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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 oximes that bind to organophosphate-inactivated acetylcholinesterase. It is used to combat poisoning by organophosphates^[1] or acetylcholinesterase inhibitors (nerve agents) in conjunction with atropine and diazepam.

Mechanism of action

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.

After some time though, some inhibitors can develop a permanent bond with cholinesterase, known as aging, where oximes 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.^[2]

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.^[3]

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.

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.^[4]^[5]^[6]^[7]

References

^ 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.
^ [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
^ 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)

External links

Chemical Bioweapons website
Drugs.com

UpToDate Contents

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1. 有機リン剤およびカルバメート中毒 organophosphate and carbamate poisoning
2. 化学テロ：早急な認識および初回薬物治療マネージメント chemical terrorism rapid recognition and initial medical management
3. 神経筋接合部に作用する毒素の概要 overview of neuromuscular junction toxins
4. 殺鼠剤中毒の概要 overview of rodenticide poisoning

English Journal

Coronary Artery Bypass Grafting in a Patient with Organophosphate Poisoning.

Pieris RR1, Fernando R2.
The heart surgery forum.Heart Surg Forum.2015 Aug 30;18(4):E167-70. doi: 10.1532/hsf.1370.
A 43-year-old male, with no previous history of mental illness, was diagnosed with coronary heart disease, after which he became acutely depressed and attempted suicide by ingesting an organophosphate pesticide. He was admitted to an intensive care unit and treated with pralidoxime, atropine, and ox
PMID 26334855

Acute severe organophosphate poisoning in a child who was successfully treated with therapeutic plasma exchange, high-volume hemodiafiltration, and lipid infusion.

Yesilbas O1, Kihtir HS1, Altiti M2, Petmezci MT1, Balkaya S1, Bursal Duramaz B2, Ersoy M3, Sevketoglu E1.
Journal of clinical apheresis.J Clin Apher.2015 Aug 14. doi: 10.1002/jca.21417. [Epub ahead of print]
Acute severe organophosphate poisoning is a serious complication seen in developing and agricultural countries. Pralidoxime and high dose atropine are the standard treatments. There is no consensus about acute severe organophosphate poisonings that are unresponsive to pralidoxime, atropine, and supp
PMID 26273819

Innovative approach for the electrochemical detection of non-electroactive organophosphorus pesticides using oxime as electroactive probe.

Dong J1, Hou J1, Jiang J1, Ai S2.
Analytica chimica acta.Anal Chim Acta.2015 Jul 23;885:92-7. doi: 10.1016/j.aca.2015.05.033. Epub 2015 Jun 3.
An innovative approach for sensitive and simple electrochemical detection of non-electroactive organophosphorus pesticides (OPs) was described in this report. The novel strategy emphasized the fabrication of an oxime-based sensor via attaching pralidoxime (PAM) on graphene quantum dots (GQDs) modifi
PMID 26231893

Japanese Journal

Effects of atropine and pralidoxime on neuronal actions of paraoxon in rat hippocampal slices

NARIMATSU E
Neurosci Res 68, 276-284, 2010
NAID 80021430677

Pros 有機リン中毒にPAMは有効である (特集 Pros & Cons 有機リン中毒にPAMは有効か)

亀井徹正
中毒研究 23(1), 31-35, 2010
NAID 40017254789

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★リンクテーブル★

リンク元	「プラリドキシム」「PAM」「2-PAM」
拡張検索	「pralidoxime compound」

「プラリドキシム」

Pralidoxime
Systematic (IUPAC) name
	2-[(hydroxyimino)methyl]-1-methylpyridin-1-ium
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy cat.	C
Legal status	℞ Prescription only
Identifiers
CAS number	6735-59-7
ATC code	V03AB04
PubChem	CID 6789253
DrugBank	DB00733
ChemSpider	5193737
UNII	P7MU9UTP52
KEGG	C07400
ChEBI	CHEBI:8354
ChEMBL	CHEMBL1420
Synonyms	1-methylpyridine-6-carbaldehyde oxime
Chemical data
Formula	C7H9N2O+
Mol. mass	137.159 g/mol
	SMILES O=[NH+]C=C1\C=C/C=C\N1C;
	InChI InChI=1S/C7H8N2O/c1-9-5-3-2-4-7(9)6-8-10/h2-6H,1H3/p+1 ; Key:JBKPUQTUERUYQE-UHFFFAOYSA-O ;
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