Antidotes pralidoxime

Figure 7.50 The mechanism of reaction of the antidote pralidoxime with phosphorylated acetylcholinesterase. The original acetylcholinesterase is thereby regenerated.

John H, Blum MM (2012) Review on UV-spectroscopic, chromatographic and electrophoretic methods for the cholinesterase reactivating antidote pralidoxime (2-PAM) 4 179-193... 

For humans, famphur is considered harmful or fatal if swallowed or absorbed through the skin, especially by children. If poisoning should occur, physicians are advised that atropine is antidotal and that pralidoxime chloride may be effective as an adjunct to atropine. Pour-on formulations are flammable, and users should keep them away from heat, sparks, and open flames including hot branding irons and cautery dehorning devices (American Cyanamid Company 1984). 

Nerve Agent Antidote Kit (NAAK or MARK I) consists of an atropine auto-injector (2 mg), a pralidoxime chloride auto-injector (2-Pam-Cl, 600 mg), the plastic clip joining the two injectors, and a foam case. The kit serve as a countermeasure to nerve agents, including tabun (GA), sarin (GB), soman (GD), GF, and VX. Military personnel can receive three MARK I for self/buddy aid. Possible side effects of atropine and/or 2-PAM-C1 are deemed insignificant in a nerve agent casualty. Intravenous atropine and 2-PAM-C1 can also be made available. The MARK I kit is manufactured by Survival Technology, Inc., Rockville, Maryland. 

Treatment — Patients should be decontaminated immediately prior to treatment using the decontamination method presented in Section 7.3.2. Ventilate the patient because of a possible increase in airway resistance due to constriction and the presence of secretions. If breathing is difficult, administer oxygen. Administer antidotes as soon as possible. The antidote for this agent is atropine alone or in combination with pralidoxime chloride (2-PAMC1) or another oxime. Diazepam may be required to control severe convulsions. 

The first investigators to show the marked antidotal properties of pralidoxime compounds (Figure 2-1) were Kewitz and Wilson. 

Pralidoxime Very high affinity for phosphorus atom but does not enter CNS Regenerates active AChE can relieve skeletal muscle end plate block Usual antidote for early-stage (48 h) cholinesterase inhibitor poisoning Intravenous every 4-6 h Toxicity Can cause muscle weakness in overdose... 

General supportive care should be provided as outlined above. Extra precautions should be taken to ensure that rescuers and health care providers are not poisoned by exposure to contaminated clothing or skin. This is especially critical for the most potent substances such as parathion or nerve gas agents. Antidotal treatment consists of atropine and pralidoxime (see Table 58-4). Atropine is an effective competitive inhibitor at muscarinic sites but has no effect at nicotinic sites. Pralidoxime given early enough is capable of restoring the cholinesterase activity and is active at both muscarinic and nicotinic sites. 

Functional interactions are those in which both of the two chemicals affect a bodily system perhaps by different mechanisms, and either increase or decrease the combined effect. For example, both atropine and pralidoxime decrease the toxic effects of organophosphate compounds by different means, a combination of the two antidotes leads to a large increase in effectiveness synergism). 

The phosphorylated esterases formed by the action of organophosphorus inhibitors are very stable, but some antidotes can reverse the inhibition. The oxime of 2-formyl-l-methylpyridinium ion (pralidoxime) is very effective.6 Its positive charge permits it to bind to the site normally occupied by the quartemary nitrogen of acetylcholine and to displace the dialkylphospho group ... 

Abbara et al. performed simultaneous quantification of different antidotes (diazepam, pralidoxime and atropine) typically co-administered for the therapy of anticholinesterase poisoning (Table 5) [44], PK data resulting from i.m. drug injection by means of a bi-compartemental auto-injector were calculated from human plasma concentrations measured by LC-ESIMS/MS with MRM settings. Administration of 2 mg atropine sulphate yielded plasma peak concentrations of about 4 ng/ml 15 min after injection. 

Lallement, G., Masqueliez, C., Baubichon, D. et al. (2004). Protection against soman-induced lethality of the antidote combination atropine-pralidoxime pro-diazepam packed as freeze-dried form. J. Med. Chem. 2 1-11. 

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