Of the class of chemical compounds called oximes, pralidoxime (2-PAM), used in the United States, and obidoxime, used in a few European nations, are the major drugs that find clinical use. P2S and HI-6 are also used in some parts of the world. These drugs were collectively developed in the 1950s with a vision to develop an antidote that could reverse the inhibition of acetylcholinesterase enzyme brought about by the exposure to organophosphate compounds.

Developed in Germany in the pre-WWII era, the initial intent for organophosphate compounds was for use as insecticides. However, it did not take long for these compounds to be weaponized, given how harmful they were due to their property of irreversibly inactivating the acetylcholinesterase enzyme. This usage of organophosphate compounds as pesticides and as weapons of mass destruction continues to this day, forming a basis for the FDA approved indications of drugs like pralidoxime:

• Pralidoxime has approval as an antidote for nerve agent poisoning. Reports indicate the usage of chemical weapons like sarin, tabun, soman, and cyclosarin in the 1980 Iran-Iraq war, the 1995 Tokyo subway attack, the Gulf war, and the 2013 Syrian civil war.[1][2]
• Pralidoxime also has approval as an antidote for organophosphate based pesticides. Today organophosphate based pesticides are widely used in agriculture all over the world. Poor yield, drought, debt, and extreme working hours often drive farmers into depression.[3][4] Thus, easy access and cheap cost make organophosphate pesticides a pathway for committing suicide; this is especially rampant in primarily agriculture-based economies like that of many developing countries today. Lack of adequate education and protection also leads to a high incidence of accidental poisonings in this cohort. Instances of over-the-counter availability of these compounds coupled with their well-known notoriety as potent poisons have led to a high incidence of suicides using organophosphate compounds in the general population as well.[5] Annually, there are about a million reported cases of accidental organophosphate poisoning globally. The number for suicidal poisonings is almost double that, and the combined death toll exceeds 200,000.[6]
• Pralidoxime also has approval for the management of an overdose of acetylcholinesterase drugs prescribed for myasthenia gravis and Alzheimer dementia.

A non-FDA approved but under-evaluation use for pralidoxime is:

• Pralidoxime shows promise when used as a universal electrochemical marker for the detection of the type of compound organophosphate, causing the poisoning.[7]

Acetylcholinesterase enzyme is responsible for the hydrolysis of the neurotransmitter acetylcholine at the various muscarinic and nicotinic sites in the body and hence does not let it accumulate. This enzyme has a serine site and an anionic site on its molecule. The serine site lies within the active site of the enzyme and is the one attacked by the organophosphate molecule; this leads to the phosphorylation of the serine site and formation of a strong covalent bond, inactivating the active site of the enzyme in the process. Unlike poisoning with carbamates, this interaction is irreversible.  

Pralidoxime is an acetylcholinesterase enzyme re-activator. It works by attaching to the anionic site of the enzyme. At this site, the pralidoxime molecule is close to the OP molecule. The pralidoxime molecule has a higher affinity to become phosphorylated by the OP compound as compared to the serine site of the enzyme, which leads to the pralidoxime molecule sacrificing itself by getting phosphorylated instead of the enzyme. The OP molecule detaches from the enzyme to do this, leading to two things. First is the formation of an organophosphate-pralidoxime complex, which quickly hydrolyzes. Second is the restoration of the active site of the acetylcholinesterase enzyme, making it available for action once again.[8]

Pralidoxime's primary action is restoring acetylcholinesterases at nicotinic sites in the body, relieving symptoms like muscle weakness, fasciculations, and paralysis. Although it has some muscarinic action as well, it is not clinically significant as that is well taken care of by the co-administration of atropine.[9]

The pressor action of pralidoxime is less clearly understood. Earlier the thought was that the stimulation of alpha-adrenergic receptors mediated this vasopressor effect, based on a study by Stavinoha et al. that demonstrated that alpha-adrenergic blockers like phentolamine effectively blocked the increase in systemic arterial pressure brought about by pralidoxime.This concept, however, was disproved by Carrier et al. when they showed that in an isolated aortic strip preparation, there was no effect of phentolamine on the response of the aorta when exposed to pralidoxime. They suggested that it is the intracellular alteration of calcium ion storage that drives the cardiovascular effects of pralidoxime.[10]

Time of Administration

Pralidoxime and atropine administration should take place as soon as the patient is decontaminated, stabilized, and there is a provisional diagnosis of organophosphate poisoning. Earlier it was believed that pralidoxime is more or less ineffective after 24 to 48 hours of the exposure. The reason for this is the phenomenon of aging.[11] Aging refers to the dealkylation of the phosphorylated enzyme, leading to the electrons shuffling in a way that further strengthens the covalent bond between the OP and the acetylcholine the enzyme to the point that even pralidoxime is unable to reactivate the enzyme. The extent and rate of aging depend on the characteristics of the given compound, but as a rule of thumb, weaponized organophosphates are expected to age very quickly and are therefore extremely dangerous. For example, the half-life of an acetylcholinesterase molecule exposed to nerve agent soman can be as low as 1.3 minutes.  

Recent studies, however, have shown that a delayed administration of pralidoxime may still be beneficial due to instances of prolonged absorption of the compound or high lipid solubility. OP compounds like fenthion and fenitrothion are notorious for the same. Sometimes it is a metabolite of the original OP compound that is toxic. All these factors form the rationale for the late administration of pralidoxime.[12]

DOSE

Traditionally, the recommended dosage of pralidoxime has been 1 to 2 g in 100 mL saline as an intravenous infusion over 15 to 30 minutes. The same can be repeated after 1 hour if the nicotinic symptoms like muscle fasciculations persist. Additional doses require caution. Recent updates dictate that pralidoxime should be administered intravenously at 30 mg/kg initially over 30 min, followed by constant infusion of 8 mg/kg/hr in dextrose 5% solution.[13] This sequence can continue either until all the nicotinic symptoms of OP poisoning resolve or until atropine is no longer needed.[5]

Even the upper limits of this WHO recommended dosage regimes, however, have been questioned by several clinicians.[14][15] A study conducted by Pawar et al. demonstrated that a higher dosage regime is more beneficial than one recommended by WHO. Also, this study sheds light on the advantage of continuous infusion of pralidoxime over repeated boluses.[16] The limitations of this study were that it did not include severely poisoned patients and that it took place in a relatively well-equipped hospital.

ROUTE OF ADMINISTRATION

Apart from the intravenous route mentioned above, pralidoxime can also be administered via the intramuscular route. An autoinjector is now available that combines it with atropine and diazepam. Drug delivery using an autoinjector has shown to be better than by using a needle and syringe—this autoinjector co-administers pralidoxime and atropine. Synergism of pralidoxime with atropine has been described later under drug interactions. Militaries around the world now issue these autoinjectors to its soldiers for quick administration in the event of a nerve agent attack.[17]

The intraosseous route of administration of pralidoxime has been explored in recent years. Studies have shown that utilizing this route can potentially reduce the time required to reach therapeutic plasma concentrations by more than eight times.[18]

A recent novel breakthrough utilizes an infusion micropump for delivery of pralidoxime has shown better results as compared to the traditional routes.[19]

ADMINISTRATION IN PEDIATRIC, PREGNANT/NURSING FEMALES AND GERIATRIC AGE GROUP

Studies have shown minimal or no adverse effects when using the pralidoxime-atropine autoinjector in children as young as 15 months, but only atropine is recommended for children under one year of age.[20][21] The doses used for children are recommended to be comparable to that of adults and have been well- tolerated.[22]

Data regarding the use of oximes in pregnant and nursing females is scanty and inconclusive.[23]

Studies highlighting dosages in the geriatric age group are also sparse. The clinician must weigh the potential benefits and harms before deciding the course of therapy. Co-morbidities like renal insufficiency merit consideration. 

•  Adverse effects of pralidoxime iodide in healthy volunteers included blurred vision, diplopia, dizziness, impaired accommodation, headache, and nausea.[24] Other rare side effects may be tachycardia, raised blood pressure, and hyperventilation. These adverse effects are, however, difficult to discern in a patient of OP poisoning as similar symptoms occur in patients not treated with pralidoxime as well. A similar adverse effect profile belongs to Atropine as well, which is almost always co-administered in OP poisoning, making it even more difficult to pin down the actual cause.
• If pralidoxime iodide is used instead of pralidoxime chloride, large doses require careful administration carefully as excess iodine can lead to thyroid toxicity.[25]
• The loading dose of oxime should be given slowly as a bolus because a rapid infusion can cause tachycardia, diastolic hypertension, vomiting, and aspiration.[8]
• Administering pralidoxime in a patient of myasthenia gravis may precipitate a myasthenic crisis. Vigilance is necessary.

• For a long time, pralidoxime has been strictly contraindicated in the management of carbamate induced toxicity. This limitation was primarily because of the studies conducted with one particular carbamate, carbaryl, showed poor outcomes.[26][27] The results were then extrapolated to other carbamates as well. However, case reports and clinical trials with other carbamates like neostigmine, rivastigmine, methomyl, and aldicarb have shown favorable outcomes when treated with pralidoxime.[26][28][29][30][29][28][26] Thus, carbaryl remains the only contraindication among carbamates. 
• Other than that, pralidoxime should be contraindicated if there is a history of prior drug allergy upon exposure.