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:
A non-FDA approved but under-evaluation use for pralidoxime is:
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.
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.
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.
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. 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.
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. This sequence can continue either until all the nicotinic symptoms of OP poisoning resolve or until atropine is no longer needed.
Even the upper limits of this WHO recommended dosage regimes, however, have been questioned by several clinicians. 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. 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.
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.
A recent novel breakthrough utilizes an infusion micropump for delivery of pralidoxime has shown better results as compared to the traditional routes.
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. The doses used for children are recommended to be comparable to that of adults and have been well- tolerated.
Data regarding the use of oximes in pregnant and nursing females is scanty and inconclusive.
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.
It has been well established that a minimum plasma concentration of 4mg/L of pralidoxime is necessary for the protection of the acetylcholinesterase enzyme against OP compounds. With the traditional dosing technique of giving a 1 g bolus of the drug over 15 to 30 minutes, computer simulations have shown that the plasma concentration will fall below therapeutic levels in as little as 1.5 hours. However, a randomized, cross-over design trial conducted on healthy volunteers proved that a loading dose followed by a continuous infusion of 9 to 19 mg/kg/hr is much more effective in maintaining the required plasma levels. Moreover, all the volunteers subjected to the short infusion regime showed adverse effects like the blurring of vision and dizziness.
Pralidoxime distributes evenly in the fluid compartments of the body and has not shown to bind to either hemoglobin or plasma proteins. Pralidoxime is a quaternary ammonium oxime and is therefore not expected to cross the blood-brain barrier.
When given via the intramuscular route, pralidoxime shows zero-order kinetics. However, co-administration with avizafone and atropine accelerates the absorption of the drug due to modified blood flow at the site of injection to the point that the best mechanical model applicable for this process shifts to first-order kinetics.
Sidell et al. determined that pralidoxime is actively secreted by the kidneys in its original form, without undergoing any significant metabolism. Most of the excretion is via urine and feces. Thus, in patients with a reduced renal function, it is advisable to adjust the dose of pralidoxime as its plasma clearance becomes markedly reduced.
Pralidoxime has no known deleterious drug interactions. There is positive evidence suggesting its synergism when co-administered with atropine. On the one hand, pralidoxime was detected in the plasma earlier and in higher concentrations when given along with atropine and avizafone. On the other hand, the signs of atropinization also occurred earlier than expected than when it is given alone. This synergy is the rationale behind including these drugs together in the auto-injector.
Pralidoxime is a relatively nontoxic drug, and instances of its toxicity are rare. In healthy volunteers, dizziness, diplopia, headache, tachycardia, and blurred vision may occur in the event of an overdose. These symptoms, however, are difficult to discern in a patient of organophosphate poisoning. Supportive therapy is sufficient to treat pralidoxime toxicity.
Time is the golden resource in the management of a case of organophosphate poisoning. It is, therefore, imperative to make a provisional diagnosis as early as possible by assessing the relevant clues from history like occupation, history of clinical depression and prior suicide attempts, and the typical smell of pesticides from clothes. Timely diagnosis and rapid initiation of treatment require flawless interprofessional communication and coordination between an emergency department clinician, anesthesiologist, intensivist, nurse practitioner, poison control center, and other specialists depending on the particular organ system involved. This process can be streamlined by equipping the hospitals in high incidence areas with the necessary drugs and supportive equipment, including adequate protection for doctors themselves. Specialized training and drills for tackling hazards like a chemical attack are essential at regular intervals. In instances where significant time has elapsed since the exposure, aging should be the assumption. The intensive care unit must be alerted without delay, but the pralidoxime administration is still recommended due to the reasons mentioned above.
Meanwhile, efforts can be directed to reducing the incidence of organophosphate poisoning itself by educating farmers about the toxic nature of these compounds and proper safety measures that needed while using these chemicals. Highly toxic pesticides, like chlorpyrifos, should be banned. The psychiatry team also holds an important place in the management as patients with a history of depression and prior suicide attempts must be counseled aggressively.
In recent years several randomized control trials and meta-analyses have questioned the advantage of the addition of pralidoxime over atropine alone in the management of OP poisoning. [Level 1] But these trials have some limitations like lack of inclusion of factors such as the age of the patient, comorbidities, intoxication severity, regional variability of the type of organophosphate compound available, and time since exposure. The dosage of pralidoxime used was also not fixed.
With hundreds of thousands of fatalities each year, the socioeconomic impact of organophosphate poisoning cannot be ignored. Until the shortcomings mentioned above are addressed in future studies, and until we have unequivocal evidence that pralidoxime is ineffective, we must continue to include it in the current therapeutic regimen.
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