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Pyridostigmine
Pyridostigmine T Dodd-Butera, California State University San Bernardino, San Bernardino, CA, USA M Broderick, California Poison Control System, San Diego Division, San Diego, CA, USA Ó 2014 Elsevier Inc. All rights reserved. l
Name: Pyridostigmine Chemical Abstracts Service Registry Number*: 155-97-5 l Synonyms: 3-((Dimethylamino)carbonyl)oxy-1-methylpyridinium, Mestinon, 5-21-02-00078 (Beilstein Handbook Reference), Regonol, Pyridostigmine bromide l Molecular Formula: C9-H13-N2-O2 l Chemical Structure: l
PB was found to offer a degree of protection in isolated human intercostal muscle. This requires future studies, however, as erythrocyte acetylcholinesterase activity was found to recover only slowly with pyridostigmine administration in studies using laboratory rats.
Exposure and Exposure Monitoring
Background Pyridostigmine bromide (PB) is a reversible cholinesterase inhibitor, which may be used as pretreatment for chemical nerve agent exposure, if there is a threat of exposure or attack. It was formulated in 1945 by Hoffman-La Roche Laboratories in Switzerland, and approved by the Food and Drug Administration (FDA) in 1955, for treatment of myasthenia gravis. An injectable form was also FDA approved for reversing the effects of some anesthetic formulations. Results of studies on veterans suggesting an association of PB exposure and symptoms experienced by those serving during the Gulf War are varied. In some studies of veterans of the 1991 Gulf War, exposure to anticholinesterase compounds was a predictor of subjective health status, and associated with the total number of neurological type symptoms reported, in a dose–response relationship. However, immunization factors, stress, and military rank were also found to influence health status in Gulf War veterans, so the relationship between symptoms and exposure remains under debate.
Uses Pyridostigmine has been used therapeutically to improve muscle strength in patients with myasthenia gravis, a chronic autoimmune neuromuscular disease characterized by skeletal muscle weakness. Pyridostigmine, used intravenously, may reverse the effects of neuromuscular blocking agents. As a reversible cholinesterase inhibitor, as mentioned above, it has been used as a pretreatment for military personnel as protection against potential chemical nerve agent exposure. It is not utilized after exposure to nerve agents, however, as it may exacerbate chemical effects of a sublethal exposure. Recently, it has been suggested for potential use as a pretreatment for farmworkers, to guard against the effects of select pesticide exposure.
1162
Pyridostigmine exposure may be through oral or parenteral pathways, as the drug is available for intravenous use in liquid form and in regular and extended release tablets. Intramuscluar administration has been noted more commonly in animal studies. Monitoring of blood and urine levels have been described in rat studies using a laboratory procedure known as high-performance liquid chromatography. Acetylcholinesterase activity has been utilized to monitor effects in cases of exposure and overdose of PB. Indirect monitoring examining enzymes that detoxify and/or clear acetylcholinesterase inhibitors from the body have been used in studies on the Gulf War Syndrome. One specific enzyme to PB is butyrylcholinesterase, which may scavenge and inactivate the compound.
Toxicokinetics PB is a quaternary ammonium anticholinesterase compound poorly absorbed after oral administration, with a bioavailability in a range of 10–20%. The equivalent parenteral dose is approximately 1/30th of the oral dose. The parent compound and quarternary alcohol are the primary metabolic compounds in urine after administration. With intravenous administration in human subjects, the biological half-life of the drug is between 14 and 37 min. The volume of distribution is approximately 19 l, indicating distribution into tissues. Pyridostigmine is hydrolyzed by cholinesterase, and is metabolized in the liver. The elimination half-life of PB is approximately 3 h. Renal clearance may be altered in patients with renal impairment.
Mechanism of Action Pyridostigmine inhibits cholinesterase, which inactivates the neurotransmitter acetylcholine. This prevents hydrolysis of acetylcholine by the enzyme cholinesterase. Thus, the action of this inhibition results in potentiating endogenous release of acetylcholine at cholinergic synapses. With neurotransmitter accumulation, due to pyridostigmine action, acetylcholine release is enhanced at the nerve endings by cholinergic impulses. Because of its quaternary structure, pyridostigmine entry into the central nervous system is limited by the blood– brain barrier.
Encyclopedia of Toxicology, Volume 3
http://dx.doi.org/10.1016/B978-0-12-386454-3.00053-1
Pyridostigmine
Acute and Short-Term Toxicity Animals In LD50 studies of mice, subcutaneous exposure to pyridostigmine elicited symptoms of constricted pupils, respiratory stimulation, and somnolence. Acute oral studies of the dose–response relationship and interaction of PB, permethrin, and N,N-diethylm-toluamide (DEET) in adult male rats found an increase in lethality with concurrent administration. Concurrent administration of PB, DEET, and chlorpyrifos in hens increased symptoms of neurotoxicity in a subchronic study. The study was designed to examine individual and coexposures, similar to the multiple exposures of military personnel during Gulf War service.
Humans Reports of pyridostigmine ingestion in acute overdoses indicated mild to moderate cholinergic symptoms in patients, resulting in abdominal cramps, diarrhea, emesis, nausea, hypersalivation, urinary incontinence, fasciculations, muscle weakness, and blurred vision. No central nervous system manifestations were evident. The symptoms developed within several minutes of exposure and lasted up to 24 h. Adverse reactions with therapeutic doses may also include abdominal cramps and diarrhea.
Chronic Toxicity Animals Experiments conducted on subcutaneous administration of chronic low-dose pyridostigmine in mice for 7 days demonstrated decreased blood acetylcholinesterase activity without accompanying cardiovascular and/or behavioral effects. In contrast, a similar study of 7 days exposure to subcutaneous pyridostigmine in mice, under conditions of stress, found exposure to pyridostigmine resulted in an exaggerated acoustic startle response and a nonsignificant decrease in locomotor activity. The behavioral changes were noted only during exposure to pyridostigmine. Rats exposed to subclinical doses of pyridostigmine, while subjected to daily stress for 14 days, were noted to have cholinesterase activity decreases 1 h after pyridostigmine challenge, and inhibition of activity of the diaphragm was greater in stressed vs. nonstressed controls in higher doses. This was not found to be significant for inhibition of acetylcholinesterase in brain regions.
Humans Surveys of groups of soldiers ingesting daily oral pyridostigmine for extended periods of time indicated nonspecific mild symptoms, most commonly including dry mouth, general malaise, fatigue, and weakness. Nausea, abdominal pain, frequent urination, and rhinorrhea were reported infrequently. No correlation was found between levels of cholinesterase and type or severity of complaints.
Immunotoxicity Female mice were examined for immunosuppression after exposure to PB, alone or in combination with DEET insect
1163
repellent, and environmental exposures to jet fuel. Suppression of antibody-specific IgM immune responses (plaque forming cells) occurred after exposure to each compound administered alone and to mixtures of all three, at both high- and low-dose levels.
Reproductive and Developmental Toxicity Animals Pyridostigmine produced no teratogenic effects when administered during organogenesis in rats and rabbits. In doses sufficient to cause maternal toxicity, a small increase in the incidence of delayed skeletal ossification was seen in rats and a slight increase in hydronephrosis in rabbits was reported. Blood vessel variations were found at all doses.
Humans Pyridostigmine is a Category C drug, under FDA listings indicating categories for pregnancy use. No well-controlled human studies have been carried out in pregnant women. Therapeutic doses do not cross the placenta in significant amounts. However, large doses of the drug may cross the placenta and reduce fetal plasma cholinesterase activity. Premature labor was associated with parenteral anticholinesterases. Use in pregnancy should be determined by a health care provider, weighing risk vs. benefit.
Lactation Exposure to infants from maternal use is minimal, due to low levels of pyridostigmine in breastmilk. Pyridostigmine is not expected to cause adverse outcomes in breastfed infants, and is considered compatible with breast-feeding by the American Academy of Pediatrics.
Genotoxicity Evidence of mutagenicity and clastogenicity is varied (Table 1). Mutagenicity tests were negative in rat micronucleus assay, the in vitro Ames Salmonella typhimurium assay, and an in vitro mammalian gene mutation assay in Chinese hamster ovary cells. Results in an in vitro assay in Chinese hamster ovary cells and an in vivo mouse micronucleus assay showed no clastogenic effect. In vitro assay in Chinese hamster ovary cells and in vivo mouse micronucleus assay were not clastogenic.
Table 1 Evidence summary for selected mutagenicity and clastogencity tests for pyridostigmine Assay Ames Mammalian gene mutation Chinese hamster ovary cells Mouse lymphoma cells Mouse micronucleus Rat micronucleus
Clastogenicity
Mutagenicity Negative
Negative (in vitro) Positive (in vitro) Negative (in vivo) Negative
Negative (in vitro) Positive (in vitro)
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Pyridostigmine
Carcinogenicity
Further Reading
There is no epidemiological evidence of a significant correlation between pyridostigmine exposure and increased cancer risks in humans. There are studies examining cancer rates in Gulf War veterans, but these have not addressed any direct link to pyridostigmine exposure and carcinogenicity. Adequate long-term carcinogenicity studies for animals were not identified for pyridostigmine.
Abou-Donia, M.B., Wilmarth, K.R., Abdel-Rahman, A.A., Jensen, K.F., Oehme, F.W., Kurt, T.L., 1996. Increased neurotoxicity following concurrent exposure to pyridostigmine bromide, DEET, and chlorpyrifos. Fundam. Appli. Toxicol. 34 (2), 201–222. Almog, S., Winkler, E., Amitai, Y., Dani, S., Shefi, M., Tirosh, M., et al., 1991. Acute pyridostigmine overdose: a report of nine cases. Isra. J. Med. Sci. 27 (11–12), 659–663. Bernatova, I., Dubovicky, M., Price, W.A., Grubbs, R.D., Lucot, J.B., Morris, M., 2003. Effect of chronic pyridostigmine bromide treatment on cardiovascular and behavioral parameters in mice. Pharmacol. Biochem. Behav. 74 (4), 901–907. Fulco C.E., Liverman C.T., Sox H.C., 2000. Committee on Health Effects Associated with Exposures During the Gulf War. Gulf War and Health, vol. 1: Pyridostigmine. National Academy Press, Washington, D.C., pp. 207–266. Golomb, B.A., 2008 (18 March). Acetylcholinesterase inhibitors and Gulf War illnesses. Proceedings of the National Academy of Sciences 105 (11), 4295–4300. McCain, W.C., Lee, R., Johnson, M., Whaley, J.E., Ferguson, J.W., Beall, P., et al., 1997 (7 February). Acute oral toxicity study of pyridostigmine bromide, permethrin, and DEET in the laboratory rat. J. Toxicol. Environ. Health 50 (2), 113–124. Nelson, L., Goldfrank, L.R., et al., 2011. Physostigmine; Goldfrank’s Toxicologic Emergencies, ninth ed. McGraw-Hill Medical, New York. Peden-Adam, M.M., Eudaly, J., Eudaly, E., Dudley, A., Zeigler, J., Lee, A., et al., 2001 (17 June). Evaluation of immunotoxicity induced by single or concurrent exposure to N, N-diethyl-m-toluamide (DEET), pyridostigmine bromide (PYR), and JP-8 jet fuel. Toxicol. Ind. Health (5–10), 192–209. Russo, W.F., 2011. Determinations Concerning Illnesses Discussed In National Academy of Sciences Reports on Gulf War and Health, vols. 4 and 8; Federal Register, Citation:76 FR 21099; 2011–8937; 21099–21107; retrieved from https://federalregister.gov/a/2011-8937. Schumm, W.R., Reppert, E.J., Jurich, A.P., Bollman, S.R., Webb, F.J., Castelo, C.S., et al., 2002 (June). Pyridostigmine bromide and the long-term subjective health status of a sample of over 700 male Reserve Component Gulf War era veterans. Psychol. Rep. 90 (3 Pt 1), 707–721. Shaikh, J., Karanth, S., Chakraborty, D., Pruett, S., Pope, C.N., 2003 (October). Effects of daily stress or repeated paraoxon exposures on subacute pyridostigmine toxicity in rats. Arch. Toxicol. 77 (10), 576–583.
Clinical Management Overdose of pyridostigmine may result in cholinergic symptoms. Reactions may be muscarinic or nicotinic. Muscarinic adverse reactions include abdominal cramps, diarrhea, vomiting, hypersalivation, urinary incontinence, increased bronchial secretion, diaphoresis, miosis, and lacrimation. Nicotinic adverse reactions comprised muscle cramps, fasciculations, and weakness including respiratory muscles. Treatment may require atropine and activated charcoal administration. Atropine antagonizes the muscarinic effects of pyridostigmine. Serum cholinesterase inhibition may be monitored as an indicator of exposure. Renal function may also be monitored in patients with renal impairment. Known hypersensitivity reactions may occur with pyridostigmine, and in persons with sensitivity to bromide. Caution with depolarizing neuromuscular blocking agents should be exercised. Further, caution should be observed with utilization in persons with cardiopulmonary conditions, such as bronchial asthma and chronic obstructive pulmonary disease, which may increase the risk of anticholinergic reactions. A number of drugs may interact with pyridostigmine, so concurrent use of other substances should be reported to a health care provider.
Ecotoxicology Abiotic degradation of pyridostigmine may result in the formation of small amounts of tar, due to chemical decomposition of solutions exposed to light, or photolytic degradation.
See also: Carbamate Pesticides; Cholinesterase Inhibition; Soman.
Relevant Websites http://www.cdc.gov/nceh/veterans/default2.htm – Centers for Disease Control. http://chem.sis.nlm.nih.gov/chemidplus – US National Library of Medicine: ChemIDplus Advanced: Search for Pyridostigmine. http://toxnet.nlm.nih.gov – Toxnet (Toxicology Data Network): search for Pyridostigmine. http://pubchem.ncbi.nlm.nih.gov – US National Library of Medicine (Pubchem): Search for Pyridostigmine.
Name: Pyridostigmine Chemical Abstracts Service Registry Number*: 155-97-5 l Synonyms: 3-((Dimethylamino)carbonyl)oxy-1-methylpyridinium, Mestinon, 5-21-02-00078 (Beilstein Handbook Reference), Regonol, Pyridostigmine bromide l Molecular Formula: C9-H13-N2-O2 l Chemical Structure: l
PB was found to offer a degree of protection in isolated human intercostal muscle. This requires future studies, however, as erythrocyte acetylcholinesterase activity was found to recover only slowly with pyridostigmine administration in studies using laboratory rats.
Exposure and Exposure Monitoring
Background Pyridostigmine bromide (PB) is a reversible cholinesterase inhibitor, which may be used as pretreatment for chemical nerve agent exposure, if there is a threat of exposure or attack. It was formulated in 1945 by Hoffman-La Roche Laboratories in Switzerland, and approved by the Food and Drug Administration (FDA) in 1955, for treatment of myasthenia gravis. An injectable form was also FDA approved for reversing the effects of some anesthetic formulations. Results of studies on veterans suggesting an association of PB exposure and symptoms experienced by those serving during the Gulf War are varied. In some studies of veterans of the 1991 Gulf War, exposure to anticholinesterase compounds was a predictor of subjective health status, and associated with the total number of neurological type symptoms reported, in a dose–response relationship. However, immunization factors, stress, and military rank were also found to influence health status in Gulf War veterans, so the relationship between symptoms and exposure remains under debate.
Uses Pyridostigmine has been used therapeutically to improve muscle strength in patients with myasthenia gravis, a chronic autoimmune neuromuscular disease characterized by skeletal muscle weakness. Pyridostigmine, used intravenously, may reverse the effects of neuromuscular blocking agents. As a reversible cholinesterase inhibitor, as mentioned above, it has been used as a pretreatment for military personnel as protection against potential chemical nerve agent exposure. It is not utilized after exposure to nerve agents, however, as it may exacerbate chemical effects of a sublethal exposure. Recently, it has been suggested for potential use as a pretreatment for farmworkers, to guard against the effects of select pesticide exposure.
1162
Pyridostigmine exposure may be through oral or parenteral pathways, as the drug is available for intravenous use in liquid form and in regular and extended release tablets. Intramuscluar administration has been noted more commonly in animal studies. Monitoring of blood and urine levels have been described in rat studies using a laboratory procedure known as high-performance liquid chromatography. Acetylcholinesterase activity has been utilized to monitor effects in cases of exposure and overdose of PB. Indirect monitoring examining enzymes that detoxify and/or clear acetylcholinesterase inhibitors from the body have been used in studies on the Gulf War Syndrome. One specific enzyme to PB is butyrylcholinesterase, which may scavenge and inactivate the compound.
Toxicokinetics PB is a quaternary ammonium anticholinesterase compound poorly absorbed after oral administration, with a bioavailability in a range of 10–20%. The equivalent parenteral dose is approximately 1/30th of the oral dose. The parent compound and quarternary alcohol are the primary metabolic compounds in urine after administration. With intravenous administration in human subjects, the biological half-life of the drug is between 14 and 37 min. The volume of distribution is approximately 19 l, indicating distribution into tissues. Pyridostigmine is hydrolyzed by cholinesterase, and is metabolized in the liver. The elimination half-life of PB is approximately 3 h. Renal clearance may be altered in patients with renal impairment.
Mechanism of Action Pyridostigmine inhibits cholinesterase, which inactivates the neurotransmitter acetylcholine. This prevents hydrolysis of acetylcholine by the enzyme cholinesterase. Thus, the action of this inhibition results in potentiating endogenous release of acetylcholine at cholinergic synapses. With neurotransmitter accumulation, due to pyridostigmine action, acetylcholine release is enhanced at the nerve endings by cholinergic impulses. Because of its quaternary structure, pyridostigmine entry into the central nervous system is limited by the blood– brain barrier.
Encyclopedia of Toxicology, Volume 3
http://dx.doi.org/10.1016/B978-0-12-386454-3.00053-1
Pyridostigmine
Acute and Short-Term Toxicity Animals In LD50 studies of mice, subcutaneous exposure to pyridostigmine elicited symptoms of constricted pupils, respiratory stimulation, and somnolence. Acute oral studies of the dose–response relationship and interaction of PB, permethrin, and N,N-diethylm-toluamide (DEET) in adult male rats found an increase in lethality with concurrent administration. Concurrent administration of PB, DEET, and chlorpyrifos in hens increased symptoms of neurotoxicity in a subchronic study. The study was designed to examine individual and coexposures, similar to the multiple exposures of military personnel during Gulf War service.
Humans Reports of pyridostigmine ingestion in acute overdoses indicated mild to moderate cholinergic symptoms in patients, resulting in abdominal cramps, diarrhea, emesis, nausea, hypersalivation, urinary incontinence, fasciculations, muscle weakness, and blurred vision. No central nervous system manifestations were evident. The symptoms developed within several minutes of exposure and lasted up to 24 h. Adverse reactions with therapeutic doses may also include abdominal cramps and diarrhea.
Chronic Toxicity Animals Experiments conducted on subcutaneous administration of chronic low-dose pyridostigmine in mice for 7 days demonstrated decreased blood acetylcholinesterase activity without accompanying cardiovascular and/or behavioral effects. In contrast, a similar study of 7 days exposure to subcutaneous pyridostigmine in mice, under conditions of stress, found exposure to pyridostigmine resulted in an exaggerated acoustic startle response and a nonsignificant decrease in locomotor activity. The behavioral changes were noted only during exposure to pyridostigmine. Rats exposed to subclinical doses of pyridostigmine, while subjected to daily stress for 14 days, were noted to have cholinesterase activity decreases 1 h after pyridostigmine challenge, and inhibition of activity of the diaphragm was greater in stressed vs. nonstressed controls in higher doses. This was not found to be significant for inhibition of acetylcholinesterase in brain regions.
Humans Surveys of groups of soldiers ingesting daily oral pyridostigmine for extended periods of time indicated nonspecific mild symptoms, most commonly including dry mouth, general malaise, fatigue, and weakness. Nausea, abdominal pain, frequent urination, and rhinorrhea were reported infrequently. No correlation was found between levels of cholinesterase and type or severity of complaints.
Immunotoxicity Female mice were examined for immunosuppression after exposure to PB, alone or in combination with DEET insect
1163
repellent, and environmental exposures to jet fuel. Suppression of antibody-specific IgM immune responses (plaque forming cells) occurred after exposure to each compound administered alone and to mixtures of all three, at both high- and low-dose levels.
Reproductive and Developmental Toxicity Animals Pyridostigmine produced no teratogenic effects when administered during organogenesis in rats and rabbits. In doses sufficient to cause maternal toxicity, a small increase in the incidence of delayed skeletal ossification was seen in rats and a slight increase in hydronephrosis in rabbits was reported. Blood vessel variations were found at all doses.
Humans Pyridostigmine is a Category C drug, under FDA listings indicating categories for pregnancy use. No well-controlled human studies have been carried out in pregnant women. Therapeutic doses do not cross the placenta in significant amounts. However, large doses of the drug may cross the placenta and reduce fetal plasma cholinesterase activity. Premature labor was associated with parenteral anticholinesterases. Use in pregnancy should be determined by a health care provider, weighing risk vs. benefit.
Lactation Exposure to infants from maternal use is minimal, due to low levels of pyridostigmine in breastmilk. Pyridostigmine is not expected to cause adverse outcomes in breastfed infants, and is considered compatible with breast-feeding by the American Academy of Pediatrics.
Genotoxicity Evidence of mutagenicity and clastogenicity is varied (Table 1). Mutagenicity tests were negative in rat micronucleus assay, the in vitro Ames Salmonella typhimurium assay, and an in vitro mammalian gene mutation assay in Chinese hamster ovary cells. Results in an in vitro assay in Chinese hamster ovary cells and an in vivo mouse micronucleus assay showed no clastogenic effect. In vitro assay in Chinese hamster ovary cells and in vivo mouse micronucleus assay were not clastogenic.
Table 1 Evidence summary for selected mutagenicity and clastogencity tests for pyridostigmine Assay Ames Mammalian gene mutation Chinese hamster ovary cells Mouse lymphoma cells Mouse micronucleus Rat micronucleus
Clastogenicity
Mutagenicity Negative
Negative (in vitro) Positive (in vitro) Negative (in vivo) Negative
Negative (in vitro) Positive (in vitro)
1164
Pyridostigmine
Carcinogenicity
Further Reading
There is no epidemiological evidence of a significant correlation between pyridostigmine exposure and increased cancer risks in humans. There are studies examining cancer rates in Gulf War veterans, but these have not addressed any direct link to pyridostigmine exposure and carcinogenicity. Adequate long-term carcinogenicity studies for animals were not identified for pyridostigmine.
Abou-Donia, M.B., Wilmarth, K.R., Abdel-Rahman, A.A., Jensen, K.F., Oehme, F.W., Kurt, T.L., 1996. Increased neurotoxicity following concurrent exposure to pyridostigmine bromide, DEET, and chlorpyrifos. Fundam. Appli. Toxicol. 34 (2), 201–222. Almog, S., Winkler, E., Amitai, Y., Dani, S., Shefi, M., Tirosh, M., et al., 1991. Acute pyridostigmine overdose: a report of nine cases. Isra. J. Med. Sci. 27 (11–12), 659–663. Bernatova, I., Dubovicky, M., Price, W.A., Grubbs, R.D., Lucot, J.B., Morris, M., 2003. Effect of chronic pyridostigmine bromide treatment on cardiovascular and behavioral parameters in mice. Pharmacol. Biochem. Behav. 74 (4), 901–907. Fulco C.E., Liverman C.T., Sox H.C., 2000. Committee on Health Effects Associated with Exposures During the Gulf War. Gulf War and Health, vol. 1: Pyridostigmine. National Academy Press, Washington, D.C., pp. 207–266. Golomb, B.A., 2008 (18 March). Acetylcholinesterase inhibitors and Gulf War illnesses. Proceedings of the National Academy of Sciences 105 (11), 4295–4300. McCain, W.C., Lee, R., Johnson, M., Whaley, J.E., Ferguson, J.W., Beall, P., et al., 1997 (7 February). Acute oral toxicity study of pyridostigmine bromide, permethrin, and DEET in the laboratory rat. J. Toxicol. Environ. Health 50 (2), 113–124. Nelson, L., Goldfrank, L.R., et al., 2011. Physostigmine; Goldfrank’s Toxicologic Emergencies, ninth ed. McGraw-Hill Medical, New York. Peden-Adam, M.M., Eudaly, J., Eudaly, E., Dudley, A., Zeigler, J., Lee, A., et al., 2001 (17 June). Evaluation of immunotoxicity induced by single or concurrent exposure to N, N-diethyl-m-toluamide (DEET), pyridostigmine bromide (PYR), and JP-8 jet fuel. Toxicol. Ind. Health (5–10), 192–209. Russo, W.F., 2011. Determinations Concerning Illnesses Discussed In National Academy of Sciences Reports on Gulf War and Health, vols. 4 and 8; Federal Register, Citation:76 FR 21099; 2011–8937; 21099–21107; retrieved from https://federalregister.gov/a/2011-8937. Schumm, W.R., Reppert, E.J., Jurich, A.P., Bollman, S.R., Webb, F.J., Castelo, C.S., et al., 2002 (June). Pyridostigmine bromide and the long-term subjective health status of a sample of over 700 male Reserve Component Gulf War era veterans. Psychol. Rep. 90 (3 Pt 1), 707–721. Shaikh, J., Karanth, S., Chakraborty, D., Pruett, S., Pope, C.N., 2003 (October). Effects of daily stress or repeated paraoxon exposures on subacute pyridostigmine toxicity in rats. Arch. Toxicol. 77 (10), 576–583.
Clinical Management Overdose of pyridostigmine may result in cholinergic symptoms. Reactions may be muscarinic or nicotinic. Muscarinic adverse reactions include abdominal cramps, diarrhea, vomiting, hypersalivation, urinary incontinence, increased bronchial secretion, diaphoresis, miosis, and lacrimation. Nicotinic adverse reactions comprised muscle cramps, fasciculations, and weakness including respiratory muscles. Treatment may require atropine and activated charcoal administration. Atropine antagonizes the muscarinic effects of pyridostigmine. Serum cholinesterase inhibition may be monitored as an indicator of exposure. Renal function may also be monitored in patients with renal impairment. Known hypersensitivity reactions may occur with pyridostigmine, and in persons with sensitivity to bromide. Caution with depolarizing neuromuscular blocking agents should be exercised. Further, caution should be observed with utilization in persons with cardiopulmonary conditions, such as bronchial asthma and chronic obstructive pulmonary disease, which may increase the risk of anticholinergic reactions. A number of drugs may interact with pyridostigmine, so concurrent use of other substances should be reported to a health care provider.
Ecotoxicology Abiotic degradation of pyridostigmine may result in the formation of small amounts of tar, due to chemical decomposition of solutions exposed to light, or photolytic degradation.
See also: Carbamate Pesticides; Cholinesterase Inhibition; Soman.
Relevant Websites http://www.cdc.gov/nceh/veterans/default2.htm – Centers for Disease Control. http://chem.sis.nlm.nih.gov/chemidplus – US National Library of Medicine: ChemIDplus Advanced: Search for Pyridostigmine. http://toxnet.nlm.nih.gov – Toxnet (Toxicology Data Network): search for Pyridostigmine. http://pubchem.ncbi.nlm.nih.gov – US National Library of Medicine (Pubchem): Search for Pyridostigmine.