosphate esters. Whereas the original inhibited enzyme is a tertiary phosphate ester, the dealkoxylated derivative is a secondary phosphate ester.
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From page 13... ...
, caused muscle depolarization that reversed spontaneously, ant increased quantal content. It was suggested that the observed changes in transmitter release resulted from an effect on the action potential invadlag the nerve terminal, although no direct evidence was offered.
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concluded that the antidromic discharges were produced by direct actions on the motor nerve terminal. Although ChE inhibitions smith later accumulation of ACh and an increase in extracellular potassium concentration, may be the cause of the observed effects, these posalbilittes are unlikely.
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. ACUTE TOXIC EFFECTS Toxicity of particular OF compounds does not vary greatly ~IBODg mammals.
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Two groups of NTE inhibitors; Group A (upper) induce delayed neuropathy, Group B (lower)
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. BIOLOGIC AND CLINICAL EFFECTS ACUTE EFFECTS: PH~COL~Y The characteristic acute pharmacologic effects of the anti-ChE agents classically are ascribed to the inhibition or inactivation of AChE at sites of cholinergic transmission, with the consequent accumulation and action of endogenous ACh liberated both by stimulated cholinergic nerve and (in much smaller amounts)
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From page 18... ...
For example, compounds containing a quaternary ammonium group do not penetrate cell membranes readily; hence, some anti-ChE agents are excluded by the bloot-brain barrier from exerting substantial action on the CNS. But quaternary ammonium compounds act relatively strongly at the neuromuscular Junctions of skeletal muscle through both their anti-ChE ant their direct cholino~lmetic mechanisms and have comparatively lesa effect at autonomic effecter sites.
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Ac Lions at Other Autonomic Sites Secretory glands thee are innervated by postgas~glionic cholinergic fibers include the bronchial, lacrimal, sweat, salivary, gastric, intestinal, and acinar pancreatic glands; low doses of anti-ChE agents cause, in general, an augmentation of their secretory responses to nerve stimulation, and higher doses increase the resting rate of secretion. Smooth muscle fibers of the bronchioles and ureters are contracted by these drugs, and the ureters may show increased pert staltic -activity.
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From page 20... ...
Thus, a small dose of anti-ChE may increase the skeletal muscle contraction produced by a Single maximal nerve stimulus, but larger doses, or repetitive nerve stimulation at a high physiologic rate, may result in depression or block of neuromuscular transmisaton. Brain The mechanisms by which anti-ChEs perturb brain function are more complex, harder to study, and consequently less well understood.
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From page 21... ...
An attractive postulate of the control of the sleep-wake cycle is that, during non-REM sleep (and waking) , an inhibitory system composed of neurons in the locus ceruleus or the dorsal Raphe nuclei tonically prevents cholinergic neurons in the gigantocellularis nuclei from firing.
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From page 22... ...
The oximea are inefficient if the phoaphorylated enzyme has aged O These optima contain quaternary ultrogen ant therefore do cot penetrate the bloot-brain barrier ant have no effect at cholinergic aynapeea in the brain or spinal cord. The acute effects of the anti-ChEa are ahort-lived and do not outlast the inhibition of the enzyme.
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leurologic examination reveals signs of damage to the spinal cord (hyperactive knee jerks) and peripheral nerves (hypoacti~re ankle jerks)
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Neuropathologic Features The limited neuropathologic information available from studisa of affected persons demonstrates that OP poisoning induces degeneration of nerve fibers in spinal cord and peripheral nerves (122)
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. The effect of anti-ChEs on the structural integrity of brain tissue has rarely been investigated, although the destructive effects of some of these compounds on spinal cord and peripheral nerves are well known.
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JUNCTIONAL NEUROMYOPATHY Pathologic changes develop aubacutely ant reversibly in some motor-nerve terminals, neuromuscular Junctions, and associated muscle fibers after a/ministration of anti-ChE drugs to laboratory animals. ChE inhibitors with long-lasting effecta-such as paraoxon, DFP, tabun, sarln, soman, ant parathion-and reveraible inhibleors, such as physostlgmine and neostlg~lne.
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From page 27... ...
Prejunctional and post~unctional subacute changes are resolved within 2 wk after administration of DEP; however, because this compound also inhibits ME and induces delayed neuropathy, a week after recovery from the subacute neuromyopathic changer motor-nerve terminals undergo a second phase of degeneration and regeneration, with reinnervation of damages endplates 6-8 wk later ~131)
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No data appear to be available on the potential mammalian terarogenicity of military nerve agents. Ef f ec t s on Male Re Droductior A s ingle dose of dichlorvos reportedly damages the germinal epithelium of mouse testes severely (143~.
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The medical records of subjects tested with EA 3148 comprise doctors' orders, observations of the patient recorded largely by nurser, a ciluical master log recording only blood pressure and pulse before and after exposure, results of a test of numerical facility, and ChE concentrations in blood, plasma, and red cells, before and at intervals af ter exposure. Physician' workup, progress ~ and discharge notes are absent.
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The paucity of data in the medical records prevents further Study in relation to the goal of this report. However, there are published papers which appear to demonstrate long lasting EEG changes from single or repeated exposure to OPa (83)
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From page 31... ...
In particular, there are no reports of respiratory insufficiency or convulsions that could precipitate periods of hypoxia and lead to permanent damage of brain tissue. JUNCTIONS NEURO=OPATHY AM DELAYED NEUROPAT~ Medical records of the vast majority of subjects tested do not refer to induction of the muscle hyperactivity that is associated with acute neuromyopathy in laboratory animals and humans poisoned by OP insecticides.
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From page 32... ...
; because the toses used on the teat subjects were far below those needed to induce experimental neuropathy, it is moat unlikely that any subject experienced delayed onset of distal limb paralysis. However, clinical algna of neuropathy in experimental animals occur some time after the onset of CHS-PNS distal axonopathy, after a particular number of nerve fibers have undergone degeneration.
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Exposures to low doses of OP compounds have been reported (but not confirmed) to produce subtle changes in BEG, sleep pattern, and behavior that persist f or at least a year.
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TABLE 1 RF~IsOtSEI; OF }~'PE~lI QltGANS SO AUIU~MIC Nt:RW.
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' Sympathetic cholinergic system causes ~ra~odilat:ation in skeletal muscle, but this is not involved in most phy siological responses. 6 It has been proposed that adrenergic f lbers terminate at inhibitory B receptors on smooth muscle fibers, and at inhibitory a receptors on parasympathetic cholinergic (excitatory)
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TABLE 2 Effects, of Cholinergice tn Nor.~1 and Paychotic Persone* Drug ~ffect on Norea1 P rson Effect on PsYchotlc Person Phy8O8~tg~DC Depreselon; Paychoootor retertation beproveeent, particularly antichEa of thought disorder; No effect; antagonise of eathylphenid-te activat,lon Organophoaphorus Dysphorta; Dlghteares; ascessive So~e ~sproveeent tn antichEa dreaming; hallucinations a~d hebrephrenice; exacerbation deluston,~; ·chizold reactions; in most ceses (paranolda)
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From page 37... ...
11 11 A-13 Pyridostig~ice 27 A-14b Halathion 10 5 Ao20 Methacholine 9 A 21f Urechollne 1S 5 Sotal 1~406 aTvo 6eta of recorts, one based on high dose, another beaed on random selection; each set contains 219 recorde. bOrganophosphate ester.
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From page 39... ...
6. Karezmar, A.G., 1967: Pharmacologic, toxicologic and therapeutic properties of anticholinesterase agents.
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19. Heilbronn-Wikstrom, E., 1965: Phosphorylatet cholinesterases, their formation, reactions ant intucet hydrolysis.
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From page 41... ...
and Wescoe, W.C., 1946: The tirect action of prostigmine on skeletal muscle; lts relationship to the choline esters.
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From page 42... ...
and Bowman, WOC., 19636: Studies on the repetitive discharges evoked in motor nerve and skeletal muscle after in jection of anticholinesterase drugs.
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From page 43... ...
and Sanders, H.D., 1963: A proposed mechanist of action for general and local anesthetics in the central nervous system.
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From page 44... ...
and Lal, H., 1978, Dy~functions of cholinergic process in schizophrenia 1~: Developments in Psychiatry, Proceetings of 2nd World Cbugress Blological Psychiatry, Barcelona pp. 438~439, VOle IIae 80e Karczmar, AeGe and Richardson, DeLe ~ 1982, Cholinergic mechanisms, schizophrenia and neuropsychiatric adaptive dyofunctions in: Cholinergic mechanisme and adaptive dyofunctions ede by Helle Singh, DeMe Warburton, and H
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From page 45... ...
and Goon, M.D . 1956: Observations an acute and multiple exposure to anticholinesterase agents.
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From page 46... ...
* Gaon, M.D., 1959 Report of medical experience on acute and repeated exposure a in humane with nerve gsa (GB)
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for monkeys exposed to GA, GB and GE Capote (U)
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Rowntree, D.W., Nevin, S., ant Wilaon, A., 1950: The effects of disopropylfluorophosphonate in schi20phrenia ant manic tepreaslve paychosis.
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From page 49... ...
135. Lowntes, H.E., Bal~er, T., and Riker, W.F., Jr., 1974: Motor nerve dy~function in telayet DFP neuropathy.
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From page 50... ...
and Holmes, J.~.: Changes in blood coagulation following exposure to antlchollnestersse agents (parathion and sari n) Semi-sanual progre so report .
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