Analgesics （镇痛药）

1. Analgesics（镇痛药） Yin Ming 2011.11.1

2. Pain • an unpleasant sensation often caused by intense or damaging stimuli • the most common reason for physician consultation • interfering with a person's quality of life and general functioning • protective response of human body

5. Pain killers • Opiates and morphinomimetics (阿片类及类似物） • NSAIDs: son-selective cyclooxygenases (COX-1 and COX-2) inhibitors: aspirin, ibuprofen, … • COX-2 inhibitors: celecoxib (塞来昔布）, … • Flupirtine （氟吡汀）: K+ channel opener with weak NMDA antagonist properties • other and specific agents: amitriptyline, cabamazepine, rotundine, ziconotide, …

6. Drug classification

7. Opioid analgesics • Natural • phenanthrene • morphine 10%（吗啡） • codeine 0.5% （可待因） • semisynthetic • heroin （海洛因），not used clinically • Buprenorphine （丁丙诺啡）, partial agonist • synthetic • Pethidine （哌替啶） • Methadone （美沙酮） • Fentanyl （芬太尼） • Remifentanil （瑞芬太尼） • Oxygodone （羟考酮）

8. Opiate receptors and opioid peptides • 1962, Zou Gang（邹冈）, morphine injected into periaqueductal gray matter （中脑导水管周围灰质）, sites found • 1973, Snyder, radioligand binding（放射配基结合） and autoradiography（放射自显影）, opiate receptors found • 1975, enkephalins isolated • Endorphins and dynorphins, … found

9. 阿片受体分类及其效应

10. Receptor classification and functions • Mu μ • P hysical dependence • E uphoria • A nalgesia (supraspinal) • R espiratory depression

11. Kappa κ • S edation • A nalgesia (spinal) • M iosis

12. Delta δ • analgesia (spinal & supraspinal) • release of growth hormone    • Sigma Σ • dysphoria (opposite of euphoria) • hallucination (both visual & auditory) • respiratory and vasomotor stimulation • mydriasis

13. NH NH 2 2 Extracellular Extracellular Cytoplasmic Cytoplasmic HOOC OPIOID receptors • CNS distribution is not uniform • they are at areas concerned with pain • receptor locations beginning with highest concentration areas 1. cerebral cortex 2. amygdala 3. septum 4. thalamus 5. hypothalamus 6. midbrain 7. spinal cord

17. Pharmacokinetics • readily absorbed from GI tract, nasal mucosa, lung subcutaneous, intramuscular, and intravenous route • Distributed to breast

18. CNS action of morphine • analgesia • sedation • euphoria • mood change • mental cloudiness

19. Morphine analgesia Changes our reaction and our perception of pain • severe cancer pain is tolerated more when person is given morphine • relieves all types of pain, but most effective against continuous dull aching pain • sharp, stabbing, shooting pain also relieved by morphine • Morphine given to a pain free individual • first experience is dysphoric • not experienced in person in pain

20. Morphine sedation - morphine causes sedation effect, but no loss of consciousness • Morphine euphoria • sense of well being • reason why morphine is abused

21. Effects of morphine on respiration a primary and continuous depression of respiration related to dose • decrease rate • decrease volume • decrease tidal exchange

22. Effects on respiration • mureceptor activation produces respiratory depression; with increase in dose can cause further respiratory depression • CNS becomes less responsive to pCO2 thereby causing a build up of CO2 • irregular breathing patterns; • periods of apnea

23. nausea and vomiting – Stimulation of CTZ, in the area postrema of medulla • stimulation by stretch receptors causes nausea and vomiting • receiving afferents from gut and ear • involved in motion sickness

24. pupil size • morphine causes miosis (pinpoint pupils) • kappa receptor effect • pinpoint pupils still responsive to bright light • oculomotor nerve is stimulated by kappa receptor site • if kappa receptor is blocked, mydriasis from sigma effect will appear • atropine partially blocks effect indicating parasympathetic system involved

25. Cardiovascular effects • Cardiovascular effects of morphine lead to vasodilation, thus a decrease in blood pressure • morphine causes the release of histamine and • suppression of central adrenergic tone and • suppression of reflex vasoconstriction

26. effects on gastrointestinal system • increase in tone and decrease in mobility leads to constipation （便秘） • decreased concentration of HCl secretion • increased tone in stomach, small and large intestine • delay of passage of food (gastric contents) , so more reabsorption of water • tolerance does not develop (i.e. same amount of effect each time) to this constipation effect

27. effects on various smooth muscles • billiary tract • marked increase in the pressure in the billiary tract • 10 fold increase over normal (normal is 20 mm H20 pressure) • increase due to contraction of sphincter of Oddi • urinary bladder • tone of detrusor muscle increased • feel urinary urgency • urinary retention due to increased muscle tone where sphincter shrinks • bronchial muscle • bronchoconstriction • contraindicated in asthma, particularly before surgery • uterus • contraction of uterus results in prolonged labor

28. Neuroendocrine Effects release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing factor (CRF) inhibited ↓ decreased circulating luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and β- endorphin ↓ concentrations of testosterone and cortisol in plasma declined

29. Therapeutic uses of morphine • relief of severe pain • preoperative medications • postoperative medications • acute pulmonary edema • constipating effect • cough

30. Tolerance to morphine • nausea • analgesia • sedation • respiratory depression         • cardiovascular • euphoric • not to: • miosis • constipation

31. Dependence and withdrawal syndrome • Strong cravings • Nausea • Cramps • Sweating • Chills • Goose bumps • Vomiting • Diarrhea • Shakes • Irritation • Agitation • Anxiety • Muscle aches • Runny nose • Yawning • Insomnia • Dilated pupils physical dependence; psychological dependence

32. Animals will self-administer drugs Results obtained from animals that self-administer drugs can be compared with animals that receive the same drug given passively

33. Acute toxicity of morphine • acute overdose • respiratory depression • pinpoint pupils (miosis) • coma • Treatment • establishing adequate ventilation • giving OPIOID antagonist (naloxone)

34. Naloxone • no agonist activity • displacing morphine from all receptors, reversing all of the effects of morphine • effects immediate (3-5 min) • lasting 30-45 minutes, then reinjected

35. Other opiate drugs Codeine • one tenth the potency of morphine • withdrawal from codeine is mild in relation to morphine • antitussive drug for cough

36. pethidine（哌替啶） same CNS actions as morphine often used clinically

37. Fentanyl (芬太尼） • different structure than morphine • 80 to 100 times more potent than morphine • rapidly acting drug and short acting (30-45 min) • often used as preoperative medication • highly abused, known as china white as street name analogue: remifentanil （瑞芬太尼）

38. Methadone • pharmacological activity similar to morphine, same potency as morphine • orally absorbed well • 16 to 20 hour duration of action • used in treatment of opioid dependence

39. Non-opioid analgesics • Rotundine （罗通定） • Alkaloid isolated from plant Stephania • As a mild pain reliever, used in visceral pain and other mild pain. • Flupirtine （氟吡汀） • Potassium channel opener and mild NMDA antagonist • Used for acute and chronic pain, in moderate to severe cases

41. 癌症患者止痛的阶梯疗法 • 轻度疼痛：非甾体镇痛药阿司匹林、布洛芬等 • 中度疼痛：可待因、曲马多等 • 重度疼痛：吗啡、哌替啶、芬太尼、美沙酮等。不易产生依赖性 • 《麻醉药品和精神药品管理条例》（国务院令第442号） 2005年08月03日 发布

42. Antagonists of opiates Naloxone （纳洛酮） naltrexone (纳曲酮) Used for treatment of opiate intoxication and diagnosis of opiate dependence

43. Suggested reading Fareed A, Vayalapalli S, Stout S, Casarella J, Drexler K, Bailey SP. Effect of methadone maintenance treatment on heroin craving, a literature review. J Addict Dis. 2011 Jan; 30(1):27-38.