A33: Antidotes in Depth

Pralidoxime chloride (2-PAM) is the only cholinesterase-reactivating xenobiotic currently available in the United States. 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 can 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.

It was recognized in the 1950s that certain phosphate esters were potent and irreversible inhibitors of acetylcholinesterase (AChE).^84,85 Identification of an anionic site on AChE led to the theory that a compound could be developed that would bind to this site and remove the phosphate ester, thereby reactivating AChE. A few hydroxylamine derivatives were studied and led to the design of pralidoxime.⁸⁵

Chemistry

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

Related Xenobiotics

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).^{3,11,37,40,44,65,88,89}­Unfortunately, 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

Mechanism of Action

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 t_1/2 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 t_1/2 are increased.⁷⁸ A Vd of 2.77 L/kg, an elimination t_1/2 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 t_1/2 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 t_1/2 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 t_1/2 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

The sooner after exposure to an OP, the more likely pralidoxime is to be effective. Timely administration reduces the likelihood that aging of the OP–AChE complex has occurred and is completed. However, there is no absolute time limitation on reactivation function, as long as the patient remains symptomatic.

Early in vitro evidence suggested that the successful use of cholinesterase reactivators depended on administration within 24 to 48 hours of exposure to the OPs; afterward, the acetylcholinesterases would be irreversibly inactivated.^{4,14,31,32,67} The 48 hour limit was derived from in vitro experiments using a small number of tightly bound compounds and reactivators and data from plasma cholinesterase enzyme activity, which is now recognized to be relatively resistant to oxime-nucleophilic attack. These early data were accepted without consideration of their relevance to human systems, the use of newer and less tightly bound OP compounds, temperature and pH variation, blood flow, fat solubility, active metabolites, and species specificity. Fat soluble OP compounds redistribute from fat stores over time and can continue to newly inhibit AChE for days.

An in vitro experiment assessed the effect of aging on the ability of pralidoxime to regenerate rat erythrocyte and brain cholinesterases using three different OP compounds.⁸⁰ The rate of reactivation of erythrocyte and brain cholinesterases was significantly decreased over time for fenitrothion and methyl parathion, with no reactivation occurring at 48 hours. This is partly because dimethylated (dimethyl, dimethoxy) OP pesticides age more quickly than diethylphosphorylated pesticides.¹⁹ In contrast, a very high reactivation rate for ethyl parathion was still apparent at 48 hours. Thus the structure of the OP compound is important in the rates of aging and reactivation with pralidoxime. Fenitrothion and methyl parathion are both O’O-dimethyl OP compounds as is dimethoate, whereas ethyl parathion is an O’O-diethyl OP compound.⁸⁰ Other studies also suggest that pralidoxime remains effective for more than 48 hours following exposure.^{2,5,8,13,16,19,21,53,62,82}

There are four randomized clinical trials examining the efficacy of pralidoxime for the management of OP poisoning. Two of these trials were done in the 1990s in India using doses of pralidoxime now considered to be inadequate.¹⁹ Neither study demonstrated a benefit for pralidoxime and, in fact, suggested an increase in mortality in patients receiving the higher but still inadequate dose of pralidoxime. Other criticisms include a delay in administration and an inadequate duration of treatment. The third clinical trial included 200 patients in India who were moderately to severely poisoned with an OP pesticide.⁵⁸ All patients received a 2 g loading dose of pralidoxime iodide over 30 minutes before being randomized to receive 1 g over 1 hour every 4 hours for 48 hours or a continuous infusion of 1 g/h for 48 hours. Beyond 48 hours, all patients received 1 g every 4 hours until no longer ventilator dependent. In the continuous pralidoxime infusion arm, the authors demonstrated reduced atropine requirements, a smaller number of patients requiring intubation, fewer days of intubation, and a reduction in mortality from 8% to 1%. It should be noted that the iodide salt of pralidoxime was used and would equate to about 650 mg/h of the chloride salt.²² Even though the majority of the patients by history ingested dimethoate, a dimethoxy compound with high lethality and rapid aging, the time to admission and administration of pralidoxime was very short with a median time of 2 hours. Criticisms of the study include a lack of blinding, no measurement of AChE or pesticide concentrations, and no objective monitoring of neuromuscular function.²² In contrast, the most recent trial performed in Sri Lanka was unable to demonstrate a beneficial effect of pralidoxime in 121 patients compared to 114 patients treated with placebo.²⁰ There was no difference in mortality between groups, although pralidoxime effectively reactivated red cell AchE inhibited by diethyl OP insecticides. It also reactivated red cell AchE inhibited by dimethyl OP insecticides, but less so, as expected. In comparison to the third study,⁵⁸ these patients arrived later (4.4 versus 2 hours), and the extent of supportive care was inferior. The exact reasons for these disparate results are unclear.

Acetylcholinesterases inactivated by most carbamates spontaneously reactivate with half-lives of 1 to 2 hours, and typical clinical recovery occurs in several hours. However, in severe cases, cholinergic findings may persist for 24 hours.^10,28 Pralidoxime is rarely indicated for carbamate poisoning, but it is not contraindicated as previously suggested. This erroneous conclusion was based solely on data regarding a single carbamate, carbaryl, and inappropriately applied to all carbamates. Pralidoxime decreased the rate of carbamylation of 16 insecticidal carbamates, though it modestly increased the rates for three, one of which was carbaryl.¹⁵ In another experiment, pralidoxime had no effect on the reactivation of human erythrocyte AChE carbamylated by aldicarb, methomyl, and carbaryl.⁴¹ Furthermore, animal studies demonstrated the beneficial effects of pralidoxime in decreasing the lethality of several carbamate insecticides,^57,73 though worsened the toxicity of carbaryl. It was suggested that this is possibly because the carbamate-oxime complex may actually be a more potent cholinesterase inhibitor than carbaryl alone.^28,57,73 However, even in the presence of carbaryl, the combination of atropine plus an oxime, a more clinically relevant situation, resulted in survival data comparable to that of atropine alone.²⁸ Previous animal data may also be confounded by the use of excessive doses of pralidoxime.⁵¹ This evidence suggests that pralidoxime is not usually a necessary adjunct to atropine for a patient with a pure carbamate overdose. However, there are cases reports, particularly with aldicarb, where pralidoxime appears to improve outcome.¹⁰ Thus pralidoxime should never be withheld in a seriously poisoned patient out of concern that a cholinergic xenobiotic may be a carbamate.⁴¹ Pralidoxime should be used in conjunction with atropine and rarely as the sole therapy in OP or carbamate poisoning.

At therapeutic doses of pralidoxime in humans, adverse effects are minimal.^{26,27,54, 55, and 56,63,77} Transient dizziness, blurred vision, and elevations in diastolic blood pressure may be related to the rate of administration.^33,49 Doses of 45 mg/kg produce blood pressure elevations that may persist for several hours, but may be reversed with IV phentolamine.⁷⁰ The most recent randomized clinical trial revealed a higher percentage of patients with tachycardia and hypertension associated with pralidoxime compared to placebo after both the loading dose and the continuous infusion (75% versus 49% and 30% versus 14%). Rapid IV administration has produced sudden cardiac and respiratory arrest due to laryngospasm and muscle rigidity,^59,69,86 whereas IM administration in volunteers produced diplopia, dizziness, headache, drowsiness, nausea, tachycardia, increased systolic blood pressure, hyperventilation, decreased kidney function, muscular weakness, and pain at the injection site.⁶¹ Elevations in liver enzyme concentrations were observed in volunteers administered autoinjector doses of 1200 to 1800 mg; these enzyme concentrations returned to normal in 2 weeks.⁶¹ An important safety issue is inadvertent provider or patient contact with the “active” needle end of autoinjectors or autoinjector systems, triggering unintended administration, self-administration, needle injury, or delivery to an ­unintended site.

Pralidoxime is FDA pregnancy risk category C. Reproduction studies have not been done, and human case reports are limited. However, considering the maternal benefit of pralidoxime, it should be used as clinically indicated to protect the maternal fetal dyad. The use of pralidoxime should not be withheld because of pregnancy.⁹ It is unknown whether pralidoxime is excreted into breast milk.

The optimal dosage regimen for pralidoxime is unknown. A maintenance dose in adults of 1 g/h of the iodide salt of pralidoxime was used in the study from India and is approximately equal to 650 mg of pralidoxime chloride.⁵⁸ The package insert, last updated in 2010, recommends a pediatric loading dose of 20 to 50 mg/kg (not to exceed 2000 mg/dose) over 15 to 30 minutes followed by a continuous infusion of 10 to 20 mg/kg/h.⁶² It r­ecommends an adult dose of 1 to 2 g in 100 mL of 0.9% sodium chloride given intravenously over 15 to 30 minutes, with additional doses given every 3 to 8 hours as long as signs of poisoning recur.⁶² However, it does give the pharmacokinetics of a loading dose followed by a continuous infusion and comments that a loading dose followed by a continuous infusion is more likely to maintain therapeutic serum concentrations as compared to intermittent dosing.⁶²­Difficulties arise because a target serum concentration in humans has not been established, although in vitro studies suggest a target concentration closer to 17 μg/mL compared with the 4 μg/mL previously suggested.^21,23,35 This is complicated by the possibility that there is a ceiling dose and that some OP compounds are likely to be more easily reactivated than others. In addition, pharmacokinetic studies in volunteers suggest that a continuous infusion maintains a target concentration with less variation compared with intermittent boluses. Based on all of the above, we recommend a loading dose of pralidoxime chloride of 30 mg/kg (up to2 g) over 15 to 30 minutes followed by a maintenance infusion of 8 to 10 mg/kg/h for adults (up to 650 mg/h) and 10 to 20 mg/kg/h for children (up to 650 mg/h).

The addition of 20 mL of sterile water for injection to the 1 g vial of pralidoxime results in a 5% solution (50 mg/mL). Following reconstitution, the pralidoxime should be used within several hours. This solution can be further diluted to a volume of 100 mL of 0.9% sodium chloride solution for IV infusion, or a concentration of 10 to 20 mg/mL. The loading dose can be infused over 15 to 30 minutes. If fluid overload is a concern, the 1 g of pralidoxime in 20 mL can be infused slowly over not less than 5 minutes.⁶²

Although IV administration is preferred, IM administration is acceptable using a 1 g vial of pralidoxime reconstituted with 3 mL of sterile water or 0.9% sodium chloride for injection to provide a solution containing 300 mg/mL (concentrations above 35% weight/volume produce muscle necrosis in animals).⁷¹ This could be used until an IV site is established. Patients with reduced kidney function may require dosage adjustment, but there are no specific recommendations on how to accomplish this. In patients with ARDS, the dose can be given as a 5% solution by a slow IV injection over at least 15 to 30 minutes.⁷¹

Depending on the severity of a nerve agent exposure, one to three injections with a pair of autoinjectors containing atropine and pralidoxime should be administered. The number of autoinjector doses administered to a child depends on the age and weight of the child.^29,46 For children aged 3 to 7 (13–25 kg), one autoinjector of atropine and one autoinjector of pralidoxime should be administered, which should result in a projected pralidoxime dose of 24 to 46 mg/kg. For children aged 8 to 14, two autoinjectors of atropine and two autoinjectors of pralidoxime should be administered. These injections should result in a projected pralidoxime dose of 24 to 46 mg/kg. For anyone older than 14 years of age, three autoinjectors of atropine and pralidoxine should be administered. This results in a projected dose of pralidoxime of less than 35 mg/kg. For children younger than 3 years, during an emergency, one autoinjector of atropine and one of pralidoxime may be administered in accordance with a risk-to-benefit analysis. If time permits and only autoinjector doses are available, its contents may be transferred to a small sterile vial for traditional IM administration with a needle and syringe.³⁰

Duration of Treatment

The signs and symptoms of OP poisoning usually manifest within minutes but may be delayed up to 24 hours.⁵⁶ Delayed manifestations occur with the fat soluble compounds, such as fenthion or chlorfenthion. The route of exposure may also influence the onset of systemic symptoms. For example, there may be a delay following dermal contact, which does not occur following ingestion or inhalation. When symptoms are either delayed or prolonged, or when treatment is delayed, extended therapy with pralidoxime may be indicated.^1,7,53 In one case of poisoning with the fat soluble compound fenthion, 5 days elapsed before cholinergic symptoms appeared, and some symptoms then persisted for 30 days.⁵³ Pralidoxime and atropine were administered continuously in varying doses for the time that the patient was symptomatic. Therefore, the most practical recommendation is to continue the pralidoxime until symptoms have resolved and atropine has not been needed for 12 to 24 hours.¹⁸ Other recommendations for estimating the duration of pralidoxime therapy include; (1) measuring the serum or urinary concentration of the OP compound, (2) measuring serial determinations of plasma cholinesterase (increasing concentrations suggests the elimination of the OP compound), (3) incubating the patient’s serum with an exogenous source of AChE or butyrylcholinesterase to assess inhibition, (4) incubating the patient’s inhibited red blood cell cholinesterase with a high concentration of oxime in vitro, to assess reactivation.²¹ However, measurements of ­urinary concentrations of OP or AChE or plasma cholinesterase are not likely to happen in real time. Furthermore, plasma cholinesterase is not always a good surrogate for OP inhibition. In all cases, patients should be observed for the recrudescence of toxicity after termination of pralidoxime. If symptoms return, therapy should be continued for at least an additional 24 hours.

Pralidoxime chloride (Protopam) is supplied in 20 mL vials containing 1 g of powder, ready for reconstitution with sterile water or 0.9% sodium chloride for injection.^60,62

As noted above, pralidoxime chloride is also available for IM administration by an autoinjector containing 600 mg of pralidoxime in 2 mL of sterile water for injection with 20 mg of benzyl alcohol and 11.26 mg of glycine. The 2-PAM autoinjector is also packaged in a kit containing 600 mg of pralidoxime in 2 mL of sterile water for injection with 40 mg of benzyl alcohol and 22.5 mg of glycine, accompanied by an autoinjector containing 2.1 mg of atropine in 0.7 mL of a sterile solution containing 12.47 mg of glycerin and not more than 2.8 mg of phenol. This kit is called a “Mark 1 Nerve Agent Antidote Kit (NAAK)” and is designed to be used IM by first responders in case of a nerve agent attack. The needles extend 0.8 inch in length. The Mark 1 NAAK was recently replaced by the DuoDote Autoinjector System and the analagous, military designated Antidote Treatment Nerve Agent Autoinjector (ATNAA), which use technology that sequentially administers 2.1 mg of atropine in 0.7 mL followed by 600 mg of pralidoxime chloride in 2 mL IM through the same syringe.^15a The 23 gauge needle is 0.8 inches in length. Pralidoxime is maintained as part of the the Strategic National Stockpile (SNS) formulary in repositories in numerous locations throughout the US.

• Pralidoxime is an effective reactivator of AChE in many OP compound poisonings primarily reversing neuromuscular manifestations.

• The sooner pralidoxime is administered after OP toxicity, the more effective it is likely to be, although there is no absolute time limitation on reactivation function.

• Pralidoxime and atropine are synergistic and should be used together in the management of patients with OP poisonings.

• If a patient requires multiple doses of atropine for muscarinic symptoms or has neuromuscular weakness, then the use of 2-PAM is ­indicated.

• The resolution of all signs or symptoms does not indicate that the enzyme systems are fully active; patients may still benefit from enzyme regeneration with the safe and effective antidote pralidoxime.

• Because newer highly fat soluble OP pesticides are currently available, it may be necessary to administer atropine and 2-PAM for more prolonged periods of time than previously suggested.

Acknowledgment

Cynthia K. Aaron, MD, contributed to this chapter in previous editions.

References