神经系统药理—吴希美(解热镇痛药.ppt

Chapter 27 Antipyretic-Analgesic and Antiinflammatory Drugs A.General Pharmacological properties 1.Inhibition of prostaglandin synthesis inhibiting cyclooxygenase(COX，环氧酶环氧酶),decreasing the synthesis of PGs and TXA2,resulting antipyretic,analgesic,and anti-inflammatory effects non-steroidal anti-inflammatory drugs(NSAIDs,非甾体抗炎药非甾体抗炎药）。）。2.Antipyretic effects Inhibition of PGE2 production in the hypothalamus induced by endogenous pyregens after pathological stimuli 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 解热镇痛药氯丙嗪作用机制抑制前列腺素合成，使散热增加而解热抑制下丘脑体温调节中枢，使其调节功能减弱，不能随外界温度变化而调节体温作用只能使升高的体温降到正常氯丙嗪配合物理降温，不仅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途用于各种发热用于低温麻醉、人工冬眠不良反应胃肠道反应等锥体外系统反应等Comparison of properties of two types of drugs 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.A.General Pharmacological properties 解热镇痛药阿片类镇痛药作用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兴奋阿片受体起效；对各种疼痛均有效用途头痛、牙痛、神经痛、肌肉或关节痛、痛经等用于其他药物无效的急性锐痛，晚期肿瘤的剧烈疼痛不良反应胃肠道反应等，但无成瘾性有成瘾性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 非甾体抗炎药糖皮质激素作用抑制前列腺素合成起效；缓解软组织、骨骼、关节的炎症抑制炎症细胞、炎症分子，多环节炎症炎症病变用途风湿性、类风湿性炎症，外伤损伤可用于多种炎症，作用强不良反应胃肠道反应等抑制机体防御反应，干扰代谢，不良反应广泛Comparison of properties of two types of drugs 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（）（）（）（）（）（）（）（）B.Salicylates Aspirin 阿司匹林阿司匹林 Acetylsalicylic acid 乙酰水杨酸乙酰水杨酸 CH3COOHOCOCOOHOHCOONaOHAspirin 阿司匹林阿司匹林 Salicylic acid 水杨酸水杨酸 Salicylic sodium 水杨酸钠水杨酸钠 Aspirin 阿司匹林阿司匹林 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(1g/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(0.30.6 g):antipyretic and analgesic effects larger doses(35 g/d):anti-inflammatory and anti-rheumatic effects;only relieves symptoms.to treat acute rheumatic fever(急性风湿热急性风湿热),to abate pain and symptoms of rheumatic&rheumatoid arthritis (风湿性和类风湿性关节炎风湿性和类风湿性关节炎).B.Salicylates (2)Inhibition of platelet aggregation small doses(30100 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(血小板解聚血小板解聚).B.Salicylates 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 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(凝血酶原减少症凝血酶原减少症).B.Salicylates (3)Allergic reactions urticaria(荨麻疹荨麻疹),angioneurotic edema,aspirin-induced asthma,occasionally anaphylactic shock.Contraindications:bronchial asthma B.Salicylates Aspirin-induced asthma:Phospholipids of cell menbrane Aspirin Phospholipase A2(PLA2)(-)Arachidonic acid Cyclooxygenase Lipoxygenenase (环氧酶环氧酶)PGH2 5-HPETE (脂氧酶脂氧酶)Prostaglandins(PGs)Leukotrienes(LTs)(前列腺素前列腺素)(白三烯白三烯)(4)Salicylism dose 5g/d:CNS symptoms,including mental confusion;hyperventilation.i.v.NaHCO3 can promote the excretion of aspirin.(5)Hepatic damage Overdose:hepatic damage Reyes syndrome(瑞夷综合征瑞夷综合征):in children,severe hepatic damage(严重的肝损害严重的肝损害)and encephalopathy(脑病脑病)B.Salicylates Dose-response relationship of aspirin:therapeutic effects;adverse effects 4.Drug interactions B.Salicylates C.Para-aminophenol derivatives Acetaminophen 对乙酰氨基酚对乙酰氨基酚 Paracetamol 扑热息痛扑热息痛 NHCOCH3OH Acetaminophen（对乙酰氨基酚对乙酰氨基酚）：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.overdo