Organophosphate Pesticide Poisoning
Pralidoxime chloride is used concomitantly with atropine and supportive measures (e.g., removal of secretions, maintenance of an adequate airway, and artificial ventilation) to reverse muscle paralysis (particularly of respiratory muscles) associated with toxic exposure to organophosphate anticholinesterase pesticides and chemicals. Pralidoxime appears to be most effective when given soon after exposure; the drug may still be effective if more than 48 hours have elapsed. Clinical cases in which atropine and pralidoxime have been used include toxic exposure to azodrin, bidrin, carbophenthion, coumaphos (Co-ral), DFP, diazinon, dichlorvos, dichlorvos with chlordane, dicrotophos, dimethoate, disulfoton, EPN, guthion, isoflurophate, Metasystox 1® and fenthion, methyl demeton, methyl parathion, mevinphos, OMPA, parathion, parathion and mevinphos, phosdrin, phosphamidon, sarin, Systox®, trithion, and TEPP. Results of animal studies indicate that pralidoxime may be an effective antidote in toxic exposure to various other organophosphates possessing anticholinesterase activity, but the drug appears to be ineffective or only marginally effective against toxic exposure to Ciodrin®, dimefox, dimethoate, methyl diazinon, methyl phencapton, mipafox, phorate, schradan, and Wepsyn®. Pralidoxime is not effective in the treatment of toxic exposure to phosphorus, inorganic phosphates, or organophosphates which do not possess anticholinesterase activity.
Chemical Warfare Agent Poisoning
Pralidoxime chloride is used concomitantly with atropine for the treatment of nerve agent poisoning in the context of chemical warfare or terrorism.101, 102, 103 Pralidoxime chloride must be administered within minutes to hours following exposure to nerve agents to be effective.101, 104
The most toxic of the known chemical warfare agents are the nerve agents.101, 102, 103, 104 Most nerve agents are liquid at room temperature (although most are volatile at ambient temperatures, the term nerve gas is a misnomer); nerve agents are readily absorbed after inhalation of aerosols (e.g., following an explosion), ingestion, or dermal contact.101, 102, 103 Nerve agents (e.g., sarin, soman, tabun, VX [methylphosphonothionic acid]) are chemically similar to the organophosphate pesticides and exert their biologic effects by inhibiting acetylcholinesterase enzymes.101, 102, 103, 104 Nerve agents alter cholinergic synaptic transmission at neuroeffector junctions (muscarinic effects), at skeletal myoneural junctions and autonomic ganglia (nicotinic effects), and in the CNS.101, 103 Manifestations of nerve agent exposure include rhinorrhea, chest tightness, pinpoint pupils, dyspnea, excessive salivation and sweating, nausea, vomiting, abdominal cramps, involuntary defecation and/or urination, muscle twitching, confusion, seizures, flaccid paralysis, coma, respiratory failure, and death.101, 102, 103, 104 While initial effects of nerve agent exposure depend on the dose and route of exposure, signs and symptoms generally are similar regardless of the route of exposure.101 Manifestations may not be apparent until as long as 18 hours following dermal exposure, and CNS effects (e.g., fatigue, irritability, nervousness, memory impairment) may persist as long as 6 weeks following recovery from the acute effects of nerve agent exposure.101
Initial management of nerve agent poisoning includes aggressive airway control and ventilation (administration of nebulized β-adrenergic agonist [e.g., albuterol] and antimuscarinics [e.g., ipratropium bromide] may be necessary), and administration of atropine and pralidoxime chloride.101, 102, 103 Diazepam may be needed for seizure control.101 Rapid decontamination using standard hazardous materials (HAZMAT) procedures is important to prevent further absorption by the victim and to prevent contamination of others (e.g., emergency personnel, health-care workers) by direct contact or off-gassing of nerve agents from contaminated clothing.101, 102, 103 Following initial therapy and decontamination, additional treatment with atropine and supportive measures in a hospital setting are likely to be necessary.101, 102, 103
Atropine is generally used alone in the treatment of muscarinic toxicity resulting from exposure to carbamate insecticides; pralidoxime is not generally used. Pralidoxime is contraindicated in the treatment of toxic exposure to carbaryl since it appears to increase the toxicity of carbaryl.
Pralidoxime has been used for the management of overdosage of drugs that carbamylate cholinesterase, such as ambenonium, neostigmine, and pyridostigmine, particularly in the treatment of cholinergic crisis in patients with myasthenia gravis. However, pralidoxime is reportedly less effective against these agents than against organophosphate anticholinesterases and may precipitate a myasthenic crisis in these patients. (See Cautions: Precautions and Contraindications.)
Reconstitution and Administration
Pralidoxime chloride is usually administered IV, preferably as an infusion given over 15-30 minutes. (See Cautions: Adverse Effects.) In patients with pulmonary edema or if IV infusion is not practical or a more rapid effect is desired, pralidoxime chloride solutions containing 50 mg/mL may be administered by slow IV injection over a period of at least 5 minutes. Pralidoxime chloride may also be administered by IM injection.
Pralidoxime chloride sterile powder for injection is reconstituted by adding 20 mL of sterile water for injection to the vial labeled as containing 1 g of the drug to provide a solution containing approximately 50 mg/mL. Because of the relatively large volume of diluent required, sterile water for injection containing preservatives should not be used to reconstitute pralidoxime chloride sterile powder for injection. Following reconstitution, pralidoxime chloride solutions should be used within a few hours. For IV infusion, the calculated dose of the reconstituted solution is further diluted in 100 mL with 0.9% sodium chloride injection.
To facilitate out-of-hospital IM administration in the event of pesticide or nerve agent poisoning, pralidoxime chloride injection is available as an auto-injector (pralidoxime chloride injection auto-injector). In addition, pralidoxime chloride is available in an auto-injector that also contains atropine (DuoDote® auto-injector, ATNAA auto-injector). Each prefilled DuoDote® auto-syringe and each prefilled ATNAA auto-syringe provides a single IM dose of atropine 2.1 mg and pralidoxime chloride 600 mg. When activated, the auto-injector sequentially administers atropine and pralidoxime chloride through a single needle. For self-administration or administration by a partner or civilian emergency responder in an out-of-hospital setting, the contents of a pralidoxime chloride auto-injector or atropine and pralidoxime chloride auto-injector (DuoDote®) should be injected IM into the anterolateral aspect of the thigh. In an out-of-hospital setting, the contents of an atropine and pralidoxime chloride auto-injector (ATNAA) should be injected IM into the anterolateral aspect of the thigh or into the buttock.
For IM administration, some authorities suggest that pralidoxime chloride sterile powder for injection be reconstituted by adding 3 mL of sterile water for injection or 0.9% sodium chloride for injection to the vial labeled as containing 1 g of the drug to provide a solution containing 300 mg/mL.101
Organophosphate Pesticide Poisoning
For the treatment of toxic exposure to organophosphate cholinesterase inhibitors, pralidoxime therapy should be initiated at the same time as atropine. The usual initial IV dose of pralidoxime chloride is 1-2 g given over 15 to 30 minutes for adults, or 20-40 mg/kg given over 30 minutes for children. Dosage of pralidoxime chloride should be reduced in patients with renal insufficiency. The dose of pralidoxime chloride may be repeated in about 1 hour if muscle weakness has not been relieved. Additional doses may be administered cautiously if muscle weakness continues. Alternatively, some clinicians recommend continuous IV infusion of 500 mg of the drug per hour. In severe cases, especially after ingestion of the poison, the manufacturer recommends electrocardiographic monitoring because the anticholinesterase may cause heart block. Continued absorption of the anticholinesterase from the lower bowel constitutes new exposure; in such cases, additional doses of pralidoxime may be needed every 3-8 hours. As in all cases of organophosphate poisoning, the patient should be observed closely for at least 24 hours.
To facilitate out-of-hospital administration, pralidoxime is available in a prefilled auto-injector containing atropine 2.1 mg and pralidoxime chloride 600 mg (e.g., DuoDote®); the auto-injector should be used by emergency medical service personnel. For administration in an out-of-hospital setting, the dose of pralidoxime and atropine (DuoDote®) is based on severity of symptoms. For the treatment of adults with 2 or more mild symptoms of pesticide exposure (e.g., miosis or blurred vision, tearing, runny nose, hypersalivation or drooling, wheezing, muscle fasciculations, nausea/vomiting), administer contents of one auto-injector (atropine 2.1 mg and pralidoxime chloride 600 mg) by IM injection. If the patient develops any severe symptoms (behavioral changes, severe breathing difficulty, severe respiratory secretions, severe muscle twitching, involuntary defecation or urination, seizures, unconsciousness), administer contents of two additional auto-injectors IM in rapid succession. For the treatment of adults who present with any severe symptoms, administer contents of three auto-injectors (total dose: atropine 6.3 mg and pralidoxime chloride 1800 mg) IM in rapid succession. Additional doses should not be administered unless definitive medical care is available.
The dose and route of administration of pralidoxime chloride for the treatment of nerve agent (e.g., sarin, soman, tabun, VX [methylphosphonothiotic acid]) poisoning in the context of chemical warfare or terrorism is based on the severity of symptoms (i.e., mild/moderate or severe), the victim's age, and the treatment setting.101 Mild to moderate symptoms include localized sweating, muscle fasciculations, nausea, vomiting, weakness, and/or dyspnea; severe symptoms include apnea, flaccid paralysis, seizures, and/or unconsciousness.101 Pralidoxime chloride must be administered within minutes to hours following exposure to nerve agents to be effective.101 Pralidoxime is administered concomitantly with atropine.
For the immediate treatment of nerve agent poisoning in an out-of-hospital setting, pralidoxime chloride usually is administered IM.101 The usual out-of-hospital IM adult dose is 600 mg for those with mild to moderate symptoms and 1800 mg for those with severe symptoms; frail geriatric adults with mild to moderate symptoms may receive 10 mg/kg and those with severe symptoms may receive 25 mg/kg.101 In an out-of-hospital setting, the usual IM dose of pralidoxime chloride for children 0-10 years of age and adolescents older than 10 years of age with mild to moderate symptoms is 15 mg/kg, and the usual dose for children 0-10 years of age and adolescents older than 10 years of age with severe symptoms is 25 mg/kg.101
To facilitate out-of-hospital administration, pralidoxime chloride injection is available in a prefilled auto-injector; the auto-injector should be used by individuals who have received adequate training in the recognition and treatment of nerve agent poisoning. For the initial treatment of adults with symptoms of nerve agent poisoning, one 600-mg IM dose of pralidoxime chloride should be administered; pralidoxime is administered after atropine. If symptoms are still present after 15 minutes, another dose of atropine and another 600-mg dose of pralidoxime chloride should be administered. If symptoms persist after an additional 15 minutes, another dose of atropine and another 600-mg dose of pralidoxime chloride should be administered. If symptoms persist after the third doses, medical care should be sought.
Another option for out-of-hospital administration is to administer atropine and pralidoxime using a prefilled auto-injector containing atropine 2.1 mg and pralidoxime chloride 600 mg (e.g., DuoDote®, ATNAA). For the treatment of adults with 2 or more mild symptoms of nerve agent poisoning (e.g., miosis or blurred vision, tearing, runny nose, hypersalivation or drooling, wheezing, muscle fasciculations, nausea/vomiting), the contents of one auto-injector (atropine 2.1 mg and pralidoxime chloride 600 mg) should be administered by IM injection. If the patient develops any severe symptoms (behavioral changes, severe breathing difficulty, severe respiratory secretions, severe muscle twitching, involuntary defecation or urination, seizures, unconsciousness), the contents of 2 additional auto-injectors should be administered by IM injection in rapid succession. For the treatment of adults who present with any severe symptoms, the contents of 3 auto-injectors (total dose: atropine 6.3 mg and pralidoxime chloride 1800 mg) should be administered by IM injection in rapid succession. Additional doses should not be administered unless definitive medical care is available.
In an emergency department or similar setting, pralidoxime chloride generally is administered by slow IV injection.101 When pralidoxime chloride is administered IV in such a setting for the treatment of nerve agent poisoning, the usual adult dose is 15 mg/kg (maximum 1 g) for those with mild to moderate or severe symptoms; frail geriatric adults with mild to moderate or severe symptoms may receive 5-10 mg/kg.101 In an emergency department setting, the usual IV dose of pralidoxime chloride for children 0-10 years of age and adolescents older than 10 years of age with mild to moderate or severe symptoms is 15 mg/kg.101 Atropine is administered concomitantly with pralidoxime.101
Diazepam may be administered for seizure control.101
As an antagonist to carbamate anticholinesterase agents used in the treatment of myasthenia gravis (e.g., ambenonium, neostigmine, pyridostigmine), 1-2 g of pralidoxime chloride has been given IV initially, followed by 250 mg every 5 minutes.
Although pralidoxime is generally well-tolerated, dizziness, blurred vision, diplopia and impaired accommodation, headache, drowsiness, nausea, tachycardia, hyperventilation, maculopapular rash, and muscular weakness have been reported following administration of the drug. However, it is difficult to differentiate the toxic effects produced by atropine or organophosphates from those of pralidoxime, and the condition of patients suffering from organophosphate intoxication will generally mask minor signs and symptoms reported in normal subjects who receive pralidoxime. When atropine and pralidoxime are used concomitantly, signs of atropinism may occur earlier than when atropine is used alone, especially if the total dose of atropine is large and administration of pralidoxime is delayed. Excitement, confusion, manic behavior, and muscle rigidity have been reported following recovery of consciousness, but these symptoms have also occurred in patients who were not treated with pralidoxime.
Rapid IV injection of pralidoxime has produced tachycardia, laryngospasm, muscle rigidity, and transient neuromuscular blockade; therefore, the drug should be administered slowly, preferably by IV infusion. IV administration of pralidoxime reportedly may also cause hypertension which is related to the dose and rate of infusion. Some clinicians recommend that the patient's blood pressure be monitored during pralidoxime therapy. For adults, IV administration of 5 mg of phentolamine mesylate reportedly quickly reverses pralidoxime-induced hypertension.
IM administration of pralidoxime may produce mild pain at the injection site.
Precautions and Contraindications
Pralidoxime should always be used under close medical supervision.
Pralidoxime should be used with caution in patients with myasthenia gravis who are receiving anticholinesterase agents, since the drug may precipitate a myasthenic crisis.
Pralidoxime should be used with caution and in reduced dosage in patients with impaired renal function.
The use of succinylcholine, theophylline, aminophylline, reserpine, and respiratory depressants (e.g., barbiturates, morphine, phenothiazines) should be avoided in patients with toxic exposure to anticholinesterase compounds.
Safe use of pralidoxime during pregnancy has not been established.
The principal pharmacologic effect of pralidoxime is reactivation of cholinesterase which has been recently inactivated by phosphorylation as the result of exposure to certain organophosphates. Pralidoxime removes the phosphoryl group from the active site of the inhibited enzyme by nucleophilic attack, regenerating active cholinesterase and forming an oxime complex. Pralidoxime also detoxifies certain organophosphates by direct chemical reaction and probably also reacts directly with cholinesterase to protect it from inhibition. Pralidoxime must be administered before aging of the inhibited enzyme occurs; after aging is completed, phosphorylated cholinesterase cannot be reactivated, and newly synthesized cholinesterase must replace the inhibited enzyme. Pralidoxime is not equally antagonistic to all anticholinesterases, partly because the time period required for aging of the inhibited enzyme varies and depends on the specific organophosphate bound to the cholinesterase.
Pralidoxime also reactivates cholinesterase which has been inactivated by carbamylation. However, carbamylated cholinesterase has a much faster rate of spontaneous reactivation than does phosphorylated cholinesterase.
Cholinesterase reactivation produced by pralidoxime occurs principally at the neuromuscular junction and results in reversal of anticholinesterase-induced paralysis of respiratory and other skeletal muscles. The drug also reactivates cholinesterase at autonomic effector sites and, to a lesser degree, within the CNS. Pralidoxime is effective against nicotinic manifestations of anticholinesterase poisoning (e.g., muscular twitching, fasciculation, cramps, weakness, pallor, tachycardia, elevated blood pressure). The drug does not substantially influence muscarinic effects (e.g., bronchoconstriction, dyspnea, cough, increased bronchial secretion, nausea, vomiting, abdominal cramps, diarrhea, increased sweating, salivation, lacrimation, bradycardia, fall in blood pressure, miosis, blurred vision, urinary frequency, and incontinence). Therefore, pralidoxime is used in conjunction with atropine, which ameliorates muscarinic symptoms and directly blocks the effects of accumulation of excess acetylcholine at various sites including the respiratory center.
Other reported pharmacologic effects of pralidoxime include depolarization at the neuromuscular junction, anticholinergic action, mild inhibition of cholinesterase, sympathomimetic effects, potentiation of the depressor action of acetylcholine in nonatropinized animals, and potentiation of the pressor action of acetylcholine in atropinized animals. However, the contribution of these effects to the therapeutic action of the drug has not been established.
Absorption of pralidoxime chloride is variable and incomplete following oral administration (oral tablets of the drug are no longer commercially available in the US). Based on results of animal studies, the minimum therapeutic plasma concentration of pralidoxime is considered to be 4 mcg/mL. Peak plasma oxime concentrations are reached 5-15 minutes after IV administration and 10-20 minutes after IM administration of pralidoxime chloride. In a study in healthy adults, IV pralidoxime chloride doses of 7.5-10 mg/kg were needed to produce plasma oxime concentrations of 4 mcg/mL or greater at 1 hour after administration; IM doses of 7.5-10 mg/kg were needed to achieve initial plasma concentrations of 4 mcg/mL or greater, and only IM doses of 10 mg/kg maintained plasma oxime concentrations at 4 mcg/mL or greater for 1 hour.
Pralidoxime is distributed throughout the extracellular water. Because of its quaternary ammonium structure, the drug is not generally believed to enter the CNS, but recent animal studies and human clinical responses observed by some investigators have raised some controversy on this point. Pralidoxime does not readily penetrate the cornea following systemic or topical administration, but therapeutic concentrations are reportedly achieved in the eye following subconjunctival injection. Pralidoxime is not appreciably bound to plasma proteins.
It is not known if pralidoxime is distributed into milk.
Although the exact metabolic fate of pralidoxime has not been completely elucidated, the drug is believed to be metabolized in the liver. The half-life of pralidoxime in patients with normal renal function varies and has been reported to range from 0.8-2.7 hours. Pralidoxime is rapidly excreted in urine as unchanged drug and as a metabolite. Approximately 80-90% of an IV or IM dose of pralidoxime chloride is excreted unchanged within 12 hours after administration. A recent study has suggested that active tubular secretion may be involved, although the specific mechanism has not been identified.
Pralidoxime chloride, a quaternary ammonium oxime, is a cholinesterase reactivator. The drug occurs as a white to pale yellow, crystalline powder and is freely soluble in water. Following reconstitution with sterile water for injection, pralidoxime chloride solutions containing 50 mg/mL have a pH of 3.5-4.5. The pKa of pralidoxime is 7.8-8.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection | 1 g | Protopam® Chloride | |
Injection | 600 mg* | Pralidoxime Chloride Injection Auto-Injector |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection | 600 mg/2 mL Pralidoxime Chloride and 2.1 mg/0.7 mL Atropine | ATNAA Auto-Injector (each drug is in a separate chamber) | |
600 mg/2 mL Pralidoxime Chloride and 2.1 mg/0.7 mL Atropine | DuoDote® Auto-Injector (each drug is in a separate chamber) | Meridian |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions May 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
101. Agency for Toxic Substances and Disease Registry. Nerve agents: tabun (GA) CAS 77-81-6; sarin (GB) CAS 107-44-8; soman (GD) CAS 96-64-0; and VX CAS 50782-69-9. From the CDC website. Accessed Nov 19, 2007. [Web]
102. DeLorenzo RA. Exposed: signs, symptoms & EMS management of nerve-agent poisoning. J Emerg Med Serv JEMS . 2001; 26:48-57. [PubMed 11409202]
103. In Ellenhorn MJ, Schonwald S, Ordog G, Wasserberger J, eds. Ellenhorn's medical toxicology: diagnosis and treatment of human poisoning. 2nd ed. Baltimore: Williams & Wilkins; 1997:1267-90.
104. Anon. Prevention and treatment of nerve gas poisoning. Med Lett Drugs Ther . 1990; 32:103-5. [PubMed 2233511]
105. Goldfrank's toxicologic emergencies. 7th ed. Goldfrank LR, Howland MA, Flomenbaum NE et al, eds. New York: McGraw-Hill; 2002:1346-66.