Tendencies and perspectives of central alpha2-adrenomimetic application in medicobiological research

Abstract

The pharmacodynamic effects of the administration of α2-adrenergic agonists both in a monovariant and in combination with drugs of other pharmacological groups are considered. Based on analysis of safety nonclinical studies the characteristics of main physiological effects of α2-adrenergic receptors as well as physiological effects of α2-agonists on various organs and systems are presented. For the determination of tendencies and directions in research of central α2-AM (dexmedetomidine) the analysis of bibliographical data, accumulated and extracted from Medline database with 5 year time-filter (VOSviewer, 1.6.11 version) has been carried out. For the further research of central α2-adrenomimetics and their application in clinical practice the following perspective directions have been determined: the study of effects and mechanisms of cytoprotectant and antioxidant action, the study of the use of drugs in a monovariant and in combinations for the development of analgesic drugs, anesthesia and development of combined formulations with a delayed release of antagonists designed to mitigate side effects.

Keywords

Alpha2-adrenomimetics / α2-agonists / dexmedetomidine / combinations / antioxidant / cytoprotection / lipid peroxidation

References

[1] 1.Giovannitti J, Thoms S, Crawford J. Alpha-2 Adrenergic Receptor Agonists: A Review of Current Clinical Applications. Anesth Prog. 2015;62(1):31-38. doi:10.2344/0003-3006-62.1.31

[2] 2.Lamont LA, Burton SA, Caines D, Troncy ED. Effects of 2 different infusion rates of medetomidine on sedation score, cardiopulmonary parameters, and serum levels of medetomidine in healthy dogs. Can J Vet Res. 2012;76(4):308–316.

[3] 3.Zhang Z, Ferretti V, Güntan İ, et al. Neuronal ensembles sufficient for recovery sleep and the sedative actions of α2 adrenergic agonists. Nat Neurosci. 2015;18(4):553–561. doi:10.1038/nn.3957

[4] 4.Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin P. Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Clin Pharmacokinet. 2017;56(8):893–913. doi:10.1007/s40262-017-0507-7

[5] 5.Mannelli L, Micheli L, Crocetti L, et al. α2 Adrenoceptor: a Target for Neuropathic Pain Treatment. Mini reviews in medicinal chemistry. Mini Rev Med Chem. 2017;17(2):95-107. doi:10.2174/1389557516666160609065535. (2016).

[6] 6.Ostopovici-Halip L, Curpăn R, Mracec M, Bologa CG. Structural determinants of the alpha2 adrenoceptor subtype selectivity. J Mol Graph Model. 2011;29(8):1030-1038. doi:10.1016/j.jmgm.2011.04.011

[7] 7.Fukuda M, Vazquez AL, Zong X, Kim SG. Effects of the α₂-adrenergic receptor agonist dexmedetomidine on neural, vascular and BOLD fMRI responses in the somatosensory cortex. Eur J Neurosci. 2013;37(1):80–95. doi:10.1111/ejn.12024

[8] 8.Gyires K, Zádori Z, Török T, Mátyus P. α2-Adrenoceptor subtypes-mediated physiological, pharmacological actions. Neurochemistry International. 2009 dec.;55(7):447-453. https://doi.org/10.1016/j.neuint.2009.05.014

[9] 9.Sinclair MD. A review of the physiological effects of alpha2-agonists related to the clinical use of medetomidine in small animal practice. Can Vet J. 2003;44(11):885–897.

[10] 10.Funai Y, Pickering AE, Uta D, et al. Systemic dexmedetomidine augments inhibitory synaptic transmission in the superficial dorsal horn through activation of descending noradrenergic control: an in vivo patch-clamp analysis of analgesic mechanisms. Pain. 2014;155(3):617–628. doi:10.1016/j.pain.2013.12.018

[11] 11.Naaz S, Ozair E. Dexmedetomidine in current anaesthesia practice- a review. J Clin Diagn Res. 2014;8(10):GE01–GE4. doi:10.7860/JCDR/2014/9624.4946

[12] 12.Sharma S, Jain P. Dexmedetomidine and Anesthesia. Indian Journal of Clinical Practice. 2013;24(3):223-225.

[13] 13.Shah Z, Ding M. A Review on the Current Use of Alpha2 Agonists in Small Ruminants. Kafkas Universitesi Veteriner Fakultesi Dergisi. 2014;20(4):633-639. doi:10.9775/kvfd.2013.10541

[14] 14.Ozaki M, Takeda J, Tanaka K, et al. Safety and efficacy of dexmedetomidine for long-term sedation in critically ill patients. J Anesth. 2014;28(1):38–50. doi:10.1007/s00540-013-1678-5

[15] 15.Thomas B, Bantel C, Stone L, Wilcox GL. Alpha(α) 2-Adrenergic Agonists in Pain Treatment. In: Gebhart GF, Schmidt RF (eds) Encyclopedia of Pain. Springer, Berlin, Heidelberg; 2013. p.79-86.

[16] 16.Ferdousi M. Structure-Affinity Relationship Study of Novel Imidazoline Ligands at Imidazoline Binding Sites and α-Adrenoceptors [A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science]. Department of Pharmacology, University of Alberta; 2014.

[17] 17.Bell A. The neurobiology of acute pain. Vet J. 2018;(237):55-62. doi:10.1016/j.tvjl.2018.05.004

[18] 18.Root-Bernstein R, Turke M, Subhramanyam UKT, Churchill B, Labahn J. Adrenergic Agonists Bind to Adrenergic-Receptor-Like Regions of the Mu Opioid Receptor, Enhancing Morphine and Methionine-Enkephalin Binding: A New Approach to "Biased Opioids"?. Int J Mol Sci. 2018;19(1):272. doi:10.3390/ijms19010272

[19] 19.Chabot-Doré AJ, Schuster DJ, Stone LS, Wilcox GL. Analgesic synergy between opioid and α2 -adrenoceptors. Br J Pharmacol. 2015;172(2):388–402. doi:10.1111/bph.12695

[20] 20.Kaur M, Singh PM. Current role of dexmedetomidine in clinical anesthesia and intensive care. Anesth Essays Res. 2011;5(2):128–133. doi:10.4103/0259-1162.94750

[21] 21.Bajwa SJ, Bajwa SK, Kaur J, et al. Dexmedetomidine and clonidine in epidural anaesthesia: A comparative evaluation. Indian J Anaesth. 2011;55(2):116–121. doi:10.4103/0019-5049.79883

[22] 22.Baumgartner C, Bollerhey M, Ebner J, Schuster T, Henke J, Erhardt W. Effects of medetomidine-midazolam-fentanyl IV bolus injections and its reversal by specific antagonists on cardiovascular function in rabbits. Can J Vet Res. 2010;74(4):286–298

[23] 23.Egger CM, Love L, Doherty T. Pain Management in Veterinary Practice. Wiley Blackwell, Chichester, UK, 2013. 464 p.

[24] 24.Murrell JC, Hellebrekers LJ. Medetomidine and dexmedetomidine: a review of cardiovascular effects and antinociceptive properties in the dog. Veterinary Anaesthesia and Analgesia. 2005;32(3):117-127. doi:10.1111/j.1467-2995.2005.00233.x

[25] 25.Adam M, Raekallio MR, Salla KM, et al. Effects of the peripherally acting α2-adrenoceptor antagonist MK-467 on cardiopulmonary function in sheep sedated by intramuscular administration of medetomidine and ketamine and reversed by intramuscular administration of atipamezole. Am J Vet Res. 2018;79(9):921-932. doi:10.2460/ajvr.79.9.921

[26] 26.Ingersoll-Weng E, Manecke GJ, Thistlethwaite PA. Dexmedetomidine and cardiac arrest. Anesthesiology. 2004;100(3):738-9. doi:10.1097/00000542-200403000-00040

[27] 27.Page RL, O'Bryant CL, Cheng D, et al. Drugs That May Cause or Exacerbate Heart Failure: A Scientific Statement From the American Heart Association. Circulation. 2016;134(6):e32-69. doi:10.1161/CIR.0000000000000426

[28] 28.Carter JE, Campbell NB, Posner LP, Swanson C. The hemodynamic effects of medetomidine continuous rate infusions in the dog. Vet Anaesth Analg. 2010;37(3):197-206. doi:10.1111/j.1467-2995.2009.00522.x

[29] 29.Nelson W, Couto CG. Small Animal Internal Medicine. St. Louis, MO: Elsevier/Mosby; 2015. 1473 p.

[30] 30.Kaartinen MJ, Cuvelliez S, Brouillard L, Rondenay Y, Kona-Boun JJ, Troncy E. Survey of utilization of medetomidine and atipamezole in private veterinary practice in Quebec in 2002. Can Vet J. 2007;48(7):725–730.

[31] 31.Wu J, Lei E, Zhou J, Zhao D. Impacts and mechanisms of dexmedetomidine HCl on heart rate in rabbit with bilateral vagotomy or sympathectomy. Biomedical Research. 2017;28(17):7509-7513.

[32] 32.Yaygingül R, Belge А. The comparison of clinical and cardiopulmonary effects of xylazine, medetomidine and detomidine in dogs. Ankara Üniv. Vet. Fak. Derg. 2018;65:313–322.

[33] 33.Berg T. β- and α2-Adrenoceptor Control of Vascular Tension and Catecholamine Release in Female Normotensive and Spontaneously Hypertensive Rats. Front Neurol. 2017;8:130. doi:10.3389/fneur.2017.00130

[34] 34.Chittick E, Horne W, Wolfe B, Sladky K. Cardiopulmonary assessment of medetomidine, ketamine, and butorphanol anesthesia in captive Thomson's gazelles (Gazella thomsoni). J Zoo Wildl Med. 2001;32(2):168-75. doi:10.1638/1042-7260(2001)032[0168:CAOMKA]2.0.CO;2

[35] 35.Raillard M, Michaut-Castrillo J, Spreux D, et al. Comparison of medetomidine-morphine and medetomidine-methadone for sedation, isoflurane requirement and postoperative analgesia in dogs undergoing laparoscopy. Vet Anaesth Analg. 2017;44(1):17-27. doi:10.1111/vaa.12394.

[36] 36.Muller LI, Osborn DA, Doherty T. Optimal medetomidine dose when combined with ketamine and tiletamine-zolazepam to immobilize white-tailed deer. J Wildl Dis. 2012;48(2):477- 482.

[37] 37.Rauser P, Zatloukal J, Neâas A, et al. Combined Medetomidine and Ketamine for Short-term Anaesthesia in Ferrets - A Clinical Study. Acta Veterinaria Brno. 2012;71(2):243- 248. doi:10.2754/avb200271020243

[38] 38.Schmitz S, Tacke S, Guth B, Henke J. Repeated anaesthesia with isoflurane and medetomidine-midazolam-fentanyl in guinea pigs and its influence on physiological parameters. PLoS One. 2017;12(3):e0174423. doi:10.1371/journal.pone.0174423

[39] 39.Le Chevallier D, Slingsby L, Murrell J. Use of midazolam in combination with medetomidine for premedication in healthy dogs. Vet Anaesth Analg. 2019;46(1):74-78. doi:10.1016/j.vaa.2018.08.001

[40] 40.Shukry M, Miller JA. Update on dexmedetomidine: use in nonintubated patients requiring sedation for surgical procedures. Ther Clin Risk Manag. 2010;6:111–121 p. doi:10.2147/tcrm.s5374

[41] 41.Scott-Warren VL, Sebastian J. Dexmedetomidine: its use in intensive care medicine and anaesthesia. BJA Education. 2016;16(7), 242-246 p. doi:10.1093/bjaed/mkv047

[42] 42.Taylor BK, Westlund KN. The noradrenergic locus coeruleus as a chronic pain generator. J Neurosci Res. 2017;95(6):1336–1346. doi:10.1002/jnr.23956

[43] 43.Cassu RN, Melchert A, Canoa JT, Martins PD. Sedative and clinical effects of the pharmacopuncture with xylazine in dogs. Acta Cir Bras. 2014;29(1):47-52. doi:10.1590/S0102-86502014000100007

[44] 44.Kallio-Kujala IJ, Turunen HA, Raekallio MR, et al. Peripherally acting α-adrenoceptor antagonist MK-467 with intramuscular medetomidine and butorphanol in dogs: A prospective, randomised, clinical trial. Vet J. 2018;240:22-26. doi:10.1016/j.tvjl.2018.08.007

[45] 45.Kanda T, Iguchi A, Yoshioka C, et al. Effects of medetomidine and xylazine on intraocular pressure and pupil size in healthy Beagle dogs. Vet Anaesth Analg. 2015;42(6):623-8. doi:10.1111/vaa.12249

[46] 46.Keegan RD, Greene SA, et al. Effects of medetomidine administration on intracranial pressure and cardiovascular variables of isoflurane-anesthetized dogs. Am J Vet Res. 1995;56(2):193-198.

[47] 47.Cao G, Zhang E. [Protective effects of dexmedetomidine against pulmonary ischemia-reperfusion injury during cardiopulmonary bypass in rats]. [Article in Chinese].Nan Fang Yi Ke Da Xue Xue Bao. 2019;39(8):980-986. doi: 10.12122/j.issn.1673-4254.2019.08.16.

[48] 48.He L, Hao S, Wang Y, et al. Dexmedetomidine preconditioning attenuates ischemia/reperfusion injury in isolated rat hearts with endothelial dysfunction. Biomed Pharmacother. 2019;53(2):74-81. doi: 10.1016/j.biopha.2019.108837.

[49] 49.Cheng X, Hu J, Wang Y, et al. Effects of Dexmedetomidine Postconditioning on Myocardial Ischemia/Reperfusion Injury in Diabetic Rats: Role of the PI3K/Akt-Dependent Signaling Pathway. J Diabetes Res. 2018;2018:3071959. doi:10.1155/2018/3071959

[50] 50.Sha J, Zhang H, Zhao Y, et al. Dexmedetomidine attenuates lipopolysaccharide-induced liver oxidative stress and cell apoptosis in rats by increasing GSK-3β/MKP-1/Nrf2 pathway activity via the α2 adrenergic receptor. Toxicol Appl Pharmacol. 2019;1;364:144-152. doi: 10.1016/j.taap.2018.12.017.

[51] 51.Chen Y, Luan L, Wang C, et al. Dexmedetomidine protects against lipopolysaccharide-induced early acute kidney injury by inhibiting the iNOS/NO signaling pathway in rats. Nitric Oxide. 2019;1;85:1-9. doi: 10.1016/j.niox.2019.01.009.

[52] 52.Sha J, Zhang H, Zhao Y, et al. Dexmedetomidine attenuates lipopolysaccharide-induced liver oxidative stress and cell apoptosis in rats by increasing GSK-3β/MKP-1/Nrf2 pathway activity via the α2 adrenergic receptor. Toxicol Appl Pharmacol. 2019;364:144-152. doi: 10.1016/j.taap.2018.12.017.

[53] 53.Li F, Wang X, Deng Z, et al. Dexmedetomidine reduces oxidative stress and provides neuroprotection in a model of traumatic brain injury via the PGC-1α signaling pathway. Neuropeptides. 2018;72:58-64. doi: 10.1016/j.npep.2018.10.004.

[54] 54.Chen Y, Feng X, Hu X, et al. Dexmedetomidine Ameliorates Acute Stress-Induced Kidney Injury by Attenuating Oxidative Stress and Apoptosis through Inhibition of the ROS/JNK Signaling Pathway. Oxid Med Cell Longev. 2018:4035310. doi:10.1155/2018/4035310

[55] 55.Kallio-Kujala IJ, Bennett RC, Raekallio MR, et al. Effects of dexmedetomidine and MK-467 on plasma glucose, insulin and glucagon in a glibenclamide-induced canine hypoglycaemia model. Vet J. 2018;242:33-38. doi: 10.1016/j.tvjl.2018.09.012

[56] 56.Beloeil H, Laviolle B, Menard C, et al. POFA trial study protocol: a multicentre, double-blind, randomised, controlled clinical trial comparing opioid-free versus opioid anaesthesia on postoperative opioid-related adverse events after major or intermediate non-cardiac surgery. BMJ Open. 2018;8(6):e020873. doi:10.1136/bmjopen-2017-020873

[57] 57.Shankar P, Mueller A, Packiasabapathy S, et al. Dexmedetomidine and intravenous acetaminophen for the prevention of postoperative delirium following cardiac surgery (DEXACET trial): protocol for a prospective randomized controlled trial. Trials. 2018;19(1):326. doi:10.1186/s13063-018-2718-0

[58] 58.Louis C, Godet T, Chanques G, et al. Effects of dexmedetomidine on delirium duration of non-intubated ICU patients (4D trial): study protocol for a randomized trial. Trials. 2018;19(1):307. doi:10.1186/s13063-018-2656-x

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Vengerovich N.G., Ivanov I.M., Proshina Y.A.