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Urinary tract disorders
Published in Henry J. Woodford, Essential Geriatrics, 2022
Anticholinergic drugs used in the treatment of UI act at muscarinic receptors. Five subtypes of muscarinic receptors have been identified (M1 to M5).105 The main subtypes found on smooth muscle are M2 and M3, whereas the other subtypes are more commonly found in brain tissue. Available agents include darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine and trospium. They aim to suppress detrusor muscle contractions and thus reduce symptoms of OAB and incontinent episodes.
Neurotransmitters and Receptors, Ion Channels, G Proteins and Second Messengers
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Muscarinic receptors are widely distributed throughout the central nervous system (CNS), in cardiac and smooth muscle and in exocrine, endocrine and paracrine glands. The M1, M3 and M5 are coupled to Gq proteins and activate IP3 and DAG to mediate hydrolysis of membrane phospholipids and release Ca++ from intracellular stores. This opens the calcium-gated K+ channel and hyperpolarizes the cell. M1 receptors are found in sympathetic ganglia and have a high affinity for the antagonist pirenzepine. M2 and M4 receptors activate Gi proteins to decrease cAMP concentration. M2 receptors are found in the heart and depress autorhythmicity by opening inward, rectifying K+ channels. The molecular structure of M1 receptors has been identified as a sequence of seven α helices that cross the cell membrane repeatedly (see Figure 3.5).
Visualization of Cholinergic Tracers in Alzheimer Brains in vivo by Positron Emission Tomography
Published in Robert E. Becker, Ezio Giacobini, Alzheimer Disease, 2020
Agneta Nordberg, Per Hartvig, Hans Lundqvist, Andres Lilja, Matti Viitanen, Kaarina Amberla, J. Ulin, Bengt Winbald, Bengt Bengt Långström
The muscarinic receptors represent together with the nicotinic receptors the cholinergic receptor systems in the brain. Modern molecular biology techniques have recently revealed a whole family of muscarinic receptor genes coding for the muscarinic receptors in the brain (Bonner et al. 1987). Pharmacological agonists/antagonists to characterize all these receptor subtypes is still lacking. In Alzheimer’s disease the muscarinic receptors have mainly been preserved when analysed in postmortem brain tissue (Nordberg and Winblad 1986a). The muscarinic antagonists 11C-benztropine mesylat and 11C-3-quinuclidinylbenzilate (11C-QNB) have been used in attempts to visualize muscarinic receptors in vivo in baboon brains (Dewey et al. 1989, Mazière et al 1989). Hollman et al. (1985) used the muscarinic antagonist I-quinuclidinyl-4-iodobenzilate and single photon emission tomography (SPECT) to visualize muscarinic receptors in human brain. In this very limited study of one control and one Alzheimer patient the binding of 123I-quinuclidinyl-4-iodo benzilate was uniformly and only moderately decreased in brain of the Alzheimer patient compared to the control subject.
Where do we go next in antidepressant drug discovery? A new generation of antidepressants: a pivotal role of AMPA receptor potentiation and mGlu2/3 receptor antagonism
Published in Expert Opinion on Drug Discovery, 2022
Andrzej Pilc, Agata Machaczka, Paweł Kawalec, Jodi L. Smith, Jeffrey M. Witkin
The structures of two muscarinic receptor antagonists that have clinical use in patients are shown in Figure 5. Biperiden is used in the clinical management of Parkinson’s disease [80]. Both scopolamine and biperiden have been studied for their antidepressant effects with scopolamine being the most widely investigated in depressed patients. Scopolamine is a naturally derived alkaloid of a species of plant from the Solanaceae family. Scopolamine is a nonselective antagonist of muscarinic acetylcholine receptors and is widely used as a butyl bromide salt in the treatment of abdominal pain, irritable bowel syndrome and bladder spasms (in this form it does not readily penetrate into the CNS). A hydrobromide derivative (which enters the brain) is used as a motion sickness reliever and sometimes as a preoperative medication [81]. Scopolamine induces hyperactivity and dream-like ‘hallucinations,’ and at a dose of 24 ug/kg i.m., produced delirium in humans [82]. Scopolamine belongs to a separate group of drugs that have been termed deliriants [83].
Anticholinergics and falls in older adults
Published in Expert Review of Clinical Pharmacology, 2022
Acetylcholine is a neurotransmitter synthesized from choline and acetyl-CoA during catalysis of choline acetyltransferase [36], and produces nerve signaling by binding to nicotinic and muscarinic receptors on the postsynaptic membrane of neurons. Muscarinic receptors are abundant in the effector cells innervated by the post-ganglionic fibers of parasympathetic nerves [37]. Receptor binding leads to excitation of parasympathetic nerve endings [38], leading to the inhibition of heart activity and bronchial smooth muscles, smooth muscles of the gastrointestinal tract, contraction of the bladder and pupillary sphincters, and increased secretion of digestive glands [39]. Nicotinic receptors are found in the postsynaptic membranes of sympathetic and parasympathetic neurons and the terminal membranes of neuromuscular junctions [40,41]. Excitation of post-ganglionic neurons through nicotinic acetylcholine receptor binding then leads to activation of skeletal muscles.
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].