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