anti-inflammatory and immunomodulating agents 항염증 - 면역조절제
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Anti-inflammatory andImmunomodulating 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 Inflammation염증 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
PG: Prostaglandin
炎症 誘發 物質 :bacteria, virus, radiation, cell mediators, cytokines
細胞 外
( 受容體 )
細胞膜
細胞 內細胞質
Nucleus 核
Cytoplasm細胞質
염증반응 Bacterial ( 細菌 ) / Virus 感染 Stress, Cytokines (TNF
)ionizing radiation, toxic substances, PG, TX, NO
IKK
P PIKK - Phosphate
PPIkB
p50
Rel A
P P
Rel A
p50IkB265 proteasome
Rel A
p50NF-kB responsive gene
Cell proliferation,Cell growthCell differentiation
Cytokines, ReceptorsAdhesion moleculesRel, Ikb, proteins etc.
Aspirin, SalicylateFlavonoids
Lactacystin, Cyclosporin A
IkB superrepressor
GlucocorticoidsSteroids
--Ub – Ub – Ub – Ub - Ub
-Ub- Ub- Ub- Ub- Ub
NF-kB
kinase
UbL
NF-kB
Pathway of NF-kB ActivationCytokine such as TNF-, and environmental hazards such as inonizingradiation, 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 Relfamily proteins such as p65 and p50. This phosphorylation is the signal forubiquitination 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 nucleuswhere it binds to specific DNA elements and activates transcription of NF-kB-dependent genes.
prostaglandin
COX 1& 2
thromboxane
inflammation
inhibition
NSAIDs 약물 : Inhibitors of Cox-1 & Cox-2
fatty acids
Blocking enzymes(1,2)- 부작용 (GI mucosa damage)
COX 1 & 2
NHCOCH3HO
acetaminophen
NSAIDs
Nitric Oxide (NO)
- a cell mediator regulates numerous physiological processes• neuro-transmission• smooth muscle contractility• platelet reactivity• cytotoxic activity of immune cellsinappropriate release of NO has been linked to the patho- genesis of a number of disease states !! Overproduction of NO by synthase: septic shock, neuro- degenerative disorders, and inflammationInhibitors of NO synthase
Nitrous oxide (N2O): agent for general anesthesia
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.
Mechanism of Action of NO
second messenger
substrate
inhibitor=drugs
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.
Steroid Hormones: 효과 발현 시간이 오래 걸림
NF-kB
Gout – 疼痛 치료제
Uric Acid: 尿酸 이 joint 에 침착
Xanthine ------- Uric Acid용해도 큼 용해도 작음
oxidase
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: cromolynH1 receptor Antagonists: diphenhydramine, ChloropheniramineH2 receptor: ( 위산 방출 억제 )Cimetidine(Tagamet), Ranitidine (Zantac), Famotidine, Nizatidine