1、第二十一章第二十一章 镇痛药镇痛药（Analgesics）教学目的和要求教学目的和要求掌握吗啡的药理作用、作用机制、临床应用、不良反应和禁忌症。掌握哌替啶的药理作用、作用机制、临床应用、不良反应和禁忌症。熟悉喷他佐辛的作用特点。了解纳洛酮、可待因、美沙酮、二氢埃托啡的作用特点。CGRP:降钙素基因相关肽降钙素基因相关肽 IP3:肌醇三磷酸肌醇三磷酸NK-1:神经激肽神经激肽-1-1受体受体NMDA:N-甲基甲基-D-天冬氨酸天冬氨酸AMPA:a a-氨基氨基-3-羟基羟基-5-甲基甲基-4-异唑丙酸异唑丙酸1.阿片类镇痛药阿片类镇痛药（Opioid-analgesics）又称成瘾性或麻醉性镇痛
2、药(narcotics)。代表药：代表药：阿片生物碱类及其合成代用品2.解热镇痛抗炎药解热镇痛抗炎药（antipyretic-analgesic and antiinflammatory drugs）干扰PGs生物合成，产生镇痛作用 代表药：代表药：阿司匹林3.局麻药局麻药（Local anaesthetics）4.某些特殊神经止痛药某些特殊神经止痛药阿片生物碱类阿片生物碱类:吗啡（morphine）可待因（codeine）半合成阿片类半合成阿片类:海洛因（heroin）人工合成阿片类人工合成阿片类:哌替啶（pethidine）芬太尼（fentanyl）内源性阿片肽内源性阿片肽:b-内啡肽（b
3、-endorphin）甲硫氨酸脑啡肽（met-enkephalin）亮氨酸脑啡肽（leu-enkephalin）边缘系统和蓝斑核受体：边缘系统和蓝斑核受体：与情绪和精神活动有关；脊髓胶质区、丘脑内侧、脑室及导水管周围灰质脊髓胶质区、丘脑内侧、脑室及导水管周围灰质受体：受体：与疼痛刺激的传入、痛觉的整合及感受有关；孤束核受体：孤束核受体：与镇咳、呼吸抑制、中枢交感张力降低有关；脑干极后区、孤束核、迷走神经背核受体：脑干极后区、孤束核、迷走神经背核受体：与胃肠活动有关，肠肌本身也有阿片受体；中脑盖前核受体：中脑盖前核受体：与缩瞳有关钙调素依赖性蛋白激酶基因调控机制基因调控机制 效效 应应受受 体体
4、 镇痛镇痛 脊髓以上水平脊髓以上水平 脊髓水平脊髓水平呼吸抑制呼吸抑制缩瞳缩瞳止咳止咳镇静（欣快）镇静（欣快）焦虑，烦燥不安焦虑，烦燥不安胃肠活动胃肠活动免疫抑制免疫抑制l吸收吸收(absorption)：口服易吸收，首关消除明显（70%），生物利用度低，常注射给药。l分布分布(distribution):约1/3与血浆蛋白结合；未结合型吗啡迅速分布于全身，仅有少量通过血脑屏障，但足以发挥中枢药理作用。l代谢代谢(metabolism):在肝内与葡萄糖醛酸结合，代谢物吗啡-6-葡糖醛酸具药理活性。l排泄排泄(excretion):主要以吗啡-6-葡糖醛酸的形式经肾排泄，小量经乳腺排泄，可通过胎
5、盘进入胎儿体内。1.具有强大的镇痛作用，对各种疼痛都有效；镇痛时不影响意识和其他感觉；对持续性慢性钝痛的效力大于间断性锐痛。能消除由疼痛所引起的焦虑、紧张、恐惧等情绪反应，显著提高机体对疼痛的耐受力。随着疼痛的缓解，可出现欣快症状（euphoria）。治疗量：治疗量：抑制呼吸，使呼吸频率减慢、潮气量降低；剂量增大：剂量增大：抑制作用增强；急性中毒：急性中毒：呼吸频率可减慢至34次/分。抑制呼吸的机制抑制呼吸的机制 降低呼吸中枢对血液CO2张力的敏感性；对桥脑内呼吸调整中枢也有抑制作用；与中枢抑制药合用，加重呼吸抑制作用。抑制咳嗽中枢，使咳嗽反射消失。催吐催吐(emesis)：兴奋延髓催吐化学感
6、受区缩瞳缩瞳(miosis)：针尖样瞳孔为吗啡中毒特征神经内分泌神经内分泌(neuroendocrine)促进抗利尿激素(ADH)释放；抑制促性腺激素释放激素(GnRH)和促肾上 腺 皮 质 激 素 释 放 激 素 的 释 放(CRH)，降低促黄体生成激素(LH)和卵泡刺激素水平(FSH)。(gastrointestinal tract)兴奋胃肠平滑肌，提高其张力；引起便秘原因：原因：平滑肌张力；肠道推进性蠕动；括约肌张力；消化液分泌；中枢抑制。胆道胆道:胆道oddis括约肌痉挛性收缩，引起上腹不适甚至胆绞痛。胆绞痛、肾绞痛选用吗啡+阿托品。大剂量吗啡促进组胺释放，引起支气管收缩；治疗量吗啡可
7、降低子宫张力，延长产程；治疗量吗啡能提高膀胱括约肌张力，导致尿潴留。扩张血管，降低血压扩张血管，降低血压可能机制：可能机制：促进释放组胺 抑制血管运动中枢升高颅内压升高颅内压:抑制呼吸，体内CO2蓄积，扩张脑血管，升高颅内压。抑制细胞免疫和体液免疫。抑制人类免疫缺陷病毒（HIV）蛋白诱导的免疫反应。对各种疼痛都有效，但易成瘾，一般仅用于其它药物无效的剧痛（癌症剧痛、严重创伤、烧伤等急性锐痛及心肌梗塞引起的剧痛）。急、慢性消耗性腹泻，选用阿片酊或复方樟脑酊；若伴有细菌感染，应同时服用抗菌药。扩张外周血管，减轻心脏负荷；镇静作用有利于消除患者的焦虑恐惧情绪；降低呼吸中枢对CO2的敏感性，缓解急促浅
8、表的呼吸。心源性哮喘伴休克、昏迷和严重肺功能不全者禁用；支气管哮喘者禁用。NSAIDs与阿片类镇痛药镇痛作用比较与阿片类镇痛药镇痛作用比较药物药物作用部位作用部位 作用机制作用机制 作用性质作用性质成瘾性成瘾性NSAIDs外周抑制PGs合成慢性钝痛 不易成瘾镇痛药镇痛药中枢激动中枢阿片受体各种疼痛易成瘾l一般不良反应一般不良反应(Common Side Effects)l耐受性及依赖性耐受性及依赖性 (Tolerance and Physical Dependence)l急性中毒急性中毒(Acute Poisioning)l禁忌证禁忌证(Contraindication)治疗量吗啡可引起眩晕、
9、恶心、呕吐、便秘、排尿困难、胆绞痛、呼吸抑制、嗜睡等。戒断症状戒断症状（abstinent symptom)流涕、流泪、失眠、出汗、呕吐、虚脱、大小便失禁、意识丧失等昏迷；针尖样瞳孔；呼吸高度抑制；血压剧降、休克。呼吸麻痹是致死的主要原因。禁用于分娩和哺乳妇女止痛；禁用于支气管哮喘及肺心病患者；禁用于颅内压增高和肝功能严重减退患者。罂粟、鸦片吗啡古柯叶仙人球毒碱海洛因可待因可卡因黑西哥致幻蕈碱蒂巴因大麻（小量）大麻（大量）大麻美沙酮呱替啶苯丙胺麦角酸二乙酰胺芬太尼镇痛新甲基苯丙胺苯环已哌啶苯巴比妥安定利他林二甲色胺 海洛因海洛因 大大麻麻 我国记录在册的吸毒者人数我国记录在册的吸毒者人数7 7
10、525286861051050 020204040606080801001001201201990年1990年1995年1995年2001年2001年2003年2003年人数（万）人数（万）口服易吸收，主要在肝脏代谢，10%可待因脱甲基转变为吗啡而发挥作用。镇痛作用为吗啡的1/12，镇咳作用为吗啡的1/4，成瘾性吗啡。主要用于中等疼痛止痛和中枢性止咳。度冷丁（度冷丁（dolantin）1.1.镇痛：镇痛：可取代吗啡2.2.麻醉前给药：麻醉前给药：镇静作用3.3.心源性哮喘心源性哮喘4.4.人工冬眠：人工冬眠：与氯丙嗪、异丙嗪合用组成冬眠合剂治疗量与吗啡相似，可致眩晕、出汗、口干、恶心、呕吐、心
11、悸及体位性低血压。中毒时发生惊厥（代谢产物去甲哌替啶所致）。镇痛作用弱于吗啡，持续时间短；镇静、呼吸抑制、扩血管作用与吗啡相当，可致体位性低血压，颅内高压。中等程度提高胃肠道平滑肌张力，作用时间短，不引起便秘，无止泻作用；不延长产程。l m受体激动剂，镇痛作用为吗啡的镇痛作用为吗啡的100倍倍，作用维持时间短，可用于各种剧痛，成瘾性小。l 与麻醉药合用可减少麻醉药用量，与氟哌啶（氟哌利多）合用有安定镇痛作用，用于神经松弛镇痛，可完成某些令病人痛苦的小手术或医疗检查。l 大剂量产生明显肌肉僵直，纳洛酮能对抗；静脉注射过速易抑制呼吸，应加注意。l 禁用于支气管哮喘、颅脑肿瘤或颅脑外伤引起昏迷的患者
12、以及二岁以下小儿。又称美散痛，是一种人工合成的麻醉药品。其盐酸盐为无色或白色的结晶形粉末，无嗅、味苦，溶解于水，常见剂型为胶囊，口服使用。药理作用性质与吗啡相似，口服口服与注射同样有效有效。镇痛作用强度与持续时间与吗啡相当。耐受性与成瘾性发生慢耐受性与成瘾性发生慢，戒断症状轻，易于治疗。适用于创伤、手术及晚期癌症等所致剧痛以及吗啡成适用于创伤、手术及晚期癌症等所致剧痛以及吗啡成瘾者戒毒。瘾者戒毒。二氢埃托啡（二氢埃托啡（dihydroetorphine)为我国研制的强镇痛药，镇痛效力是吗啡的吗啡的500-1000倍倍。主要激动激动m m受体受体。临床用于哌替啶、吗啡等无效的顽固性疼痛和晚期癌痛
13、。小剂量间断用药不易产生耐受性，反复用药产生耐受和依赖。过量引起呼吸抑制呼吸抑制是致死的主要原因，可用纳洛酮对抗。第三节第三节 阿片受体部分激动剂阿片受体部分激动剂(Partial Agonist)本类药以镇痛为主，呼吸抑制作用较弱，依赖性较小。部分药物对一种受体亚型起激动作用，而对另一种亚型起阻断作用，称混合型激动-拮抗药。又名镇痛新又名镇痛新 阿片受体部分激动药，激动激动k k、s s受体受体，拮抗拮抗m m受体受体；镇痛效力为吗啡的1/3；适用于各种慢性剧痛；呼吸抑制作用约为吗啡的1/2，增加剂量至30mg以上，呼吸抑制作用不按比例增强呼吸抑制作用不按比例增强；拮抗受体，减弱吗啡镇痛作用
14、；吗啡耐受者可促进戒断症状产生；拮抗吗啡抑制呼吸的作用不明显；肝脏代谢个体差异大，导致镇痛效果个体差异大镇痛效果个体差异大；剂量增大引起呼吸抑制、血压升高血压升高、心率增快心率增快，出现焦虑、恶梦、幻觉等症状。纳洛酮能对抗喷他佐辛的呼吸抑制作用。临床应用：临床应用：外科手术及内科急慢性疾病（如癌症、溃疡等）的疼痛，也可用于牙科、产科止痛，但不适用于缓解心肌梗死时的疼痛。本品成瘾性小，在药政管理上已列入非麻醉品。适用于各种慢性疼痛。但仍有产生依赖性的倾向。有报道，连续用药1年以上出现成瘾者，不可滥用。镇痛作用强度与喷他佐辛相似（镇痛机制未完全阐明）。治疗剂量时不抑制呼吸，也不影响心血管功能，不产
15、生便秘等副作用。口服易于吸收，生物利用度约90%，t1/2约6小时。不良反应和其他镇痛药相似，偶有多汗、头晕、恶心、呕吐、口干、疲劳等。适用于中度及重度急慢性疼痛及外科手术。不宜用于轻度疼痛，长期应用也可能发生成瘾。第四节第四节 其他镇痛药其他镇痛药 纳洛酮（纳洛酮（naloxone）对对4 4型阿片受体都有拮抗作用型阿片受体都有拮抗作用；对吗啡中毒者，小剂量肌内或静脉注射能迅速翻转吗啡的作用能迅速翻转吗啡的作用，消除呼吸抑制现象，增加呼吸频率。吗啡成瘾者可迅速诱发戒断症状；临床适用于吗啡类镇痛药急性中毒的解救；是镇痛药的理论研究中的重要工具药。纳曲酮（纳曲酮（naltrexone）作用与纳洛
16、酮相同，口服生物利用度较高，作用维持时间长。癌痛治疗三阶梯方法：对癌痛的性质和原因作出正确的评估根据疼痛程度和原因适当选择相应的镇痛药。SUMMARY Alleviation of pain depends on its type.In many cases,for mild to moderate pain,nonsteroidal anti-inflammatory drugs(NSAIDs)are effective.Neurogenic pain responds best to tricyclic antidepressants or serotonin/norrepinephrin
17、e reuptake inhibitors rather than NSAIDs or opioids.However,for severe or chronic malignant pain,opioids are usually the drugs of choice.All opioids act by binding to specific opioid receptors in the CNS to produce effects that mimic the action of endogenous peptide neurotransmitters.Although the op
18、ioids have a broad range of effects,their primary use is to relieve intense pain and the anxiety that accompanies it,whether that pain is from surgery or a result of injury or a disease,such as cancer.Distribution of Opioid ReceptorsReceptors in the limbic system and neucleus ceruleus(蓝斑核）are involv
19、ed in emotion.Receptors in periaqueductal gray,spinal substantia gelatinosa(脊髓胶质区）,ventriculus cerebri and thalamus regions of the brain are involved in pain perception and associated with morphine analgesia.Receptors in the nucleus of the solitary tract（孤束核）,consistent with the ability of morphine
20、to respiration depression and antitussive effect.Receptors of the nucleus of the solitary tract（孤束核）,dorsal nucleus of vagus nerve(迷走神经背核)region in which morphine has been shown to cause nausea and induce vomiting.analgesiarespiratory depressionmiosisrelieving coughsedation(euphoria)gastro-intestina
21、l activity immune suppressionMorphinePHARMACOLOGICAL EFFECTS1.Central Nervous Systeml Analgesia Effective for all types of pain.Analgesia in consciousness.More effective against dull constant pain than against sharp,severe intermittent pain.l Sedation and Euphoria Morphine ameliorates the fear and a
22、nxiety associated with pain,elevates the tolerance of patients to pain and causes euphoria(a powerful sense of contentment and well-being).MECHANOSM Opioids exert their major effects by interacting with opioid receptors in the CNS.Inhibition of adenyl cyclaseFacilitate K+conductance(hyperpolarized)I
23、nactivation of Ca2+channelsReducing the release of neurotransmitters at presynaptic membraneInducing the hyperpolarization of the postsynaptic membraneMorphinePHARMACOLOGICAL EFFECTS1.Central Nervous SystemlRespiratory Depression Morphine cause respiratory depression at therapeutic doses.MECHANISM R
24、educing the sensitivity of the respiratory center to CO2.Depressing pneumotaxic center Respiratory depression is the most common cause of death in an acute morphine overdose.lAntitussive Action Depression of cough reflex in the medulla.MorphinePHARMACOLOGICAL EFFECTS1.Central Nervous System lEmesis:
25、Direct stimulation of the chemoreceptor trigger zone in the area postrema of the medulla that causes vomiting.l Miosis:The pinpoint pupils was showed at toxic dose of morphine(stimulate,k receptors and parasympathetic pathway to the eye).All morphine abusers demonstrate pinpoint pupils.lNeuroendocri
26、ne System:Morphine inhibits the release of gonadotropin-releassing hormone(GnRH)and corticotropin-releasing hormone(CRH),decreases the concentration of LH,FSH and ACTH.It increases antidiuretic hormone(ADH)and leads to urinary retention.MorphinePHARMACOLOGICAL EFFECTS2.Effects on Smooth MuscleslGast
27、rointestinal Tract(GI)Constipation:morphine decreases the motility and increases the tone of the gastrointestinal smooth muscle.Morphine also increases the tone of the anal sphincter.Biliary Tract:Morphine increase biliary tract pressure by contracting the gallbladder and constricts the biliary sphi
28、ncter.lEffects on Other Smooth Muscles Provoking histamine release,causing bronchoconstriction.Decreasing uterine tone,prolonging labor Elevating the tone of sphincter muscle of urinary bladder MorphinePHARMACOLOGICAL EFFECTS3.Cardiovascular System Morphine has no major effects on the blood pressure
29、 or heart rate except at large doses,when hypotension and bradycardia may occur.Because of respiratory depression and CO2 retention,cerebral vessels dilate and increase the cerebrospinal fluid(CSF)pressure.morphine is usually contraindicated in individuals with severe brain injury.4.Immune System In
30、hibiting cell immunity and humoral immunity.MorphinePHARMACOKINETICS lAdministration Significant first-pass-metabolism of morphine occurs when given orally,therefore morphine usually is administered intravenously,subcutaneously or rectally.lDistribution Morphine rapidly enters all body tissues,inclu
31、ding the fetuses of pregnant women.Only a small percentage of morphine crosses the blood-brain barrier,because of its low lipophilicity.l Fate Morphine is conjugated in the liver to glucuronic acid and the conjugates are excreted primarily in the urin,with small quantities appearing in the bile.Morp
32、hineTHERAPEUTIC USES lAnalgesia Morphine can relieve moderate to severe pain e.g.cancer pain,postoperative pain,visceral pain,the pain of acute trauma and the pain of myocardial infarction.lCardiac Asthma（Dyspnea）Intravenous(iv)morphine dramatically relieves dyspnea caused by pulmonary edema associa
33、ted with left ventricular failure.lTreatment of Diarrhea MECHANISM$decrease cardiac preload and afterload by lowering peripheral resistance;$reduce patients anxiety and fear due to the sedative effects;$decrease the sensitivity of respiratory center to CO2 and relieve shallow breathing.MorphineADVER
34、SE EFFECTS lCommon Side Effects Severe respiratory depression occurs and can result in death in acute poisoning.Other effects include vomiting,drowsiness,dizziness,constipation,biliary spasm,orthostatic hypotension,etc.lTolerance and Physical Dependence Repeated use produces tolerance.Physical and p
35、sychological dependence readily occur and withdrawal produces a series of abstinent symptom.lContraindication Prohibit labor and nursing women,bronchial asthma patients,patients with intracranial hypertension,patients with hepatic functional impairment.CodeineWeak opioid analgesicsMuch less potent a
36、nalgesic effect than morphine；higher oral efficacy A good antitussive activity at doses that do not cause analgesia.Mainly used for antitussive and antidiarrhea effects.Pethidine（Meperidine,Dolantin）Artificial synthetic analgesic,high lipid soluble,rapid onset;Short duration of action(24 hours);Anal
37、gesic potency is about one tenth of morphine;Respiratory depression is similar to morphine;Seldom cause constipation,miosis,and no antidiarrhea effect;uCLINIC USES Analgesia;Preanesthetic medication and Artificial hibernation;Dyspnea;uSIDE EFFECTS similar to morphineFentanylA synthetic analgesic,lip
38、id soluble,80-100 times analgesic potency of morphine.Often be used intravenously,occasionally administered intramuscularly as a premedication.A rapid onset and short duration of action(1530min)High doses of fentanyl produce pronounced muscular rigidity,respiratory depression,euphoria,addiction.Fent
39、anyl alone or in combination with droperidol(氟哌利多)is usually used as an anesthetic for postoperative pain and neuroleptic analgesia.Methadone Methadone is a synthetic,orally effective analgesic drug with the similar potency to those of morphine,but induce less euphoria and has a long duration of act
40、ion.Tolerance and dependence develop slowly.Increase biliary pressure,and cause epigastric discomfort(上腹部不适）Increase the tone of the gastrointestinal tract and cause constipation.Cause a withdrawal syndrome that is milder but more protracted(days to weeks)than with other opioids,and often be used to
41、 the maintenance of a narcotic addict.Pentazocine Partial AgonistAn agonist on k k receptor,weak antagonist on m m and d d receptor.less addict because of antagonist action of m m receptor.It may be administered either orally or parenterally.Pentazocine weaken analgesic action of mophine,precipitate
42、 withdrawal symptoms in patients dependent on other opiods,thus,it should not be used with agonists such as morphine Less respiratory depression than morphine,and the respiration depression is not dose-dependent.Causing thought disturbance and hallucinations due to its action on d d receptor.Dislike
43、 morphine,pentazocine may raise blood pressure,increase heart rate(raising NA levels in plasma).Tolerance and dependence develop on repeated use.TramadolOne tenth as potent as morphine.It is used to manage moderate to moderately severe pain.MECHANISMS (1)a weak opioid agonist at m receptors (2)an en
44、hancement of serotonergic and adrenergic pathways by inhibiting the reuptake of serotonin and norepinephrine.Fewer of the typical morphine-like opioids side-effects(notably,less respiratory depression,less constipation and less addiction potential)Psychiatric reactions have been reported。Naloxone Na
45、loxone is an competetive antagonist at m,d,and k receptors,with a ten-fold higher affinity for m receptors than for k.It can reverse the coma and respiratory depression of opioid overdose.Naloxone produces no pharmacologic effects in normal individuals,but it precipitates withdrawal symptoms in opio
46、id abusers.Naltrexone Naltrexone has actions similar to those of naloxone.It has a longer duration of action than naloxone.Naltrexone is hepatotoxic.STUDY QUESTIONS1.A young man is brought into the emergency room.He is unconscious,and he Has pupillary constriction and depressed respiration.You note
47、needle marks on his legs.You administer naltrexone,and he awakens.This agent was effective because:A.The patient was suffering from an overdose by an opioid.B.Naltrexone antagonizes opiates at the receptor site.C.Naltrexone is a stimulant of the CNS.D.Naltrexone binds to the opioid and inactivates i
48、t.2.A heroin addict has entered a rehabilatation program that requires she take methadone.Methadone is effective in this situation because it:A.is an antagonist at the morphine receptors.B.has less potent analgesic activity than heroin.C.is longer acting than heroin;hence,the withdrawal is milder th
49、an with the latter drug.D.does not cause constipation.E.is nonaddictive.STUDY QUESTIONSSTUDY QUESTIONS3.Which of the following statements about morphine is correct?A.It is used therapeutically to relieve pain caused by severe head injury.B.Its withdrawal symptoms can be relieved by naloxone.C.It cau
50、ses diarrhea.D.It is most effective by oral administration.E.It rapidly enters all body tissues,including the fetus of a pregnant woman.STUDY QUESTIONS4.The pain of a patient with bone cancer has been managed with a morphine pump.However,he has become tolerant to morphine.Which of the following migh
