CHAPTER 3-68: PRALIDOXIME (2-PAM) AND OTHER OXIMES

Pharmacology. Although antimuscarinic agents (atropine and glycopyrrolate) are the most important therapy of cholinesterase inhibitor poisoning, they affect only muscarinic receptors and create no clinical effects at the four sites enervated by nicotinic receptors. Oximes reverse acetylcholinesterase (AChE) inhibition (thus reversing cholinergic excess at both muscarinic and nicotinic receptors) by reactivating the phosphorylated AChE and protecting the enzyme from further inhibition. Several recent reviews have called into question the efficacy of oximes and pointed out the lack of randomized trials supporting their utility and safety. However, they are the only agents available capable of reactivating AChE and reversing the excess acetylcholine at the nicotinic receptors of the (1) neuromuscular junction (reversing skeletal muscle weakness and fasciculations), (2) parasympathetic and (3) sympathetic ganglia, and at (4) CNS nicotinic receptors (reversing agitation, confusion, coma, and central respiratory failure). Although this effect is most pronounced with organophosphorus (OP) insecticides, positive clinical results have been seen with carbamate (CBM) insecticides that have nicotinic toxicity and variably with cholinesterase inhibitors formulated as "nerve gas" chemical weapons.

1. Pralidoxime chloride (2-PAM) is the only oxime currently approved for use in the United States. Oximes differ in their effectiveness against specific agents, recommended doses, and side effect profiles. Oximes commonly used in other countries include obidoxime, trimedoxime, and HI-6.

2. Oximes are more effective when given before AChE has been bound irreversibly ("aged") by the organophosphate. The rate of aging varies considerably with each OP compound. For dimethyl compounds (eg, dichlorvos, malathion), the aging half-life is approximately 3.7 hours, whereas for diethyl compounds (eg, diazinon, parathion), the aging half-life is approximately 33 hours. For some chemical warfare agents, aging may occur within several minutes (soman phosphorylated AChE aging half-life is about 2–6 minutes). However, late therapy with 2-PAM may still be appropriate even several days after exposure, for example, in patients poisoned by highly fat-soluble compounds (eg, fenthion, demeton) that can be released from tissue stores over days, causing continuous or recurrent intoxication.

3. "Nerve" agents prepared as chemical warfare weapons, such as sarin, soman, tabun, and VX, are mechanistically similar to AChE-inhibiting insecticides. However, they are far more potent and are responsive only to certain oximes. Pralidoxime is not effective against tabun, for example, but HI-6 has been found to be. Current oxime research seeking drugs with broader activity against nerve agents is evaluating HI-6, K027, K048, K074, and K075.

4. Inadequate dosing of 2-PAM may be linked to the "intermediate syndrome," which is characterized by prolonged muscle weakness.

5. Peak plasma concentrations are reached within 5–15 minutes after intravenous 2-PAM administration. Pralidoxime is eliminated by renal excretion and hepatic metabolism, with a half-life of 0.8-2.7 hours.

Indications

1. Oximes are used to treat poisonings caused by cholinesterase inhibitor insecticides and nerve agents, including OPs, mixtures of OP and CBM insecticides, and pure CBM insecticides. Pralidoxime has low toxicity, is able to reverse nicotinic as well as muscarinic effects, and may reduce atropine requirements. For these reasons, pralidoxime should be considered early and empirically for suspected cholinesterase inhibitor poisoning, particularly in the context of muscle fasciculation or weakness.

2. With carbamate (CBM) poisoning, cholinesterase inhibition spontaneously resolves without "aging" of the enzyme. As a result, many references state that pralidoxime is not needed for CBM poisoning. However, spontaneous reversal of enzyme inhibition may take up to 30 hours, and case reports suggest that pralidoxime is effective in human CBM poisoning. Data suggesting increased toxicity of pralidoxime in carbaryl (Sevin) poisoning are based on limited animal studies, and the results are not applicable to humans.

Contraindications

1. Use in patients with myasthenia gravis may precipitate a myasthenic crisis.

2. Use with caution and in reduced doses in patients with renal impairment.

Adverse effects

1. Nausea, headache, dizziness, drowsiness, diplopia, and hyperventilation may occur.

2. Rapid intravenous administration may result in tachycardia, hypertension, laryngospasm, muscle rigidity, and transient neuromuscular blockade. Hypertension is reversible with drug cessation or by administration of a vasodilator (eg, sodium nitroprusside).

3. Use in pregnancy. FDA Category C (indeterminate). This does not preclude its acute, short-term use in a seriously symptomatic patient (see Section III).

Drug or laboratory interactions. Reversal of muscarinic blockade may occur more quickly when atropine (or glycopyrrolate) and pralidoxime are administered concurrently.

Dosage and method of administration. Start pralidoxime at the earliest possible time (before AChE aging occurs) and via the intravenous route (to rapidly achieve predictable serum levels). Intermittent intramuscular or subcutaneous administration is possible, if circumstances dictate, but may result in wide fluctuation in serum levels and erratic clinical effects. Pralidoxime has a short elimination half-life, so the loading dose should be followed by a continuous infusion. However, no standard continuous infusion rate has been established, and rates cited below should be considered as guidelines to be modified by clinical response (ie, relief of muscle fasciculations and muscle weakness).

1. Adult intravenous dosing. A typical loading dose is 1,000-2,000 mg in 100 mL of saline infused over 15–30 minutes. Repeat the initial dose after 1 hour if muscle weakness or fasciculations are not relieved. This is followed by a continuous infusion of 1% pralidoxime in saline (eg, 1 g in 100 mL). The manufacturer cites continuous infusion rates of 400–600 mg/h, and rates as high as 8–10 mg/kg/h have been utilized. (The World Health Organization recommends a bolus dose of 2 g, followed by a continuous infusion of 8–10 mg/kg/h.)

2. Pediatric intravenous dosing (for patients aged 16 years and younger). A typical loading dose is 30 mg/kg (range 20–50 mg/kg), not to exceed 2,000 mg, as a 1% solution in saline, infused over 15–30 minutes. Repeat the initial dose after 1 hour if muscle weakness or fasciculations are not relieved. This is followed by a continuous infusion of 1% pralidoxime in saline. The manufacturer cites continuous pediatric infusion rates of 10–20 mg/kg/h.

3. Immediate field treatment of suspected nerve agent poisoning is by intramuscular injection. The dose is 600 mg IM for mild to moderate symptoms and up to 1,800 mg for severe poisonings. The Mark I autoinjector kit contains 600-mg pralidoxime plus 2-mg atropine and is designed for self-administration.

4. Duration of therapy. Despite earlier recommendations that pralidoxime should be given for only 24 hours, therapy may have to be continued for several days, particularly when long-acting, lipid-soluble organophosphates are involved. Gradually reduce the dose and carefully observe the patient for signs of recurrent fasciculations, muscle weakness, or other signs of toxicity. Note: Pralidoxime may accumulate in patients with renal insufficiency.

Formulations

1. Parenteral. Pralidoxime chloride (2-PAM, Protopam), 1 g with 20-mL sterile water.

2. The suggested minimum stocking level to treat a 70-kg adult for the first 24 hours is 18 × 1 g (20 mL) vials. Note: In agricultural areas or urbanized regions preparing for possible accidental or terrorist release of a large amount of cholinesterase inhibitor agent, much larger stockpiling may be appropriate. Pralidoxime is stockpiled by the Strategic National Stockpile (SNS) program as Mark I autoinjector kits and 1-g vials of pralidoxime chloride.