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Anesthesiology:
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Cholinesterase Inhibitors, Neuromuscular Blocking Drugs and Perioperative Memory Enhancement

Fodale, Vincenzo M.D.*; Tescione, Marco M.D.; Praticò, Caterina M.D.

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To the Editor:—

I read the fascinating review by Dr. Ghoneim1 with great interest, especially the section on memory-enhancing or memory-impairing drugs. Anesthetics impair memory function in perisurgical periods, whereas cholinesterase inhibitors enhance memory1 and act at central muscarinic cholinergic receptors involved in the process of memory consolidation.2 Cholinesterase inhibitors donepezil, galanthamine, and rivastigmine, currently in clinical use,1,3 represent the first line of treatment in Alzheimer disease and the only drugs of proven benefit.4,5 Other cholinesterase inhibitors (i.e., physostigmine) are under clinical evaluation.3
Drugs affecting central cholinergic activity also influence the anesthetic effect. Increasing central cholinergic tone with physostigmine antagonizes the hypnotic effect of propofol, shown by the return of consciousness (defined as responsiveness to commands) or wakefulness (appearance of being awake with open eyes but without cognitive content).6 Plourde et al.,7 measuring the action of physostigmine on the hypnotic effect of inhaled volatile anesthetics, conclude that physostigmine can, at least partially, antagonize the hypnotic effect of sevoflurane (subanesthetic concentrations) and that the resulting arousal is reflected by an increase in the amplitude of auditory steady-state response and, to a lesser extent, of the bispectral index. An interesting possibility is the antagonism of the anesthetic effect with physostigmine that results from potentiation of 40 Hz oscillations via increased muscarinic tone,8 whereas anesthetic-induced unconsciousness is associated with a reduction of gamma or 40 Hz oscillations in thalamocortical systems.7 These rhythms constitute background activity reflecting depolarization of thalamic and cortical neurons, a physiologic condition required for consciousness.9 In addition, Hill et al.10 demonstrated that physostigmine decreased the time for return of consciousness after halothane anesthesia.
These data, taken together, suggest not only that if reversal of the neuromuscular blockade occurs during anesthesia using cholinesterase inhibitors patients could be at risk of intraoperative awareness, as we recently underlined,11 but also that these drugs may promote an enhancement of implicit memory for any awareness event that occurs. It may occur above all during light levels of anesthesia, common during the final period of anesthesia. During this period, cholinesterase inhibitors are given by anesthesiologists to reverse neuromuscular block. In other words, patients may better recall memories of the awareness experienced intraoperatively.
It was also reported that inhibition of central nicotinic acetylcholine receptors contributes to secondary effects attributed to anesthesia such as impairment in memory and cognitive performance,12 whereas nicotinic acetylcholine receptors agonists improve memory.13 Other drugs used in anesthesia, as well as the neuromuscular blocking drugs atracurium and the atracurium and cisatracurium metabolite laudanosine, activate nicotinic acetylcholine receptors at concentrations comparable to those measured in the central nervous system during, and for several hours after, general anesthesia.14,15 Administration of these neuromuscular blocking drugs, resulting in laudanosine production, has been suggested to improve postoperative cognitive functions,16,17 with the clinical relevance that they could have a potentially therapeutic effect in patients with Parkinson’s disease.18 We ask if atracurium, cisatracurium, and their metabolite laudanosine should be included in the list of drugs acting at the cholinergic receptors and therefore potentially enhancing memory, with advantages and disadvantages mentioned above, and if these data merit, as do the anticholinergic agents, more detailed exploration by laboratory and clinical studies.
Vincenzo Fodale, M.D.,*
Marco Tescione, M.D.
Caterina Praticò, M.D.
* University of Messina, Messina, Italy. vfodale@unime.it
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References

1. Ghoneim MM: Drugs and human memory (part 2). Clinical, theoretical, and methodologic issues. Anesthesiology 2004; 100:1277–97

2. Boccia MM, Acosta GB, Baratti CM: Memory improving actions of gabapentin in mice: Possible involvement of central muscarinic cholinergic mechanism. Neurosci Lett 2001; 311:153–6

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7. Plourde G, Chartrand D, Fiset P, Font S, Backman SB: Antagonism of sevoflurane anaesthesia by physostigmine: Effects on the auditory steady-state response and bispectral index. Br J Anaesth 2003; 91:583–6

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9. Llinas RR, Pare D: Commentary of dreaming and wakefulness. Neuroscience 1991; 44:521–35

10. Hill GE, Stanley TH, Sentker CR: Physostigmine reversal of postoperative somnolence. Can Anaesth Soc J 1977; 24:707–11

11. Fodale V, Santamaria LB: Different actions of sevoflurane and propofol on central nicotinic receptors may explain differences in hypnotic antagonism by cholinesterase inhibitors. Br J Anaesth 2004; 92:773–4

12. Andoh T: Effects of general anesthetics on neuronal nicotinic acetylcholine receptors and their roles in the mechanism of anesthesia. Masui 2001; 50:1072–84

13. Addy NA, Nakijama A, Levin ED: Nicotinic mechanisms of memory: effects of acute local DHbetaE and MLA infusions in the basolateral amygdala. Brain Res Cogn Brain Res 2003; 16:51–7

14. Fodale V, Santamaria LB: Laudanosine, an atracurium and cisatracurium metabolite. Eur J Anaesth 2002; 19:466–73

15. Tassonyi E, Fathi M, Hughes J, Chiodini F, Bertrand D, Muller D, Fuchs-Buder T: Cerebrospinal fluid concentrations of atracurium, laudanosine and vecuronium following clinical subarachnoid hemorrhage. Acta Anaesthesiol Scand 2002; 46:1236–41

16. Fodale V, Santamaria LB: Drugs of anesthesia, central nicotinic receptors and post-operative cognitive dysfunction. Acta Anaesthesiol Scand 2003; 47:1180

17. Fodale V, Santamaria LB: The inhibition of central nicotinic nAch receptors is the possible cause of prolonged cognitive impairment after anesthesia. Anesth Analg 2003; 97:1207

18. Fodale V, Praticò C, Santamaria LB: Drugs of anesthesia, central nicotinic receptors and Parkinson’s disease. Parkinsonism Relat Disord 2004; 10:189–90

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