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Neuromuscular blockade and opioids
Published in Hemanshu Prabhakar, Charu Mahajan, Indu Kapoor, Manual of Neuroanesthesia, 2017
Prasanna U. Bidkar, Lakshmi K. Narmadha
When two ACh molecules bind at two α-subunits of a nicotinic ACh receptor, an opening is created in the center of the rosette, allowing sodium and calcium ions to enter the cell and potassium ions to exit,1,2 generating an end-plate potential. The quantum of ACh release from a single vesicle (104 molecules per quantum) produces a miniature end-plate potential. The quanta released by each nerve impulse are very sensitive to extracellular ionized calcium concentration. When enough receptors are occupied by ACh, the end-plate potential is sufficiently strong to depolarize the perijunctional membrane. The resulting action potential propagates along the muscle membrane and T-tubule system, opening sodium channels and releasing calcium from the sarcoplasmic reticulum. This intracellular calcium allows the contractile proteins actin and myosin to interact, bringing about muscle contraction. The amount of ACh usually released and the number of receptors subsequently activated normally far exceed the minimum required for the initiation of an action potential. The nearly 10-fold margin of safety is overwhelmed in Eaton–Lambert myasthenic syndrome (decreased release of ACh) and myasthenia gravis (decreased number of receptors).
Electrodiagnosis
Published in Mark V. Boswell, B. Eliot Cole, Weiner's Pain Management, 2005
Ross E. Lipton, David M. Glick
Bioelectrical signals obtained during needle EMG are categorized by activity noted at rest versus active muscle contraction. Resting muscle EMG reveals two subtypes of activity: spontaneous activity (that activity noted while the needle is resting in muscle after cessation of insertion) and insertional activity (that activity noted during crisp short insertions). Needle insertion causes a burst of shortlived relatively high frequency activity. Silence immediately follows in normal muscle. Both the examiner and the subject must hold still after each insertion, to avoid movement artifact. This artifact is sometimes responsible for misdiagnosis of abnormal insertional activity by a less-experienced examiner. Normal insertional activity should last no longer than 0.5 ms. Activity lasting beyond 0.5 s suggests irritability. This may be the earliest evidence of increased insertional activity, especially if coupled with a sharp wave or fibrillation potential (Bromberg, 1993). Needle insertion into the neuromuscular junction begets normal “end plate” activity, exemplified by the miniature end plate potential (MEPP), a tiny sharp monophasic negative wave (less than 10 microvolts, less than 3 ms duration) that occurs randomly and is difficult to isolate, due to coalescence with end plate noise. End plate noise appears as many end plate spikes with an irregular baseline. This activity produces the characteristic “seashell” murmur. Miniature end plate potentials are random, monophasic, upward-deflecting (negative) waves, occurring spontaneously with irregular rhythm representing presynaptic calcium release, leading to subthreshold levels of acetylcholine. Therefore, no action potential is generated (Dumitru, 1991a, b).
Review of the mechanism underlying mefloquine-induced neurotoxicity
Published in Critical Reviews in Toxicology, 2021
Airton C. Martins, Monica M. B. Paoliello, Anca O. Docea, Abel Santamaria, Alexey A. Tinkov, Anatoly V. Skalny, Michael Aschner
The proposed role of altered Ca2+ homeostasis in mefloquine-induced neurotoxicity, and its relationship to other pathogenetic mechanisms are shown in Figure 2. Mefloquine has been found to be a noncompetitive inhibitor of both acetylcholinesterase (AChE, located in neural synapses), and butyrylcholinesterase (BChE, located in the liver and blood) (Lim and Go 1985). Inhibition of AChE alters both peripheral and central cholinergic synaptic transmission. AChE catalyzes the hydrolysis of acetylcholine to acetate and choline to clear acetylcholine from the cholinergic synapse, attenuating neurotransmission. Inhibition of acetylcholinesterase by mefloquine prolongs the stimulation of muscarinic or nicotinic acetylcholine receptors, disrupting neurotransmission. Indeed, mefloquine significantly increases mean miniature endplate potential (MEPP) frequency, increases MEPP amplitude, and prolongs its duration at the neuromuscular junction at minimum mefloquine concentration of 10 μM (McArdle et al. 2005, 2006), suggesting that mefloquine may contribute to neurotoxicity through altered cholinergic synaptic transmission. The prolonged neurotransmission by acetylcholine may be responsible for the disruption of calcium (Ca2+) homeostasis, resulting in neurotoxic effects. Acetylcholine binds and interacts with nicotinic (nAChR) and muscarinic acetylcholine receptors (mAChR), which results in increased intracellular Ca2+concentrations. nAChRs are ionotropic receptors that bind acetylcholine and are permeable to sodium, potassium, and Ca2+ (Siegel et al. 1999) (Figure 2). mAChRs bind acetylcholine and induce the catalysis of inositol 1,4,5-triphosphate (IP3) by phospholipase C (PLC) or the catalysis of cyclic adenosine monophosphate (cAMP) by adenylate cyclase (Siegel et al. 1999). These second messengers regulate Ca2+ homeostasis via modulation of plasma membrane and endoplasmic reticulum membrane ion channels (Figure 2). Traditionally, AChE inhibition and disruption of Ca2+ homeostasis have been associated with memory deficit, seizures, and neurodegeneration of hippocampal pyramidal neurons (Ijomone et al. 2019). These observations are consistent with earlier reported associations, showing that anticholinesterase agents not only induce neurodegeneration of pyramidal neurons residing in CA1 hippocampal area, but also potentiated neuronal oxidative damage (Gupta et al. 2007).