Transcript 幻灯片 1
Welcome to Pharmacology 1 Chapter 21 Analgesics 2 Section 1 Overview 3 1. Concept somatic sensation affective (emotion) two components 4 mood effect, the affective aspect of pain Limbic system Somatosensory cortex Midbrain Primary afferent fibres (C/Aδ) Noxious stimuli the sensory aspect of pain Medulla Dorsal horn PGs BK 5-HT K+、H+ Spinal cord nociceptor 2. Pain transmission pathway 5 Endogenous opioid peptides Ascending pain transmission pathways Descending pain inhibitory pathways Pain Local inhibitory interneuron in spinal cord 6 Cortex Ventral caudal thalamus Midbrain Medulla NSAIDs Opioid analgesics， Antidepressants and General anaesthetics Dorsal horn PGs BK Spinal cord 5-HT K+、H＋ Local anesthetics Sites of action of different drugs 7 Pain a. 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 fibers 8 3. Durg treatment of pain severe, sharp pain inflammation, elevated temperature, chronic- dull pain opioid analgesics (eg. Morphine) NSAIDs (eg. Aspirin) smooth muscle colic (eg. biliary or renal colic) cholinoceptor-blocking drugs (eg. Atropine) angina pectoris induced by coronary artery spasm vasodilator drugs (eg. Nitroglycerin) trigeminal pain Carbamazepine 9 Analgesics 1. Concept Drugs which act on CNS , could relieve or alleviate severe pain and unhappy mood without affecting other sense perception, and consciousness 10 2. Classification Full agonist of opioid receptors Partial agonist of opioid receptors Other analgesics 11 Section 2 Full agonist of opioid receptors 12 Opium Alkaloids • Phenanthrenes morphine, codeine • Benzylisoquimolines papaverine --has no analgesic effect --dilates the vessel 13 The flower of papaver somniferum 14 Opium 15 Morphine 16 1803 Serturner isolated a pure active alkaline substance from opium . He proposed the name“morphine”for it after Morpheus. 17 structure-activity relationship 海洛因 吗啡 OH 纳洛酮 18 Pharmacokinetics distribution absorption little cross the BBB, but enough for its function placental excretion fetus blood sc. im. free drug morphine-6glucuronide oral First pass elimination metabolism liver kidney, breast 19 Pharmacological actions 1. CNS 2. Smooth muscles 3. Cardiovascular system 4. Others 20 Pharmacological actions 1.CNS effects :principal effects analgesia euphoria sedation respiratory depression tolerance 21 1. CNS (1) Analgesia powerful pain-relieving effect all types of pains: * constant, dull ﹥intermittent, sharp poor efficiency on neuropathic pain without affecting consciousness and other sense perception duration：4-6h 22 (2) Sedation and euphoria relieve anxiety and distress tolerance of pain Sedation drowsiness and clouding of mentation *Euphoria sleep induced and aroused easily a sense of contentment and well-being the main reason for drug abuse 23 Mechanisms: Activate the opioid receptor at limbic system and locus ceruleus (蓝斑） 24 (3) Respiratory depression respiratory rate ，tidal volume occurs 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 center 25 (4) Cough suppression Has antitussive effect by inhibiting cough center directly 26 (5) Others Miosis: pinpoint pupils is characteristic of acute poisoning blocked by naloxone and atropine Nausea and vomiting: activate the brain stem CTZ 27 (5) Others • ↓release of gonadotropin-releasing hormone (GnRH) • ↓ release of corticotropin-releasing hormone (CRF) • ↓concentration of luteinizing hormone (LH) ,fol licle-stimulating hormone(FSH) • ↓adrenocorticotropic hormone(ACTH) • ↑prolactin release 28 Pharmacological actions • 2. SM Stimulating Gastrointestinal system Biliary tract Urinary Bronchia 29 2. Smooth muscle system (1) Gastrointestinal tract GIT tone GIT motility delays passage absorption of water sphincter tone secretion of digestive gland central inhibition indigestion a call of nature defecation reflex constipation Clinical uses? 30 (2) Biliary tract constrict biliary smooth muscle constrict Oddi's sphincter pressure in the biliary tract biliary colic Medicine? 31 (3) Other smooth muscle ① constrict ureteral smooth muscle constrict bladder sphincter urinary retention ② constrict bronchial smooth muscle bronchial asthma ③ antagonize oxytocin (缩宫素） uterine tone prolong labor 32 3. Cardiovascular system (1) peripheral arterial and venous dilatation orthostatic hypotension Mechanisms: release of histamine vasomotor center (2) intracranial pressure secondary to respiratory depression 33 4. Other actions inhibit immune system histamine release bronchospasm flushing arteriolar dilatation 34 Research on analgesic mechanisms 1992~1993 1975 1973 1962 cloned three opioid receptors: μ κ δ isolated the first “endogenous opioid peptide” and named enkephalin put forward “receptors” for opiate analgesics in brain analgesic site is laminae III of periventricular 35 and periaqueductal gray area Sites of analgesia Supraspinal areas: thalamus, periventricular, periaqueductal gray area Spinal cord: substantia gelatinosa 36 Opioid receptors *: supraspinal analgesia, sedation, euphoria, respiratory depression, miosis, dependence : spinal analgesia, sedation : spinal analgesia, respiratory depression, sedation, euphoria, dependence : dysphoria, hallucination 37 Opioid receptors NH2 Extracellular Cytoplasmic HOOC G protein-coupled receptors 38 Endogenous opioid peptides Three main families: Enkephalins met-enkephalin leu-enkephalin Endorphins: β-endorphine Dynorphins: dynorphine A, B 39 Mechanisms of analgesia Supraspinal areas: combined with receptors, activate desending inhibitory system Spinal cord： 40 41 Presynaptic terminal 谷氨酸 Ca2+ 神经肽 Ca2+ Dorsal horn Postsynaptic neuron enkephalins enkephalins Spinal cord 42 morphine Presynaptic terminal Postsynaptic neuron enkephalins The cellular mechanisms of analgesia 43 The cellular mechanisms of analgesia Presynaptic inhibition: activation of opioid receptors on presynaptic nerve terminals. Close a voltage-gated Ca2+ channel, decrease Ca2+ input, and thereby reduce transmitter release. Postsynaptic inhibition: activation of postsynaptic opioid receptors. Open K+ channels on postsynaptic neurons, increase K+ output , and thereby cause hyperpolarization and thus inhibit postsynaptic neurons. 44 Clinical uses 1.Analgesia acute, severe pain, particularly in terminal cancer myocardial infarction renal and biliary colic（atropine) short-term use only when others failed 2. *Cardiac asthma 3. Antidiarrhea 45 Acute left ventricular dysfunction Reduce cardiac preload and afterload Pulmonary edema Alveolar hypoventilation dyspnea morphine CO2 retention short of breath (respiratory center) Reduce the sensitivity of the respiratory center to increased CO2 Sedation anxiety and distress Cardiac asthma and morphine therapy 46 Cardiac asthma (1) Mechanisms: ① peripheral arterial and venous dilation preload and afterload ② sedation pulmonary edema anxiety and distress oxygen consumption ③ the sensitivity of respiratory center to CO2 shortness of breath 47 Adverse effects 1. General adverse effects 1 dysphoria 5 Biliary colic 2 Respiratory depression 6 Urinary retention 3 Nausea and vomiting 7 Postural hypotension accentuated by hypovolemia 4 Constipation 8 Increased intracranial pressure 48 2. Acute Morphine Poisoning • Clinical overdose • Accidental poisoning in addicts • 30mg – toxic threshold • 120mg – lethal threshold The triad： Pinpoint pupils Deep respiratory depression Coma Treatments: Establish patent airway Adequate ventilation Naloxone Iv. 49 3. 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 , constipation 50 (2) Dependence physical dependence： withdrawal syndrome psychological denpendence: euphoria promote compulsive use and craving 51 52 53 54 Withdrawal syndrome of Opioid rhinorrhea lacrimation chills gooseflesh (piloerection) yawning sweating muscular aches vomiting diarrhea anxiety hostility hyperventilation 55 Contraindications 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 colic 56 Codeine (methyl－morphine) Characteristics: 1. has a higher oral efficacy 2. weaker analgesia, about 1/10－1/12， antitussive：1/4 3. used in moderate pain 4. maily use as antitussive, severe dry cough. 57 Pethidine (dolantin, meperidin) 1. Metabolisms normeperidine muscle tremors, witches, convulsion 2. Pharmacological properties (1) CNS analgesia: weaker(1/7-1/10) and shorter(2-4h) sedation, euphoria, respiratory depression: equal no antitussive action 58 (2) smooth muscle less constipation and urinary retention do not prolong labor may induce biliary colic large doses the contraction of bronchial smooth muscle (3) Cardiovascular system similar to morphine 59 3. 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) Premedication in anesthesia sedative, anxiolytic, and analgesia 60 (4) Artificial hibernation pethidine chlorpromazine lytic cocktailⅠ promethazine 4. Adverse effects (1) CNS excitatory symptoms muscle tremors, twitches, convulsion should be combined with anticonvulsive drugs when treat overdose poisoning (2) some symptoms like atropine 61 Absolute contraindication to pethidine , relative contraindication to other opioid analgesics , because of high incidence of hyperpyretic coma MAOIs Opioid analgesics Tricyclic antidepressants Sedativehypnotics chlorpromazine promethazine Increased CNS depression, particularly respiratory depression Drug – Drug interactions 62 Methadone Characteristics: 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 dependent addict 63 Fentanyl Characteristics: 1. more analgesic potentcy than morphine:100 times 2. has a rapid onset and short duration of action 3. high lipid- soluble, transdermal administration 4. + droperidol (氟哌利多） neuroleptanalgesia(神经阻滞镇痛术） or usually combined with anaesthetics 5. high dose cause truncal rigidity 64 Classification of opioid analgesics Agonists WEAK: codeine mixed Agonists /Antagonists Antagonists pentazocine STRONG: long acting methadone morphine pethidine Short acting fentanyl sufentanil alfentanil buprenorphine nalbuphine naltrexone naloxone 65 Section 2 Partial agonists of opioid receptor 66 Pentazocine Characteristic: κ, σ agonist , μ weak antagonist 1. CNS analgesia: 1/3 respiratory depression : 1/2 * psychomimetic action (60-90mg) dysphoric and hallucination (action on σ) 2. Smooth muscle: weaker 67 Pentazocine 3. Cardiovascular system high doses *increase blood pressure and cause tachycardia (catecholamine ) not use in myocardial infarction 4. weak action on μ * little addictive liability * precipitate the withdrawal syndrome of a morphine abuser 5. various chronic pain 68 Section 4 Other analgesics 69 Tramadol 70 71 Section 5 Antagonists of opioid receptors 72 Naloxone Characteristics: 1. competitive antagonist for opioid receptors: potency μ﹥κ﹥δ reverse the opioid effects 2. iv. 3. rapid onset (1~3 min), short duration of action 73 Naloxone 4. acute opioid poisoning : reverses the coma and respiratory depression 5. differential diagnosis in morphine or heroin abuser : precipitates withdrawal symptom 6. As a tool agent in pharmacological research 74 Appendix Three step analgesia therapy for cancer patients 75 Freedom from cancer pain e.g. morphine, pethidine Opioid for severe pain Pain persisting or increasing e.g. codeine， tramadol Opioid for moderate pain Pain persisting or increasing Non-opioid for mild pain Pain NSAIDs e.g. aspirin, acetaminophen 76 病例： 张某,男, 30岁,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, 病人痛苦貌,多处皮肤擦伤, 左小腿前侧有一长 约20厘米的皮肤裂伤,伴有骨折端外露, 病人左 上腹部亦有轻微疼痛感但较软无明显压痛。随 即行双下肢,骨盆x线检查,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 剧,不能配合清创,于是值班医生给予度冷丁 50mg 肌肉注射, 病人疼痛感减轻,并行简单清创 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? 77 病人转入手术室以后准备行手术治疗,麻醉 前测量血压发现病人血压80/50mmhg 睑结膜,口 唇苍白,四肢冷且苍白,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, 穿出大量不凝血性液体.立即给予快速多通道补 液输血治疗,并请普外科医师会诊,考虑脾脏破裂, 随即给予手术修补治疗. 78 79