神经阻滞镇痛术.ppt

Analgesics,Zhang, Bin,pain,a. Acute pain (sharp pain) b. Chronic pain (dull pain),Pain transmission pathway,Noxious stimuli,Primary afferent fibres,nociceptor,Spinal cord,Limbic system,Somato-sensory cortex,mood effect, the affective aspect of pain,the sensory aspect of pain,Dorsal horn,Drug treatment of pain,cholinoceptor-blocking drugs,vasodilator drugs (eg. Nitroglycerin),Carbamazepine,Local anaesthetics,Cortex,Spinal cord,Dorsal horn,PGs,K+、H,BK,5-HT,NSAIDs,Opioids,Sites 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 alkaloid 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 opioid receptors and mimic the effect of morphine-like compounds.,Widely use term,Opium,The flower of papaver,Opium (阿片),Opiate (阿片剂),Morphine Codeine Papaverine (罂粟碱) ,structure-activity relationship,海洛因,吗啡,纳洛酮,Opioid (阿片样物质),Endogenous opioid peptides:,Enkephalins,Endorphins,Dynorphins,Orphanin,1992,1973,1962,1975,analgesic site is laminae III of periventricular and periaqueductal gray area,put forward “receptors” for opiate analgesics in brain,isolated the first “endogenous opioid peptide” and named enkephalin,Cloned opioid receptors: ,Research history,Opioid receptors,G protein-coupled receptors,Opioid receptors,supraspinal analgesia, sedation, euphoria, dependence, respiratory depression, miosis,spinal analgesia, sedation,dysphoria (烦躁不安), hallucination,spinal analgesia, sedation, euphoria, dependence, respiratory depression,:,:,:,:,Spinal cord,Dorsal horn,enkephalins,Ca2+,Ca2+,Presynaptic terminal,Postsynaptic neuron,enkephalins,The cellular mechanisms,enkephalins,Presynaptic terminal,Postsynaptic neuron,The cellular mechanisms,Morphine + receptors,Open K+channel,Close Ca2+channel,抑制冲动传导,Ach, NA, Glu, 5-HT, P release ,presynaptic,postsynaptic,Excitability ,The cellular mechanisms,The cellular mechanisms,Presynaptic 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 thereby cause hyperpolarization and thus reduce postsynaptic neuronal excitability.,Descending pain inhibitory pathways,Local inhibitory interneuron in spinal cord,Ascending pain transmission pathways,Endogenous opioid peptides,Pharmacological actions,CNS Smooth muscles 3. Cardiovascular system,1.CNS 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 of cancers relieve anxiety and distress, tolerance of pain,1. 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 contentment and well-being,Sedation:,the main reason for drug abuse,Site: limbic system and locus ceruleus,respiratory rate ，tidal volume the most common cause of death from acute poisoning influenced by stimulus Mechanisms: the sensitivity of respiratory center to increased CO2 tension,(3) Respiratory depression,(4) Cough suppression,antitussive effect by inhibiting cough center,codeine,(5) Other CNS effects,Miosis: pinpoint pupils Nausea and vomiting: CTZ muscular tension:限制 胸廓活动,影响呼吸 Hormone: LH ,FSH, prolactin, GH, ADH,2. Smooth muscle system Gastrointestinal system Biliary tract Urinary system genital system,(1) Gastrointestinal tract,delays passage,secretion of digestive gland,indigestion,central inhibition,a call of nature defecation reflex,GIT tone,GIT motility,absorption of water,biliary colic,constrict biliary smooth muscle constrict Oddis sphincter,pressure in the biliary tract,(2) Biliary tract,(3) Urinary tract,constrict ureteral smooth muscle bladder sphincter tone,urinary retention,uterine tone,prolong labor,(4) Genital tract,orthostatic hypotension,Mechanisms: release of histamine vasomotor center,3. Cardiovascular system,(1),peripheral arterial and venous dilatation,(2) intracranial pressure,secondary to respiratory depression,Clinical uses,Analgesia Cardiac asthma Antidiarrhea Antitussive Combined anesthesia,Analgesia terminal cancer myocardial infarction renal and biliary colic (atropine) trauma, burn, operation,at regular time and quantity,Pulmonary edema,dyspnea,Acute left ventricular dysfunction,short of breath (respiratory center),CO2 retention,anxiety and distress,Alveolar hypoventilation,Cardiac asthma and morphine therapy,2. Cardiac asthma,oxygen consumption,(1) Mechanisms: 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 asthma,Opioid analgesic drugs,Morphine (吗啡) Heroin (海洛因，二醋吗啡) Codeine (可待因) Pethidine (哌替啶) Methadone (美沙酮) Fentanyl (芬太尼) buprenorphine (丁丙诺啡) Tramadol (曲马多),Morphine,1803 Serturner isolated a pure active alkaline substance from opium. He proposed the name “morphine” for it after Morpheus.,absorption,excretion,distribution,free drug,blood,liver,iv.,Bioavailability25-30%,metabolism,美施康定（硫酸吗啡缓释片） 1. 强效，作用持续12 hr。主要用于晚期癌症患者第三阶梯止痛。 2. 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、身体依赖性和成瘾性。,Heroin (diamorphine),Semisynthetic substance, prodrug of morphine More lipid soluble than morphine More rapid onset,德国拜尔公司 heroin在德文中意为英雄 万能药 药品转变为毒品 白粉,Codeine,higher oral efficacy 2. lower efficacy than morphine 3. use as antitussive, severe dry cough. 联邦止咳露 ： 麻黄碱+可待因+氯苯那敏+氯化铵,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 Lyticcocktail,Methadone,1. synthetic compound, equal analgesia to morphine 2. milder abstinence syndrome 3. routinely used in detoxification of morphine addicts,Fentanyl,1. 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): neuroleptanalgesia (神经阻滞镇痛术),Used for minor surgery,5. breakthrough cancer pain:,口腔经粘膜芬太尼拘橼酸盐 (Oral Transmucosal Fentanyl Citrate, OTFC),Fentanyl lollipop,ACTIQ,芬太尼口腔粘膜贴片 (Fentanyl sublingual tablets),ABSTRAL,芬太尼透皮贴剂 (Fentanyl transdermal system),多瑞吉,high lipid- soluble,Pentazocine, agonist , partial agonist,increase blood pressure and cause tachycardia ( NA),weak action on : little addictive liability precipitate withdrawal syndrome of morphine abuser,列入非麻醉药品。但久用仍会成瘾！,analgesia and respiratory depression : weaker,Tramadol,Atypical opioid: weak activation, also interacts with monoaminergic systems (inhibit NA and 5-HT reuptake) Alternative to traditional opioid analgesics,2008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. Tolerance,Adverse effects,large doses at short intervals readily cross tolerance full agonist: more obvious,2. Dependence,physical dependence： withdrawal syndrome psychological denpendence: compulsive drug- seeking behavior,Adverse effects,身体依赖性,精神依赖性,渴求,戒断综合征,强迫性用药,依赖性,药物滥用,药物滥用（drug abuse）: 非医疗目的反复使用具有依赖性潜能的精神活性物质。体验该物质产生的特殊精神效应。,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。,Withdrawal syndrome of Opioid,3. General adverse effects,4. Acute Morphine Poisoning,Naloxone,1. competitive 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 injections,Contraindications,obstetric labor, breasting period obstructi