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=UDK 010 10.1515.SJECR-2016-0047.3.Indd REVIEW PAPER REVIJALNI RAD REVIEW PAPER REVIJALNI RAD REVIEW PAPER MECHANISM AND CLINICAL IMPORTANCE OF RESPIRATORY FAILURE INDUCED BY ANTICHOLINESTERASES Anita Ivosevic1, Natasa Miletic2, Maja Vulovic3*, Zoran Vujkovic4, Snjezana Novakovic Bursac5, Slavko S. Cetkovic6, Ranko Skrbic7, and Milos P. Stojiljkovic2,7 1Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia 2Medical Faculty, University of East Sarajevo, Foča, Republic of Srpska, Bosnia & Herzegovina 3Department of Anatomy and Forensic Medicine, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia 4Neurology Clinic, University Clinical Centre of Republic of Srpska, Medical Faculty, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia & Herzegovina 5Institute for Physical Medicine and Rehabilitation „Dr Miroslav Zotovic“, Banja Luka, Republic of Srpska, Bosnia & Herzegovina 6Military Medical Academy, Belgrade, Serbia 7Department of Pharmacology, Toxicology & Clinical Pharmacology, Medical Faculty, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia & Herzegovina MEHANIZAM I KLINIČKA VAŽNOST RESPIRATORNE INSUFICIJENCIJE IZAZVANE ANTIHOLINESTERAZAMA Anita Ivošević1, Nataša Miletić2, Maja Vulović3*, Zoran Vujković4, Snježana Novaković Bursać5, Slavko S. Ćetković6, Ranko Škrbić7, and Miloš P. Stojiljković2,7 1Katedra za internu medicinu, Fakultet medicinskih nauka, Univerzitet u Kragujevcu, Kragujevac, Srbija 2Medicinski fakultet, Univerzitet u Istočnom Sarajevu, Foča, Republika Srpska, Bosna i Hercegovina 3Institut za anatomiju i sudsku medicinu, Fakultet medicinskih nauka, Univerzitet u Kragujevcu, Kragujevac, Srbija 4Klinika za neurologiju, Univerzitetski klinički centar Republike Srpske, Medicinski fakultet, Univerzitet u Banja Luci, Banja Luka, Republika Srpska, Bosna i Hercegovina 5Zavod za fi zikalnu medicinu i rehabilitaciju „Dr Miroslav Zotović“, Banja Luka, Republika Srpska, Bosna i Hercegovina 6Vojnomedicinska akademija, Beograd, Srbija 7Zavod za farmakologiju, toksikologiju i kliničku farmakologiju, Medicinski fakultet, Univerzitet u Banja Luci, Banja Luka, Republika Srpska, Bosna i Hercegovina Received / Primljen: 24.05. 2016. Accepted / Prihvaćen: 14. 06. 2016. ABSTRACT SAŽETAK Respiratory failure is the predominant cause of death in Respiratorna insufi cijencija je dominantan uzrok smrti humans and animals poisoned with anticholinesterases. Or- kod ljudi i životinja trovanih antiholinesterazama. Orga- ganophosphorus and carbamate anticholinesterases inhibit nofosphorne i karbamatske antiholinesteraze inhibišu ace- acetylcholinesterase irreversibly and reversibly, respectively. tilholinesterazu ireverzibilno, odnosno reverzibilno. Neke od Some of them contain a quaternary atom that makes them njih sadrže kvaternerni atom koji ih čini lipofobnim, čime lipophobic, limiting their action at the periphery, i.e. outside im ograničava delovanje na periferiju, tj. van centralnog the central nervous system. Th ey impair respiratory function nervnog sistema. One oštećuju respiratornu funkciju pri- primarily by inducing a desensitization block of nicotinic marno izazivajući desenzitizujući blok nikotinskih recepto- receptors in the neuromuscular synapse. Lipophilic anticho- ra u neuromuskularnoj sinapsi. Lipofi lne antiholinesteraze linesterases inhibit the acetylcholinesterase both in the brain inhibišu acetilholinesterazu i u mozgu i u drugim tkivima, and in other tissues, including respiratory muscles. Th eir uključujući i respiratorne mišiće. Njihove doze neophodne doses needed for cessation of central respiratory drive are za prekidanje centralnog respiratornog generatora impulsa signifi cantly less than doses needed for paralysis of the neuro- su značajno niže od doza potrebnih za paralizu neuromu- muscular transmission. Antagonist of muscarinic receptors skularne transmisije. Antagonist muskarinskih receptora atropine blocks both the central and peripheral muscarinic atropin blokira i centralne i periferne muskarinske receptore receptors and eff ectively antagonizes the central respiratory i efektiveno antagonizuje centralnu respiratornu depresiju depression produced by anticholinesterases. To manage the izazvanu antiholinesterazama. U cilju kupiranjahipersti- peripheral nicotinic receptor hyperstimulation phenomena, mulacije perifernih nikotinskih receptora koriste se oksimi, oximes as acetylcholinesterase reactivators are used. Addi- kao reaktivatori acetilholinesteraze. Dodavanje diazepama tion of diazepam is useful for treatment of seizures, since je korisno u tretmanu konvulzija, pošto su one holinergičke they are cholinergic only in their initial phase and can con- samo u svojoj početnoj fazi i mogu da doprinesu pojavi respi- tribute to the occurrence of central respiratory depression. ratorne depresije. Moguća umešanost centralnih nikotinskih Possible involvement of central nicotinic receptors as well as receptora, kao i drugih neurotransmiterskih sistema – glu- the other neurotransmitter systems – glutamatergic, opioi- tamatergičkog i opioidergičkog – zahteva dalje istraživanje dergic – necessitates further research of additional antidotes. dodatnih antidota. Keywords: Anticholinesterase, Acetylcholinesterase, Ključne reči: Antiholinesteraze, Acetilholinesteraza, Acetylcholine, Atropine, Oxime, Diazepam, Respiratory de- Acetilholin, Atropin, Oksim, Diazepam, Respiratorna depre- pression, Muscarinic receptors, Nicotinic receptors sija, Muskarinski receptori, Nikotinski receptori UDK: 615.27.099; 616.24-008.4 / Ser J Exp Clin Res 2017; 18 (4): 349-355 DOI: 10.1515/SJECR20160047 Corresponding author: Department of Anatomy and Forensic Medicine, Faculty of Medical Sciences, University of Kragujevac, 349 Svetozara Markovića 69, RS-34000 Kragujevac, Serbia, e-mail: [email protected] ACETYLCHOLINE, ACETYLCHOLINESTERASE Acetylcholinesterase (AChE) is an enzyme located in AND THEIR PHYSIOLOGICAL FUNCTIONS cholinergic synapses within the synaptic cleft. It is very ac- tive, which means that it breaks down the molecules of ace- Acetylcholine is a neurotransmitter of vital importance in tylcholine into choline and acetate in split-second assuring the central nervous system (CNS), but also peripherally, i.e. thus that there is no surplus of acetylcholine to induce the in the vegetative nervous system (VNS) ganglia and at the overstimulation of the cholinergic receptors located at the endings of the postganglionic parasympathetic fibers, such as postsynaptic membrane (2). heart, smooth muscle cells and exocrine glands (1). A specifi- While in the CNS the types of cholinergic receptors or cally important role of acetylcholine is to mediate transmis- cholinoceptors through which acetylcholine exerts its ac- sion at the neuromuscular junction of skeletal muscles (2). tion are believed to be both muscarinic and nicotinic, this When the action potential reaches the motoneuron division is much simpler at the periphery – muscarinic re- ending, it opens the voltage-dependent calcium channels ceptors are located at the endings of postganglionic para- and causes the influx of calcium ions into the nerve end- sympathetic fibers, while nicotinic ones are located in the ing. As a result, acetylcholine vesicles fuse with the pre- both sympathetic and parasympathetic ganglia and at the synaptic membrane and the neurotransmitter is released neuromuscular junction (1, 2). into the synaptic cleft by exocytosis. After reaching the postsynaptic membrane, acetylcholine binds to nicotin- ic receptors and opens the sodium channels. The ensu- ANTICHOLINESTERASES ing influx of sodium cations into the skeletal muscle cell AND THEIR MODE OF ACTION triggers the action potential that reaches the myofibrils and causes a muscle contraction (3). All these details are Acetylcholinesterase (AChE) inhibitors or anticholin- shown in Figure 1. esterases comprise various chemical entities whose com- Figure 1. Schematic presentation of neuromuscular junction. (1) Nerve impulse reaches the nerve ending. (2) It opens the volt- age calcium channels triggering a calcium ion infl ux. (3) Vesicles with acetylcholine fuse with the presynaptic membrane and the transmitter is excreted into the synaptic cleft. (4) Acetylcholine binds to the postsynaptic nicotinic receptors and opens the sodium ion channels. (5) Sodium ions enter the muscle fi ber. (6) Sodium ion infl ux triggers the action potential in the myofi brils and causes muscle contraction. A = motor neuron axon, B = axon terminal, C = synaptic cleft, D = muscle cell, E = myofi bril. 350 mon characteristics is ability to inhibit AChE, an enzyme neostigmine and pyridostigmine, the latter being also used crucial for the breakdown of acetylcholine. They can be in prophylaxis against nerve agents (17). divided into irreversible and reversible inhibitors, with or- The remaining anticholinesterases are, more or less, li- ganophosphates belonging to the former group and car- pophilic and readily pass the BBB inhibiting thus the brain bamates belonging to the latter one. Some of them have AChE, as the most important target. Best examples of such a role in medicine as therapeutic agents and are used (i) molecules are nerve agents tabun, sarin, soman and VX, in treatment of poisonings with anticholinergic drugs - insecticides dichlorvos (DDVP) and paraoxon (metabolite physostigmine, (ii) Alzheimer’s disease - rivastigmine, and of parathion) and the oldest known anticholinesterase car- donepezil, (iii) glaucoma - phospholine (echothiophate), bamate, physostigmine, which had
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