Details About Overdose or Poisoning Generic Salt :: Pralidoxime, 2 PAM And Other Oximes
Pralidoxime (2-PAM) and Other Oximes
Drug Pharmacology ::
I. Pharmacology. Oximesreverse acetylcholinesterase (AChE) inhibition by reactivating thephosphorylated cholinesterase enzyme and protecting the enzyme fromfurther inhibition. Although this effect is most pronounced withorganophosphate pesticides, positive clinical results have been seenwith carbamate insecticides that have nicotinic toxicity and variablywith cholinesterase inhibitors formulated as “nerve gas” chemicalweapons. The clinical effects of oximes are most apparent at nicotinicreceptors, with reversal of skeletal muscle weakness and musclefasciculations. Their impact on muscarinic symptoms (salivation,sweating, bradycardia, and bronchorrhea) is significantly lesspronounced than that of the antimuscarinic agents atropine andglycopyrrolate, along with which oximes invariably are administered(see Atropine and Glycopyrrolate).
Pralidoximechloride (2-PAM) is the only oxime currently approved for use in theUnited States. Oximes differ in their effectiveness against specificagents, doses, and side-effect profiles. In the United Kingdom, themethanesulfonate salt of pralidoxime, P2S, is used. In other Europeancountries and South Africa, TMB4 and obidoxime (Toxogonin) areemployed. 2-PAM methiodide is used in Japan. HI-6 is a promising oximelong under development.
Oximes are effective when given before the enzyme has been boundirreversibly (“aged”) by the organophosphate, although they may haveadditional modes of action. The rate of aging varies considerably witheach organophosphorus compound. For dimethylphosporylated AChE (eg,from dichlorvos, Malathion poisoning), the aging half-life isapproximately 3.7 hours, whereas for diethylphosphorylated AChE (eg,from diazinon or parathion poisoning), the aging half-life isapproximately 33 hours. For some chemical warfare agents, aging mayoccur in several minutes (soman-phosphorylated AChE aging half-life isabout 2–6 minutes). However, late therapy with 2-PAM is appropriate(even several days after exposure), especially in patients poisonedwith diethylating compounds and by fat-soluble compounds (eg, fenthion,demeton) that can be released from tissue stores over days, causingcontinuous or recurrent intoxication.
“Nerve”agents prepared as chemical warfare weapons, such as sarin, soman,tabun, and VX, are mechanistically similar to AChE-inhibitinginsecticides. However, they are far more potent and are responsive onlyto certain oximes. Pralidoxime is not effective against tabun, forexample, but trimedoxime (TMB4) may be. Current oxime research seekingagents with broader activity against nerve agents is evaluating the Hoximes HLO-7 and HI-6.
Inadequate dosing of 2-PAM may be linked to the “intermediate syndrome,” which is characterized by prolonged muscle weakness.
E.Peak plasma concentrations are reached within 5–15 minutes afterintravenous 2-PAM administration. Pralidoxime is eliminated by renalexcretion and hepatic metabolism, with a half-life of 0.8–2.7 hours.
Drug Indications ::
Oximesare used to treat poisoning caused by cholinesterase inhibitorinsecticides and nerve agents, ie, organophosphates, mixtures oforganophosphorus and carbamate insecticides, and pure carbamateinsecticide intoxication with nicotinic-associated symptoms.Pralidoxime has low toxicity, is possibly ineffective if treatment isdelayed until after the cholinesterase enzyme has aged, is able toreverse nicotinic as well as muscarinic effects, and can reduceatropine requirements. For these reasons, pralidoxime should be usedearly and empirically for suspected cholinesterase inhibitor poisoning.
Withcarbamate poisoning, cholinesterase inhibition spontaneously resolveswithout “aging” of the enzyme. As a result, many references state thatpralidoxime is not needed for carbamate poisoning. However, spontaneousreversal of enzyme inhibition may take up to 30 hours, and case reportssuggest that pralidoxime is effective in human carbamate poisoning.Data suggesting increased toxicity of pralidoxime in carbaryl (Sevin)poisoning are based on limited animal studies, and the results are notgeneralizable to humans.
Drug Contra-Indications ::
Usein patients with myasthenia gravis may precipitate a myasthenic crisis;however, in severe suspected cholinesterase inhibitor poisoning,benefit may exceed anticipated risk.
Use with caution and in reduced doses in patients with renal impairment.
Drug Adverse Effects ::
IV. Adverse effects
Nausea, headache, dizziness, drowsiness, diplopia, and hyperventilation may occur.
Rapidintravenous administration may result in tachycardia, laryngospasm,muscle rigidity, and transient neuromuscular blockade. Hypertension,which is reversible with drug cessation or by administration ofphentolamine, 5 mg IV, is also ascribed to rapid infusion.
Use in pregnancy. FDAcategory C (indeterminate). This does not preclude its acute,short-term use in a seriously symptomatic patient (see Table III–1).
Drug Lab Interactions ::
Drug or laboratory interactions
Muscarinic blockade may occur more quickly when atropine (or glycopyrrolate) and pralidoxime are administered concurrently.
Red blood cell cholinesterase (ChE) activity is reactivated more readily reactivated by pralidoxime than by plasma ChE.
Drug Dose Management ::
Dosage and method of administration. Forpralidoxime, the intravenous route is preferred. Intramuscular orsubcutaneous injection is possible when the intravenous route is notimmediately available. The Mark 1 autoinjector kit contains 600 mgpralidoxime (and 2 mg atropine) for IM use in the event of nerve gasattack.
Initial dose. Give1–2 g (children, 25–50 mg/kg up to 1 g) as a continuous intravenousinfusion in 100 mL of saline (1–2 mL/kg) over 15–30 minutes. Repeat theinitial dose after 1 hour if muscle weakness or fasciculations are notrelieved. Several grams may be required in some cases.
Immediate field treatmentof nerve agent poisoningis accomplished with intramuscular 2-PAM. The dose is 600 mg IM formild to moderate symptoms and up to 1800 mg for severe poisonings. TheMark I autoinjector kit contains 600 mg 2-PAM and 2 mg atropine and isdesigned for self-administration
Maintenance infusion. Becauseof the short half-life of 2-PAM and the longer duration of manyorganophosphorus compounds, toxicity frequently recurs, requiringrepeated doses.
1. Discreteintermittent boluses may result in wide fluctuation in serum levels anderratic clinical effects. Therefore, after the initial dose it ispreferable to give 2-PAM as a continuous intravenous infusion in a 1%solution (1 g in 100 mL saline) at a rate of 200–500 mg/h (children,5–10 mg/kg/h) and titrate to the desired clinical response.
2. Despiteearlier recommendations that 2-PAM should be given for only 24 hours,therapy may have to be continued for several days, particularly whenlong-acting, lipid-soluble organophosphates are involved. Graduallyreduce the dose and carefully observe the patient for signs ofrecurrent muscle weakness or other signs of toxicity.
3. Note: 2-PAM may accumulate in patients with renal insufficiency.
Drug Chemical Formulations ::
Parenteral. Pralidoxime chloride (2-PAM, Protopam), 1 g with 20 mL sterile water.
The suggested minimum stocking level to treat a 70-kg adult for the first 24 hours is 12 vials. Note:In agricultural areas or urbanized regions preparing for possibleaccidental or terrorist release of a large amount of cholinesteraseinhibitor agent, much larger stockpiling may be appropriate.Pralidoxime has been stockpiled by the Strategic National Stockpile(SNS) program as Mark I autoinjector kits and 1-g vials of pralidoximechloride.