Part 13 Antipyretic-Analgesic Drugs

A. General Pharmacological properties §1. Inhibition of prostaglandin (PG) synthesis §inhibitingcyclooxygenase ( COX ，环氧酶 ), §inhibiting cyclooxygenase ( COX ，环氧酶 ), §decreasing the synthesis of PGs and TXA 2, §resulting antipyretic, analgesic, and anti- inflammatory effects §non-steroidal anti-inflammatory drugs ( NSAIDs, 非 甾体抗炎药）

§2. Antipyretic effects §Inhibition of PGE 2 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. A. General Pharmacological properties

Comparison of properties of two types of drugs

§3. Analgesic effects §Analgesic effect is resulted from inhibition of PGE 2 production. §Effective on the pain of low to moderate intensity related to inflammatory responses. §PGE 2 : a pain stimulant and hyperalgesic agent §The analgesic effect is different from opioid analgesics. A. General Pharmacological properties

Comparison of properties of two types of drugs

§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. A. General Pharmacological properties

Comparison of properties of two types of drugs 多环节抑制炎症病 变

§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. A. General Pharmacological properties

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B. Salicylates Aspirin 阿司匹林 Acetylsalicylic acid 乙酰水杨酸 Aspirin阿司匹林 Salicylic acid 水杨酸 Salicylic sodium 水杨酸钠

§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 anti- inflammatory effects § moderate doses (0.3 ～ 0.6 g): antipyretic and analgesic effects § larger doses (3 ～ 5 g/d): anti-inflammatory and anti- rheumatic 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 TXA 2 synthesis, preventing thrombosis. § used to treat ischemic heart disease, reduce the mortality of myocardiac infarction, and prevent cerebral thrombosis. § larger doses: inhibiting PGI 2 synthesis, promoting thrombosis. PGI 2 : vasodilation and platelet depolymerization ( 血小板解聚 ). PGI 2 : vasodilation and platelet depolymerization ( 血小板解聚 ). B. Salicylates

The mechanism of aspirin: Target enzymes acetylated

The mechanism of aspirin: Target enzymes acetylated

§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 Contraindications: ulcerous disorders B. Salicylates

§(2) Prolongation of bleeding time §small doses: inhibiting platelet aggregation §larger doses: inhibiting synthesis of thrombogen Contraindications: Contraindications: one week prior to surgery; one week prior to surgery; severe hepatic damage; severe hepatic damage; vitamin K deficiency; vitamin K deficiency; prothrombinopenia ( 凝血酶原减少症 ). 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 B. Salicylates

Aspirin-induced asthma: Phospholipids of cell menbrane Aspirin Phospholipase A 2 ( PLA 2 ) Aspirin Phospholipase A 2 ( PLA 2 ) (-) Arachidonic acid (-) Arachidonic acid Cyclooxygenase Lipoxygenase ( 脂氧酶 ) Cyclooxygenase Lipoxygenase ( 脂氧酶 ) ( 环氧酶 ) PGH 2 5-HPETE ( 环氧酶 ) PGH 2 5-HPETE ↓Prostaglandins (PGs) ↑Leukotrienes (LTs) ↓Prostaglandins (PGs) ↑Leukotrienes (LTs) ( 前列腺素 ) ( 白三烯 ) ( 前列腺素 ) ( 白三烯 )

§(4) Salicylism （ 水杨酸反应 ） § dose > 5 g/d: CNS symptoms, including mental confusion; hyperventilation. dose > 5 g/d: CNS symptoms, including mental confusion; hyperventilation. i.v. NaHCO 3 can promote the excretion of aspirin. i.v. NaHCO 3 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 ) Reye’s syndrome ( 瑞夷综合征 ): in children, severe hepatic damage ( 严重肝损害 ) and encephalopathy ( 脑病 ) B. Salicylates

Dose-response relationship of aspirin: therapeutic effects; adverse effects

4. Drug interactions B. Salicylates

C. Para-aminophenol derivatives Acetaminophen 对乙酰氨基酚 Paracetamol 扑热息痛

§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. mainly used in cold, fever, and headache, etc. overdose can damage liver and kidney. overdose can damage liver and kidney. C. Para-aminophenol derivatives

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 indomethacin, sulindac, etodolac Propionic acid derivatives: ibuprofen, naproxen, fenopofen, ketoprofen ibuprofen, naproxen, fenopofen, ketoprofen COX-2 selective inhibitors: meloxicam, celecoxib, rofenxid Others: phenylbutazone, diclofenac

indomethacin吲哚美辛 piloxicam吡罗昔康 ibuprofen 布 洛 芬

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 (t 1/2 20 h) weaker GI reactions Celecoxib 塞来昔布 Celecoxib 塞来昔布 Selective COX-2 inhibitor