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{{Short description|Chemical compound used as antidote for nerve agent poisoning}}
{{Refimprove|article|date=June 2010}}
{{More citations needed|date=March 2023}}
{{Drugbox
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 464212974
| verifiedrevid = 464212974
| IUPAC_name = 2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium
| IUPAC_name = 2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium
| image = Pralidoxime-2D-skeletal.png
| image = E-Pralidoxim.svg
| width = 200
| width = 200
| image2 = Pralidoxime-3D-vdW.png
| image2 = Pralidoxime-3D-vdW.png
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| legal_UK = <!-- GSL / P / POM / CD -->
| legal_UK = <!-- GSL / P / POM / CD -->
| legal_US = <!-- OTC / Rx-only -->
| legal_US = <!-- OTC / Rx-only -->
| legal_status = RX-only
| legal_status = Rx-only
<!--Identifiers-->
<!--Identifiers-->
| IUPHAR_ligand = 4652
| IUPHAR_ligand = 4652
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<!--Chemical data-->
<!--Chemical data-->
| C=7 | H=9 | N=2 | O=1| charge = +
| C=7 | H=9 | N=2 | O=1| charge = +
| smiles = ON=Cc1cccc[n+]1C
| molecular_weight = 137.159 g/mol
| smiles = O=[NH+]C=C1\C=C/C=C\N1C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C7H8N2O/c1-9-5-3-2-4-7(9)6-8-10/h2-6H,1H3/p+1
| StdInChI = 1S/C7H8N2O/c1-9-5-3-2-4-7(9)6-8-10/h2-6H,1H3/p+1
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}}


'''Pralidoxime''' (2-pyridine aldoxime methyl chloride,) or '''2-PAM''', usually as the chloride or [[methiodide]] salts, belongs to a family of compounds called [[oxime]]s that bind to [[organophosphate]]-inactivated [[acetylcholinesterase]]. 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]].
'''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 | vauthors = Jokanović M, Stojiljković MP | title = Current understanding of the application of pyridinium oximes as cholinesterase reactivators in treatment of organophosphate poisoning | journal = European Journal of Pharmacology | volume = 553 | issue = 1–3 | pages = 10–7 | date = December 2006 | pmid = 17109842 | doi = 10.1016/j.ejphar.2006.09.054 }}</ref> It is used to treat [[organophosphate poisoning]]<ref name="pmid19519385">{{cite journal | vauthors = Jokanović M, Prostran M | title = Pyridinium oximes as cholinesterase reactivators. Structure-activity relationship and efficacy in the treatment of poisoning with organophosphorus compounds | journal = Current Medicinal Chemistry | volume = 16 | issue = 17 | pages = 2177–88 | year = 2009 | pmid = 19519385 | doi = 10.2174/092986709788612729 }}</ref> in conjunction with [[atropine]] and either [[diazepam]] or [[midazolam]]. It is a white solid.


==Chemical synthesis==
==Chemical synthesis==
Pralidoxime, 2-pyridinaldoxime methylchloride, is synthesized by reacting picolinaldehyde ([[2-formyl pyridine]]) with [[hydroxylamine]], giving pyridine-2-aldoxime, which is further reacted with [[methyl iodide]], giving the desired pralidoxime.<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>
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>{{cite patent | inventor = Nachmansonn E, Ginsburg S | country = US | number = 2816113 | pubdate = 1957}}</ref><ref>{{cite patent | inventor = Black LP | country = US | number = 3123613 | pubdate = 1964}}</ref><ref>{{cite patent | inventor = Easterday DE, Kondritzer AA | country = US | number = 3140289 | pubdate = 1964}}</ref><ref>{{cite patent | inventor = McDowell WB | country = US | number = 3155674 | pubdate = 1964}}</ref>
[[File:Pralidoxime synthesis.png|500px|center]]
[[File:Pralidoxime synthesis.png|500px|center]]


== Mechanism of action ==
== Mechanism of action ==
Pralidoxime is typically used in cases of organophosphate poisoning. Organophosphates such as [[sarin]] bind to the hydroxy component (the {{not a typo|esteric}} site) of the active site of the [[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 conjugates continue to react after the phosphate docks to the {{not a typo|esteric}} site, evolving into a more recalcitrant state. This process is known as aging. Aged phosphate-acetylcholinesterase conjugate is 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 may have limited beneficial effects if the acetylcholinesterase enzyme is carbamylated, as occurs with [[neostigmine]], [[pyridostigmine]], or insecticides such as [[carbaryl]].
Pralidoxime is typically used in cases of organophosphate poisoning. The acetylcholinesterase enzyme has two parts to it. An acetylcholine molecule, bound at both ends 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.


⚫
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 muscarinic 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 name="pmid24625936">{{cite journal | vauthors = Banerjee I, Tripathi SK, Roy AS | title = Efficacy of pralidoxime in organophosphorus poisoning: revisiting the controversy in Indian setting | journal = Journal of Postgraduate Medicine | volume = 60 | issue = 1 | pages = 27–30 | date = 2014 | pmid = 24625936 | doi = 10.4103/0022-3859.128803 | doi-access = free }}</ref>
⚫
After some time though, some inhibitors can develop a permanent bond with cholinesterase, known as aging, where -doximes such as pralidoxime cannot reverse the bond. 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 (i.e. it does not have an effect if the acetylcholinesterase enzyme is carbamylated, as occurs with [[neostigmine]] or [[physostigmine]]).

⚫
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. This is why [[atropine]], which has excellent blood–brain barrier penetration, is concomitantly administered with 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>


== Dosage ==
== Dosage ==
⚫
*Adults: 30&nbsp;mg/kg (typically 1–2&nbsp;g), administered by [[intravenous therapy]] over 15–30 minutes, repeated 60 minutes later. It can also be given as a 500&nbsp;mg/h continuous IV infusion.

⚫
*Adults: 30&nbsp;mg/kg (typically 1-2&nbsp;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&nbsp;mg/h continuous IV infusion.
*Children: 20–50&nbsp;mg/kg followed by a maintenance infusion at 5–10&nbsp;mg/kg/h.
*Children: 20–50&nbsp;mg/kg followed by a maintenance infusion at 5–10&nbsp;mg/kg/h.


Line 75: Line 74:
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.
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==
== See also ==
*[[Pyridostigmine]]
* [[Galantamine]]
*[[Mark I NAAK]]
* [[Mark I NAAK]]
* [[Pyridostigmine]]


==References==
== References ==
{{Reflist}}
{{Reflist}}


==External links==
== External links ==
*[http://www.drugs.com/pdr/PRALIDOXIME_CHLORIDE.html Drugs.com]
*[https://www.drugs.com/pdr/PRALIDOXIME_CHLORIDE.html Drugs.com]


{{Antidotes}}
{{Antidotes}}
{{Acetylcholine metabolism and transport modulators}}
{{Cholinergics}}


[[Category:Antidotes]]
[[Category:Cholinesterase reactivators]]
[[Category:Oximes]]
[[Category:Aldoximes]]
[[Category:Peripherally selective drugs]]
[[Category:Peripherally selective drugs]]
[[Category:Quaternary ammonium compounds]]
[[Category:Quaternary ammonium compounds]]

Latest revision as of 03:52, 13 December 2024

Pralidoxime
Clinical data
Other names1-methylpyridine-6-carbaldehyde oxime
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • C
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • 2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.027.080 Edit this at Wikidata
Chemical and physical data
FormulaC7H9N2O+
Molar mass137.162 g·mol−1
3D model (JSmol)
  • ON=Cc1cccc[n+]1C
  • InChI=1S/C7H8N2O/c1-9-5-3-2-4-7(9)6-8-10/h2-6H,1H3/p+1 checkY
  • Key:JBKPUQTUERUYQE-UHFFFAOYSA-O checkY
  (verify)

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 treat organophosphate poisoning[2] in conjunction with atropine and either diazepam or midazolam. It is a white solid.

Chemical synthesis

[edit]

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

[edit]

Pralidoxime is typically used in cases of organophosphate poisoning. Organophosphates such as sarin bind to the hydroxy component (the esteric site) of the active site of the 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 conjugates 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 is 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 may have limited beneficial effects if the acetylcholinesterase enzyme is carbamylated, as occurs with neostigmine, pyridostigmine, 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 muscarinic 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

[edit]
  • Adults: 30 mg/kg (typically 1–2 g), administered by intravenous therapy over 15–30 minutes, 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

[edit]

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

[edit]

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

[edit]

References

[edit]
  1. ^ Jokanović M, Stojiljković MP (December 2006). "Current understanding of the application of pyridinium oximes as cholinesterase reactivators in treatment of organophosphate poisoning". European Journal of Pharmacology. 553 (1–3): 10–7. doi:10.1016/j.ejphar.2006.09.054. PMID 17109842.
  2. ^ Jokanović M, Prostran M (2009). "Pyridinium oximes as cholinesterase reactivators. Structure-activity relationship and efficacy in the treatment of poisoning with organophosphorus compounds". Current Medicinal Chemistry. 16 (17): 2177–88. doi:10.2174/092986709788612729. PMID 19519385.
  3. ^ US 2816113, Nachmansonn E, Ginsburg S, published 1957 
  4. ^ US 3123613, Black LP, published 1964 
  5. ^ US 3140289, Easterday DE, Kondritzer AA, published 1964 
  6. ^ US 3155674, McDowell WB, published 1964 
  7. ^ Banerjee I, Tripathi SK, Roy AS (2014). "Efficacy of pralidoxime in organophosphorus poisoning: revisiting the controversy in Indian setting". Journal of Postgraduate Medicine. 60 (1): 27–30. doi:10.4103/0022-3859.128803. PMID 24625936.
  8. ^ Baxter Healthcare Corporation 2006, Protopam Prescribing Information
[edit]
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