Non-steroidal Anti-Inflammatory Drugs Non-opioid Analgesics & Drugs Used in Gout

1. Non-steroidal Anti-Inflammatory Drugs Non-opioid Analgesics & Drugs Used in Gout Shi-Hong Zhang (张世红), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University shzhang713@zju.edu.cn

2. Introduction Treatment inflammation: • Slow down or arrest of the tissue-damaging process • Relief of pain Pharmacological treatment • Non-steroidal anti-inflammatory drugs (NSAIDs) & Drugs used in gout • Glucocorticoids • Disease-modifying antirheumatic drugs (DMARDs) • Biologic response modifiers: eg. TNF-α inhibitors (etanercept依那西普, infliximab英夫利昔单抗, adalimumab阿达木单抗)，etc. • Hyaluronic acid substitutes: hyalgan透明质酸钠, synvisc欣维可

4. Phospholipid ⊕ Brandykinin Angiotensin Corticosteroids Phospholipase A2 Arachidonic acid Cyclooxygenase（COX） NSAIDs 5-lipoxygenase PGG2 Prostacyclin(PGI2) hydroperoxidase PGE2 PGF2α PGH2 Leukotrienes Thromboxane A2 Dipyridamole

5. 花生四烯酸 PGG2 COX 5-LOX

6. 机 体 内热原（细胞因子IL-1、IL-6、TNF等） NSAIDs （—） 中枢PGE2的合成增加 体温调节中枢 体温升高（发热） 感染原和细菌内毒素等外源性致热原 COX

7. Comparison of COX-1 and COX-2

8. 抑制COX-2 解热、镇痛、抗炎 胃黏膜损害、出血 损害肾脏 抑制COX-1

9. Classification of NSAIDs : Aspirin and other salicylates（阿司匹林及水杨酸类） Aniline derivatives（苯胺类衍生物）：对乙酰氨基酚 Indole derivatives（吲哚类衍生物）：吲哚美辛 Propionic acid derivatives（丙酸类衍生物）：布洛芬 Others (选择性COX-2抑制剂，烯醇酸类，杂环芳基乙酸类，茚乙酸类，吡唑酮类，以及灭酸类等)

10. 1. Aspirin The mechanism of aspirin: acetylating COX enzyme irreversibly

11. 1. Aspirin 1.1 Actions and therapeutic uses: A Antipyretic and analgesic actions: -- resets the thermostat toward normal and lowers the body temperature by increasing heat dissipation; -- alleviates pain of low to moderate intensity arising from integument, especially with inflammation.

12. 1. Aspirin 1.1 Actions and therapeutic uses: B Anti-rheumatic actions:atlarge dose (4-6 g/d). C Anti-aggregation of platelets and vasoconstriction:at small dose (~100 mg/d), irreversibly inhibits thromboxane production in platelets without markedly affecting PGI2 in the endothelial cells of the blood vessel.

13. 1. Aspirin 1.2 Adverse effects: Gastrointestinal effects:epigastric distress, nausea and vomiting, bleeding, ulcer (long term use). Allergic effects: Urticaria （风疹） Bronchoconstriction (aspirin asthma) angioneurotic edema

14. 1. Aspirin 1.2 Adverse effects: Prolonged bleeding time Excessive ventilation: respiratory alkalosis Salicylism (水杨酸反应)：toxicity in the CNS (headache, dizziness, nausea, vomiting, tinnitus) Reye’s syndrome: liver and brain injury in children with virus infection

15. Case Study A 14-year-old white female was evaluated after a single ingestion of 120 tablets of aspirin 81 mg/tablet, extended-release, and 6 tablets of ciprofloxacin环丙沙星 approximately 2 hours prior to arrival to the emergency department. Upon arrival, she denied nausea, diaphoresis发汗, abdominal pain, shortness of breath, or tinnitus. Vital signs were RR 18 breaths/min, HR 100 beats/min, BP 134/74 mm Hg, and T 36.5 °C. The patient received 50 g of oral activated charcoal 活性炭with sorbitol山梨醇 for decontamination; no gastric emptying techniques were used. The first salicylate concentration, drawn 4 hours after ingestion, was 1 mg/dL (therapeutic range 10–20 mg/dL). Salicylate concentration 6 hours after ingestion was 13 mg/dL, and the patient remained asymptomatic.

16. Case Study Serial salicylate concentrations were drawn every 4 hours due to the persistent non-decreasing concentrations: 13 mg/dL at 8 hours, 14 mg/dL at 13 hours, 14 mg/dL at 17 hours, and 18 mg/dL at 27 hours. The patient remained asymptomatic until 35 hours after exposure, when she developed dizziness, tinnitus, and epigastric discomfort. Her salicylate concentration at that time was 46 mg/dL. Vital signs were RR 20 breaths/min, HR 80 beats/min, and BP 110/75 mm Hg. Laboratory tests showed sodium 142 mEq/L, potassium 3.8 mEq/L, chloride 109 mEq/L, CO2 19 mEq/L, anion gap 14 mEq/L, pH 7.5, pCO2 29 mm Hg, and pO2 96 mm Hg.A second dose of activated charcoal 50 g with sorbitol was administered. A continuous infusion of sodium bicarbonate was started for enhanced elimination. Intravenous potassium supplementation was also started. The bicarbonate infusion was continued for approximately 30 hours with a steady decrease of the salicylate concentration to 10 mg/dL 60 hours after ingestion

17. 2. Acetaminophen (对乙酰氨基酚Tylenol) • Together with phenacetin, they are aniline derivatives (苯胺类衍生物 ) • Slow and prolonged antipyretic and analgesic effects • No obvious anti-inflammatory effect • Less stimulation to gastrointestinal tract • Causes damage of liver and kidney if used for a long time and at high doses. Alcohol increases the chance of hepatotoxicity.

18. 3. Indomethacin（吲哚美辛） • One of the most potent inhibitors of COX • High potency of anti-inflammatory, analgesic, and antipyretic activity • Used for severe rheumatic diseases: ankylosing spondylitis (强直性脊柱炎AS)，Osteoarthritis (骨关节炎OA) and gout (痛风). • Effective in treating patent ductus arteriosus （动脉导管未闭）

19. 3. Indomethacin • High incidence of adverse effects like: central nervous system effect gastrointestinal complaints allergic reactions hematopoietic (造血的) reactions • Sulindac (舒林酸) and Etodolac (依托度酸) are less toxic and used for OA, RA, AS and acute gout.

20. 4. Propionic acid derivatives （丙酸类） • Include ibuprofen布洛芬, naproxen萘普生, ketoprofen酮洛芬, etc • Anti-inflammatory, analgesic and antipyretic activities • Less gastrointestinal effects • Change platelet function and prolong bleeding time • Widely used for the treatment of inflammation induced by rheumatic diseases and dysmenorrhea (痛经)

21. 5. COX-2 inhibitors • Include celecoxib塞来昔布（selective）, meloxicam美洛昔康, nimesulide尼美舒利, etc • Less adverse effects than non-selective COX inhibitors (platelets aggregation, stomach mucus damage, gastrointestinal hemorrhage) • Used for the treatment of rheumatoid arthritis, osteoarthritis, and other inflammatory pain, including acute gout. • Selective COX2 inhibitors are suspected to be related to an increase in the risk for heart attack, thrombosis and stroke.

22. 6. Other NSAIDs • Piroxicam(吡罗昔康): similar efficacy to aspirin in anti-inflammatory effect, used for long term treatment of OA and RA, less side effects in GI tract. • Phenylbutazone (保泰松) : high potency of anti-inflammatory activity, low potency of antipyretic effect, more adverse effects than other NSAIDs. Chiefly prescribed in short term therapy of acute gout and in acute rheumatoid arthritis.

23. 抑制环加氧酶 抑制PGE2的合成和释放 解热镇痛药与氯丙嗪降温作用比较 氯丙嗪 NSAIDs 增加散热 抑制体温调节 效应 作用机制 抑制体温调节中枢 特点 • 1．环境温度低——降温 • 环境温度越低，降温越显著 • 可降发热、正常体温 • 2．高温环境——升温 只降发热体温 不降正常体温 用途 人工冬眠疗法（降温） 治疗发热

24. 解热镇痛药 外周（主） 作用部位 中枢 作用机制 激动阿片受体 抑制环氧酶， 使PG合成减少 镇痛特点 强大，伴有镇静作用及欣快感 中等强度，无镇静作用 及欣快感 适应证 慢性炎性痛及体表部位手术后疼痛 不良反应 易成瘾，抑制呼吸 无成瘾性及呼吸抑制 解热镇痛药与阿片类镇痛药镇痛作用比较 阿片类镇痛药 用其他药无效的急慢性锐痛

25. Glucocorticoid NSAIDs 抑制多种炎症因子，包括抑制PLA2，抑制COX表达 作用机制 抑制COX，减少PG合成 风湿、类风湿、创伤导致的炎症 各种炎症 临床应用 多种不良反应如代谢障碍,免疫抑制 主要不良反应 胃肠道反应 解热镇痛药与糖皮质激素的抗炎作用比较

26. Other drugs used for rheumatic diseases • Disease-modifying antirheumatic drugs (DMARDs) • 甲氨蝶呤, 羟氯喹, 柳氮磺胺吡啶, 硫唑嘌呤，来氟米特, 金制剂，青霉胺，雷公藤，etc. • 用于NSAIDs疗效不好的患者，常采用二药或三药的联合用药方案； • 不能迅速抗炎和止痛，通常2-4个月显示效果； • 可改善病情和延缓病情进展，患者血沉、血浆蛋白、类风湿因子(rheumatoid factor , RF)等较NSAIDs更有效地恢复正常; • 需长期治疗，不能使已经受到破坏的关节复原.

27. Other drugs used for rheumatic diseases • Biologic response modifiers • TNF-α inhibitors (etanercept依那西普, infliximab英夫利昔单抗, adalimumab阿达木单抗); • abatacept阿巴西普，是IgG1的Fc片段与CLTA-4胞外区域的融合蛋白，传递抑制信号到T细胞，抑制免疫攻击作用； • B细胞CD20单克隆抗体(rituximab利妥昔单抗): 抑制B细胞功能; • IL-1 受体拮抗剂 (anakinra,阿那白滞素).

28. Other drugs used for rheumatic diseases • Corticosteroids:prednisone, methylprednisolone,etc • 抑制免疫和炎症反应，改善症状；停药易复发，长期用药不良反应多，不作为首选或单独应用; • 小剂量(泼尼松<10mg/d或等效其他激素)缓解症状,作为DMARDs起效前的桥梁; • 关节腔注射，减轻症状, 改善功能 19 H 12 18 16 13 D C 14 15 1 9 2 10 8 A B 3 5 7 4 6

29. Pharmacology of Local Anesthetics (LAs)

30. Local Anesthetics (LAs) • Reversibly block nerve conduction • Act on every type of nerve fibers: non/thin myelinated sensory fibers myelinated sensory fibers autonomic fibers motor fibers • Also act on cardiac muscle, skeletal muscle and the brain • No structural damage to the nerve cell

31. 酯类 可卡因 普鲁卡因 丁卡因 苯佐卡因

32. 酰胺类 利多卡因 甲哌卡因 布比卡因 依替卡因 丙胺卡因

33. Action site: voltage-gated Na+ channels

34. Actions of LAs • Ionic gradient and resting membrane potential are unchanged • Only bind in the inactivated state: use dependent • Decrease the amplitude of the action potential • Slow the rate of depolarization • Increase the firing threshold • Slow impulse conduction • Prolong the refractory period

35. Types of local anesthesia Topical local (surface) anesthesia: for eye, ear, nose, and throat procedures and for cosmetic surgery Infiltration anesthesia: local injection around the region to be operated. Conduction anesthesia: local injection around the peripheral nerve trunk Epidural anesthesia: local injection into the epidural space Subarachnoid anesthesia or Spinal anesthesia: local injection into the cerebrospinal fluid in subarachnoid cavity

36. Epidural anesthesia Infiltration anesthesia Conduction anesthesia (cervical plexus) Spinal anesthesia

37. Pharmacokinetics • LAs bind in the blood to a1-glycoprotein and albumin • There is considerable first-pass uptake of LAs by the liver • LAs enter the blood stream by: • Direct injection • Absorption • Epinephrine decreases this via vasoconstriction • Peak concentrations vary by site of injection

38. Metabolism of LAs • Esters (rapid) • Hydrolyzed in the plasma by pseudocholinesterase • Break down product – para-aminobenzoic acid (对苯氨甲酸) • Amides (slower) • Occurs in the endoplasmic reticulum of hepatocytes • Tertiary amines are metabolized into secondary amines that are then hydrolyzed by amidases

39. Allergic Reactions • Metabolite of ester LAs • Para-aminobenzoic acid • Allergen • Allergy to amide LAs is extremely rare

40. CNS Toxicity • Correlation between potency and seizure threshold • Bupivacaine • 2 ug/ml • Lidocaine • 10 ug/ml

41. Cardiovascular Toxicity • Attributable to their direct effect on cardiac muscle • Contractility • Negative inotropic effect that is dose-related and correlates with potency • Interference with calcium signaling mechanisms • Automaticity • Negative chronotropic effect • Rhythmicity and Conductivity • Ventricular arrhythmias

42. Comparison of LAs

43. Pharmacology of General Anesthetics

44. General Anesthetics General anesthesia:analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic reflexes, and skeletal muscle relaxation. Intravenous anesthetics (barbiturates, etc) Inhalational anesthetics (gases, or volatile liquids)

45. Intravenous Anesthetics Usually activate GABAA receptors, or block NMDA receptors

46. Induction of iv Anesthesia Commonly used for initial anesthesia induction along with inhalational anesthetics

47. Inhalational Anesthetics • Many different, apparently unrelated molecules produce general anesthesia – inert gases (xenon), simple inorganic (N2O) & organic compounds (diethyl ether), more complex organic compounds (Halothane, etc) • Characteristics – rapid onset (emergence), rapid recovery, relationship between lipid solubility & potency

48. Stages of Anesthesia (ether) • Stage I: analgesia – sensory block in spinal cord, and later amnesia • Stage II: paradoxical excitation (irregular respiration, retching, vomiting, struggle, possible asphyxia) due to loss of some inhibitory tone and direct stimulation of excitatory transmission • Stage III: surgical anesthesia – block of the ascending reticular activating system, loss of eyelash reflex, recovery of regular breath and cessation of spontaneous respiration • Stage IV: failure – cardiovascular and respiratory collapse due to excessive inhibition

49. Tachycardia Hypertension Eyelid reflex Lacrimation Swallowing Laryngospasm (involuntary spasm of the laryngeal cords) Movement Signs for Anesthesia Depth TOO LIGHT TOO DEEP • Hypotension • Organ failure

50. Inhalational anesthetic delivery system