Opioid Receptor Antagonists. from the Present to the Future
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Medicine of Extreme Situations, 2018; 20(3) THE PROBLEM OF ENSURING SAFETY IN THE USE OF NARCOTIC ANALGESICS IN THE RUSSIAN FEDERATION GROUP OF AUTHORS, 2018 V.V. Uyba1, D.V. Krivorotov2, M.V. Zabelin1, A.S. Radilov2, V.R. Rembovskiy2, S.A. Dulov2, V.A. Kuznetsov2, G.G. Erofeev1, N.N. Martinovitch2, A.V. Sosnov3 OPIOID RECEPTOR ANTAGONISTS. FROM THE PRESENT TO THE FUTURE 1 Federal Medical-Biological Agency of Russia, Moscow, 123182, Russian Federation; 2 Research Institute of Human Hygiene, Occupational Pathology, and Ecology, Saint Petersburg, 188663, Russian Federation; 3 Institute of Physiologically Active Compounds Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation The article considers information indicating an increase in the danger of “designer drugs” created on the basis of highly active narcotic analgesics of the central action, to the human life and health. Aspects of the use of opioid receptor antagonists in the treatment of acute opioid poisoning and in the treatment of socially significant diseases such as alcoholism and drug addiction are discussed. The adequacy of naloxone use in the emergency treatment of the acute poisoning with narcotic analgesics has been evaluated. Approaches to the improvement of drugs for the treatment of acute opioid poisoning have been determined. The task of the directional design and chemical synthesis of drugs more effective than naloxone was formulated, and the prospect of using nalmefene to develop innovative drugs for the treat- ment of acute poisonings and socially significant diseases was evaluated. Keywords: opioid receptors; narcotic analgesics; acute poisonings; drug addiction; alcoholism; opioid receptor antagonists; lipophilicity; partition-coefficients; naloxone; naltrexone; nalmefene; dosage form. For citation: Uyba V.V., Krivorotov D.V., Zabelin M.V., Radilov A.S., Rembovskiy V.R., Dulov S.A., Kuznetsov V.A., Erofeev G.G., Martinovitch N.V., Sosnov A.V. Opioid receptor antagonists. From the present to the future. Meditsina ekstremal’nykh situatsiy (Medicine of Extreme Situations) 2018; 20(3): 371-382. (In Russ.). For correspondence: Denis V. Krivorotov, Ph.D., Research Institute of Human Hygiene, Occupational Pathology, and Ecology, Saint Petersburg, 188663, Russian Federation. E-mail: [email protected] Conflict of interest.The authors declare no conflict of interest Acknowledgments. The study had no sponsorship. Received 01June 2018 Accepted 19 September 2018 In 1817 the isolation of morphine from opium In some countries, even clinically valid doses de- was a breakthrough in the development of Europe- termine up to 43% of cases of lethal HA poisoning, an pharmacology, which determined the progress and uncontrolled morphine’s use gave rise to the of science and technology for many years to come first outbreaks of opioid epidemics in the XVIII- [1]. Opioids in modern medicine do not have an ad- XIX centuries [1, 3]. The pathogenesis of the le- equate alternative due to their unique analgesic and thal and addictive potential of opioid analgesics of other pharmacological properties. There are more the central action is determined by the nature of than ten drugs, except morphine, which relate to neurochemical regulation of the organism with the the pharmacological group of opioid narcotic an- system of opioid receptors (OP) and endogenous algesics (HA) in Russian Federation. A number of opioids (Table 1) [4]. highly active opioid analgesics, such as sufentanil, μ-opioid receptors are the most widely repre- are considered by the native pharmaceutical indus- sented in the central nervous system; when taking try as promising medicines [2]. Despite the invalu- opioids, they are responsible for the implementa- able medical importance of opioid analgesics, their tion of the analgesic effect, euphoria, miosis, respi- use poses a certain danger to human life and health. ratory depression and peristalsis. By the δ-opioid Opioid receptor antagonists. From the present to the future. 371 Медицина экстремальных ситуаций. 2018; 20(3) ПРОБЛЕМА ОБЕСПЕЧЕНИЯ БЕЗОПАСНОСТИ ПРИ ИСПОЛЬЗОВАНИИ НАРКОТИЧЕСКИХ АНАЛЬГЕТИКОВ В РОССИЙСКОЙ ФЕДЕРАЦИИ Table 1 Classification of opioid receptors and their ligands [4] Receptor Agonist Antagonist Agonist’s effect µ Standard ligand – morphine Naloxone Analgesia Morphineceptin Naltrexone Respiratory depression DAGO (-) - Cyclophane Miosis Normorphine Samodorf Disturbance / decreased motility of Sufentanil Naldemidine (PNS) the gastrointestinal tract Alvimopan (PNS) Nausea Methylnaltrexone (PNS) Vomiting 6-beta-Naltrexol BU-128 Euphoria δ Standard ligand - deltorphin ICI 154.126 Supraspinal analgesia DPDPE ICI 174.864 DADLE 7-benzylidenenaltrexone κ Standard ligand – ketocyclozacin MR2266 Supraspinal analgesia Agonist CERC-501 Miosis (weak) U50,488 Antagonist Agonist’s effect Тrifluadom LY-255582 Respiratory depression (weak) 5'-ghuanidinonaltrindole Dysphoria MR2266 BU-10119 3-methoxynaltrexone Note. PNS - antagonists of the peripheral nervous system OR; DAGO, Tyr-D-Ala-Gly-ol; DPDPE, [D-Pen2, D-Pen5] enkephalin; Pen, penicillamine; DADLE, [D-Ala2, D-Leu5] encephalin; deltorphin II, Tyr-D-Ala-Phe-Glu-Val-Val-Gly- NH2; morphiceptin, β-casomorphin- (1-4) - amide or Tyr-Pro-Phe-Pro-NH2. BU-128; ICI 154,126; ICI 174,864; MR2266; CERC-501; LY-255582; MR2266; BU-10119 – Pharmacological agents (OP’s antagonists). receptors the analgesic and antidepressant effect is decreasing the sensitivity to the increase in the realized; stimulation of κ-opioid receptors provides content of carbon dioxide in the blood, causing a analgesia and sedation, dysphoria and suppression violation in the reflex mechanism of respiration, of arginine vasopressin production. The expressed the development of acute respiratory failure and physiological response under the action of single death of an organism [7]. Clinical symptoms of molecules of opioids on the organism is provided acute opioid poisoning include oppression of con- biochemical cascades of signal amplification, de- sciousness to coma, respiratory depression, apnea, scribed by the concept of «secondary messengers» cyanosis of the skin, miosis, atony, areflexia. The - signal molecules, the content of which determines development of hypoxia leads to heart failure and the excited or depressed state of the nerve cell, the death. Poisoning is often accompanied by mani- key of which is: cyclic 3 ‹, 5-adenosine monophos- festations of convulsive syndrome, hypothermia, phate ( cAMP), cyclic 3 ‹, 5›-guanosine monophos- pyrogenic reactions and vomiting, which contrib- phate (cGMP), intracellular free Ca2 +, metabolic utes to the development of severe complications products of phosphoinositides, in particular inosi- of intoxication, including toxic pulmonary edema toltriphosphates and diacylglycerol and others [5]. and pneumonia, cerebral edema, aspiration syn- According to the hypothesis of cAMP-opioid’s drome and sepsis [8]. The most life-threatening dependence, the chronic effects of opioids lead to factor of acute poisoning by NA is respiratory de- pathological changes in the production of cAMP pression, up to a complete stop, which determines in nerve cells, as a result of which the initial cause the importance of conducting emergency resusci- of the development of opioid dependence at the tation in the treatment of patients with opioid poi- cellular level is a painful reaction to a sharp de- soning, including the use of antidotes [9]. As the crease in the induction of adenylatecyclase when interaction of opioid analgesics with receptors is opioids are cancelled [6]. In acute poisoning, NA reversible, opioid antagonists, such as naloxone, inhibits the activity of the chemoreceptor neurons can interfere with these processes, restoring the and the respiratory center of the brain, disrupt- vital functions of the nervous system and respira- ing the generation of the respiratory rhythm and tion [7]. 372 Uyba V.V., Krivorotov D.V., Zabelin M.V., Radilov A.S., Rembovskiy V.R., Dulov S.A., Kuznetsov V.A., Erofeev G.G., Martinovitch N.V., Sosnov A.V. Medicine of Extreme Situations, 2018; 20(3) THE PROBLEM OF ENSURING SAFETY IN THE USE OF NARCOTIC ANALGESICS IN THE RUSSIAN FEDERATION 100 90 80 70 60 50 Fentanyl deaths 40 Fentanyl analog 30 20 10 Percentage of opioid overdose 0 Оhio Мaine Total isconsin Мissouri Оklahoma W est Virginia New Mexico W Rhode Island МаssachusettsNew Hampshire State Fig. 1. The contribution of fentanyl and its analogs to the overall statistics of deaths from overdose of HA in some US states in December 2016. (https://www.cdc.gov/mmwr/volumes/66/wr/mm6643e1.htm). 100-250 thousand people worldwide die from treatment of overdoses in specialized toxicological drug overdose every year. In 2016, in Russia, about hospitals. The reason for this situation is associated 10% of patients of the total quantity of poisoning with the replacement of illegal morphine and hero- were hospitalized with this diagnosis, but in the in with synthetic drugs, such as methadone, fentan- statistic of fatal poisoning, opioids became the yl derivatives and “designer drugs” based on them leading cause of death. According to the UN and [13-15]. In Russia, from 2000 to 2015 the frequen- WHO position, the growing public health problem cy of heroin poisoning decreased by 5.8 times, with associated with HA poisoning can be controlled by a 4.4- times increase in the incidence of methadone increasing the use of the OP antagonist - naloxone, poisoning. There is currently no adequate antidote as well as taking actions for limiting the availabil-