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<ul><li> 1. Opioid analgesia and antagonist </li></ul> <p> 2. History 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 versed in the use of opium; Arabian trader introduced the drug to the orient, where it was employed mainly for the control of dysenteries. By the middle of the sixteenth century, many of the uses of opium were appreciated. 3. Opium contains more than 20 distinct alkaloids. In 1806,Sertuner reported that 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 preparation began to spread throughout the medical world. poppy 4. In the USA , opioid abuse was accentuated by the unrestricted availability of opium that prevailed until the early years of the 20th century and by the influx of opium-smoking immigrants from the Orient. opium 5. The problem of addiction to opioids stimulated a search for potent analgesics free of addictive potential. Just prior to and following World War , synthetic compounds such as meperidine and methadone were induced into clinical medicine, but proved to have typical morphine-like actions. heroin 6. Nalorphine ,a derivative of morphine ,was an exception. Nalorphine antagonized the effects of morphine and was used to reverse morphine poisoning in the early 1950s. but the drug is not used clinically as an analgesic because of side effects such as anxiety and dysphoria. 7. However ,its pharmacological profile ushered in the development of new drugs, such as the relatively pure antagonist naloxone and compounds with mixed actions. 8. Endogenous opioid peptides A) Alcohol is thought to stimulate the release of endogenous opioids, which may produce the euphoric feelings associated with alcohol consumption. B) Endogenous opioids (e.g., beta-endorphin) are released into the synapse (the space between the signaling and target neurons) and C) stimulate activity at opiate receptors, which produces a signal in the target neuron. D) Exogenous opiates such as morphine also stimulate opiate receptors. E) Naltrexone is thought to block opioids from activating opiate 9. Multiple opioid receptors Mu receptors: Most of the clinically used opioid are relatively selective for receptors, reflecting their similarity to morphine. receptors initially were defined by their affinity for morphine. -endorphin has high affinity for receptors, which also have high affinity for the enkephalins. Dynorphin A also binds to receptors potently , but not as potently as to 1 receptors. 10. Kappa receptors: Dynorphin A is the endogenous ligand for the 1 receptors . Unlike 1 receptors ,which produce analgesia spinally, 3 receptors relieve pain through supraspinal mechanisms. 11. Delta receptors: The enkephalins are the endogenous ligands for the receptors. The consequences of stimulating receptors with morphine and morphine -like opioid agonists in human beings are unclear. In animals, relatively specific agonists produce analgesia and positive reinforcing effects at supraspinal sites and antinociception for the thermal stimuli at spinal sites. 12. Profiles of opioid actions 13. Morphine and other morphine -like opioid agonists produce analgesia primarily through interaction with receptors . Other consequences of receptor activation include respiratory depression , miosis, reduced gastrointestinal motility, and feeling of well-being( euphoria) 14. Classification Natural opiates: morphine, codeine, papaverine Synthetic analgesics: meperidine, methadone, fentanyl, anadol, etorphine, pentazocine. 15. natural opiates 16. Morphine 17. pharmacokinetics Absorption It is well absorbed from the gastrointestinal tract and but, undergoes a significant first-pass effect. so subcutaneous injection is commonly used. In addition, readily absorbed from nasal mucosa, intramuscular, and intravenous route 18. Distribution When therapeutic concentrations of morphine are present in plasma, about one- third the drug is protein bound, although the primary site of action of morphine is in the CNS, in the adult only small quantities pass the BBB. 19. Metabolism The major pathway for the metabolism of morphine is conjugation with glucuronic acid to form both active and inactive products. morphine -6-glucuronide, a major metabolite of morphine, has pharmacological actions indistinguishable from those of morphine. 20. Excretion Very little morphine is excreted unchanged. It is eliminated by glomerular filtraton, primarily as morphine- 3-glucuronide ; 90%of the total excretion takes place during the first day. 21. Pharmacological effects 22. A)Opiates affect the limbic system, which controls emotions, increasing pleasure, relaxation and contentment. B.) The brainstem controls automatic activity, like breathing or coughing. Opiates can act on the brainstem to stop coughing or slow breathing. C.) The spinal cord transmits pain signals from the body. Opiates act here to block pain messages 23. CNS effects Analgesia and sedation : Strong analgesia Effective on various pains: chronic dull pain and acute sharp pain, especially continued severe dull pain. No effects on other senses and consciousness Sedation Analgesia with euphoria in partial patients 24. Nauseant and emetic effects Nausea and vomiting produced by morphine like drugs are unpleasant side effects caused by direct stimulation of the chemoreceptor trigger zone(CTZ) for emesis , in the area postrema of the medulla. 25. Respiratory depression Morphine depresses respiration , at least in part by virtue of a direct effect on the brainstem respiratory center. The respiratory depression is discernible even with doses too small to disturb consciousness and increases progressively as the dose is increased. In human beings, death from morphine poisoning is nearly always due to respiratory arrest. the diminished respiratory volume is due primarily to slow rate of breathing, and with toxic amounts the rate may fall to 3 or 4 breaths per minute. 26. Stops coughing Morphine and related opioid also depress the cough reflex at least in part by a direct effect on a cough center in the medulla. 27. Miosis Morphine and most and agonists cause constriction of the pupil by an excitatory action on the parasympathetic nerve innervating the pupil. 28. Cardiovascular effects Peripheral vasodilation to the produce orthostatic hypotension due to inhibition of vasomotor center and promotion of release of histamine. Cerebral vasodilation to increase intracranial pressure via depressed respiration and increased blood CO2. Shifting of blood from pulmonary to systemic circulation . Reduces peripheral resistance so cause decrease work load. 29. Gastrointestinal effects Constipation due to reduced peristalsis and stomach motility as well as increase spasmodic nonpropulsive contraction. Decreased biliary and pancreatic secretions to cause indigestion. Increased biliary pressure by constriction of Oddis sphincter to induce biliary colic. 30. Other effects Bronchoconstriction. Retention of urine by increasing sphincter tone of bladder. 31. Clinical uses Analgesia Morphine is useful in acute sharp pain , anginal pectoris, biliary and kidney colic, etc. morphine should be combined with atropine in the treatment of biliary and kidney colic, and relieve aginal pectoris by analgesic, sedative and vasodilative effects. 32. Acute pulmonary edema caused by acute left ventricular failure. Morphine relieves acute pulmonary edema by vasodilation which results in decreased peripheral resistance and increased capacity of peripheral vessels. Severe diarrhea. Relieve of anxiety and depression Balanced anaesthesia and surgical anaesthesic Pre anaesthetic medication 33. Adverse reaction Side effects: Nausea, vomiting ,constipation ,respiratory depression, dysphoria. 34. Tolerance and addiction Persisting use of morphine for 1~2 weeks may produce tolerance and addiction. Addiction include physical dependence and withdrawal syndrome( pupillary dilation, sweating, tachycardia, yawning, fever,etc). 35. The first and most common used depends on cross- tolerance and consists of transfer to a prescription of opioid medication and then gradual dose reduction. Cold turkey therapy and Methadone plan Pharmacological interventions 36. A second approach to detoxification involve the use of clonidine, a medication approved for the treatment of hypertension . Clonidine , is an 2- adrenergic agonist that decreases adrenergic neurotransmission from the locus ceruleus. Many of the autonomic symptoms of opioid withdrawal such as nausea, vomiting cramp, sweating , tachycardia, and hypertension result from the loss of opioid suppression of the locus ceruleus system during the abstinence syndrome. 37. Clonidine ,acting via distinct receptors but by cellular mechanism that mimic opioid effects, can alleviate many of the symptoms of opioid withdrawal . However ,clonidine dose not alleviate generalized aches and opioid craving charateristic of opioid withdrawal. 38. A third method of treating opioid withdrawal is theoretically but not practically useful, it involves activation of endogenous opioid system with medication. The techniques proposed include acupuncture and several methods of CNS activation involving transcutaneous electrical stimulation. 39. Codeine Codeine is the 3- methyether of morphine. Pharmacological effects of codeine are similar to those of morphine, but its analgesic potency is of morphine, cough depressant potency is of morphine. 40. Analgesic effect of codeine is stronger than that of aspirin,30mg of codeine is equivalent to 600mg of aspirin. Less sedation ,respiratory depression and fewer gastrointestinal effects. It is used for mild to moderate pains and severe cough. Addiction in long term administration 41. synthetic analgesia 42. Pethidine Pharmacological effects of pethidine are similar to those of morphine, but less potencies and shorter duration in analgesis(1/10),sedative and respiratory depression. Pethidine has no effect on cough, bronchial and gastrointestinal smooth muscles. 43. Pethidine may replace morphine to relieve pains and treat acute pulmonary edema and induce artificial hibernation as one of lytic cocktail components. Pethidine has mild adverse effects and produces tolerance and addiction in long- term use. 44. Methadone It is used for analgesia, suppression of withdrawal syndrome, treatment of heroin user. Physical dependence of methadone occurs slowly and withdrawal syndrome is less severe. 45. Fentanyl Analgesic effect of fentanyl is 100 times as effective as morphine with short duration and rapid onset, it is mainly used for anesthesia, especially for postoperation pain. 46. opioid receptor antagonists 47. Partial antagonists: pentazocine. It may precipitate a withdrawal syndrome in opioid addicts. 48. Full antagonists: naloxone and naltrexone. Naloxone may reverse the acute poisoning effects of opioids agonists and precipitate a withdrawal syndrome in opioid addiction. 49. Opium Poppy, Crude Opium, Codeine, Heroin, and Morphine Morphine Powdered Heroin Hydromorphone (Dilaudid) </p>


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