Hypothesis for synergistic toxicity of organophosphorus poisoning-induced cholinergic crisis and anaphylactoid reactions.
The neurotoxicity of organophosphorus (OP) compounds involves the inhibition of acetylcholinesterase (AChE), causing accumulation of acetylcholine (ACh) at synapses. However, cholinergic crisis may not be the sole mechanism of OP toxicity. Adverse drug reactions caused by synergistic toxicity between drugs with distinct pharmacological mechanisms are a common problem. Likewise, the multiple pharmacological activities of a single molecule might also contribute to either toxicity or efficacy. For example, certain OP compounds (e.g. soman) exhibit anti-AChE activity and also act as secretagogues by inducing mast cell degranulation with associated autacoid release and anaphylactoid reactions. Anaphylactoid shock can produce a lethal syndrome with symptoms of respiratory failure and circulatory collapse similar to the physiological sequelae observed for OP poisoning. Moreover, the major classes of drugs used as antidotes for OP intoxication can affect anaphylaxis. Acetylcholine can act as an agonist of autacoid release, and autacoids such as histamine can augment soman-induced bronchial spasm. In concert with the demonstrably critical role of cholinergic crisis in OP toxicity, the precepts of neuroimmunology indicate that secondary adverse reactions encompassing anaphylactoid reactions may complicate OP toxicity.
Cowan
F M
FM
Biochemical Pharmacology Branches, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5425, USA.
Shih
T M
TM
Lenz
D E
DE
Madsen
J M
JM
Broomfield
C A
CA
D000707:Anaphylaxis / Q000473:pathology*; D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D006224:Cricetinae; D004357:Drug Synergism; D062025:Organophosphate Poisoning; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010275:Parasympathetic Nervous System
D009943:Organophosphorus Compounds