Organic Phosphorus Poisoning and Its Therapy William F

University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Public Health Resources Public Health Resources 7-1962 Organic Phosphorus Poisoning and Its Therapy William F. Durham U.S. Department of Health, Education, and Welfare Wayland J. Hayes Jr. U.S. Department of Health, Education, and Welfare Follow this and additional works at: http://digitalcommons.unl.edu/publichealthresources Durham, William F. and Hayes, Wayland J. Jr., "Organic Phosphorus Poisoning and Its Therapy" (1962). Public Health Resources. 531. http://digitalcommons.unl.edu/publichealthresources/531 This Article is brought to you for free and open access by the Public Health Resources at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Public Health Resources by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. 11-031 21 Organic Phosphorus Poisoning and Its Therapy PUBLICATION With Special Reference to Modes of Action and Compounds That 107 Reactivate Inhibited Cholinesterase TOXICOl.OGY PROGRAM WILLIAM F. DURHAM, Ph.D., AND WAYLAND J. HAYES, JR., M.D., Ph.D., ATLANTA TeChnology Brant'h . COmmunicable Disease Cont''t'' Atlanta 22, Ga. Contents This therapy produces relief of symptoms Introduction based on blocking the action of excess acetyl Nature and Physiologic Function of Cholinesterase choline. Symptoms of Organic Phosphorus Poisoning Mechanism of Inhibition of Cholinesterase More recently, a number of specific anti Measurement of Cholinesterase Activity and Its dotes have been developed which act to repair Relationship to Symptomatology the basic biochemical lesion in organic phos Measurement of Metabolites and Their Relationship phorus poisoning by freeing the cholinester to Symptomatology Use and Action of Atropine and Other Nonspecific ase from its combination with the inhibitor. Antidotes In the present paper, some of the pertinent Development of Specific Antidotes background material relative to' organic phos Chemical and Physiologic Properties of Oximes phorus poisoning will be reviewed, and the Antidotal Efficacy of Oximes in Poisoned Experimental Animals properties and usage of these specific anti Application of 2-PAM in Poisoning in Man dotes will be discussed in some detail. Em Suggestions for Treatment phasis will be given to those aspects of Prevention of Poisoning symptomatology and treatment which might Comment and Summary be of most value to the physician faced with Introduction a presumptive case of poisoning. Organic phosphorus compounds are of Nature and Physiologic Function considerable interest and importance by vir of Cholinesterase ture of their widespread use as insecticides; their effectiveness in the treatment of my There are 2 general types of cholinesterase asthenia gravis, glaucoma, and abdominal present in the animal organism.9 These are: distention; and their potential application as ( 1) the true, specific enzyme, acetylcholin war gases. These compounds owe their esterase, which has an almost specific affinity pharmacologic effect primarily, if not entire for the naturally occurring substrate acetyl ly, to their ability to inhibit the enzyme choline, although it will hydrolyze several cholinesterase with a resultant overstimula synthetic esters; and (2) the nonspecific tion of the parasympathetic nervous system enzyme, pseudocholinesterase, which has the by the acetylcholine which accumulates. ability to hydrolyze quite a wide range of Atropine has been the drug of choice for the naturally occurring and synthetic esters in addition to acetylcholine. Acetylcholinester treatment of organophosphorus poisoning. ase occurs in the nervous system, where it is Submitted for publication Dec. 12, 1961. of great functional importance; in muscles; From the Toxicology Section, Technology Branch, and in glands; and it also occurs incidentally Communicable Disease Center, Public Health Service, U.S. Department of Health, Education, in erythrocytes. The pseudoenzyme is found and Welfare, Wenatchee, Wash. (Dr. Durham) and in the blood plasma and in various tissues, Atlanta (Dr. Hayes). including the central nervous system. 22 ARCHIVES OF ENVIRONMENTAL HEALTH In addition to location and substrate speci muscle; and probably (4) from certain struc ficity, there are other differences between tures within the central nervous system. true and pseudocholinesterases. The latter Normally, in the presence of the usual con functions well in the presence of an excess centration of cholinesterase, the acetylcholine of substrate, while the former is inhibited formed during the process of transmission under this condition. A number of inhibitors is hydrolyzed almost instantly so that the show considerable specificity for 8ne type of synapse is again ready to transmit a physio enzyme. For example, diisopropyl fluorophos logic impulse. A small abnormal accumula phate (DFP) in low concentrations is almost tion of acetylcholine at the synapse or completely specific for pseudocholinester myoneural junction produces an abnormal ase. 73 increase in function (e.g., fasciculation of It has been suggested that certain direct muscle), while greater accumulation rapidly effects of the anticholinesterase organic produces a decrease in function (e.g., paral phosphorus compounds do not depend on ysis). A decrease in cholinesterase activity inhibition of cholinesterase.w5 Von Kaulla is accompanied by an accumulation of acetyl and Holmes 142 have reported that patients choline. The symptoms caused by organic poisoned by organic phosphorus compounds phosphorus poisoning are, therefore, very show abnormalities in the blood-clotting similar to those resulting from overstimula mechanism, but the changes were in both tion of the parasympathetic nervous system. directions from normal and must be consid ered unconfirmed. Some of the compounds Symptoms of Organic do produce a delayed reaction similar to Phosphorus Poisoning "J ake-Ieg paralysis," 11,41,94 but the clinical Absorption of the organic phosphorus picture is quite distinct from that of ordinary anticholinesterases may occur through the poisoning. Although any statement about the lungs, gastrointestinal tract, or skin. Absorp relationship between cholinesterase inhibition tion of these materials is more rapid and and the classical picture of poisoning must be more complete through the former 2 routes qualified in terms of the rate of depression, than through the latter. Respiratory exposure the degree of depression, and perhaps other may be of predominant importance wherever factors, the evidence for a lack of relation there is a sufficient concentration of vapor ship is indefinite. On the contrary, the evi or of aerosol fine enough to inhale. However, dence for a lack of relationship between in many agricultural and public health usages, cholinesterase inhibition and paralytic effect workers get contamination predominantly on is much more clear. In spite of these excep their skins.13,3o,42 The oral route of 'exposure tions, it is true that the predominant pharma occurs in accidental poisoning (particularly cologic effect of the organic phosphorus of children), in murder, and in suicide. In compounds is inhibition of the enzyme acetyl gestion has not been considered of impor cholinesterase. tance in occupational exposurt; but a case In order to have an understanding of the has been reported in which a parathion spray action of acetylcholinesterase and of the man became severely poisoned, presumably effect of its inhibition on the animal organ from eating a candy bar which he had been ism, it is first necessary to look at the physio carrying for 6 hours in an open outside logic action of acetylcholine. Acetylcholine is pocket of his work clothes.120 the chemical mediator of the parasympathetic Although many of the organic phosphorus nervous system and is necessary for trans compounds have a high acute toxicity, agri mission of the nervous impulse (1) from cultural residues of these materials on food preganglionic fibers to autonomic ganglia; have not been a problem, due to their rapid (2) from postganglionic, cholinergic nerves breakdown and the fact that they are not to smooth and cardiac muscle and to secre stored in the animal body.40 Direct contami tory cells: (3) from motor nerves to striated nation of food by concentrated formulations Vol. 5, July, 1962 ORGANIC PHOSPHORUS POISONING 23 of these insecticides during shipment has lacrimation, profuse sweating, pallor, and been the cause of several outbreaks of poison dyspnea. In some subjects there is audible ing in other countries. wheezing. More severe signs and symptoms The symptom picture in organic phos include involuntary defecation and urination, phorus poisoning may vary in severity, in excessive bronchial secretions, and (accord rapidity of onset, in duration, and in range, ing to some authors) pulmonary edema. depending upon the route and the magnitude Nicotine-like effects appear usually after of exposure. Minor exposure to a vapor or the muscarine-like effects have reached mod aerosol of a direct inhibitor of cholinesterase erate severity. These include muscle twitch may produce local effects on the eye or re ing, fasciculations, and cramps. At about the spiratory system through local absorption same time, there appears increased fatigabil and without systemic effect. The optic effects ity and mild, generalized weakness which is consist of miosis, a sensation of pressure in increased by exertion. Extensive exposure

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