The neurologic approach
Stanley Berent, James W. Albers in Neurobehavioral Toxicology, 2012
The electrical response to repetitive motor nerve stimulation can be used to evaluate neuromuscular transmission (Ozdemir & Young, 1976). When neuromuscular transmission is impaired, there is a decrement in the motor response at low stimulation rates (3 Hz) (Massey, 1990; Albers & Leonard, 1992). At this stimulation rate, normal subjects show no evidence of a decremental response. Acetylcholine is released from the nerve terminal when the nerve is depolarized. Acetylcholine molecules diffuse across the neuromuscular junction and interact with acetylcholine receptors (AChR) on the muscle membrane. This interaction results in a configurational change in sodium channels, producing an endplate potential. If the endplate potential is sufficiently large, a muscle action potential is generated and the muscle fiber contracts. Factors important to this response include, among other factors, sufficient availability of acetylcholine, appropriate inactivation of acetylcholine in the synaptic cleft, and intact AChR. Abnormality of any of these factors can impair neuromuscular transmission.
Quantitative Changes in Receptor Concentrations as a Function of Disease
William C. Eckelman, Lelio G. Colombetti in Receptor-Binding Radiotracers, 2017
Receptor mechanisms vary quite broadly. The precise means by which the ligand-receptor combination leads to physiological effect is generally not known. The binding of ligand may lead to an activation of the ligand-receptor complex, as in the beta-adrenoceptor, which subsequently interacts with adenylate cyclase.11 Other receptors cause transient changes in membrane permeability to ions through specific ion channels, e.g., the nicotinic acetylcholine receptor.12 The binding of the natural ligand may follow a simple mass-action relationship or exhibit either positive or negative cooperativity in the binding of more than one ligand to oligomeric receptors. Irrespective of these complexities, a simple expression for ligand-receptor interactions is valuable as a first estimate of the concentration of bound ligand, [RL], and the bound-to-free ligand ratio, r, the latter which we suggest is representative of the target-to-blood ratio. We have reported two equilibrium equations,13 Equations 1 and 2, which are useful for predicting the quantities [RL] and r, respectively:
Neuromuscular disorders
Angus Clarke, Alex Murray, Julian Sampson in Harper's Practical Genetic Counselling, 2019
In the usual adult form of myasthenia gravis associated with antibodies to the acetylcholine receptor, genetic risks are extremely low. In one series of over 400 patients, one pair of affected sibs was the only familial case. A risk of around 1% for myasthenia gravis is appropriate for first-degree relatives, along with an increase in autoimmune thyroid disease. An association has been found between myasthenia gravis and the antigens HLA-DRw3 and HLA-B8. This is a good illustration of the fact that such associations do not necessarily imply high risks to family members. Transient congenital myasthenia gravis is seen in about 20% of the offspring of affected mothers, but, unlike the corresponding situation in myotonic dystrophy, rarely has permanent effects.
Isolating the Superficial Peroneal Nerve Motor Branch to the Peroneus Longus Muscle with Concentric Stimulation during Diagnostic Motor Nerve Biopsy
Published in The Neurodiagnostic Journal, 2022
Ashley Rosenberg, Rachel Pruitt, Sami Saba, Justin W. Silverstein, Randy S. D’Amico
Admission neurological exam was consistent with hypoxic hypercapnic encephalopathy, as well as a distal predominant polyneuropathy likely related to his history of diabetes mellitus and/or alcohol use. Electrodiagnostic studies demonstrated bilateral phrenic nerve impairment and diffusely decreased motor potentials, suggestive of either a motor neuropathy, myopathy, or, least likely, motor neuron disease. Acetylcholine receptor binding, blocking, and modulating antibodies were negative. At this point, neurosurgery was consulted for a possible muscle/nerve biopsy. A lumbar puncture was performed to evaluate for possible inflammatory neuropathy, which was negative, and a normal creatine kinase level and a lack of spontaneous activity on electromyography argued against inflammatory myopathy. Due to bilateral phrenic nerve impairment, the decision was made to pursue a muscle and motor nerve biopsy for further evaluation. Peroneal nerve decompression at the fibular head with biopsy of the motor branch to the peroneus longus muscle and biopsy of the peroneus longus muscle were performed.
Indacaterol/glycopyrronium/mometasone fixed dose combination for uncontrolled asthma
Published in Expert Review of Respiratory Medicine, 2022
Corrado Pelaia, Claudia Crimi, Nunzio Crimi, Luisa Ricciardi, Nicola Scichilone, Giuseppe Valenti, Ornella Bonavita, Stefano Andaloro, Paolo Morini, Andrea Rizzi, Girolamo Pelaia
Anticholinergic bronchodilators antagonize the parasympathetic system by acting on the acetylcholine receptors expressed on airway smooth muscles and lung parasympathetic nerves. There are two groups of acetylcholine receptors: nicotinic- and muscarinic- and the muscarinic subtypes M1, M2 and M3 are primarily involved in the regulation of bronchoconstriction. All muscarinic receptor subtypes are widely expressed in different tissues (smooth muscles, brain, heart and the sinoatrial node, gastrointestinal tract, pupils, blood vessels and the parasympathetic nervous system). Muscarinic M2 receptors in the heart regulate heart beating by reducing the activation of the sinus node, while the M3 subtypes are responsible of contraction of the muscles of gastrointestinal tract, or blood vessel vasodilation [32,33]. Specifically referring to airway tract activity, M1 receptors are widely distributed in all parasympathetic ganglia and they act by regulating cholinergic transmission. M2 receptors are found in the pre-junctional membranes of the neuromuscular junctions of airway smooth muscles and reduce acetylcholine transmission through a negative feedback. M3 receptors are mainly expressed in smooth muscle cells in the lungs, regulating muscle contraction, while within the submucosal glands of the lung, M3 receptors regulate mucus secretion. Thus, it is preferable that antimuscarinic bronchodilators present higher affinity for M1 and M3 receptors, and lower affinity for M2 receptors [34].
The role of sugammadex, a novel cyclodextrin compound in modern anesthesia practice: conventional neuromuscular physiology and clinical pharmacology
Published in Expert Review of Clinical Pharmacology, 2019
Alan D. Kaye, Rachel J. Kaye, Elyse M. Cornett, Ivan Urits, Vwaire Orhurhu, Omar Viswanath, Amit Prabhakar
As a review of human physiology, the neuromuscular junction is comprised of several key components, including the presynaptic nerve terminal, synaptic cleft, and the post-synaptic nicotinic acetylcholine receptors on motor end-plates [2]. Action potentials propagated along the presynaptic neuron result in the release of acetylcholine into the synaptic cleft. These molecules then bind to two alpha subunits of the ionic post-junctional nicotinic acetylcholine receptors. Binding results in a conformational change in the ion channel prompting an influx of sodium and efflux of potassium. Dosing for neuromuscular blocker agents is typically based on an effective dose (ED) 95, which is the dose in which 95% twitch depression occurs in 50% of individuals [3]. For induction, one, two or three times the ED95 dose is typically administered and for maintenance dosing, the ED95 dosage is employed [3].
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