History of the development of antagonists for neuromuscular blocking agents
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History of the development of antagonists for neuromuscular blocking agents Keiko Suzuki1 · Tomonori Takazawa1 · Shigeru Saito1,2 Received: 25 March 2020 / Accepted: 27 July 2020 © Japanese Society of Anesthesiologists 2020
Abstract Muscle relaxation induced by neuromuscular blocking agents (NMBAs) is necessary for tracheal intubation and immobilization during surgery. Although acetylcholinesterase inhibitors have been successfully used as antagonists for NMBAs, they have their limitations; their effects are transient and ineffective against profound neuromuscular blockade. In the past, alternative antagonists were developed, such as germine and 4-aminopyridine, which are effective for the treatment of diseases causing muscle weakness and could potentially be used as antagonists for NMBAs. Unfortunately, these drugs did not come into practical use due to unwanted side-effects. Sugammadex is an almost ideal antagonist because it rapidly forms a rigid complex with rocuronium and produces less adverse effects. The development of novel NMBAs and antagonists, especially sugammadex, has revolutionized anesthesia practice. Recently, novel short-acting NMBAs, such as gantacurium and CW002 have been developed. Their effects can be reversed by the amino-acid l-cysteine. More recently, calabadions have been developed, which can form complexes with both steroidal and bisbenzyl-isoquinolinium NMBAs, in a similar fashion as sugammadex. Understanding the history of the NMBA antagonist’s development is interesting and useful for modern anesthesiologists since it enhances their knowledge about the mechanisms involved in neuromuscular transmission and might lead to the development of ideal NMBA antagonists. Keywords Non-depolarizing neuromuscular blocking drug · Acetylcholinesterase inhibitor · Neostigmine · Sugammadex
Introduction Muscle relaxation using neuromuscular blocking agents (NMBAs) is necessary for various types of surgery to prevent muscle contraction and movement in response to surgical stimulation. Muscle relaxation is also essential for endotracheal intubation. NMBAs are often classified into two broad classes depending on the presence or absence of depolarizing activity. An example of a depolarizing NMBA is suxamethonium, which has a rapid onset and short duration of action, making it convenient for a rapid sequential induction of anesthesia. However, adverse effects, such as hyperkalemia, increase in intracranial pressure and risk of * Tomonori Takazawa takazawt@gunma‑u.ac.jp 1
Intensive Care Unit, Gunma University Hospital, 3‑39‑15 Showa‑machi, Maebashi, Gunma 371‑8511, Japan
Department of Anesthesiology, Gunma University Graduate School of Medicine, 3‑39‑15 Showa‑machi, Maebashi, Gunma 371‑8511, Japan
2
malignant hyperthermia, limit its use [1, 2]. Since non-depolarizing NMBAs do not have these side-effects, the main focus in drug development has been on this class of NMBAs. NMBAs can cause postoperative complications if their effects are not completely reversed. Indeed, one cause o
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