Analgesics

1. Department of Pharmacology, DSMA Analgesics 1. Opioid Analgesics. 2. Nonopioid Analgesics.

2. Department of Pharmacology, DSMA Opioid Analgesics "Thou has the keys of Paradise, oh just, subtle and mighty opium"Thomas de QuincyConfessions of an English Opium-Eater

3. Department of Pharmacology, DSMA General mechanisms of pain reception Nociceptive and antinociceptive systems: Nociceptive system - is the system of pain reception and it's psychical appreciation with launching of some defensive conditional and inconditional reflexes. Antinociceptive system - is the system of excessive pain receptionsupression. If feeling of pain reaches excessive level, pain from the distress signal turns to source of distress and may cause shock.

4. Department of Pharmacology, DSMA The phases of pain

9. Department of Pharmacology, DSMA Schematic presentation of pain pathway and potential therapeutic options for achieving pain relief.

10. Department of Pharmacology, DSMA Mechanism of pain transmission and interference

11. Department of Pharmacology, DSMA Classification of opioid receptors and effects of their exitation μ-(mju)-receptors: analgesia, euphoria, physical dependence, inhibition of breathing, decrease of digestive tract's motility, bradycardia, myosys. K-(kappa)-receptors: analgesia, sedative effect, disphoria, psychosomymetic effect. δ-(delta)-receptors: analgesia. ε-(epsylon)-receptors: are insufficiently discovered. σ-(sigma)-receptors: are insufficiently discovered.

12. Department of Pharmacology, DSMA Opiates are drugs derived from opium and include morphine, codeine, and a wide variety of semisynthetic congeners derived from them and from thebaine, another component of opium. The term opioid is more inclusive, applying to all agonists and antagonists with morphine-like activity as well as to naturally occurring and synthetic opioid peptides. Endorphin is a generic term referring to the three families of endogenous opioid peptides: the enkephalins, the dynorphins, and b- endorphins Opiate receptor Endorphin Morphine

15. Department of Pharmacology, DSMA Source and Composition of Opium. Because the laboratory synthesis of morphine is difficult, the drug is still obtained from opium or extracted from poppy straw. Opium is obtained from the unripe seed capsules of the poppy plant, Papaver somniferum. The milky juice is dried and powdered to make powdered opium, which contains a number of alkaloids. Only a fewѕmorphine, codeine, and papaverineѕhave clinical usefulness. These alkaloids can be divided into two distinct chemical classes, phenanthrenes and benzylisoquinolines. The principal phenanthrenes are morphine (10% of opium), codeine (0.5%), and thebaine (0.2%). The principal benzylisoquinolines are papaverine (1.0%), which is a smooth muscle relaxant, and noscapine (6.0%). • Opium is withered milky juice educed from the unripe seed pots of opium poppy. • Opium contains about 20 alcaloids.                                   

16. Department of Pharmacology, DSMA Morphineis the ancestor of the group of opioid analgesics derived from the opium History. Although the psychological effects of opium may have been known to the ancient Sumerians, the first undisputed reference to poppy juice is found in the writings of Theophrastus in the third century B.C. The word opium itself is derived from the Greek name for juice, the drug being obtained from the juice of the poppy, Papaver somniferum. Arabian physicians were well versed in the uses of opium. Paracelsus (1493-1541) is credited with repopularizing the use of opium in Europe after it had fallen into disfavor because of its toxicity. By the middle of the sixteenth century, many of the uses of opium were appreciated. In 1680, Sydenham wrote, "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium."

17. Department of Pharmacology, DSMA Opium contains more than 20 distinct alkaloids. In 1806, Serturner reported the isolation of a pure substance in opium that he named morphine, after Morpheus, the Greek god of dreams. The discovery of other alkaloids in opium quickly followed that of morphine (codeine by Robiquet in 1832, papaverine by Merck in 1848). By the middle of the nineteenth century, the use of pure alkaloids rather than crude opium preparations began to spread throughout the medical world.

18. Department of Pharmacology, DSMA • Classification of opioid analgesics • Agonists of opioid receptors: • - Opium alcaloids: • ■  phenanthrenes - MORPHINE, CODEINE, OMNOPON; • ■  isochinalines - PAPAVERIN, NARCOTIN. • -Syntetic drugs: • ■  phenylpiperidines - PROMEDOLUM [Trimeperidine], FENTANYL, PYRITRAMIDE; • ■  phenylheptylamines - PHENADONE. • 2. Agonists-antagonists: • ■phenanthrenes - NALBUFINE (agonist-K; antagonist-μ), BUPRENORPHINE (agonist- μ, k; antagonist-δ); • ■  phenylpiperidines - PENTAZOCIN (agonist-K, δ; antagonist- μ), BUTORPHANOL (agonist-K; antagonist- μ) • 3. Antagonists of opioid analgesics(blockers of opioid receptors) NALOXONE, NALTREXONE.

19. Department of Pharmacology, DSMA Pharmacological effects of morphine • Central effects: - Analgesic - opression of pain of any origin. - Psychotropic: • influence upon the psychical appreciation of pain - opression fear of pain; • euphoria - unreasonable improvement of mood, feeling of mental comfort. - Sedative - decrease of emotional exitability. - Effects upon hypothalamus: • hypothermic - decrease of body temperature below normal level; • increase of antidiuretic hormone production. - Exitation of centre of Nervus oculomotorius - myosis. - Inhibition of breathing centre. - Opression of coughing centre. - Inhibition of vomiting centre (but exitation of chemoceptors of the trigger-zone). - Exitation of centres of Nervus vagus.

20. Department of Pharmacology, DSMA Pharmacological effects of morphine 2. Peripheral effects: - Increase of smooth muscle tonus and sphincters' tonicity of GIT organs - • constipation, abdominal pain. • Increase of smooth muscle tonus and sphincters' tonicity of biliferous and urinary tracts - Increase of tonicity of bronchial smooth muscles - Increase of hystamine release. - Dilation of peripheral veins.

21. Department of Pharmacology, DSMA Repeated use of Morphine • Psychological dependence • Physical dependence • Tolerance • Withdrawal syndrome

22. Department of Pharmacology, DSMA Tolerance and Physical Dependence. The development of tolerance and physical dependence with repeated use is a characteristic feature of all the opioid drugs. Tolerance and dependence are physiological responses seen in all patients and are not predictors of abuse. For example, cancer pain often requires prolonged treatment with high doses of opioids, leading to tolerance and dependence. Yet, abuse in this setting is very unusual. Neither the presence of tolerance and dependence nor the fear that it may develop should interfere with the appropriate use of opioids. Opioids can be discontinued in dependent patients without subjecting them to withdrawal. Suppression of withdrawal requires only minimal doses. Clinically, the dose can be decreased by 50% every several days and eventally stopped without signs and symptoms of withdrawal. However, decreases in dosage may lead to a reduction in the degree of pain control.

23. Department of Pharmacology, DSMA Methadone • Methadone is primarily a μ agonist with pharmacological properties qualitatively similar to those of morphine. • The outstanding properties of methadone are its effective analgesic activity, its efficacy by the oral route, its extended duration of action in suppressing withdrawal symptoms in physically dependent individuals, and its tendency to show persistent effects with repeated administration. Miotic and respiratory-depressant effects can be detected for more than 24 hours after a single dose and, upon repeated administration, marked sedation is seen in some patients. Effects on cough, bowel motility, biliary tone, and the secretion of pituitary hormones are qualitatively similar to those of morphine. • The primary uses of methadone hydrochloride (DOLOPHINE) are relief of pain, treatment of opioid abstinence syndromes, and treatment of heroin users.

24. Department of Pharmacology, DSMA Acute Opioid Poisoning The patient who has taken an overdose of an opioid is usually stuporous or, if a large overdose has been taken, may be in a profound coma. The respiratory rate will be very low (sometimes only 2 to 4 breaths per minute), and cyanosis may be present. As respiratory exchange decreases, blood pressure, at first likely to be near normal, will fall progressively. If adequate oxygenation is restored early, the blood pressure will improve; if hypoxia persists untreated, there may be capillary damage, and measures to combat shock may be required. The pupils will be symmetrical and pinpoint in size; however, if hypoxia is severe, they may be dilated. Urine formation is depressed. Body temperature falls, and the skin becomes cold and clammy. The skeletal muscles are flaccid. Frank convulsions occasionally may be noted in infants and children. When death occurs, it is nearly always due to respiratory failure. Even if respiration is restored, death still may occur as a result of complications that develop during the period of coma, such as pneumonia or shock.

25. Department of Pharmacology, DSMA Treatment of acute poisoning The first step is to establish a patent airway and ventilate the patient. Opioid antagonists can produce dramatic reversal of the severe respiratory depression, and the antagonist naloxone is the treatment of choice. However, care should be taken to avoid precipitating withdrawal in dependent patients, who may be extremely sensitive to antagonists. The safest approach is to dilute the standard naloxone dose (0.4 mg) and slowly administer it intravenously, monitoring arousal and respiratory function.

26. The End