Analgesics

1. Analgesics Zhang, Bin

2. PGs BK 5-HT K+、H+ mood effect, the affective aspect of pain Limbic system Somato-sensory cortex the sensory aspect of pain Primary afferent fibres Dorsal horn Noxious stimuli Spinal cord nociceptor Pain transmission pathway

3. Drug treatment of pain Local anaesthetics cholinoceptor-blocking drugs vasodilator drugs (eg. Nitroglycerin) Carbamazepine

4. Cortex Ventral caudal thalamus Opioids NSAIDs Dorsal horn PGs BK Spinal cord 5-HT K+、H＋ Sites of action of different drugs

5. Freedom from cancer pain WHO analgesic ladder e.g. morphine, fentanyl, methadone Strong Opioids for severe pain Pain persisting or increasing e.g. codeine， tramadol Weak Opioids for moderate pain Pain persisting or increasing NSAIDs e.g. aspirin, acetaminophen Non-opioid for mild pain Three steps analgesia therapy for cancer patients

6. opioid analgesics(narcotic analgesic, addictive analgesics)

7. 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

8. Opium (阿片) Opium The flower of papaver The plant of joy

9. Opiate (阿片剂) • Morphine • Codeine • Papaverine … …

10. Opioid (阿片样物质) Endogenous opioid peptides: • Enkephalins • Endorphins • Dynorphins • Nociceptin and nocistatin • Endomorphin-1/2 Others:

11. Research history 1992~1993 Cloned opioid receptors: μκδ 1975 isolated the first “endogenous opioid peptide” and named enkephalin 1973 put forward “receptors” for opiate analgesics in brain 1962 analgesic site is laminae III of periventricular and periaqueductal gray area

12. Opioid receptors NH2 Extracellular Cytoplasmic HOOC    G protein-coupled receptors

13. The cellular mechanisms • Presynaptic inhibition: activation of opioid receptors on presynaptic nerve terminals. Close a voltage-gated 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.

14. Presynaptic terminal Ca2+ Postsynaptic neuron Ca2+ Dorsal horn enkephalins enkephalins Spinal cord

15. morphine Presynaptic terminal Postsynaptic neuron enkephalins The cellular mechanisms

16. Pharmacological actions • CNS • Smooth muscles 3. Cardiovascular system 4. Others

17. 1.CNS effects: principal effects • Analgesia • Sedation & euphoria • Respiratory depression • Cough suppression • Others: miosis, nausea, hormone

18. 2.Smooth muscle system Gastrointestinal system Biliary tract Urinary system genital system

19. 3. Cardiovascular system (1) peripheral arterial and venous dilatation orthostatic hypotension Mechanisms: release of histamine vasomotor center (2) intracranial pressure secondary to respiratory depression

20. Clinical uses • Analgesia • Cardiac asthma • Antidiarrhea • Antitussive

21. Analgesia (severe pain) • terminal cancer • myocardial infarction • renal and biliary colic (atropine) • trauma, burn, operation • at regular time and quantity

22. 2. Cardiac asthma Reduce cardiac preload and afterload morphine Reduce the sensitivity of the respiratory center to increased CO2 Sedation Acute left ventricular dysfunction Pulmonary edema Alveolar hypoventilation CO2 retention dyspnea short of breath (respiratory center) anxiety and distress Cardiac asthmaand morphine therapy

23. Opioid analgesic drugs Morphine (吗啡) Codeine (可待因) Pethidine (哌替啶) Methadone (美沙酮) Fentanyl (芬太尼) Tramadol (曲马多)

24. little cross the BBB, but enough for its function placental fetus kidney,breast sc. im. morphine-6-glucuronide First pass elimination oral metabolism Morphine distribution excretion absorption blood free drug iv. active liver Bioavailability25-30%

25. 美施康定（硫酸吗啡控释片） 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。

26. Codeine 1. has a higheroralefficacy, demethylation to morphine 2. lower efficacy than morphine 3. mainly use as antitussive, severedry cough. 联邦止咳露 ：麻黄碱+可待因+氯苯那敏+氯化铵 • 抑制支气管腺体分泌，使痰液粘稠难以咳出，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。 注意事项

27. Pethidine (dolantin) • Synthetic substance • Weaker potency than Morphine, no antitussive action • More sedative, more rapid onset and shorter duration (2-4h) than morphine • Metabolite: normeperidine  convulsion • Lyticcocktail

28. Methadone 1. synthetic compound, oral bioavailability is 80% 2. milder physical abstinence syndrome 3. routinely used in detoxification of the morphine and heroin addicts

29. Fentanyl 1. more analgesic potentcy than morphine: 100 times 2. rapid onset and short duration of action 3.fentanyl, alfentanil, remifentanil: adjunctive drug for general anaesthesia 4. breakthrough cancer pain: 癌症患者的突发性疼痛，突然出现，不能被患者的常规疼痛治疗方案缓解。

30. Fentanyl lollipop 口腔经粘膜芬太尼拘橼酸盐(Oral Transmucosal Fentanyl Citrate, OTFC) ACTIQ 芬太尼口腔粘膜贴片(Fentanyl sublingual tablets) ABSTRAL 适应证：年龄18岁以上，已连续24小时使用阿片类药，对高剂量阿片类药物耐受者。

31. Tramadol • Atypical opioid • Weak μactivation, also interacts with monoaminergic systems • Alternative to traditional opioid analgesics (improved side effect profile)

32. Adverse effects 1. Tolerance 2. Dependence • physical dependence： withdrawal syndrome • psychological denpendence: compulsive drug- seeking behavior When are used for the relief of pain, tolerance and dependence are not significant and prevalent problem

33. 3. General adverse effects

34. 4. Acute Morphine Poisoning

35. Naloxone 1. competitive full antagonist for opioid R (μ) 2. Uses: opioid overdose 3. short t1/2 (1h) , repeated injections

36. Contraindications • obstetric labor, breasting period • obstructive airway disease, bronchial asthma • head injuries • seriously impaired hepatic or renal function

37. Mode of administration of opioids • Oral administration • Sublingual administration • Rectal administration • Intravenous administration • Intramuscular administration • Intrathecal and epidural administration • Transdermal patch administration Patient Controlled Analgesia (病人自控镇痛，PCA)

38. Non-opioid analgesics

39. Introduction Non-steroidal anti-inflammatory drugs (NSAIDs) Antipyretic-analgesic and anti- inflammatory drugs Aspirin-like drugs

40. 共同作用机制: Inhibition of cyclo-oxygenase enzymes (COX), and resulting inhibition of the synthesis of prostaglandins (PGs)

41. 花生四烯酸的代谢途径及主要代谢产物的生物活性花生四烯酸的代谢途径及主要代谢产物的生物活性 保护胃粘膜

42. 比较COX-1 & COX-2生物学作用

43. 【COX isoforms:】

44. 【Three major actions of NSAIDs】 Antipyretic effect Analgesic effect Anti-inflammatory effect

45. coxNSAIDs Antipyretic effect pathogen and toxins neutrophils endogenous pyrogens (ILs, TNF) PGE2(hypothalamus) heat production body temperature set point heat dissipation

46. Characteristics ①Central ② “Elevated” temperature — reduced “Normal ” temperature — no influence Clinical applications symptomatic treatment

47. PGs BK 5-HT K+、H+ Limbic system Somato-sensory cortex Analgesic effect NSAIDs Dorsal horn Noxious stimuli Spinal cord nociceptor Pain transmission pathway

48. Characteristics ① Peripheral (probably also inhibit pain stimuli at a subcortical site) ② mild to moderate pain ③ No addiction or respiratory inhibition

49. Clinical applications ① have good effects on chronic dull pain— headache , toothache, neuralgia, muscle pain, arthralgia, dysmenorrhea ② are not very effective for traumatic pain, severe visceral pain—myocardial infarction or renal or biliary colic Three steps analgesia therapy for cancer patients

50. morphine (+)opium receptor CNS periphery (-)PG synthesis aspirin 比较NSAIDs和吗啡的镇痛作用 • powerful • dull and sharp pain • inflammatory pain • cause euphoria and addiction • respiratory inhibition • moderate • chronic dull pain • cancer pain • not addictive • norespiratory inhibition