1、Introduction to Anti-inflammatory Drugs,Weiping Zhang Department of Pharmacology Zhejiang University School of Medicine,2012.10,Peripheral mechanisms of pain,Classification of anti-inflammatory drugs,non-steroid anti-inflammatory drugs (NSAIDs)(Antipyretic-Analgesic and Anti-inflammatory Drugs)解热-镇痛
2、-抗炎药eg. aspirin, acetaminophen, indomethacin, COX inhibitor, ibuprofen(2) Steroid anti-inflammatory drugsglucocorticoids: eg. dexamethasone (3) 5-LOX inhibitors and leukotriene receptor antagonistsZafirlukast, zileuton,NSAIDs are just that - drugs that act to relieve inflammation, but are not struct
3、urally related to the corticosteroids,1. The classification of NSAIDs,2. The mechanisms of NSAIDs,2. The mechanisms of NSAIDs,2. The mechanisms of NSAIDs,Cyclooxygenases: COX 1, COX 2,- PGs, mostly by COX-1, are constitutively expressed in almost all tissues; COX-2 appears to only be constitutively
4、expressed in the brain, kidney, bones, reproductive organs, and some neoplasms- Under normal physiologic conditions, PGs play an essential homeostatic role in cytoprotection of gastric mucosa, hemostasis, renal physiology, gestation, and parturitionIn platelets there is only COX-1exist (converts ara
5、chidonic acid to TxA2)- COX-1 predominant in gastric mucosa (source of cytoprotective PGs)- The production of PGs, (inducible COX-2 activity COX-1) at sites of inflammation propagate pain, fever,2. The mechanisms of NSAIDs,NSAID inhibition of PG production alleviates most of the pathologic effects a
6、ssociated with inflammation, but it also interferes with the physiologic role of these molecules Consequently, long-term therapy with nonspecific NSAIDs is frequently limited by their adverse effects, particularly those caused by erosion of gastric mucosal protection, GI bleeding,2. The mechanisms o
7、f NSAIDs,3. Pharmacodynamic Effects of NSAIDs,Positive Analgesic (0.3-0.6 g/day) - refers to the relief of pain by a mechanism other than the reduction of inflammation (for example, headache); - produce a mild degree of analgesia which is much less than the analgesia produced by opioid analgesics su
8、ch as morphineanti-inflammatory (3-5 g/day) - these drugs are used to treat inflammatory diseases and injuries, and with larger doses - rheumatoid disordersantipyretic (0.3-0.6 g/day) - reduce fever; lower elevated body temperature by their action on the hypothalamus; normal body temperature is not
9、reducedantiplatelet (30-100 mg/day)- inhibit platelet aggregation, prolong bleeding time; have anticoagulant effects,antipyretic : compared with chlorpromazine,NSAIDs,Chlorpromazine,Effects,Clinical usage,Side effects,GI reactions，no addiction,Lower the abnormal high temperature to normal. Used for
10、various fever.,artificial hibernation, Hypothermic anesthesia,Extrapyramidal effects,Inhibit PGs synthesis and enhance thermolysis,Inhibit thermotaxic center in hypothalamus. The body temperature change according to the environment.,3. Pharmacodynamic Effects of NSAIDs,Analgesic : compared with Opio
11、ids,3. Pharmacodynamic Effects of NSAIDs,Anti-inflammatory: compared with glucocorticoid,3. Pharmacodynamic Effects of NSAIDs,NSAIDs and Platelets/Endothelial Cells,3. Pharmacodynamic Effects of NSAIDs,Reduces platelet aggregationMost of these drugs will potentiate the action of oral anticoagulants
12、such as coumadin, by their effects on platelet aggregationAn 80 mg dose will increase bleeding time for 2 folds,NSAIDs and Platelets/Endothelial Cells,Note: Selective inhibition of COX-2 will inhibit the production of PGI2 but not of thromboxaneA2, which is produced by COX-1. SO ?,3. Pharmacodynamic
13、 Effects of NSAIDs,Negative or adverse effectsGastric irritantDecreased renal perfusionBleeding,4. Adverse Effects associated with NSAIDsNon-selective,For patients presenting to hospital with upper gastrointestinal (UGI) bleeding - a significant percent were using NSAIDs,Note: OTC use of NSAIDs was
14、more prevalent than was prescribed NSAID usage,4. Adverse Effects associated with NSAIDsGastrointestinal reactions,NSAIDs - Gastric Irritant Effects: Molecular Mechanisms,PGs reduce H+ secretion and increase mucous production Consequently, NSAIDs cause some degree of gastric upset due to inhibition
15、of PG synthesis,- Misoprostol. a synthetic prostaglandin analogue, can also decrease the risk of NSAID-induced ulceration and complications,- PPIs can reduce the risk of peptic ulcer formation,4. Adverse Effects associated with NSAIDs,Afferent arteriole,Efferent arteriole,ACEI/ ARB,NSAIDS, Low volum
16、e Poor renal perfusion,normal,4. Adverse Effects associated with NSAIDs,NSAIDs Effects on Renal Function,PGs not participated,PGs vasodilator when angiotensin II or catercholamines elevated,5. Drug interactions,丙磺舒 苯磺唑酮,胆红素 苯妥英 萘普生 戊硫代巴比妥 甲状腺素,Salicylates - aspirin,History - Salicylates,Salicylates
17、were first discovered when the observation was made that chewing willow bark could relieve pain Hippocrates: Willow bark as a pain killer during childbirth Stone (1700) Extract of willow bark to reduce fever Piria (1838) Isolation of salicin from willow bark Kolbe (1853) Synthesis of salicylate (水杨酸
18、盐) from salicin (水杨苷)Von Gerhardt at Beyer Pharmaceutical Co. synthesized acetyl SA (ASA) in 1850 Hoffman, at Beyer gave ASA to his rheumatoid father Beyer started sales of Aspirin in1899Acetylsalicylic acid (aspirin) was introduced as a pain reliever in 1899, at that time it was used in doses of 65
19、0 mg every 4 hours,History - Salicylates,Aspirin-Mechanism of Action: Covalent Binding to COX,ASA covalently and irreversibly modifies both COX-1 and COX-2 by acetylating serine-530 in the active siteAcetylation results in a steric block, preventing arachidonic acid from binding,Note: Acetylation of
20、 COX-2 retains the COX activity although the reaction produces a different product, 15-R-HETE,Aspirin Metabolism Pathways,acetylsalicylic acid (ASA),ASA: t1/2 20 min,salicylate t1/2 3-5 hrs,irreversible acetylation of COX,- Salicylate elimination is 1st order at low and moderate doses; - When total
21、body salicylate 600mg (3.5g/d), elimination is zero order,酯类和葡醛酸葡糖乙酯,龙胆酸,水杨酸甘氨酸,Aspirin,Dose-Dependent Effects: Low: 300mg blocks platelet aggregationIntermediate: 300-2400mg/day antipyretic and analgesic effectsHigh: 2400-4000mg/day anti-inflammatory effects,Salicylism,Side effects of aspirin,Gastr
22、ointestinal symptoms CNS toxicity Allergic reaction (urticaria(荨麻疹), angioneurotic edema, aspirin asthma, occasionally anaphylactic shock) Salicylate reaction (CNS reaction) Renal damage Hematologic effects Metabolic acidosis stimulates medullary respiratory center respiratory alkalosis,Salicylism (
23、水杨酸反应)dose 5g/d: CNS symptoms, including mental confusion; hyperventilation.Rescure: i.v. NaHCO3 promote the excretionHepatic damage Overdose: hepatic damage Reyes syndrome(瑞夷综合征) (kids)severe hepatic damage (严重的肝损害) and encephalopathy (脑病),4. Adverse Effects associated with NSAIDs,NSAIDs: Classific
24、ation by half-life,Plasma Elimination Half Lives Short Half Life ( 10 hours): slower onset of effect and slower clearance Naproxen (萘普生) (14 2 hrs) Sulindac (舒林酸) (14 8 hrs), Piroxicam (吡罗昔康) (57 22 hrs),Sleisenger & Fordtrans Gastrointestinal and Liver Disease, 8th ed., Copyright 2006 Saunders, An
25、Imprint of Elsevier,NSAIDs: Classification by COX selection Non-specific inhibition of COX-1 results in gastrointestinal and platelet side effects,In vitro assessment of COX-1 COX-2 activity,Summary of COX-1 vs COX-2 Inhibition,COX-1 compared to COX-2,COX-2 selective inhibitors are generally larger
26、molecules than NSAIDs and therefore preferentially inhibit COX-2 compared to COX-1 because the hydrophobic channel of COX-2 is larger. That is, COX-2 selective inhibitors are too bulky to access the binding pocket of the COX-1 enzyme,COX-2 Selective Drugs,COX-2 can be up-regulated in the CNS and pla
27、ys an essential role in the mediation of pain and the febrile response,Patients with rheumatoid arthritis were treated with celecoxib (100, 200, or 400 mg twice daily), naproxen 500 mg twice daily, or a placebo for 12 weeks. Rates of gastroduodenal ulceration with naproxen were statistically higher
28、(*P 0.01) than rates with celecoxib or a placebo. (Data from Simon LS, Weaver AL, Graham DY, et al: Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis. JAMA 282:19211928, 1999.),Incidence of endoscopic gastroduodenal ulcers with a COX-2 specific inhibitor Celec
29、oxib （赛来考昔）,Celecoxib is now the only selective COX-2 inhibitor available in the US- withdrawal of rofecoxib (Vioxx, Merck & Co) Sept 2004- suspension of valdecoxib (Bextra, Pfizer) Apr 2005,Note: The fact that it now carries exactly the same warning for gastrointestinal risk as the older nonselecti
30、ve NSAIDs is quite remarkable, new drugswere supposedly less risky to the gastrointestinal tract than the older nonselective agents,Celecoxib includes a boxed warning, highlighting the potential for increased risk of cardiovascular events and the well described, serious, potential life-threatening g
31、astrointestinal bleeding associated with their use.,Celecoxib: Current Status,Celecoxib: cardiovascular events,Celecoxib compared with placebo is not associated with an increased risk for cardiovascular events for duration of use from 12 to 52 weeks. Celecoxib compared with nonselective NSAIDs is no
32、t associated with increased cardiovascular endpoints.,Acetaminophen （对乙酰氨基酚）,analgesia antipyretic no significant anti-inflammatory effects no gastric irritation no platelet function interference half life 2 3 h weak inhibitor of COX-1, -2; not contraindicated for asthma not associated with Reyes Sy
33、ndrome - The major concern regarding the use of acetaminophen is the potential for high doses to cause liver toxicity,Differences between NSAIDs and Acetaminophen,indomethacin 吲哚美辛stronger efficacy, controlling special types of fever; severe adverse effects Sulindac 舒林酸Its metabolite possess 500 fol
34、d PG inhibition than itself.Strong anti-inflammation and lower adverse effects than indomethacin. Etodolac 依托度酸Used as a pain killer after operation Lower GI upset,Tolmetin 托美丁Moderate anti-inflammation and mild analgesic and antipyretic effect ibuprofen 布洛芬（芬必得）stronger antipyretic, analgesic and a
35、nti-inflammatory effects; weaker GI reactions; vision damagepiloxicam 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) wea
36、ker GI reactions,TNF- inhibitor,Etanercept (伊那西普) Infliximab (英夫西单抗) Adalimumab (阿达木单抗),They are recombinant proteins that can not orally taken; The long-term safety is not determined.,References,Basic & Clinical Pharmacology (11th edition), 2010. Goodman & Gilmans the pharmacological basis of therapeutics (12th), 2010. 人民卫生出版社，药理学（第2版），2010,
