1、 AnalgesicsZhang,Bintwo componentssomatic sensationaffective(emotion)a.Acute pain(sharp pain)b.Chronic pain(dull pain)Pain transmission pathwayNoxious stimuliPGsK+、H+BK5-HTPrimary afferent fibresnociceptorSpinal cordLimbic systemSomato-sensory cortexmood effect,the affective aspect of painthe sensor
2、y aspect of painDorsal hornsevere painOpioids(eg.Morphine)inflammatory pain NSAIDs(eg.Aspirin)local anaesthesia smooth muscle colic angina pectoris induced by coronary artery spasm trigeminal pain Drug treatment of paincholinoceptor-blocking drugs vasodilator drugs (eg.Nitroglycerin)CarbamazepineLoc
3、al anaestheticsCortex Spinal cordDorsal hornPGsK+、HBK5-HTNSAIDsOpioidsSites of action of different drugs opioid analgesics(narcotic analgesic,addictive analgesics)Opium(阿片)is the dried exudate obtained from unripe seedpods of the poppy Papaver somniferum,containing morphine,codeine,and other alkaloi
4、d substances.Opiate(阿片剂)means that a substance is extracted from opium or is similar in structure to natural substances present in opium.Opioid(阿片样物质)is a term that designates substances that are not derived from opium.It refers particularly to opioid peptides,i.e.endogenous compounds that bind to o
5、pioid receptors and mimic the effect of morphine-like compounds.Widely use termOpium The flower of papaver Opium(阿片阿片)Opiate(阿片剂阿片剂)Morphine Codeine Papaverine(罂粟碱罂粟碱)海洛因海洛因吗吗啡啡纳洛酮纳洛酮OHOpioid(阿片样物质阿片样物质)Endogenous opioid peptides:Enkephalins Endorphins Dynorphins Orphanin1992197319621975analgesic si
6、te is laminae III of periventricular and periaqueductal gray areaput forward“receptors”for opiate analgesics in brainisolated the first“endogenous opioid peptide”and named enkephalinCloned opioid receptors:Research historyExtracellularCytoplasmicNH2HOOCOpioid receptorsG protein-coupled receptors Opi
7、oid receptorssupraspinal analgesia,sedation,euphoria,dependence,respiratory depression,miosisspinal analgesia,sedationdysphoria(烦躁不安烦躁不安),hallucinationspinal analgesia,sedation,euphoria,dependence,respiratory depression :Spinal cordDorsal hornenkephalinsCa2+Ca2+Presynaptic terminalPostsynaptic neuro
8、nenkephalins The cellular mechanismsenkephalins Presynaptic terminalPostsynaptic neuronThe cellular mechanismsmorphine Morphine+receptorsOpen K+channelClose Ca2+channel 抑制冲动传导抑制冲动传导Ach,NA,Glu,5-HT,P release presynapticpostsynapticExcitability The cellular mechanismsThe cellular mechanisms Presynapti
9、c inhibition:activation of opioid receptors on presynaptic nerve terminals.Close Ca2+channel,decrease Ca2+input,and thereby reduce transmitter release(Ach,NA,Glu,5-HT,P).Postsynaptic inhibition:activation of postsynaptic opioid receptors.Open K+channels on postsynaptic neurons,increase K+output,and
10、thereby cause hyperpolarization and thus reduce postsynaptic neuronal excitability.Descending pain inhibitory pathwaysLocal inhibitory interneuron in spinal cordPainAscending pain transmission pathwaysEndogenous opioid peptidesPharmacological actions 1.CNS2.Smooth muscles3.Cardiovascular system1.CNS
11、 effects:principal effects Analgesia Sedation&euphoria Respiratory depression Cough suppression Others:miosis,nausea,hormone (1)Analgesia insensitive:muscle spasms pain,deafferentation pain partially sensitive:nerve pain,CNS compression injury,bone cancer sensitive:myocardial infarction,other types
12、of cancers relieve anxiety and distress,tolerance of pain1.CNS灼性神经痛(causalgia)系指在明确的神经损伤后，与损伤神经支配范围相一致的区域内出现的以剧烈灼样疼痛主要症状，表现为痛觉异常、痛觉过敏、交感神经机能障碍、血流障碍、出汗异常、骨、肌肉萎缩，有时表现出水肿性改变的慢性顽固性疼痛综合征。(2)Sedation and euphoria drowsiness and clouding of mentation sleep induced and aroused easily Euphoria a sense of con
13、tentment and well-being Sedation:the main reason for drug abuseSite:limbic system and locus ceruleus respiratory rate ，tidal volumethe most common cause of death from acute poisoning influenced by stimulusMechanisms:the sensitivity of respiratory center to increased CO2 tension (3)Respiratory depres
14、sion(4)Cough suppression antitussive effect by inhibiting cough centercodeine(5)Other CNS effectsMiosis:pinpoint pupilsNausea and vomiting:CTZ muscular tension:限制限制 胸廓活动胸廓活动,影响呼吸影响呼吸Hormone:LH,FSH,prolactin,GH,ADH2.Smooth muscle system Gastrointestinal system Biliary tract Urinary system genital sys
15、tem (1)Gastrointestinal tract delays passage secretion of digestive glandindigestioncentral inhibition a call of nature defecation reflex GIT tone GIT motility absorption of waterconstipation biliary colic constrict biliary smooth muscle constrict Oddis sphincter pressure in the biliary tract(2)Bili
16、ary tract(3)Urinary tractconstrict ureteral smooth muscle bladder sphincter tone urinary retention uterine tone prolong labor(4)Genital tract orthostatic hypotension Mechanisms:release of histamine vasomotor center3.Cardiovascular system(1)peripheral arterial and venous dilatation(2)intracranial pre
17、ssuresecondary to respiratory depressionClinical uses Analgesia Cardiac asthma Antidiarrhea Antitussive Combined anesthesia1.Analgesia terminal cancer myocardial infarction renal and biliary colic(atropine)trauma,burn,operation at regular time and quantityPulmonary edema dyspneaAcute left ventricula
18、r dysfunctionshort of breath(respiratory center)CO2 retention anxiety and distress Alveolar hypoventilation morphineReduce cardiac preload and afterloadReduce the sensitivity of the respiratory center to increased CO2SedationCardiac asthma and morphine therapy 2.Cardiac asthmaoxygen consumption(1)Me
19、chanisms:peripheral arterial and venous dilation preload and afterload pulmonary edema sedation anxiety and distress oxygen consumption the sensitivity of respiratory center to CO2 shortness of breath Cardiac asthmaOpioid analgesic drugs Morphine(吗啡吗啡)Heroin(海洛因，二醋吗啡海洛因，二醋吗啡)Codeine(可待因可待因)Pethidine
20、(哌替啶哌替啶)Methadone(美沙酮美沙酮)Fentanyl(芬太尼芬太尼)buprenorphine(丁丙诺啡丁丙诺啡)Tramadol(曲马多曲马多)Morphine 1803 Serturner isolated a pure active alkaline substance from opium.He proposed the name“morphine”for it after Morpheus.absorptionexcretion distribution free drugoral First pass eliminationsc.im.bloodliverplacen
21、tal fetuslittle cross the BBB,but enough for its function morphine-6-glucuronidekidney,breastiv.Bioavailability25-30%metabolism美施康定美施康定（硫酸吗啡缓释片硫酸吗啡缓释片）1.强效，作用持续强效，作用持续12 hr。主要用于晚期癌。主要用于晚期癌症患者第三阶梯止痛。症患者第三阶梯止痛。2.抑制呼吸，可引起恶心、呕吐、便秘及抑制呼吸，可引起恶心、呕吐、便秘及排尿困难，长期应用可产生耐受性、身体依排尿困难，长期应用可产生耐受性、身体依赖性和成瘾性。赖性和成瘾性。Hero
22、in(diamorphine)Semisynthetic substance,prodrug of morphine More lipid soluble than morphine More rapid onset 德国拜尔公司德国拜尔公司 heroin在德文中意为英雄在德文中意为英雄 万能药万能药 药品转变为毒品药品转变为毒品 白粉白粉Codeine 1.higher oral efficacy2.lower efficacy than morphine3.use as antitussive,severe dry cough.联邦止咳露联邦止咳露：麻黄碱+可待因+氯苯那敏+氯化铵注意事项
23、注意事项 不宜用于痰多粘稠者。连续应用不宜2周，因久用可成瘾。7岁儿童禁用。Pethidine(dolantin)Weaker potency than Morphine,no antitussive action More rapid onset and shorter duration(2-4h)than morphine Metabolite:normeperidine convulsion LyticcocktailMethadone 1.synthetic compound,equal analgesia to morphine 2.milder abstinence syndrom
24、e 3.routinely used in detoxification of morphine addictsFentanyl1.more analgesic potentcy than morphine:2.rapid onset and short duration of action 3.fentanyl,alfentanil,remifentanil:adjunctive drug for general anaesthesia 4.Fentanyl+Droperidol(氟哌利多氟哌利多):neuroleptanalgesia(神经阻滞镇痛术神经阻滞镇痛术)Used for min
25、or surgery 5.breakthrough cancer pain:口腔经粘膜芬太尼拘橼酸盐口腔经粘膜芬太尼拘橼酸盐(Oral Transmucosal Fentanyl Citrate,OTFC)Fentanyl lollipopACTIQ 芬太尼口腔粘膜贴片芬太尼口腔粘膜贴片(Fentanyl sublingual tablets)ABSTRAL 芬太尼透皮贴剂芬太尼透皮贴剂(Fentanyl transdermal system)多瑞吉多瑞吉 high lipid-solublePentazocine,agonist,partial agonist increase blood
26、pressure and cause tachycardia (NA)weak action on :little addictive liability precipitate withdrawal syndrome of morphine abuser列入非麻醉药品。但久用仍会列入非麻醉药品。但久用仍会成瘾！成瘾！analgesia and respiratory depression:weakerTramadol Atypical opioid:weak activation,also interacts with monoaminergic systems(inhibit NA and
27、 5-HT reuptake)Alternative to traditional opioid analgesics2008年1月1日国家将曲马多列为精神药品进行管理延胡索乙素和罗通定 罗通定为左旋体的延胡索乙素，是有效部分。镇静安定镇痛和中枢性肌肉松弛作用 解热镇痛抗炎药镇痛作用哌替啶，镇痛作用与阿片受体及前列腺素均无关 无明显成瘾性 口服后10-30min起效，维持2-5h，对慢性持续性钝痛效果好 不影响产程1.ToleranceAdverse effects large doses at short intervals readily cross tolerance full agon
28、ist:more obvious2.Dependence physical dependence：withdrawal syndrome psychological denpendence:compulsive drug-seeking behaviorAdverse effects 身体依赖性身体依赖性 精神依赖性精神依赖性渴求渴求 戒断综合征戒断综合征强迫性用药强迫性用药依赖性依赖性药物滥用药物滥用药物滥用（药物滥用（drug abuse）:非医疗目的反复非医疗目的反复使用使用具有具有依赖性依赖性潜能的潜能的精神活性物质精神活性物质。体验。体验该物质产生的特殊精神效应。该物质产生的特殊精神
29、效应。药物误用药物误用(drug misuse)：用药适应证选择不当/用量过大、疗程过长等错误用药行为。rhinorrhea Lacrimation chills gooseflesh (piloerection)yawning sweatingmuscular achevomiting diarrhea anxiety hostility hyperventilation Withdrawalsyndrome of Opioid3.General adverse effects1 Constipation5Respiratory depression2Biliary colic6Postur
30、al hypotension3Nausea and vomiting7 Increased intracranial pressure4Urinary retention8Dysphoria Clinical overdose Accidental poisoning in addicts 30mg toxic threshold 120mg lethal thresholdPinpoint pupilsDeep respiratory depressionComaTreatments:Establish patent airway Adequate ventilation Naloxone
31、iv.The triad：4.Acute Morphine PoisoningNaloxone petitive full antagonist for opioid R()2.opioid overdose:reverses coma and respiratory depression 3.differential diagnosis in morphine abuser:precipitates withdrawal symptom 4.short t1/2(1h),repeated injectionsContraindications obstetric labor,breastin
32、g period obstructive airway disease,bronchial asthma head injuries seriously impaired hepatic or renal function联合国禁毒机构估计全球约联合国禁毒机构估计全球约2 2亿人在滥用四类毒品，亿人在滥用四类毒品，占全球占全球1515 6464岁人口的岁人口的5%5%。阿片类阿片类 苯丙胺类苯丙胺类 大麻大麻 可卡因可卡因Mode of administration of opioids Oral administration Sublingual administration Rectal
33、administration Intravenous administration Intramuscular administration Intrathecal and epidural administration (鞘内给药)(硬膜外给药)Transdermal patch administration(透皮贴剂)Patient Controlled Analgesia(病人自控镇痛病人自控镇痛，PCA)根据病人对镇痛药需求的个体差异，使用专门设计的具有安全控制系统的微电脑输液泵，由医生设定给药剂量，病人可以根据个人需要，通过按压给药按扭自行给药，以满足镇痛治疗个体化需要。术后镇痛很多
34、采取这种方法。医生会根据您的情况设置一个安全剂量范围，不必担心按压次数过多而引起药物过量。Non-opioid for mild painPain persisting or increasingWeak Opioids for moderate painPain persisting or increasingStrong Opioids for severe painFreedom from cancer painNSAIDs e.g.aspirin,acetaminophene.g.codeine，tramadole.g.morphine,fentanyl,methadone WHO analgesic ladder
