Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Part 13 Antipyretic-Analgesic Drugs A. General Pharmacological properties 1. Inhibition of prostaglandin (PG) synthesis inhibiting cyclooxygenase (COX,环氧酶), decreasing the synthesis of PGs and TXA2, resulting antipyretic, analgesic, and antiinflammatory effects non-steroidal anti-inflammatory drugs (NSAIDs, 非 甾体抗炎药) A. General Pharmacological properties 2. Antipyretic effects Inhibition of PGE2 production in the hypothalamus induced by endogenous pyregens after pathological stimulation temperature notes: symptomatic control only, not be indicated in all patients with fever. The effect on body temperature is different from that of chlorpromazine. Comparison of properties of two types of drugs 作用机制 作用 用途 不良反应 解热镇痛药 氯丙嗪 抑制前列腺素合成,使 抑制下丘脑体温调节中枢, 散热增加而解热 使其调节功能减弱,不能随 外界温度变化而调节体温 只能使升高的体温降到 氯丙嗪配合物理降温,不仅 正常 可使升高的体温降到正常, 也可使正常体温降到正常以 下 用于各种发热 用于低温麻醉、人工冬眠 胃肠道反应等 锥体外系统反应等 A. General Pharmacological properties 3. Analgesic effects Analgesic effect is resulted from inhibition of PGE2 production. Effective on the pain of low to moderate intensity related to inflammatory responses. PGE2: a pain stimulant and hyperalgesic agent The analgesic effect is different from opioid analgesics. Comparison of properties of two types of drugs 作用 用途 不良反应 解热镇痛药 抑制前列腺素合成起效; 对慢性钝痛有效,对剧烈 疼痛或内脏绞痛无效 头痛、牙痛、神经痛、肌 肉或关节痛、痛经等 阿片类镇痛药 兴奋阿片受体起效; 对各种疼痛均有效 用于其他药物无效的急性 锐痛,晚期肿瘤的剧烈疼 痛 胃肠道反应等,但无成瘾 有成瘾性 性 A. General Pharmacological properties 4. Anti-inflammatory effects PGs induce inflammatory responses. Inhibition of PG production can relieve inflammatory responses, such as congestion, exudation, pain. The effect is different from that of glucocorticosteroids. Comparison of properties of two types of drugs 作用 用途 不良反应 非甾体抗炎药 抑制前列腺素合成起效; 缓解软 组织 、骨骼 、关节 的炎症 风湿性 、类 风湿性 炎症, 外伤损伤 胃肠道反应等 糖皮质激素 抑制炎症细胞、炎症分 子,多环节炎症炎症病变 多环节抑制炎症病 变 可用于多种炎症,作用强 抑制机体防御反应,干扰 代谢,不良反应广泛 A. General Pharmacological properties 5. COX-1 / COX-2 and selectivity of the drugs COX-1: constructive; involved in physiologic regulatory functions in GI tract, kidney, etc.; inhibition of COX-1 is related to the adverse effects. COX-2: inducible; involved in pathological responses such as inflammation, and pregnancy; inhibition of COX-2 is related to the therapeutic effects. (-) (+) (+) (-) B. Salicylates Aspirin 阿司匹林 Acetylsalicylic acid 乙酰水杨酸 COOH Salicylic acid COOH OH O O C 水杨酸 CH 3 COONa Salicylic sodium Aspirin 阿司匹林 OH 水杨酸钠 B. Salicylates Aspirin 阿司匹林 1. ADME transformed to salicylic acid form in the body hepatic metabolism is primarily conjugation. excretion from urine, the excretion of unchanged forms of aspirin is increased in the alkalinized urine. larger doses ( > 1 g/d): non-linear elimination, zero order kinetic process, easier to accumulation and intoxication. B. Salicylates 2. Pharmacological effects and clinical uses (1) Antipyretic, analgesic and antiinflammatory effects moderate doses (0.3~0.6 g): antipyretic and analgesic effects larger doses (3~5 g/d): anti-inflammatory and antirheumatic effects; only relieves symptoms. to treat acute rheumatic fever(急性风湿热), to abate pain and symptoms of rheumatic & rheumatoid arthritis (风湿性和类风湿性关节炎). B. Salicylates (2) Inhibition of platelet aggregation small doses (30~100 mg/d): inhibiting TXA2 synthesis, preventing thrombosis. used to treat ischemic heart disease, reduce the mortality of myocardiac infarction, and prevent cerebral thrombosis. larger doses: inhibiting PGI2 synthesis, promoting thrombosis. PGI2: vasodilation and platelet depolymerization (血小板解聚). The mechanism of aspirin: Target enzymes acetylated The mechanism of aspirin: Target enzymes acetylated B. Salicylates 3. Adverse effects (1) GI reactions stimulating gastric mucosa and CTZ (larger doses); inhibiting PG synthesis in GI tract irritant symptoms; gastric bleeding; ulcerous disorders Contraindications: ulcerous disorders B. Salicylates (2) Prolongation of bleeding time small doses: inhibiting platelet aggregation larger doses: inhibiting synthesis of thrombogen Contraindications: one week prior to surgery; severe hepatic damage; vitamin K deficiency; prothrombinopenia (凝血酶原减少症). B. Salicylates (3) Allergic reactions urticaria (荨麻疹), angioneurotic edema, aspirin-induced asthma, occasionally anaphylactic shock. Contraindications: bronchial asthma Aspirin-induced asthma: Phospholipids of cell menbrane Aspirin (-) Phospholipase A2 (PLA2) Arachidonic acid Cyclooxygenase (环氧酶) PGH2 Lipoxygenase (脂氧酶) 5-HPETE ↓Prostaglandins (PGs) ↑Leukotrienes (LTs) (前列腺素) (白三烯) B. Salicylates (4) Salicylism (水杨酸反应) dose > 5 g/d: CNS symptoms, including mental confusion; hyperventilation. i.v. NaHCO3 can promote the excretion of aspirin. (5) Hepatic damage Overdose: hepatic damage Reye’s syndrome (瑞夷综合征): in children, severe hepatic damage (严重肝损害) and encephalopathy (脑病) Dose-response relationship of aspirin: therapeutic effects; adverse effects B. Salicylates 4. Drug interactions C. Para-aminophenol derivatives Acetaminophen 对乙酰氨基酚 Paracetamol 扑热息痛 NHCOCH 3 OH C. Para-aminophenol derivatives Acetaminophen (对乙酰氨基酚): antipyretic and analgesic effects are mild and lasting, but almost no anti-inflammatory effects, - not a NSAID higher selectivity to COX in CNS. mainly used in cold, fever, and headache, etc. overdose can damage liver and kidney. Differences between NSAIDs and Acetaminophen Toxic metabolites of acetaminophen D. Other anti-inflammatory drugs Salicylates: aspirin Para-aminophenol derivatives: acetaminophen Indole and indene acetic acid derivatives: indomethacin, sulindac, etodolac Propionic acid derivatives: ibuprofen, naproxen, fenopofen, ketoprofen COX-2 selective inhibitors: meloxicam, celecoxib, rofenxid Others: phenylbutazone, diclofenac O H3CO CH 2C N OH CH 3 indomethacin 吲哚美辛 C Cl O CH3 ibuprofen CH3 CH CHCOOH CH2 布 洛 芬 CH 3 O O S N piloxicam CH3 吡罗昔康 CONH OH N D. Other anti-inflammatory drugs indomethacin 吲哚美辛:stronger efficacy, controlling special types of fever; severe adverse effects ibuprofen 布洛芬(芬必得):stronger antipyretic, analgesic and anti-inflammatory effects; weaker GI reactions; vision damage piloxicam 吡罗昔康: long-acting anti-inflammatory and analgesic agent; long-term use induces hemorrhage and ulcers in GI tract COX-2 selective anti-inflammatory drugs Meloxicam 美洛昔康 stronger effect on COX-2 than COX-1 long-acting (t1/2 20 h) weaker GI reactions Celecoxib 塞来昔布 Selective COX-2 inhibitor