1、1Welcome to Pharmacology2 Chapter 21 Analgesics3OverviewSection 14two componentssomatic sensationaffective(emotion)1.Concept52.Pain transmission pathwayNoxious stimuliPGsK+、H+BK5-HTPrimary afferent fibres(C/A)nociceptorSpinal cordLimbic systemSomato-sensory cortexmood effect,the affective aspect of
2、painthe sensory aspect of pain Medulla MidbrainDorsal horn6Descending pain inhibitorypathwaysLocal inhibitory interneuron in spinal cordPainAscending pain transmission pathwaysEndogenous opioid peptides7 Medulla MidbrainCortex Spinal cordDorsal hornVentral caudal thalamusPGsK+、HBK5-HTNSAIDsLocal ane
3、stheticsOpioid analgesics，Antidepressants and General anaestheticsSites of action of different drugs 8Paina.Acute pain(sharp pain),superficial pain,quick response of sudden onset,conducted by A nerve fibers b.Chronic pain(dull pain),more lingering and aching,conducted by C nerve fibers9 severe,sharp
4、 painopioid analgesics(eg.Morphine)inflammation,elevated temperature,chronic-dull pain NSAIDs(eg.Aspirin)smooth muscle colic(eg.biliary or renal colic)angina pectoris induced by coronary artery spasm trigeminal pain3.Durg treatment of paincholinoceptor-blocking drugs (eg.Atropine)vasodilator drugs (
5、eg.Nitroglycerin)Carbamazepine10 AnalgesicsDrugs which act on CNS,could relieve or alleviate severe pain and unhappy mood without affecting other sense perception,and consciousness1.Concept11 Full agonist of opioid receptors Partial agonist of opioid receptors Other analgesics2.Classification12Full
6、agonist of opioid receptors13Opium Alkaloids Phenanthrenes morphine,codeine Benzylisoquimolines papaverine -has no analgesic effect -dilates the vessel14 The flower of papaver somniferum15Opium 16Morphine 171803 Serturner isolated a pure active alkaline substance from opium.He proposed the name“morp
7、hine”for it after Morpheus.18海洛因海洛因吗啡吗啡纳洛酮纳洛酮OH19Pharmacokineticsabsorptionexcretion distribution free drugoral First pass eliminationsc.im.bloodliverplacental fetuslittle cross the BBB,but enough for its function metabolismmorphine-6-glucuronidekidney,breast20Pharmacological actions1.CNS2.Smooth mu
8、scles3.Cardiovascular system4.Others21Pharmacological actions1.CNS effects:principal effects analgesia euphoria sedation respiratory depression tolerance22(1)Analgesia powerful pain-relieving effect all types of pains:*constant,dull intermittent,sharp poor efficiency on neuropathic pain without affe
9、cting consciousness and other sense perception duration：4-6h 1.CNS23(2)Sedation and euphoria tolerance of paindrowsiness and clouding of mentation sleep induced and aroused easily *Euphoria a sense of contentment and well-being relieve anxiety and distress Sedationthe main reason for drug abuse24Act
10、ivate the opioid receptor at limbic system and locus ceruleus(蓝斑）蓝斑）Mechanisms:25 respiratory rate ，tidal volumeoccurs at ordinary doses,dose-related the most common cause of death from acute poisoning Mechanisms:the sensitivity of respiratory center to increased CO2 tension respiratory modulatory c
11、enter(3)Respiratory depression26(4)Cough suppressionby inhibiting cough center directly 27 Miosis:pinpoint pupils is characteristic of acute poisoningblocked by naloxone and atropine(5)OthersNausea and vomiting:activate the brain stem CTZ 28(5)Others release of gonadotropin-releasing hormone(GnRH)re
12、lease of corticotropin-releasing hormone(CRF)concentration of luteinizing hormone(LH),follicle-stimulating hormone(FSH)adrenocorticotropic hormone(ACTH)prolactin release29 Pharmacological actions 2.SM Stimulating Gastrointestinal system Biliary tract Urinary Bronchia30(1)Gastrointestinal tract delay
13、s passage2.Smooth muscle system secretion of digestive glandindigestioncentral inhibition a call of nature defecation reflexsphincter tone GIT tone GIT motility absorption of waterconstipationClinical uses?31 biliary colic constrict biliary smooth muscle constrict Oddis sphincter pressure in the bil
14、iary tract(2)Biliary tractMedicine?32(3)Other smooth muscle constrict ureteral smooth muscle constrict bladder sphincterurinary retention antagonize oxytocin(缩宫素）缩宫素）uterine tone prolong labor constrict bronchial smooth musclebronchial asthma 33 orthostatic hypotension Mechanisms:release of histamin
15、e vasomotor center3.Cardiovascular system(1)peripheral arterial and venous dilatation(2)intracranial pressuresecondary to respiratory depression344.Other actions inhibit immune system histamine release bronchospasm flushing arteriolar dilatation3519921993197319621975analgesic site is laminae III of
16、periventricular and periaqueductal gray areaput forward“receptors”for opiate analgesics in brainisolated the first“endogenous opioid peptide”and named enkephalincloned three opioid receptors:Research on analgesic mechanisms36 Sites of analgesiaSupraspinal areas:thalamus,periventricular,periaqueducta
17、l gray areaSpinal cord:substantia gelatinosa37Opioid receptors supraspinal analgesia,sedation,euphoria,respiratory depression,miosis,dependencespinal analgesia,sedationdysphoria,hallucinationspinal analgesia,respiratory depression,sedation,euphoria,dependence :38ExtracellularCytoplasmicNH2HOOCOpioid
18、 receptorsG protein-coupled receptors39Endogenous opioid peptidesThree main families:Enkephalinsmet-enkephalinleu-enkephalin Endorphins:-endorphine Dynorphins:dynorphine A,B40Mechanisms of analgesiaSupraspinal areas:combined with receptors,activate desending inhibitory system Spinal cord：4142 Spinal
19、 cordDorsal hornenkephalinsCa2+Ca2+谷氨酸谷氨酸神经肽神经肽Presynaptic terminalPostsynaptic neuronenkephalins 43enkephalins Presynaptic terminalPostsynaptic neuronThe cellular mechanisms of analgesiamorphine44Presynaptic inhibition:activation of opioid receptors on presynaptic nerve terminals.Close a voltage-ga
20、ted Ca2+channel,decrease Ca2+input,and thereby reduce transmitter release.The cellular mechanisms of analgesiaPostsynaptic inhibition:activation of postsynaptic opioid receptors.Open K+channels on postsynaptic neurons,increase K+output,and thereby cause hyperpolarization and thus inhibit postsynapti
21、c neurons.45Clinical uses1.Analgesia acute,severe pain,particularly in terminal cancer myocardial infarction renal and biliary colic（atropine)short-term use only when others failed2.*Cardiac asthma 3.Antidiarrhea46Pulmonary edema dyspneaAcute left ventricular dysfunctionshort of breath(respiratory c
22、enter)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 47(1)Mechanisms:peripheral arterial and venous dilation preload and afterload pul
23、monary edema sedation anxiety and distress oxygen consumption the sensitivity of respiratory center to CO2 shortness of breath Cardiac asthma481.General adverse effects1 dysphoria5Biliary colic2Respiratory depression6Urinary retention3Nausea and vomiting7Postural hypotension accentuated by hypovolem
24、ia4Constipation8Increased intracranial pressureAdverse effects49 Clinical overdose Accidental poisoning in addicts 30mg toxic threshold 120mg lethal thresholdPinpoint pupilsDeep respiratory depressionComaTreatments:Establish patent airway Adequate ventilation Naloxone Iv.The triad：2.Acute Morphine P
25、oisoning503.Tolerance and dependence(1)Tolerance a gradual loss in effectiveness in CNS with frequently repeated administration,need larger doses to achieve the same clinical effect.Characteristic:ordinary therapeutic doses 2-3 w large doses at short intervals readily develop not to miosis,constipat
26、ion51 physical dependence：withdrawal syndrome psychological denpendence:euphoria promote compulsive use and craving(2)Dependence52535455 rhinorrhea lacrimation chills gooseflesh (piloerection)yawning sweatingmuscular achesvomiting diarrhea anxiety hostility hyperventilation Withdrawalsyndrome of Opi
27、oid56Contraindications reasons that result in pain are not clear obstetric labor,breasting period cor pulmonale,bronchial asthma head injuries seriously impaired hepatic or renal function newborn infant,infant biliary and renal colic57Codeine(methylmorphine)Characteristics:oral 2.4.maily use as anti
28、tussive,dry 58Pethidine(dolantin,meperidin)analgesia:weaker(1/7-1/10)and shorter(2-4h)sedation,euphoria,respiratory depression:equal no antitussive action1.Metabolisms normeperidine muscle tremors,witches,convulsion2.Pharmacological properties(1)CNS59(3)Cardiovascular system similar to morphine(2)sm
29、ooth muscle less constipation and urinary retention do not prolong labor may induce biliary colic large doses the contraction of bronchial smooth muscle603.Clinical uses(1)Analgesia obstetric labor but should not be used in 2-4 h before labor do not longtime use in chronic pain.(2)Cardiac asthma(3)P
30、remedication in anesthesia sedative,anxiolytic,and analgesia61 (4)Artificial hibernation pethidine chlorpromazine promethazine lytic cocktail4.Adverse effects(1)CNS excitatory symptoms muscle tremors,twitches,convulsion should be combined with anticonvulsive drugs when treat overdose poisoning(2)som
31、e symptoms like atropine62Increased CNS depression,particularly respiratory depressionOpioid analgesics MAOIs Tricyclic antidepressantschlorpromazine promethazineSedative-hypnoticsAbsolute contraindication to pethidine,relative contraindication to other opioid analgesics,because of high incidence of
32、 hyperpyretic coma Drug Drug interactions63MethadoneCharacteristics:1.analgesia:equal to morphine 2.give reliable effects orally,longer duration of action 3.tolerance and physical dependence more slowly 4.withdrawal signs attenuated but protracted 5.detoxification of the morphine and heroin dependen
33、t addict64Fentanyl Characteristics:1.more analgesic potentcy than morphine:100 times2.has a rapid onset and short duration of action 3.high lipid-soluble,transdermal administration4.+droperidol(氟哌利多）氟哌利多）neuroleptanalgesia(神经阻滞镇痛术）神经阻滞镇痛术）or usually combined with anaesthetics 5.high dose cause trunc
34、al rigidity65Short actingfentanyl sufentanil alfentanilAgonistsmixed Agonists/AntagonistsAntagonists WEAK:codeine pentazocineSTRONG:methadone morphine pethidine buprenorphine nalbuphinelong actingnaltrexonenaloxoneClassification of opioid analgesics66Section 2 Partial agonists of opioid receptor 67P
35、entazocineCharacteristic:,agonist,weak antagonist 1.CNS analgesia:1/3 respiratory depression:1/2 *psychomimetic action(60-90mg)dysphoric and hallucination (action on)2.Smooth muscle:weaker68Pentazocine3.high doses *increase blood pressure and cause tachycardia (catecholamine )not use in myocardial i
36、nfarction4.weak action on *little addictive liability *precipitate the withdrawal syndrome of a morphine abuser 5.various chronic pain69Section 4 Other analgesics70Tramadol7172Section 5Antagonists of opioid receptors 73NaloxoneCharacteristics:petitive antagonist for opioid receptors:potency reverse
37、the opioid effects 2.iv.3.rapid onset(13 min),short duration of action 74Naloxone 4.acute opioid poisoning:reverses the coma and respiratory depression5.differential diagnosis in morphine or heroin abuser:precipitates withdrawal symptom6.As a tool agent in pharmacological research75 76Non-opioid for
38、 mild painPain persisting or increasingOpioid for moderate painPain persisting or increasingOpioid for severe painFreedom from cancer painPainNSAIDs e.g.aspirin,acetaminophene.g.codeine，tramadole.g.morphine,pethidine77病例：病例：张某张某,男男,30岁岁,因车祸伤导致左下肢疼痛不能因车祸伤导致左下肢疼痛不能活动送入急症科。查体发现基本生命体征平稳活动送入急症科。查体发现基本生命体
39、征平稳,病人痛苦貌病人痛苦貌,多处皮肤擦伤多处皮肤擦伤,左小腿前侧有一长左小腿前侧有一长约约20厘米的皮肤裂伤厘米的皮肤裂伤,伴有骨折端外露伴有骨折端外露,病人左病人左上腹部亦有轻微疼痛感但较软无明显压痛。随上腹部亦有轻微疼痛感但较软无明显压痛。随即行双下肢即行双下肢,骨盆骨盆x线检查线检查,提示左胫腓骨粉碎性提示左胫腓骨粉碎性骨折。病人检查过程中自觉腹部及小腿疼痛加骨折。病人检查过程中自觉腹部及小腿疼痛加剧剧,不能配合清创不能配合清创,于是值班医生给予度冷丁于是值班医生给予度冷丁50mg 肌肉注射肌肉注射,病人疼痛感减轻病人疼痛感减轻,并行简单清创并行简单清创后将病人推往手术室行骨折修复手术
40、后将病人推往手术室行骨折修复手术.问：这个给病人应用度冷丁合适么问：这个给病人应用度冷丁合适么?78 病人转入手术室以后准备行手术治疗病人转入手术室以后准备行手术治疗,麻醉麻醉前测量血压发现病人血压前测量血压发现病人血压80/50mmhg 睑结膜睑结膜,口口唇苍白唇苍白,四肢冷且苍白四肢冷且苍白,骨外科主任医师立即详细骨外科主任医师立即详细询问急症值班医生有关处理后立即行腹腔穿刺询问急症值班医生有关处理后立即行腹腔穿刺,穿出大量不凝血性液体穿出大量不凝血性液体.立即给予快速多通道补立即给予快速多通道补液输血治疗液输血治疗,并请普外科医师会诊并请普外科医师会诊,考虑脾脏破裂考虑脾脏破裂,随即给予手术修补治疗随即给予手术修补治疗.79
