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Anti-inflammatory and Immunomodulating Agents 항염증 - 면역조절제 염증: Inflammation • 발열 (heat & fever): antipyretics(해열제 투여) • 발적 (redness) • 통증 (pain): analgesics(진통제 투여) • 부종 (edema & tenderness of tissue) Cells & Tissue 의 Damage ( by microorganisms, toxic chemicals, radiation, trauma, autoimmune, etc) 를 방어하는 과정에서 발생하 는 생리현상 열을 내리고 (antipyretic), 통증을 완화(analgesic) 시키는 약물이 항염증 약물 임. 통증-발열 증상 Mild-Moderate Pain 증상 • Headache; Myalgia; Neuralgia; Postoperative pain • Dysmenorrhea Elevated body temperature Arthritis (관절염) • Rheumatoid; Juvenile, Ankylosing spondylitis •Osteoarthritis Hyperuricemia (과 뇨산) • Acute & chronic gout Control of Inflammation 염증 제어 기전 1. Inhibition of Prostaglandin production: (NSAID) -Aspirin, acetaminophen(Tylenol) 2. Suppress Immune Reaction (SAID) -Corticosteroids (nonspecific suppressant) 3. Antagonizing chemicals by immune cells -Antihistamines 4. Inhibition of NO synthase -Steroidal Anti-inflammatory Drugs:스테로이드 성 항염증약 -Non-Steroidal Anti-inflammatory Drugs (NSAID) 비 스테로이드 성 항염증약 炎症 誘發 物質: bacteria, virus, radiation, cell mediators, cytokines 細胞 外 PG: Prostaglandin (受容體) 細胞膜 細胞 內 細胞質 Bacterial (細菌) / Virus 感染Stress, Cytokines (TNF ) ionizing radiation, toxic substances, PG, TX, NO P P kinase IKK IKK - Phosphate Aspirin, Salicylate Flavonoids Rel A p50 염증반응 P UbL IkB Cytoplasm 細胞質 P --Ub – Ub – Ub – Ub - Ub Lactacystin, Cyclosporin A NF-kB Rel A P p50 IkB super repressor NF-kB Rel A p50 265 proteasomeIkB P -Ub- Ub- Ub- Ub- Ub NF-kB responsive gene Nucleus 核 Glucocorticoids Steroids Cytokines, Receptors Adhesion molecules Rel, Ikb, proteins etc. Cell proliferation,Cell growth Cell differentiation Pathway of NF-kB Activation Cytokine such as TNF-, and environmental hazards such as inonizing radiation, toxic substances trigger the nuclear translocation of NK-kB via activation of inhibitor-of- NF-kB (IkB) kinase complex (IKK). IKK phosphorylates IkB bound to NF-kB which consists of a dimer of Rel family proteins such as p65 and p50. This phosphorylation is the signal for ubiquitination of IkB by a ubiquitin ligase (UbL). This produces IkB for degradation by the proteasomes, which then results in the release of NF-kB. The transcription factor is now free to become translocated to the nucleus where it binds to specific DNA elements and activates transcription of NF-kB-dependent genes. fatty acids COX 1& 2 inhibition prostaglandin thromboxane inflammation NSAIDs 약물: Inhibitors of Cox-1 & Cox-2 NSAIDs COX 1 & 2 Blocking enzymes(1,2) - 부작용 (GI mucosa damage) acetaminophen HO NHCOCH3 Nitric Oxide (NO) - a cell mediator regulates numerous physiological processes • neuro-transmission • smooth muscle contractility • platelet reactivity • cytotoxic activity of immune cells inappropriate release of NO has been linked to the pathogenesis of a number of disease states !! Overproduction of NO by synthase: septic shock, neurodegenerative disorders, and inflammation Inhibitors of NO synthase Nitrous oxide (N2O): agent for general anesthesia Mechanism of Action of NO Most of the physiological actions are brought by its activation of the soluble guanylate cyclase; increase about ~400 fold and formation of cGMP (second messenger) Prolonged exposure of NO inhibits the activity of a number of enzymes; aconitase, cytochrome c oxidase and DNA synthesis is impaired by the inhibitory action of NO on RNA reductase; cytotoxic action of NO is produced on invading micro-organisms. substrate inhibitor=drugs second messenger NO Synthase An enzyme has four isozymes • nNOS (or NOS I); regulated by Ca++ and calmodulin, and found in neural cells and human bronchi epithelium and skeletal muscle. • iNOS (or NOS II); Ca++ -independent form and induced by inflammatory mediator, and exist a variety of cells • eNOS (or NOS III); Ca++/calmodulin requiring, exists in vascular endothelial cells and a variety of neuronal cells including brain catalyze the enzymatic reaction with L-arginine (substrate) and requires various cofactors producing NO. NF-kB Steroid Hormones: 효과 발현 시간이 오래 걸림 Gout – 疼痛 치료제 Uric Acid: 尿酸 이 joint 에 침착 oxidase Xanthine ------- Uric Acid 용해도 큼 용해도 작음 Immunomodulating Agents:면역조절제 Immunosuppressants; 면역억제제 • 장기, 골수 이식 거부반응(rejection), autoimmune, erythroblastosis fetalis 억제 -cyclosporine, azathiopurine, cyclophosphamide - corticosteroids and methotrexate, NSAIDs Immunostimulants; 면역증강제 • cell-mediated immunity 증강 -interferon and interleukin-2 Antihistamines • Chemical mediator released in response of variety of Antigens (pollen, venoms, penicillin, etc) • 주로 Mast cells 및 basophile 에 존재 • Action: binding to H1 and H2 H1: Lung (constriction), Adrenal medulla (release catecholamine) Vein (Constriction), Capillaries (increase permeability) GI muscle (contract) H2 receptors: Heart (increase rate), Stomach (increase HCl and pepsin Inhibition of histamine release from mast cells: cromolyn H1 receptor Antagonists: diphenhydramine, Chloropheniramine H2 receptor: (위산 방출 억제) Cimetidine(Tagamet), Ranitidine (Zantac), Famotidine, Nizatidine