Cholinesterase Inhibitors, Neuromuscular Blocking Drugs and Perioperative Memory Enhancement

Abstract

I read the fascinating review by Dr. Ghoneim1with great interest, especially the section on memory-enhancing or memory-impairing drugs. Anesthetics impair memory function in perisurgical periods, whereas cholinesterase inhibitors enhance memory1and act at central muscarinic cholinergic receptors involved in the process of memory consolidation.2Cholinesterase inhibitors donepezil, galanthamine, and rivastigmine, currently in clinical use,1,3represent the first line of treatment in Alzheimer disease and the only drugs of proven benefit.4,5Other cholinesterase inhibitors (i.e. , physostigmine) are under clinical evaluation.3Drugs 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).6Plourde et al. ,7measuring 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,8whereas anesthetic-induced unconsciousness is associated with a reduction of gamma or 40 Hz oscillations in thalamocortical systems.7These rhythms constitute background activity reflecting depolarization of thalamic and cortical neurons, a physiologic condition required for consciousness.9In addition, Hill et al. 10demonstrated 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,11but 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,12whereas nicotinic acetylcholine receptors agonists improve memory.13Other 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.14,15Administration of these neuromuscular blocking drugs, resulting in laudanosine production, has been suggested to improve postoperative cognitive functions,16,17with the clinical relevance that they could have a potentially therapeutic effect in patients with Parkinson’s disease.18We 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.* University of Messina, Messina, Italy. vfodale@unime.it