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Section IICoredrugs in anaesthetic practiceOAnionic site ( ) Esteratic site AChEPFigure 11.10.Organophosphorus compounds phosphorylate AChE, forming a very
stable complex.Mechanism of action
The esteratic site of AChE, is phosphorylated by organophosphorous compounds
resulting in inhibition of the enzyme (Figure11.10). The complex that is formed is
very stable and, unlike the carbamate esters, is resistant to hydrolysis or reactivation.
Inpractice recovery depends on synthesis of new enzyme. These drugs also inhibit
plasma cholinesterase.
Toxic manifestations include nicotinic and muscarinic effects, autonomic insta-
bility and initially central excitation progressing to depression, coma and apnoea.
Pralidoximeandobidoxineare reactivators of phosphorylated AChE by promot-
ing hydrolysis. Atropine, anticonvulsants and ventilation may also be necessary in
organophosphorous poisoning.Cyclodextrins
Cyclodextrins are inert doughnut-shaped molecules that have the ability to encapsu-
late other specific molecules. The gamma cyclodextrin Org25969 is currently under-
going Phase III trials for its efficacy in encapsulating rocuronium. Encapsulation
effectively removes rocuronium from the plasma and as further drug diffuses away
from the NMJ its effect there is reversed. It appears to be effective in reversing rocuro-
nium, even from profound levels of NMJ blockade, and quickly. In addition it has no
other effects unlike the anticholinesterases. The cyclodextrin/rocuronium complex
is eliminated via the kidneys.
Org25969 offers a significant advance in the reversal of NDMR blockade.