Transcript Ub - Ub -Ub- Ub

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