镇痛药

1. Analgesics 镇痛药 Liming Zhou (周黎明) Department of pharmacology 四川大学基础医学与法医学院

2. General Analgesics Information Analgesics are medications designed solely to relieve pain. Analgesics include • OTC medications (ibuprofen, aspirin) • Prescription drugs (dolantin, opium) • Natural analgesics: heat and ice application, acupuncture, breathing exercises, massage, resting & herbs.

3. narcotic analgesics Opium 阿片----- from the opium poppy (Papaver somniferum). ( drying the milky juice from unripe seed pod). Opioids 阿片类: Any substance (endogenous or synthetic) which produces ‘morphine-like’ effects Opiates 阿片制剂:The synthetic opioid-like drugs Opium alkaloid 阿片类生物碱---- • 菲类 morphine（10%）, codeine • 异喹林类 罂粟硷 papaverine

4. Opioids 阿片类 • Overview • History of opioids • Structure • The endogenous opioid system: action of mechanism • Morphine • Pharmacokinetics • Action • Therapeutic uses • Adverse reactions • Other agents • Pethidine • Methadone

5. History of Opioids • Name derived from opium, extract of juice of Papaver Somniferum • Used to produce euphoria, analgesia, sleep • 1806: Morphine isolated from opium • Named after Morpheus, Greek god of dreams • Early 20th century: invention of hypodermic needle and syringe • Parenteral use of morphine • Late 20th century: Endogenous opioid system discovered

7. 吗啡 morphine • 美沙酮 methadone • 哌替啶 pethidine • 芬太尼 fentanyl • 可待因 codeine • 喷他佐辛 pentazocine 镇痛新 • 海洛因 heroin • 纳洛酮 naloxone

9. The Endogenous Opioid System • Endogenous opioid peptides • Opioid receptor • Cellular effects of opioid receptor stimulation

10. Endogenous opioid peptides • 3 groups encoded by its distinct gene: • Endorphins(内啡肽) • Enkephalins (脑啡肽) • Dynorphins (强啡肽) • Opioid peptides widely expressed throughout CNS

11. The Endogenous Opioid System

12. Endogenous opioid peptides • Endorphins possess potent analgesic activity • Endorphins are found in the pituitary and hypothalamus

13. MSH: Melanocyte Stimulating Hormone

14. Opioid receptor • Three major classes opioid R: ,  & • G protein-coupled Rs (GPCRs) • Distribute within brain, spinal cord • Help to elicit specific physiological effects

15. Opioid receptor • δ (delta) ----analgesia. Some research suggests that they may also be related to seizures. • κ (kappa)--- in the periphery by pain neurons, in the spinal chord and in brain. ----analgesia, but activation also produces marked nausea and dysphoria.

16. Ca++ influx Voltage-gated Ca++ channel (-) K+ channel (GIRK) K+ influx (+) Cellular Effects of Opioid Receptor Stimulation Signal Transduction R* 1) R* 2)

18. Cellular Effects of Opioid Receptor Stimulation • Decreased neurotransmitter release：Ach, NA, Glu, 5-HT, P-substance (Ca++ channel inhibition) • Decreased neuronal excitability (K+ channel stimulation) • Overall inhibitory effect on the cell.

19. sp Sp receptor afferent neuron efferent neuron To the brain Opioid receptor Enkephalins neuron

20. + Pain afferent + Spinal dorsal horn analgesic action

21. classfication Based on intrinsic activity •Agonists (morphine, fentanyl 芬太尼) •Pure antagonists (naloxone 纳洛酮, naltrexone 纳曲酮) •Mixed agonist-antagonists (nalbuphine 纳布啡, pentazocine 喷他佐辛)

22. Morphine • Most common are morphine sulfate and morphine hydrochloride. • Both are fine white crystalline powders, bitter to the taste. • Both are soluble in water.

23. Morphine • Pharmacokinetics • Action • Therapeutic uses • Adverse reactions

24. pharmacokinetics • Absorption • Administered by several routes (injected, smoked, sniffed, or swallowed) • When eps. i.v, morphine can produce intense euphoria and a general state of well-being and relaxation • A certain degree of first pass elimination upon oral administration

25. Morphine--pharmacokinetics • Distribution • Throughout the body • A little can penetrate into CNS (enough to produce action) • Elimination: liver & kidney • Can penetrate into fetus through placenta • Be excreted into breast milk

26. 1. CNS effects • Analgesia • High potent (5-10mg) • Mood elevation------Euphoria & relaxation • Higher potent for acute pain than chronic pain • High selectivity (no influence to other nerve: Consciousness is not lost) • Increase the threshold of pain

27. 1. CNS effects • Sedation-Hypnosis • Drowsiness, feelings of heaviness, and difficulty concentrating are common. • Sleep may occur with relief of pain, although these drugs are not hypnotics. • Most likely to occur in elderly or debilitated patients and in those taking other CNS depressants (EtOH, benzodiazepines).

28. 1. CNS effects • Euphoria • Mood elevation, sometimes frank euphoria can occur. • Sense of well-being and cloudy detachment thought to be an important reason for opioid abuse.

29. 1. CNS effects • suppression of breath • Occurs at ordinary doses • Reduces the sensitivity of respiratory center to CO2 • Accentuates as the dose increases • Serum carbon dioxide tension (PCO2) is increased • Cerebral vasodilation can occur, causing increase in intracranial pressure

30. 1. CNS effects • Cough Suppression • Depression of cough centers in the medulla • Depression of cough reflex • Has tolerance • Pupil Constriction • Pinpoint pupil is a pathognomonic sign prior to asphyxia （窒息 ） at opioid overdose.

31. 1. CNS effects • Muscle Rigidity • Large i.v. doses can cause generalized stiffness of skeletal muscle. • Most common with fentanyl and congeners. • Nausea and vomiting • Directly stimulates the CTZ

32. 2. Peripheral effects • Cardiovascular effects: • No major effects on pressure & HR at ordinary doses • At large doses: Decrease in central sympathetic tone causes vasodilation and orthostatic hypotension. • Promotes release of histamine

33. 2. Peripheral effects • Gastrointestinal effects: constipation • Decreases motility of smooth muscle. • Delayed gastric emptying. • Both biliary and pancreatic secretions are decreased. • Constriction at the sphincter of Oddic causes an increase in biliary pressure.

34. 2. Peripheral effects • Urinary Tract effects • Increase contractions of the ureter and tone of the urinary sphincter, butdecrease force of detrusor musclecontraction. Can cause urinary retention. • Stimulate the release of ADH • Decrease in tension of uterus: Prolongation of labor can occur

35. 2. Peripheral effects • Endocrine effects • Histamine, prolactin, ADH release↑ • Inhibit gonadotropin （LH luteinizing hormone, FSH follicle stimulating hormone ）releasing • Inhibit ACTH (adrenocorticotropic hormone)

36. Morphine—indication • Be widely used in medicine as strong analgesics (pain relievers). • moderate-to-severe acute pain and chronic pain • acute pain (such as post-operative pain). • alleviate the severe, chronic, disabling pain of terminal conditions such as cancer.

37. 2. Acute pulmonary edema relief of certain types of difficult or labored breathing---------cardiac asthma • Reduces the sensitivity of respiratory center to CO2-----reduce respiratory rate. • Dilates the blood vessels--- • Sedation-----reduce the oxygen require

38. Morphine— indication 3.Suppression of severe cough (rarely) 4. Cholecystagia (胆绞痛) & nephrocolic (肾绞痛)-------be used combined with Atropine 5.Anaesthetic indication

39. Morphine—Adverse reaction • Ordinary action: vomiting, dysphoria 烦躁, elevation of intracranial pressure • Severe respiratory depression: main cause of death • Acute toxicity: hypotension, respiratory depression, miosis

40. Adverse reaction • Tolerance • Reduction in effect with repeated dosing (or higher dose to produce same effect) • Pinocytosis of Receptor & de-sensitive • Cross-tolerance to other opioids • Involved in dosage, interval, period of administration

41. Adverse reaction • Dependence • Physical Dependence • Altered physiological state caused by repeated opiate exposure such that cessation of drug administration leads to withdrawal • Physical & psychological dependence

42. Adverse reaction • Dependence • Withdrawal symptoms • If an antagonist is administered or the agonist is stopped, withdrawal symptoms will produce • Rhinorrhea(鼻液溢), lacrimation(流泪), vomiting, hyperventilation(强力呼吸), muscular aches, anxiety, diarrhea, gooseflesh(鸡皮疙瘩), mydriasis(散瞳症), shaking chills, drug seeking behavior

43. SYMPTOMS OF WITHDRAWAL 出汗

47. 我国 历史：7世纪罂粟知识传入我国 9世纪鸦片作为药输入唐都 鸦片战争前泛滥----金三角出现 现状： 既是毒品过境国，有是消费国 几十万人吸食

50. Use of Methadonein Opioid Physical Dependence • Similar analgesic action to morphine, but longer duration • Onset of tolerance & dependence is slow, induces less euphoria • Withdrawal symptoms protracted, though mild