Effects of phenytoin, ketamine, and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate.
Toxic manifestations of acetylcholinesterase inhibitors (AChE-I) include muscle twitching and muscle fiber necrosis, in addition to muscarinic manifestations of acetylcholine excess. The AChE-Is pinacolyl methylphosphonofluoridate (soman) or diisopropylphosphorofluoridate (DFP) were administered to rats to produce spontaneous muscle fiber discharges. Soman produced discharges that arose primarily from the central nervous system (CNS), while those due to DFP were generated from the peripheral nerves as well as the CNS. Three drugs were tested for their potential to reduce muscle fiber discharges: atropine methyl nitrate (AMN), ketamine, and phenytoin. Ketamine caused a significant decrease in discharges of CNS origin, while AMN and phenytoin had no effect. For muscle fiber discharges of peripheral origin, all three drugs produced a significant drop in muscle fiber discharges, but phenytoin showed slightly more efficacy than the others. AChE-I-induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different AChE-Is. Treatment for the toxicity of AChE-Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system (PNS) where AChE-Is exert their effects. By attenuating the effects of AChE-Is at specific CNS or PNS sites, the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each AChE-I.
Clinton
M E
ME
Department of Neurology, Vanderbilt University, Nashville, Tennessee 37212.
Misulis
K E
KE
Dettbarn
W D
WD
D000818:Animals; D001286:Atropine Derivatives / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000633:toxicity; D002801:Cholinesterase Reactivators; D007531:Isoflurophate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009121:Muscle Denervation; D009132:Muscles / Q000187:drug effects / Q000473:pathology; D009469:Neuromuscular Junction / Q000187:drug effects*; D010672:Phenytoin / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012999:Soman / Q000037:antagonists & inhibitors* / Q000633:toxicity
D001286:Atropine Derivatives; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D007531:Isoflurophate; D010672:Phenytoin; D007649:Ketamine; C006649:methylatropine; D012999:Soman