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

INTRODUCTION

1. 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.

2. 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 ...