Pralidoxime: Difference between revisions
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'''Pralidoxime''' (2-pyridine aldoxime methyl chloride) or '''2-PAM''', usually as the chloride or [[ |
'''Pralidoxime''' (2-pyridine aldoxime methyl chloride) or '''2-PAM''', usually as the chloride or [[iodide]] salts, belongs to a family of compounds called [[oxime]]s that bind to [[organophosphate]]-inactivated [[acetylcholinesterase]].<ref>{{cite journal|journal=Eur J Pharmacol.|year=2006|volume=553|pages=10-7||title=Current understanding of the application of pyridinium oximes as cholinesterase reactivators in treatment of organophosphate poisoning|author1=Jokanović M. |author2=Stojiljković, M. P.|doi=10.1016/j.ejphar.2006.09.054}}</ref> It is used to combat [[Organophosphate poisoning|poisoning by organophosphates]]<ref name="pmid19519385">{{cite journal |author=Jokanović M, Prostran M |title=Pyridinium oximes as cholinesterase reactivators. Structure-activity relationship and efficacy in the treatment of poisoning with organophosphorus compounds |journal=Curr. Med. Chem. |volume=16 |issue=17 |pages=2177–88 |year=2009 |pmid=19519385 |doi= 10.2174/092986709788612729|url=http://www.bentham-direct.org/pages/content.php?CMC/2009/00000016/00000017/0004C.SGM}}</ref> or [[acetylcholinesterase inhibitors]] ([[nerve agents]]) in conjunction with [[atropine]] and [[diazepam]]. It is a white solid. |
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==Chemical synthesis== |
==Chemical synthesis== |
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Pralidoxime, 2-pyridinaldoxime methylchloride, is |
Pralidoxime, 2-pyridinaldoxime methylchloride, is prepared by treating [[pyridine-2-carboxaldehyde]] with [[hydroxylamine]]. The resulting pyridine-2-aldoxime is alkylated with [[methyl iodide]] giving pralidoxime as the iodide salt.<ref>D. Nachmansonn, S. Ginsburg, {{US Patent|2816113}} (1957)</ref><ref>L. P. Black, {{US Patent|3123613}} (1964)</ref><ref>D.E. Easterday, A.A. Kondritzer, {{US Patent|3140289}} (1964)</ref><ref>W.B. McDowell, {{US Patent|3155674}} (1964)</ref> |
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[[File:Pralidoxime synthesis.png|500px|center]] |
[[File:Pralidoxime synthesis.png|500px|center]] |
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== Mechanism of action == |
== Mechanism of action == |
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Pralidoxime is typically used in cases of organophosphate poisoning. Organophosphates such as [[sarin]] bind to the hydroxy component (the esteric site) of of the active site of the enzyme [[acetylcholinesterase]] enzyme, thereby blocking its activity. Pralidoxime binds to the other half (the unblocked, anionic site) of the active site and then displaces the phosphate from the serine residue. The conjoined poison / antidote then unbinds from the site, and thus regenerates the fully functional enzyme. |
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| ⚫ | Some phosphate-acetylcholinesterase conjugate continue to react after the phosphate docks to the esteric site, evolving into a more recalcitrant state. This process is known as aging. Aged phosphate-acetylcholinesterase conjugate are resistant to antidotes such as pralidoxime. Pralidoxime is often used with atropine (a muscarinic antagonist) to help reduce the parasympathetic effects of organophosphate poisoning. Pralidoxime is only effective in organophosphate toxicity. It has no beneficial effects if the acetylcholinesterase enzyme is carbamylated, as occurs with [[neostigmine]], [[physostigmine]], or insecticides such as [[carbaryl]]. |
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Pralidoxime is typically used in cases of organophosphate poisoning. Organophosphates are a family of compounds that strongly inhibits acetylcholinesterase, an enzyme essential for proper muscle and nervous system functioning. The acetylcholinesterase enzyme has two parts to it. An acetylcholine molecule, binds at both end to both sites of the enzyme, is cleaved in two to form acetic acid and choline. In organophosphate poisoning, an organophosphate binds to just one end of the acetylcholinesterase enzyme (the esteric site), blocking its activity. Pralidoxime is able to attach to the other half (the unblocked, anionic site) of the acetylcholinesterase enzyme. It then binds to the organophosphate, the organophosphate changes conformation, and loses its binding to the acetylcholinesterase enzyme. The conjoined poison / antidote then unbinds from the site, and thus regenerates the enzyme, which is now able to function again. |
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| ⚫ | |||
Pralidoxime has an important role in reversing paralysis of the respiratory muscles but due to its poor blood–brain barrier penetration, it has little effect on centrally-mediated respiratory depression. Atropine, which is choice of drug to antagonise the muscrinic effects of organophosphates, is administered even before pralidoxime during the treatment of organophosphate poisoning. While the efficacy of atropine has been well-established, clinical experience with pralidoxime has led to widespread doubt about its efficacy in treatment of organophosphorus poisoning.<ref>[2]Banerjee I, Tripathi S K, Roy A S. Efficacy of pralidoxime in organophosphorus poisoning: Revisiting the controversy in Indian setting. J Postgrad Med 2014;60:27-30</ref> |
Pralidoxime has an important role in reversing paralysis of the respiratory muscles but due to its poor blood–brain barrier penetration, it has little effect on centrally-mediated respiratory depression. Atropine, which is choice of drug to antagonise the muscrinic effects of organophosphates, is administered even before pralidoxime during the treatment of organophosphate poisoning. While the efficacy of atropine has been well-established, clinical experience with pralidoxime has led to widespread doubt about its efficacy in treatment of organophosphorus poisoning.<ref>[2]Banerjee I, Tripathi S K, Roy A S. Efficacy of pralidoxime in organophosphorus poisoning: Revisiting the controversy in Indian setting. J Postgrad Med 2014;60:27-30</ref> |
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== Dosage == |
== Dosage == |
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*Adults: 30 mg/kg (typically 1-2 g), administered by [[intravenous therapy]] over 15–30 minutes or [[intramuscular injection]] or [[subcutaneous injection]], repeated 60 minutes later. It can also be given as a 500 mg/h continuous IV infusion. |
*Adults: 30 mg/kg (typically 1-2 g), administered by [[intravenous therapy]] over 15–30 minutes or [[intramuscular injection]] or [[subcutaneous injection]], repeated 60 minutes later. It can also be given as a 500 mg/h continuous IV infusion. |
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*Children: 20–50 mg/kg followed by a maintenance infusion at 5–10 mg/kg/h. |
*Children: 20–50 mg/kg followed by a maintenance infusion at 5–10 mg/kg/h. |
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Revision as of 00:43, 15 March 2017
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| Other names | 1-methylpyridine-6-carbaldehyde oxime |
| AHFS/Drugs.com | Micromedex Detailed Consumer Information |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.027.080 |
| Chemical and physical data | |
| Formula | C7H9N2O+ |
| Molar mass | 137.159 g/mol g·mol−1 |
| 3D model (JSmol) | |
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Pralidoxime (2-pyridine aldoxime methyl chloride) or 2-PAM, usually as the chloride or iodide salts, belongs to a family of compounds called oximes that bind to organophosphate-inactivated acetylcholinesterase.[1] It is used to combat poisoning by organophosphates[2] or acetylcholinesterase inhibitors (nerve agents) in conjunction with atropine and diazepam. It is a white solid.
Chemical synthesis
Pralidoxime, 2-pyridinaldoxime methylchloride, is prepared by treating pyridine-2-carboxaldehyde with hydroxylamine. The resulting pyridine-2-aldoxime is alkylated with methyl iodide giving pralidoxime as the iodide salt.[3][4][5][6]
Mechanism of action
Pralidoxime is typically used in cases of organophosphate poisoning. Organophosphates such as sarin bind to the hydroxy component (the esteric site) of of the active site of the enzyme acetylcholinesterase enzyme, thereby blocking its activity. Pralidoxime binds to the other half (the unblocked, anionic site) of the active site and then displaces the phosphate from the serine residue. The conjoined poison / antidote then unbinds from the site, and thus regenerates the fully functional enzyme.
Some phosphate-acetylcholinesterase conjugate continue to react after the phosphate docks to the esteric site, evolving into a more recalcitrant state. This process is known as aging. Aged phosphate-acetylcholinesterase conjugate are resistant to antidotes such as pralidoxime. Pralidoxime is often used with atropine (a muscarinic antagonist) to help reduce the parasympathetic effects of organophosphate poisoning. Pralidoxime is only effective in organophosphate toxicity. It has no beneficial effects if the acetylcholinesterase enzyme is carbamylated, as occurs with neostigmine, physostigmine, or insecticides such as carbaryl.
Pralidoxime has an important role in reversing paralysis of the respiratory muscles but due to its poor blood–brain barrier penetration, it has little effect on centrally-mediated respiratory depression. Atropine, which is choice of drug to antagonise the muscrinic effects of organophosphates, is administered even before pralidoxime during the treatment of organophosphate poisoning. While the efficacy of atropine has been well-established, clinical experience with pralidoxime has led to widespread doubt about its efficacy in treatment of organophosphorus poisoning.[7]
Dosage
- Adults: 30 mg/kg (typically 1-2 g), administered by intravenous therapy over 15–30 minutes or intramuscular injection or subcutaneous injection, repeated 60 minutes later. It can also be given as a 500 mg/h continuous IV infusion.
- Children: 20–50 mg/kg followed by a maintenance infusion at 5–10 mg/kg/h.
Intravenous infusions can lead to respiratory or cardiac arrest if given too quickly.[8]
Interactions
When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed.
The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning.
Contraindications
There are no known absolute contraindications for the use of pralidoxime. Relative contraindications include known hypersensitivity to the drug and other situations in which the risk of its use clearly outweighs possible benefit.
See also
References
- ^ Jokanović M.; Stojiljković, M. P. (2006). "Current understanding of the application of pyridinium oximes as cholinesterase reactivators in treatment of organophosphate poisoning". Eur J Pharmacol. 553: 10–7. doi:10.1016/j.ejphar.2006.09.054.
{{cite journal}}: Cite has empty unknown parameter:|1=(help) - ^ Jokanović M, Prostran M (2009). "Pyridinium oximes as cholinesterase reactivators. Structure-activity relationship and efficacy in the treatment of poisoning with organophosphorus compounds". Curr. Med. Chem. 16 (17): 2177–88. doi:10.2174/092986709788612729. PMID 19519385.
- ^ D. Nachmansonn, S. Ginsburg, U.S. patent 2,816,113 (1957)
- ^ L. P. Black, U.S. patent 3,123,613 (1964)
- ^ D.E. Easterday, A.A. Kondritzer, U.S. patent 3,140,289 (1964)
- ^ W.B. McDowell, U.S. patent 3,155,674 (1964)
- ^ [2]Banerjee I, Tripathi S K, Roy A S. Efficacy of pralidoxime in organophosphorus poisoning: Revisiting the controversy in Indian setting. J Postgrad Med 2014;60:27-30
- ^ Baxter Healthcare Corporation 2006, Protopam Prescribing Information