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Anticholinesterases, also known as cholinesterase inhibitors, are a class of drugs that inhibit acetylcholinesterase, the enzyme responsible for degrading the neurotransmitter acetylcholine at the junctions between neurons. By preventing the breakdown of acetylcholine, anticholinesterases prolong the neurotransmitter’s activity at nerve cell receptors. They are used to treat a range of neurodegenerative diseases, including Alzheimer’s and Parkinson’s,1 but are also commonly used in anesthesia.
The most frequent application of anticholinesterases in anesthesia is the reversal of non-depolarizing neuromuscular blocking agents, such as rocuronium, vecuronium, and atracurium. These muscle relaxants, administered during surgery to facilitate intubation and mechanical ventilation, could otherwise persist for hours and lead to risks of prolonged paralysis. Anticholinesterases such as neostigmine accelerate recovery by facilitating an increase of acetylcholine at the neuromuscular junction, thereby re-establishing motor function once the surgery is complete and patients can be woken up from anesthesia.2
Anticholinesterases exert their effects by binding to and inhibiting acetylcholinesterase, which under normal circumstances breaks down acetylcholine into acetate and choline within milliseconds.1 With the enzyme inhibited, acetylcholine accumulates in the synapse and repeatedly stimulates receptors. This increase in activity overcomes the competitive blockade produced by non-depolarizing neuromuscular blocking drugs, which bind to acetylcholine receptors on the motor end plate of muscle fibers and prevent the propagation of nerve signals.
Anticholinesterases have some advantages over other classes of drugs that reverse neuromuscular blockade. Sugammadex, for instance, is a selective relaxant binding agent that binds directly to certain muscle relaxers to inhibit them.3 Neostigmine is not only cheaper than sugammadex but has a wider indication: it works to reverse both aminosteroid (rocuronium vecuronium, for example) and benzylisoquinolinium (such as cisatracurium) blockers, whereas sugammadex is ineffective for the benzylisoquinolinium class.4 However, sugammadex can reverse a block of any depth, while neostigmine is best suited for a shallow or medium-depth block. Sugammadex also has a faster onset.
Additionally, neostigmine and other anticholinesterases are more likely to induce higher rates of certain side effects than sugammadex. In one study of over 45,000 patients, neostigmine use was associated with a higher rate of major pulmonary complications, likely a function of residual neuromuscular blockade.5 Sugammadex has also been shown to reduce levels of postoperative pain and nausea.
While neuromuscular reversal is the primary indication for anticholinesterases in anesthesia, other roles for anticholinesterases have been explored. Physostigmine, which crosses the blood–brain barrier, has demonstrated antinociceptive properties, reducing perioperative pain and opioid consumption. In randomized trials, physostigmine combined with morphine produced superior analgesia compared with morphine alone.6 Due to its anti-inflammatory properties, it has also been investigated in postoperative delirium and septic shock, with an eye towards mitigating cytokine release and thereby helping to improve outcomes.
Though these medications have been around for decades, new research on anticholinesterases is underway to broaden their applicability. Organometallic complexes, especially those that involve the use of ruthenium, are a newer type of anticholinesterase that may prove similarly effective with fewer side effects.7 The structure of these molecules potentially allows for greater selectivity and reversibility, as well as the ability to target multiple receptors. More research into anticholinesterases may help to further boost their usefulness in anesthesia and other fields of medicine.
References
1. Singh, R. & Sadiq, N. M. Cholinesterase Inhibitors. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2025).
2. Neely, G. A., Sabir, S. & Kohli, A. Neostigmine. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2025).
3. Chandrasekhar, K., Togioka, B. M. & Jeffers, J. L. Sugammadex. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2025).
4. Maqusood, S., Bele, A., Verma, N., Dash, S. & Bawiskar, D. Sugammadex vs Neostigmine, a Comparison in Reversing Neuromuscular Blockade: A Narrative Review. Cureus 16, e65656, 10.7759/cureus.65656
5. Kheterpal, S. et al. Sugammadex versus Neostigmine for Reversal of Neuromuscular Blockade and Postoperative Pulmonary Complications (STRONGER): A Multicenter Matched Cohort Analysis. Anesthesiology 132, 1371–1381 (2020), 10.1097/ALN.0000000000003256
6. Beilin, B., Bessler, H., Papismedov, L., Weinstock, M. & Shavit, Y. Continuous physostigmine combined with morphine-based patient-controlled analgesia in the postoperative period. Acta Anaesthesiol Scand 49, 78–84 (2005), 10.1111/j.1399-6576.2004.00548.x
7. Žužek, M. C. Advances in Cholinesterase Inhibitor Research—An Overview of Preclinical Studies of Selected Organoruthenium(II) Complexes. Int J Mol Sci 25, 9049 (2024), 10.3390/ijms25169049
