完整版镇痛药课件.ppt

1、第二十一章第二十一章镇痛药镇痛药（Analgesics）河北医科大学药理教研室梅和珊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。第一节第一节概概述述CGRP:降钙素基因相关肽IP3:肌醇三磷酸NK-1:神经激肽-1受体NMDA:N-甲基-D-天冬氨酸AMPA:a-氨基-3-羟基-5-甲基-4- 异唑丙酸镇痛药分类1. 阿片类镇痛药（Opioid-analgesics）又称成瘾性或麻醉性镇痛药(narcotics)

2、。代表药：阿片生物碱类及其合成代用品2. 解热镇痛抗炎药（antipyretic-analgesicantiinflammatory drugs）干扰PGs生物合成，产生镇痛作用代表药：阿司匹林3. 局麻药（Local anaesthetics）4.某些特殊神经止痛药and阿片类镇痛药分类阿片类镇痛药分类( (Classification) )阿片生物碱类: 吗啡（morphine）可待因（codeine）半合成阿片类: 海洛因（heroin）人工合成阿片类: 哌替啶（pethidine）芬太尼（fentanyl）内源性阿片肽:b-内啡肽（b-endorphin）甲硫氨酸脑啡肽（met-enk

3、ephalin）亮氨酸脑啡肽（leu-enkephalin）第一节第一节 阿片生物碱类阿片生物碱类(Opium Alkaloid)阿片阿片（opium） 来源来源C17H19NO3BAC吗啡（morphine）化化学学结结构构与与构构效效关关系系阿片受体（Opioid Receptor)脑内阿片受体分布脑内阿片受体分布(Distribution of Opioid Receptors)?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：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、

4、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：与缩瞳有关基因调控机制钙调素依赖性蛋白激酶阿片受体激动与效应关系阿片受体激动与效应关系(Receptor and Effects)效 应镇痛脊髓以上水平脊髓水平呼吸抑制缩瞳止咳镇静（欣快）胃肠活动免疫抑制受体焦虑，烦燥不安?体内过程体内过程 (Pharmacokinetics)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。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。代谢(metabo

5、lism):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。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，可通过胎盘进入胎儿体内。?催吐(emesis)：兴奋延髓催吐化剂量增大：抑制作用增强；?镇痛时不影响意识和其他感觉；急性中毒：呼吸频率可减慢至3学感受区能消除由疼痛所引起的焦虑、紧张、1.中枢神经系统(Central Nervous System)?对持续性慢性钝痛的效力大于间断4次/分。恐惧等情绪反应，显著提高机体对疼?缩瞳(miosis)：针尖样瞳孔为吗性锐痛。?镇痛 (analgesia)?抑制呼吸的机制痛的耐受力。随着疼痛的缓解，可

6、出啡中毒特征 降低呼吸中枢对血液CO 张力的2现欣快症状（euphoria）。抑制咳嗽中枢，使镇静、致欣快作用(sedation and euphoria)?神经内分泌(neuroendocrine)敏感性；咳嗽反射消失。 对桥脑内呼吸调整中枢也有抑促进抗利尿激素 (ADH)释放；抑制抑制呼吸(respiratory depression)制作用；促性腺激素释放激素(GnRH)和促肾与中枢抑制药合用，加重呼吸抑上 腺 皮 质 激 素 释 放 激 素 的 释 放镇咳(antitussive action)制作用。(CRH)，降低促黄体生成激素(LH)和卵泡刺激素水平(FSH)。其他作用(othe

7、rs)药理作用药理作用(Pharmacological Effects)减慢、潮气量降低；都有效；治疗量： 抑制呼吸，使呼吸频率?具有强大的镇痛作用，对各种疼痛?吗啡催吐作用部位示意图吗啡催吐作用部位示意图药理作用药理作用(Pharmacological Effects)?兴奋胃肠平滑肌，提高其张力；引起便秘2. 平滑肌作用(Effects on Smooth Muscles)?大剂量吗啡促进组胺释放，引起支原因：平滑肌张力 ；肠道推进气管收缩；性蠕动；括约肌张力 ；消化?扩张血管，降低血压?胃肠道平滑肌 (gastrointestinal tract)?治疗量吗啡可降低子宫张力，延长液分泌；

8、中枢抑制。可能机制：促进释放组胺产程；?其他平滑肌smooth muscles)?(other胆道:胆道oddis括约肌痉挛性收缩，抑制血管运动中枢?治疗量吗啡能提高膀胱括约肌张力，引起上腹不适甚至胆绞痛。胆绞痛、?升高颅内压 : 抑制呼吸，体内 CO2蓄导致尿潴留。肾绞痛选用吗啡+阿托品。积，扩张脑血管，升高颅内压。3. 心血管系统(Cardiovascular System)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4. 免疫系统应。(Immune System)脑啡肽神经元感觉神经元脑内接受神经元镇痛作用机制?临床应用临床应用对各种疼痛都有效，但易成瘾，一般

9、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(Therapeutic Uses)镇痛 (analgesia)肌梗塞引起的剧痛）。作用机制：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；心源性哮喘(cardiac asthma)急、慢性消耗性腹泻，选用阿片酊降低呼吸中枢对或复方樟脑酊；若伴有细菌感染，缓解急促浅表的呼吸。CO2的敏感性，应同时服用抗菌药。注意：心源性哮喘伴休克、昏迷和止泻( treatment of diarrhea)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药物NSAIDs作用部位作用机制作用性质外周

10、成瘾性抑制慢性钝痛不易成瘾PGs合成激动中枢各种疼痛阿片受体易成瘾镇痛药中枢呕吐、便秘、排尿困难、胆绞痛、(Adverse Effects and Contraindication) 呼吸抑制、嗜睡等。戒断症状（abstinent symptom)流涕、流泪、失眠、出汗、呕吐、?一般不良反应 (Common Side Effects)昏迷；虚脱、大小便失禁、意识丧失等针尖样瞳孔；?耐受性及依赖性呼吸高度抑制；(Tolerance and Physical Dependence)?禁用于分娩和哺乳妇女止痛；血压剧降、休克。?禁用于支气管哮喘及肺心病患者；呼吸麻痹是致死的主要原因。?急性中毒(Ac

11、ute Poisioning)?禁用于颅内压增高和肝功能严重减退患者。治疗量吗啡可引起眩晕、恶心、不良反应及禁忌不良反应及禁忌?禁忌证 (Contraindication)毒品知识简介毒品知识简介毒品的种类毒品的种类来源来源镇静类镇静类罂粟、鸦片吗啡可待因大麻（小量）呱替啶镇痛新安定作用效应作用效应兴奋类兴奋类古柯叶可卡因大麻（大量）苯丙胺甲基苯丙胺利他林致幻类致幻类仙人球毒碱黑西哥致幻蕈碱大麻麦角酸二乙酰胺苯环已哌啶二甲色胺天然天然毒品毒品合成合成毒品毒品海洛因蒂巴因美沙酮芬太尼苯巴比妥鸦片鸦片吗啡吗啡海洛因海洛因大麻大麻可卡因可卡因甲基苯丙胺甲基苯丙胺及其衍生物及其衍生物麻古麻古K粉粉苯环

12、已哌啶苯环已哌啶仙人球毒碱仙人球毒碱摇头丸摇头丸摇摇头头丸丸我国记录在册的吸毒者人数我国记录在册的吸毒者人数）万万（数数人人80806060404020200 0105105868652527 719901990年年19951995年年20012001年年20032003年年120120100100可待因（codeine)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。，第二节第二节人工合成镇痛药人工合成镇痛药(Artificial Synthetic Derivatives)哌替

13、啶（pethidine）度冷丁（dolantin）哌替啶（pethidine）药理作用临床应用不良反应镇痛作用弱于吗啡，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。1. 镇痛：可取代吗啡中等程度提高胃肠道平滑肌张力，作2. 麻醉前给药：镇静作用用时间短，不引起便秘，无止泻作用；3. 心源性哮喘不延长产程。4. 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）。芬太尼（ Fentanyl）?m 受体激动剂，镇痛作用为吗啡的100倍，作用维持时间短，可用于各种

14、剧痛，成瘾性小。?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。?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。?禁用于支气管哮喘、颅脑肿瘤或颅脑外伤引起昏迷的患者以及二岁以下小儿。美沙酮 （Methadone）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，口服与注射同样有效。?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，戒断症状轻，易于治疗。?适用于创伤、手术及晚期癌症等所

15、致剧痛以及吗啡成瘾者戒毒。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。主要激动m 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。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 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。喷他佐辛（Pentazocine）又名镇痛新?阿片受体部分激动

16、药，激动k、s受体，拮抗m 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；?拮抗受体，减弱吗啡镇痛作用；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；喷他佐辛（Pentazocine）?剂量增大引起呼吸抑制、 血压升高、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： 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

17、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。第四节第四节 其他镇痛药其他镇痛药曲马朵（tramadol）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。第五节第五节 阿片受体拮抗剂阿片受体拮抗剂(Antagonists of Opioid Receptor) 纳洛酮（naloxone）

18、对4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，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（naltrexone）作用与纳洛酮相同，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。癌症病人三级止痛阶梯治疗SUMMARYAlleviation of pain depends on its type. In many cases, formild to moderate pain

19、, nonsteroidal anti-inflammatory drugs(NSAIDs) are effective. Neurogenic pain responds best totricyclic antidepressants or serotonin/norrepinephrine reuptakeinhibitors rather than NSAIDs or opioids. However, for severeor chronic malignant pain, opioids are usually the drugs ofchoice.All opioids act

20、by binding to specific opioid receptors intheCNSto produceeffectsthatmimictheactionofendogenous peptide neurotransmitters. Although the opioidshave a broad range of effects, their primary use is to relieveintense pain and the anxiety that accompanies it, whether thatpain is from surgery or a result

21、of injury or a disease, such ascancer.Distribution of Opioid Receptors?Receptors in the limbic system and neucleus ceruleus(蓝斑核）are involved in emotion.?Receptors in periaqueductal gray, spinal substantia gelatinosa(脊髓胶质区）, ventriculus cerebri and thalamus regions of thebrain are involved in pain pe

22、rception and associated withmorphine analgesia.?Receptors in the nucleus of the solitary tract（孤束核）,consistent with the ability of morphine to respiration depressionand 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 whichmorph

23、ine has been shown to cause nausea and induce vomiting.Receptors and EffectsEFFECTSRECEPTORSanalgesiarespiratory depressionmiosisrelieving coughsedation (euphoria)gastro-intestinal activity immune suppressionMECHANOSMOpioidsexerttheirmajoreffectsbyPHARMACOLOGICALEFFECTSinteracting with opioid recept

24、ors in the CNS .1.Central Nervous System?Inhibition of adenyl cyclase?Analgesia?Facilitate K+conductance (hyperpolarized)?Effective for all types of pain.?Inactivation of Ca2+channels?Analgesia in consciousness.?Reducing the release of neurotransmitters at?More effective againstmembranedull constant

25、 pain than against sharp,presynapticsevere intermittent pain.?Inducingthehyperpolarizationofthe?Sedation and EuphoriamembranepostsynapticMorphine ameliorates the fear and anxiety associated with pain,elevates the tolerance of patients to pain and causes euphoria ( apowerful sense of contentment and

26、well-being).MorphineMorphinePHARMACOLOGICAL EFFECTS1. Central Nervous System?Respiratory DepressionMorphine cause respiratory depression at therapeutic doses.MECHANISM?Reducing the sensitivity of the respiratory center to CO2.?Depressing pneumotaxic centerRespiratory depression is the most common ca

27、use of death inan acute morphine overdose.?AntitussiveActionDepression of cough reflex in the medulla.MorphinePHARMACOLOGICALEFFECTS1. Central Nervous System?Emesis:Direct stimulation of the chemoreceptor trigger zone inthe area postrema of the medulla that causes vomiting.?Miosis:The pinpoint pupil

28、s was showed at toxic dose ofmorphine ( stimulate, k receptors and parasympathetic pathway tothe eye) .All morphine abusers demonstrate pinpoint pupils.?Neuroendocrine System:Morphine inhibits the release ofgonadotropin-releassing hormone( GnRH) and corticotropin-releasing hormone (CRH ), decreases

29、the concentration of LH ,FSH and ACTH. It increases antidiuretic hormone (ADH) andleads to urinary retention.MorphinePHARMACOLOGICALEFFECTS2. Effects on Smooth Muscles?Gastrointestinal Tract (GI)?Constipation: morphine decreases the motility and increases thetone of the gastrointestinal smooth muscl

30、e. Morphine also increasesthe tone of the anal sphincter.?Biliary Tract: Morphine increase biliary tract pressure bycontracting the gallbladder and constricts the biliary sphincter.?Effects on Other Smooth Muscles?Provoking histamine release, causing bronchoconstriction.?Decreasing uterine tone, pro

31、longing labor?Elevating the tone of sphincter muscle of urinary bladderMorphinePHARMACOLOGICAL EFFECTS3. Cardiovascular SystemMorphine has no major effects on the blood pressure or heartrate except at large doses, when hypotension and bradycardia mayoccur.Because of respiratory depression and CO2ret

32、ention, cerebralvessels dilate and increase the cerebrospinal fluid (CSF) pressure.morphine is usually contraindicated in individuals with severebrain injury.4. Immune SystemInhibiting cell immunity and humoral immunity.MorphinePHARMACOKINETICS?AdministrationSignificant first-pass-metabolism of morp

33、hine occurs whengivenorally,thereforemorphineusuallyisadministeredintravenously, subcutaneously or rectally.?DistributionMorphine rapidly enters all body tissues, including the fetusesof pregnant women. Only a small percentage of morphine crossesthe blood-brain barrier, because of its low lipophilic

34、ity.?FateMorphine is conjugated in the liver to glucuronic acid and theconjugates are excreted primarily in the urin, with small quantitiesappearing in the bile.MECHANISM?decrease cardiac preload and afterload byTHERAPEUTICUSESlowering peripheral resistance;?Analgesia?reduce patients anxiety and fea

35、r due to Morphine canthe sedative effects;relieve moderate to severe pain e.g. cancer?decrease the sensitivityrespiratorypain, postoperative pain, visceral pain, theofpain of acutecenter to CO2andinfarction.relieve shallow breathing.trauma and the pain of myocardialMorphine?Cardiac Asthma （Dyspnea）I

36、ntravenous (iv) morphine dramatically relieves dyspneacaused by pulmonary edema associated with left ventricularfailure.?Treatment of DiarrheaMorphineADVERSE EFFECTS?Common Side EffectsSevere respiratory depression occurs and can result in death inacute poisoning.Othereffects include vomiting,drowsi

37、ness,dizziness, constipation, biliary spasm, orthostatic hypotension, etc.?Tolerance and Physical DependenceRepeated use produces tolerance. Physical and psychologicaldependence readily occur and withdrawal produces a series ofabstinent symptom.?ContraindicationProhibit labor and nursing women, bron

38、chial asthma patients,patientswithintracranialhypertension,patientswithhepaticfunctional impairment.Codeine?Weak opioid analgesics?Much less potent analgesic effect than morphine；?higher oral efficacy?A good antitussive activity at doses that do notcause analgesia.?Mainly used for antitussive and an

39、tidiarrhea effects.Pethidine（Meperidine, Dolantin）?CHARACTERISTICS?Artificial synthetic analgesic, high lipid soluble, rapid onset;Short duration of action (24 hours) ;Analgesic potency is about one tenth of morphine;Respiratory depression is similar to morphine;Seldom cause constipation, miosis, an

40、d no antidiarrhea effect;?CLINIC USES?Analgesia;?Preanesthetic medication andArtificial hibernation;?Dyspnea;?SIDE EFFECTSsimilar to morphineFentanyl?A synthetic analgesic, lipid soluble, 80-100 times analgesicpotency of morphine.?Often be used intravenously, occasionallyadministeredintramuscularly

41、as a premedication.?Arapid onset and short duration of action (1530min)?High doses of fentanylproduce pronouncedmuscularrigidity, respiratory depression, euphoria, addiction.?Fentanyl alone or in combination with droperidol (氟哌利多)is usually used as an anesthetic for postoperative pain andneuroleptic

42、 analgesia.MethadoneMethadone is a synthetic, orally effectiveanalgesic drugwith the similar potency to those of morphine, but induce lesseuphoria and has a long duration of action.?Tolerance and dependence develop slowly.?Increase biliary pressure, and cause epigastric discomfort(上腹部不适）?Increase th

43、e tone of the gastrointestinal tract and causeconstipation.?Cause a withdrawal syndrome that is milder but moreprotracted (days to weeks) than with other opioids, and often beused to the maintenance of a narcotic addict.Pentazocine Partial Agonist?An agonist on k receptor, weak antagonist on mand dr

44、eceptor.?less addict because of antagonist action of mreceptor.?It may be administered either orally or parenterally.?Pentazocine weaken analgesic action of mophine, precipitatewithdrawal symptoms in patients dependent onother opiods,thus, it should not be used with agonists such as morphine?Less re

45、spiratory depression than morphine, and the respirationdepression is not dose-dependent.?Causing thought disturbance and hallucinations due to its actionon dreceptor.?Dislikemorphine,pentazocinemayraisebloodpressure,increase heart rate( raising NAlevels in plasma).?Tolerance and dependence develop o

46、n repeated use.Tramadol?One tenth as potent as morphine. It is used to managemoderate to moderately severe pain.?MECHANISMS(1) a weak opioid agonist at mreceptors(2) an enhancement of serotonergic and adrenergic pathwaysby inhibiting the reuptake of serotonin and norepinephrine.?Fewer of the typical

47、 morphine-like opioids side-effects(notably, less respiratory depression, less constipation and lessaddiction potential)?Psychiatric reactions have been reported。Antagonists of Opioid ReceptorsNaloxoneNaloxoneis an competetive antagonist at m , d, and kreceptors, with a ten-fold higher affinity for

48、mreceptors thanfor k. It can reverse the coma and respiratory depression ofopioid overdose. Naloxone produces no pharmacologic effectsin normal individuals, but it precipitates withdrawal symptomsin opioid abusers.NaltrexoneNaltrexone has actions similar to those of naloxone. It hasa longer duration

49、 of action than naloxone. Naltrexone ishepatotoxic.STUDY QUESTIONS1. A young man is brought into the emergency room. Heis unconscious, andhe Has pupillary constriction anddepressed respiration. You note needle marks on his legs.You administer naltrexone, and he awakens. This agentwas effective becau

50、se: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 it.STUDY QUESTIONS2. A heroin addict has entered a rehabilatation programthat requires she ta