Transcript Morphine
镇痛药 Analgesics 北京协和医学院基础医学院药理学系 叶菜英 Analgesics Primary effect on CNS, eliminate or ease pain selectively, to lessen the nervous of patients, these agents relieve pain without producing a loss of consciousness. They are used primarily to relieve acute and chronicity pain of any origin. Analgesics It has been know for centuries that extracts of the opium poppy can be used to relieve pain and treat diarrhea. In 1806, Morphine was first isolated from the juice of the opium poppy by German pharmacist Friedrich Sertürner. During the 1950s, a series of morphine-like potent analgesics were synthesized, such as pethidine,methadone, etorphine,fentanyl. Analgesics Pain is a complex subjective sensation, and a kind of protective response when organism suffer the nociceptive stimulus. Pain is also the basis for the doctors diagnosing diseases. It usually accompany anxiety, dread, horror, discomfort and so on, to cause the patients disorder, even shock. Acute pain that has been made a definite diagnosis, should use analgesics immediately. But it is inadvisable to use narcotic analgesics when a pain hasn`t be certified, in order to avoid misdiagnosis. Opium (阿片类药物) 【Classification】 chemical constitution affinity and intrinsic activity Agonists: Morphine, Pethidine, adanton…… Antagonists: Naloxone, Naltrexone Partial agonist: Pentazocine, Nalorphine 【 Physiological disposition 】 take orally, injection→pass through the blood brain barrier→hepatic metabolism→renal excretion Opiate alkaloids (阿片生物碱类) Phenanthrene Morphine (1806，10% of opium total base） Codeine （1832,methyl-morphine） Heroin （1874, acetomorphine, powerful addictive drugs） HO Isoquinoline O Papaverine N HO morphine CH3 Poppy 阿片生物碱类 Fresh capsule of opium poppyP Cut capsule showing latex exuding from cut Poppy 镇痛药 阿片生物碱类 含阿片生物碱类植物： 罂粟 Morphine Chemical constitution Structural features 17position R is －CH3……agonists 17 position R is －CH2CH＝CH2……antagonists 7 position NCH2CH－……inreversible compound Mechanisms and Effects Opioid receptor In 1973, three American labs discovered the receptor at the same time. Exist on cell membrane, glycoprotein High affinity Saturability Stereospecificity Distribution of definite area Specificity antagonists Types and effects μ(mu) δ(delta) Analgesia κ(kappa) above spinal cord level spinal cord level spinal cord level ＋＋ ＋＋ ＋ Pupil myosis myosis － Stomach intestine decrease decrease － SM spasm ＋＋ ＋＋ － Psychoactivity euphoria＋＋ euphoria＋＋ restlessness ＋ sedative＋＋ sedative＋＋ sedative＋ Physical dependence ＋＋ ＋＋ ＋ Respiratory depression Mechanisms and Effects Endopioid peptide Regulate algesthesia Endogenous pain control system Effects on angiocarpy and gastrointestinal tract Mechanism: Inhibit sensory nerve ending to release SP，thus preventing transmission of pain impulses to CNS. Enkephalin and pain When a person is injured, pain impulses travel up the spinal cord to the brain, which then releases endorphins and enkephalins. Enkephalins block pain signals in the spinal cord, while endorphins are thought to alleviate pain principally at the brainstem. Mechanisms Morphine It binds to opioid recepters which are discretely distributed in the human brain, exerts its principal pharmacological effect like internal opioid peptides Cerebral ganglion——analgesia Nucleus ceruleus——euphoria Limbic system—— emotional reaction、Sedation NTS——tussis, stomach intestine Pharmacological effect of Morphine CNS： Analgesia 、 Sedation Inhibition of cough reflex Respiratory depression Euphoria Miosis、Nausea and vomiting Pharmacological effect of Morphine Gastrointestinal and biliary effects Constipation(increased intestinal smooth muscle tone) Increased biliary sphincter tone and pressure Pharmacological effect of Morphine Cardiovascular effects: Postural hypotension and vasodilation Decreased myocardial oxygen demand Pharmacological effect of Morphine Immune system effects: Immune suppression. Inhibit proliferation of lymphocytes,reduce secretion of cytokines. Inhibit the immune reaction which induced by HIV protein. Clinical application of morphine Analgesia: acute sharp pain,serious trauma, adustum,myocardial infarct,terminal cancer Cardiac asthma AT Antidiarrheal Aombined anesthesia Morphine Untoward reaction Respiratory depression Addiction euphoria—morphine is a highly addictive substance, both psychologically and physically. withdrawal syndrome—stimulation, insomnia, lacrimation, perspiration, thrill, vomit, diarrhea, collapse, unconscious. (feelings of “euphoria”, ambition, nervousness, relaxation, drowsiness, or sleepiness) morphine 镇痛药 阿片生物碱类 吗啡 不良反应 不良反应 反复应用（一般剂量连用1w左右）引起成瘾！ 镇痛药 阿片生物碱类 成瘾性 镇痛药 阿片生物碱类 成瘾性 戒断综合症状 出汗 衰弱 头痛、 肌痉挛 腹泻 震颤 寒战 抑郁 渴求药物 镇痛药 阿片生物碱类 鸦片战争 Mechanism of morphine addiction Nucleus ceruleus: intensive opioid and NA receptors. Morphine and endogenous opioid peptides inhibit the firings of nucleus ceruleus, the firings of addicts are decrease significantly. The firings of nucleus ceruleus are increase when addicts stop using morphine, naergic neurons are hyperfunction, withdrawal symptom appearance. Pethidine (dolantin） 【Pharmacologic action】 It interacts predominantly with the μ-opioid receptor. CNS effects is similar with morphine but weaker than morphine,action time is 2~4h less than morphine. Addiction is weaker than morphine. 【Application】 Succedaneum of morphine Analgesia, preanesthetic medication and induced hibernation, cardiac asthma Pethidine (dolantin) Artificial Untoward reaction Addiction Respiratory depression Codeine（3-o-methyl derivative of morphine, 可待因） Characteristics： Analgesia:1/12 of morphine Preventing cough:1/4 of morphine Addiction is weaker than morphine. Application： central antitussive Moderate analgesics:simple recipe or mixture Dihyentophine (二氢埃托啡) Characteristics Strong opioid agonists,1000 times of morphine IM10 μg 5~15 min → analgesia last 6 hr Hypoglossis20 μg 5~20 min Use to traumatic occlusion pain, TCA, postop analgesia Tolerance, addiction Overdose→Respiratory depression Methadone (美沙酮) 【Pharmacologic action】 It interacts predominantly with the μ-opioid receptor. CNS effects is similar with morphine, action time is longer than morphine. Addiction is weaker than morphine. 【Application】 Succedaneum of morphine detoxification Opioid antagonists Naloxone (纳洛酮) H3C HCH2C OH Competitive opioid receptor antagonist that can rapidly O reverse the effects of morphine and other opioid agonists. N O Naloxone Application The treatment of opioid overdose and the prevention The treatment of toxic shock CH3 Fentanyl(芬太尼) Characteristics: Strong analgesic effect（100 times of morphine） Many kinds of pain, use with anesthetic Less addiction Untoward reactions are similar with morphine Contraindication: bronchial asthma，intracranial tumour and coma caused by cerebral trauma Pentazocine (镇痛新) Characteristics: Mixed opioid agonist-antagonist, agonist κ,δ, antagonistμ Analgesia is 1/4 of morphine Less addiction――Non-Narcotics Use to chronic pain Abuse analgesics Drug abuse: take a psychoactive drug or performance enhancing drug for a non-therapeutic or non-medical effect. Morphine: 3 times a day, last 1-2 weeks→addition Treatment of withdrawal syndrome: convince, decrement step by step, use methadone, benzodiazepine to relieve symptoms. Detoxification: gastric lavage by 1:2000 KMnO4 artificial respiration,O2 IM.naloxone Respiratory Stimulants Examples of Pain Scales 按疼痛的性质分类：锐痛、纯痛、绞痛 Three-Step Analgesic Ladder 2000,WHO has developed a standardized cancer pain treatment plan that is recognized and used worldwide. April 1991, Ministry of Public Health announced that our conutry should develop Three-Step Analgesic Ladder in cancer pain therapy. It is based on the idea that analgesic (pain reliever) drug therapy provides the most effective pain relief for cancer patients. The three different steps refer to different combinations of analgesics. Three-step Analgesic Ladder Mild to moderate pain: use of non-opioids （Aspirin,Ibuprofen,Indometacin） Moderate pain: a combination of opioids and non- opioids should be tried （Codeine,Tramadol） Severe pain: opioids should be used （Morphine、Dihydroetorphine、 Pethidine） Thanks!