Pralidoxime chloride is a quaternary pyridinium oxime with a molecular weight of 173 Da. The chloride salt exhibits excellent water solubility and physiologic compatibility. Pralidoxime iodide has a molecular weight of 264 Da, is less water soluble, and can potentially induce iodism.3
Organic phosphorous pesticides and nerve agents both cross the CNS. A disadvantage of pralidoxime is that in vivo rat studies it demonstrates only a 10% CNS penetration.66 Strategies to enhance the penetration of oximes across the blood–brain barrier (BBB) include enhancing lipophilicity by adding a fluorine atom into the ring structure, designing a glucose-oxime drug which could use facilitated glucose transporters to cross the BBB, designing a prodrug of pralidoxime that could be oxidized to the active drug once it had crossed the BBB, conjugating the oxime with amidine, and by using a targeted nanoparticle drug delivery system.50
Obidoxime (Toxogonin, LuH-6) is an oxime used outside the United States that contains two active sites per molecule and is considered by some to be more effective than pralidoxime.23,24,88 An in vitro study using human erythrocyte AChE supported the superiority of obidoxime to pralidoxime in reactivating AChE inhibited by the dimethyl phosphoryl (malaoxon, mevinphos) and diethyl phosphoryl OP compounds (paraoxon). On a molar basis, obidoxime is approximately 10 to 20 times more effective in reactivating AChE than pralidoxime.88 A potential disadvantage is the concern that the phosphorylobidoxime generated from the reactivation of AChE by obidoxime could reinhibit AChE if not metabolized by a plasma enzyme similar or identical to human paraoxonase 1 (PON1). PON1 exhibits polymorphism21 and one in 20 patients may not be able to metabolize this phosphorylobidoxime compound. Phosphorylpralidoxime is unstable and does not accumulate. A molecular docking simulation study demonstrated that pralidoxime had better positioning at the oxyanion hole compared to obidoxime, allowing better reactivation of methamidophos inhibited AChE.43 The H series of oximes (named after Hagedorn; HI-6, HIo-7) were developed to act against the chemical warfare nerve agents6 (Chap. 132). These oximes have superior effectiveness against sarin, VX, and certain types of newer pesticides (eg, methyl-fluorophosphonylcholines).3,11,37,40,44,65,88,89Unfortunately, they are less efficacious for traditional OP insecticide poisoning, and their toxicity profile is inadequately defined.11,37,40,44,65,88,89 In addition to reactivating AChEs, the Hagedorn oximes demonstrate direct central and peripheral anticholinergic effects at supratherapeutic concentrations.65
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).55 The OP binds firmly to the serine-containing esteratic site on the enzyme, inactivating it by phosphorylation (Fig. 113–3).36,56,76 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. Following 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 and render it incapable of reactivation by oximes.
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. 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. 113–3). Pralidoxime then exerts a nucleophilic attack on the phosphate moiety, successfully releasing it from the AChE enzyme.83 This action liberates the enzyme to a variable extent depending on the OP in question and restores enzymatic function.45 Diethylorganophosphates (eg, parathion, chlorpyriphos, phorate) take days to age in comparison to 12 hours for dimethylorganophosphates (eg, dimethoate, dichlorvos, monocrotophos).17,25
Pralidoxime is important at nicotinic sites where atropine is ineffective, most often typically improving muscle strength within 10 to 40 minutes after administration.56,76 This effect is vital to maintaining the muscles of respiration. Pralidoxime is also synergistic with atropine; it liberates cholinesterase enzyme so that additional acetylcholine can be metabolized while atropine inhibits the effects of acetylcholine at cholinergic receptors. This suggests that pralidoxime should always be used with atropine.24,56 Some OP compounds respond much better to pralidoxime than others, depending on the affinity of pralidoxime for the particular type of phosphorylated enzyme, its reactivating ability, concentrations of both the oxime and the OP, aging, and OP redistribution from a depot site such as fat.23,88
The central nervous system (CNS) benefits of pralidoxime are controversial, as the molecule is a quaternary nitrogen compound and not expected to cross the blood–brain barrier.47,56 A rat experiment using a microdialysis technique demonstrated only 10% CNS penetration of pralidoxime.66 Following exposure to IV fenitrothion, IV administration of pralidoxime in rats failed to improve survival or to reactivate brain cholinesterase, whereas with direct brain instillation pralidoxime partially restored brain cholinesterase and eliminated fatalities.79 Clinical observations, however, have certainly suggested a CNS action of pralidoxime with a prompt return of consciousness reported in some cases.55,56,63,83 A 3 year-old child who was comatose from parathion was given 500 mg of 2-PAM IV over 15 minutes with continuous electroencephalographic (EEG) monitoring. Within 2 minutes there was a dramatic response on the EEG, followed rapidly by normalization of consciousness.35
Early work with feline models led to a proposal that a serum concentration of greater than or equal to 4 μg/mL was a desired therapeutic concentration for pralidoxime.75 However, more recent in vitro work with human erythrocytes and a mouse hemidiaphragm model suggests that higher serum concentrations are actually needed.88 Twenty percent reactivation was achieved in 5 minutes with serum concentrations of 10 μg/mL.88 A simulation and analysis suggests that serum concentrations between 10 and 15 μg/mL (50–100 μmol/L) are necessary for optimal treatment of severely poisoned patients.21,90 These recommendations await validation in poisoned patients. Serum concentrations are not available in a timely manner, but may help in the design of future pralidoxime dosing protocols.
Organic phosphorous compounds inhibit butyrylcholinesterase (plasma cholinesterase) and AChE to different extents.18 If performed correctly, butyrylcholinesterase may act as a surrogate marker for OP or carbamate elimination from the body.38 Likewise, the reactivation of butyrylcholinesterase by pralidoxime is dependent on the concentration of pralidoxime and often has a flat dose response. For example, in an in vitro model of human blood taken from healthy volunteers and treated with paraoxon, pralidoxime was able to reactivate 1.3% and 18.1% of AChE at pralidoxime concentrations of 10 μmol and 100 μmol, respectively, compared with only 1% and 5.5% of butyrylcholinesterase with 10 and 100 μmol concentrations of pralidoxime.35 Unless the effect of the specific OP on butyrylcholinesterase is known, there is no role for following serial butyrylcholinesterase concentrations.
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 (Chap. 113).74 However, if cholinergic receptor desensitization is responsible for the cause of the muscle weakness, then pralidoxime would be unlikely to prevent the syndrome, especially after large intentional ingestions.12 Additionally, certain OP pesticides may lead to the development of delayed onset neurotoxicity, which involves inhibition of neurotoxic esterases that cannot be prevented or treated by pralidoxime.19,48
Pharmacokinetics and Pharmacodynamics
Pralidoxime chloride pharmacokinetics are characterized by a two-compartment model. Pharmacokinetics values vary depending on whether calculations are determined in healthy volunteers or poisoned patients. The volume of distribution (Vd) is larger in poisoned patients and most likely accounts for the prolonged elimination phase.21
In volunteers, the Vd is about 0.8 L/kg and the t1/2 is 75 minutes.33,61,72 Pralidoxime is renally excreted, and within 12 hours, 80% of the dose is recovered unchanged in the urine.34,71
A dose of 10 mg/kg of pralidoxime administered intramuscularly (IM) to volunteers results in peak serum concentrations of 6 μg/mL (reached 5–15 minutes after IM injection) and a half-life of approximately 75 minutes.71 Following a standard 30 minute IV infusion dose of 1 g of pralidoxime in a 70 kg man, the serum concentration fell to less than 4 μg/mL (no longer thought to be considered a goal serum concentration) at 1.5 hours. In a simulated model, a continuous infusion of 500 mg/h of pralidoxime led to a concentration greater than 4 μg/mL after 15 minutes, which could be maintained throughout the infusion.77 In a human volunteer study, an IV loading dose of 4 mg/kg over 15 minutes followed by 3.2 mg/kg/h for a total of 4 hours maintained serum pralidoxime concentrations greater than 4 μg/mL for 4 hours. The approximately same total dose, 16 mg/kg, administered over 30 minutes only maintained those concentrations for 2 hours.49 In poisoned patients receiving continuous infusions of pralidoxime as opposed to intermittent infusions, both the Vd and the t1/2 are increased.78 A Vd of 2.77 L/kg, an elimination t1/2 of 3.44 hours, and a clearance of 0.57 L/kg/h were reported in poisoned adults given a mean loading dose of 4.4 mg/kg followed by an infusion of 2.14 mg/kg/h.83 In poisoned children and adolescents, the Vd varied with severity of poisoning from 8.8 L/kg in the severely poisoned patients to 2.8 L/kg in moderately poisoned patients.68 After a mean loading dose of 29 mg/kg followed by a continuous infusion of about 14 mg/kg/h, a steady-state serum concentration of 22 μg/mL, a t1/2 of 3.6 hours, and a clearance of 0.88 L/kg/h were calculated.68
Oral administration of salts of pralidoxime (not used clinically because of OP poisoning–induced vomiting) demonstrated a peak concentration at 2 to 3 hours, a t1/2 of 1.7 hours, and an average urine recovery of 27% of unchanged pralidoxime in humans.39 Oral administration demonstrated clinical efficacy in a mice model.8
Autoinjector administration of 600 mg of pralidoxime chloride in an adult man (9 mg/kg) produced a concentration above 4 μg/mL at 7 to 16 minutes, a maximum serum concentration of 6.5 μg/mL at about 28 minutes, and a t1/2 of 2 hours.61,70 Using traditional needle and syringe IM administration requires a longer time to achieve comparable serum concentrations. The autoinjectors more widely disperse the medication in the tissues resulting in faster absorption.64,72