Pralidoxime chloride (2-PAM) is the only cholinesterase-reactivating xenobiotic currently available in the United States.55 It is used concomitantly with atropine in the management of patients poisoned by organic phosphorus (OP) compounds. Administration should be initiated as soon as possible after exposure, but could be effective even days after an exposure and therefore should be administered to all symptomatic patients independent of delay. Continuous infusion is preferable to intermittent administration for patients with serious toxicity, and a prolonged therapeutic course may be required.
Pralidoxime chloride is a quaternary pyridinium oxime with a molecular weight of 173 daltons. The chloride salt exhibits excellent water solubility and physiologic compatibility. Another salt, pralidoxime iodide, with a molecular weight of 264 daltons, is less water soluble and can potentiallly induce iodism.3
Organic phosphorus compounds are powerful inhibitors of carboxylic esterase enzymes, including acetylcholinesterase (AChE; true cholinesterase, found in red blood cells, nervous tissue, and skeletal muscle) and plasma cholinesterase or butyrylcholinesterase (found in plasma, liver, heart, pancreas, and brain).49 The OP binds firmly to the serine-containing esteratic site on the enzyme, inactivating it by phosphorylation (Fig. 113–3).32,50,73 This reaction results in the accumulation of acetylcholine at muscarinic and nicotinic synapses in the peripheral and central nervous systems, leading to the clinical manifestations of OP poisoning. After phosphorylation, the enzyme is inactivated and can undergo one of three processes: endogenous hydrolysis of the phosphorylated enzyme; reactivation by a strong nucleophile, such as pralidoxime; and aging, which involves biochemical changes that stabilize the inactivated phosphorylated molecule.
Endogenous hydrolysis of the bond between the enzyme and the OP is generally extremely slow and is considered insignificant. This is in contrast to the rapid hydrolysis of the related bond between the enzyme and many carbamates. Studies in the 1950s demonstrated the ability of oximes to reactivate cholinesterase bound to OP compounds.81,83,84 The positively charged quaternary nitrogen of pralidoxime is attracted to the negatively charged anionic site on the phosphorylated enzyme, bringing it in close proximity to the phosphorous moiety (Fig. 113–6). Pralidoxime then exerts a nucleophilic attack on the phosphate moiety, successfully releasing it from the AChE enzyme.80 This action liberates the enzyme to a variable extent depending on the OP in question and restores enzymatic function.40 It was previously believed that OP compounds with small substituted side chains were more easily reversed by oximes because of better steric positioning, allowing easier access for the oximes.83 However, available data now refute that theory, but continue to emphasize the importance of spatial and steric considerations.86
In contrast to the usefulness of pralidoxime in the management of the cholinergic syndrome, current understanding of the pathophysiology of the intermediate syndrome is inadequate to determine whether pralidoxime can prevent the development of the syndrome.71 However, if cholinergic receptor desensitization is responsible for the cause of the ...