镇痛药 Analgesics 北京协和医学院基础医学院药理学系 叶菜英

镇痛药 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.

镇痛药 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.

镇痛药 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.

阿片类药物 Opium 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

HO HO O N CH 3 吗啡 morphine 阿片 (opium) 生物碱类 (opiate alkaloids) Morphine (1806 ， 10% of opium ） Morphine (1806 ， 10% of opium total base ） Codeine （ 1832, ） Codeine （ 1832,methyl-morphine ） Heroin （ 1874, acetomorphine ， powerful addictive drugs ） Phenanthrene Isoquinoline Papaverine

阿片生物碱类 镇痛药 阿片生物碱类 罂粟 (poppy ）

Fresh capsule of opium poppy Cut capsule showing latex exuding from cut

镇痛药 阿片生物碱类 罂粟 (poppy ）

镇痛药 阿片生物碱类 含阿片生物碱类植物： 罂粟

吗啡 morphine Chemical constitution Structural features  17position R is － CH 3 ……agonists  17 position R is － CH 2 CH ＝ CH 2 ……antagonists  7 position NCH 2 CH － ……inreversible compound

Mechanisms and Effects 阿片受体 opioid receptor In 1973,three American labs dicovered 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)κ(kappa) Analgesia above spinal cord level spinal cord level spinal cord level Respiratory depression ＋＋＋＋＋ Pupilmyosis myosis － Stomach intestinedecreasedecrease － SM spasm ＋＋＋＋－ Psychoactivity euphoria ＋＋ euphoria ＋＋ restlessness ＋ sedative ＋＋ sedative ＋＋ sedative ＋ Physical dependence ＋＋＋＋＋

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.

吗啡 morphine Clinical application Analgesia ： acute sharp pain, serious trauma 、 adustum, myocardial infarct, terminal cancer Cardiac asthma AT Antidiarrheal Aombined anesthesia

吗啡 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( 吗啡 ) 一词来源 于西腊文 Morpheus( 梦之神 ) 。

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 戒断综合症状 SYMPTOMS OF WITHDRAWAL 腹泻 出汗 抑郁 震颤 衰弱 肌痉挛 寒战 渴求药物 头痛、

镇痛药 阿片生物碱类 鸦片战争

镇痛药 阿片生物碱类 吗啡成瘾机制 吗啡成瘾机制 : NA receptors 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.

哌替啶 pethidine (dolantin, 度冷丁） Pharmacologic action Application succedaneum of morphine analgesia 、 preanesthetic medication and induced hibernation 、 cardiac asthma 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.

度冷丁 dolantin （哌替啶 pethidine ） Artificial Untoward reaction Addiction Respiratory depression

可待因 codeine （ 3-o-methyl derivative of morphine ） Characteristics ： Analgesia:1/12 of morphine Preventing cough:1/4 of morphine Addiction is weaker than morphine. Application ： central antitussive （如 氨酚待因片） Moderate analgesics:simple recipe or mixture （如 氨酚待因片）

二氢埃托啡 dihyentophine 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

镇痛药 人工合成类 哌替啶 美沙酮 methadone Pharmacologic action Application succedaneum of morphine succedaneum of morphine detoxification detoxification 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.

镇痛药 阿片受体拮抗剂 Opioid antagonists 纳洛酮 naloxone Application The treatment of opioid overdose and the prevention The treatment of opioid overdose and the prevention The treatment of toxic shock The treatment of toxic shock Competitive opioid receptor antagonist that can rapidly reverse the effects of morphine and other opioid agonists 。

芬太尼 fentanyl 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

镇痛新 (Pentazocine) Characteristics: Mixed opioid agonist-antagonist,agonist κ 、 δ ， antagonist μ 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 detoxification ：  gastric lavage by 1:2000 KMnO4  artificial respiration ， O 2  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 ）

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