Laine et al, Gastroenterology 2008;135:41-60

Pathogenesis for Damage of Gastric Mucosa

DEFENSIVE FACTORS Mucous membrance barrier Mucus Bicarbonate ion Blood supply in the mucosa Proliferating factors PG in the mucous membrane

OFFENSIVE FACTORS Gastric acid, Pepsin Drug (such as : NSAIDs) Stress Alcohol H. Pylori Free Radical

OTHER FACTORS Internal secretion system Central nerves system Constituion Heredity Environment
Akira Terano, 1991
8

Mekanisme kerja OAINS berakibat efek samping GI Hambatan sintesa tromboxan & produksi trombosit Hambatan agregasi trombosit Masa perdarahan memanjang Akibatnya: Perdarahan GI Iritasi topikal Peningkatan permeabilitas GI Obat terperangkap dalam sel epitel Gangguan oksidatif fosforilasi dalam mitochondria Hilangnya kontrol sistoskletal melalui

tight junction Berkurangnya hidrofobisitas

Hambatan sintesa Pg Penurunan sekresi mukus dan bikarbonat Vasokonstriksi Akibatnya: Gangguan ketahanan dan perbaikan mukosa Akibatnya: Erosi/Ulkus GI

OAINS

Kerusakan pembuluh darah Adhesi molekul meningkat Akumulasi lekosit Kerusakan sel endotel Akibatnya: Erosi/Ulkus GI Efek lain OAINS : Hambatan beberapa enzim termasuk fosfolipase ( sulindac) Terbentuknya ROS Interaksi dengan iNOS dan NO Efek langsung terhadap gen ( aspirin)

Hambatan mekanisme perbaikan Hambatan proliferasi sel Peningkatan apoptosis Hambatan angiogenesis Akibatnya: Gangguan perbaikan GI
Halter et al, Gut 49:2001

Role of NSAIDs in Peptic Ulcer Disease

Pg and Acid`secretion: Prostaglandins stimulate Gi cAMP and reduce acid secretion Pg Acid secretion Nsaids inhibit Pg secretion & Acid secretion Nsaids AF & DF

PUD

Aggressive Factors
Acid/Pepsin H. pylori infection NSAIDs Smoking

Mucus-bicarbonate barrier Barrier of apical membrane Mucosal blood flow Prostaglandins Epithelial cell restitution

Defensive Factors

Aggressive Factors
Aggressive Factors + Defensive Factors

Defensive Factors

Mekanisme lesi mukosa gaster akibat OAINS

A. Efek sistemik Hambat COX OAINS Ekspresi Perlengketan perlengketan mol netrofil pada intersel endotel endotel vaskular gaster B. Efek topikal Lumen Gaster (pH = 2) Prostaglandin Asam lambung Prod bikarb-mukus Aliran darah Kerusakan mukosa akibat netrofil melepaskan radikal bebas & protease

Sel epitel gaster (pH = 7)

Kerusakan sel

OAINS / Aspirin (Asam lemah)

13

GI damage ulcer formation

Early stage Late stage

Epithelium Mucosa Erosion Ulcer

Submucosa

Muscle layer

Ulcer penetrates the submucosa

Free radicals play an important role in NSAIDs-induced gastric mucosal injuries

NSAIDs
Inhibition

Phospholipid Phospholipase Arachidonic acid Lipoxygenase Increase of LTs LTC4 LTB4 H+ dependent pathway

Cyclooxygenase
Decrease of PGs

Mucus reduction Decrease of HCO3- secretion Microcirculation injury

LTD4 Vasospasm Neutrophil activation

Liposoluble Accumulation in cells

Ischemia-reperfusion Decrease mucosal defense

Increase free radicals Gastric mucosal injury

Directly damage cells

Hiraishi H et al., Mebio 1994;11(19):86 (Japanese)

Molecular Mechanism for Various Pharmacological Activities of NSAIDS

Mizushima T. Pharmaceuticals 2010; 3: 1614-36

ROS, pengaruh dan penetralannya (Rosenberg AE, 2005 )

Peran SOD dalam mengkontrol O2 (Afonso V , et al, 2007 )

Management Nsaids gastropathy with bleeding :

Stop Nsaids consumed
Active bleeding ome IV bolus 1 amp

followed by continous infusion 8 mg/hour 24-48/h depend on clinical condition Bleeding stop followed by oral ome 2X20 mg, during 4-8 weeks To continue Nsaids choose Cox-2 selective or Nsaids + OME

Mechanism of Action Therapy

Anti-Free Radical, Anti-Inflammatory Modulator : PG Inducer : A B C

HCl

HCl

A 8
H. Pylori adhesion To mucosa
Increasing of Mucus synthesia

Stress

B
Enhancement of Prostaglandin synthesis

Pepsin

Acceleration of Cell proferation

Free radical elastase

H2O2

1
Inflammatory 3 X cytokines

5 4

Free radical

neutrophil X

2 X 7 macrophage

adhesion expression of neutrophil

Ischemia - Reperfusion 20

Therapy : Anti Free Radical Stress

H. pylori

LIPID PEROXIDATION

2 1 X O2 _ H2O2
.OH

Ischemia Reperfusion

21

Generation of Free Radicals Hypoxanthine Xanthine Oxidase Polymorphonuclear leukocytes Arachidonic acid cascade Mitochondria Drug

Free Radical Iron Oxygen Complex

O2
Lipid Radical L

Lipid (Unsaturated Fatty Acid) LH

Lipid Peroxyl Radical LOO

Lipid Peroxide
LOOH Membrane & Protein
T. Yoshikawa, Reactive Oxygen. Free Radical 1990

Lipid LH

Gastric Mucosal Damage

22

Damage

Brzozowski dkk., 2006

Brzozowski dkk., 2006

Choi S.R, Lee S.Aa, Kim Y.J, Ok J.Y, Lee H.J, Hahm K.B, 2008

26

Diagnosis of NSAID Gastropathy

History of NSAID consumption & dyspepsia
Physical examination Supporting examinations: laboratory,

esophagogastroduodenoscopy examination, Barium meal(OMD)

ENDOSCOPICAL APPEARANCES
Lesions: Hyperemia, erosion &

ulcer
Bleeding: active/not, oozing,

spurting
Lesions in stomach,

duodenum & jejunum

Bleeding duodenal ulcer

Duodenal ulcer

Freytag et al., Atlas of gastrointestinal endoscopy

Bleeding gastric ulcer

Peptic ulcer

Ulcer

Freytag et al., Atlas of gastrointestinal endoscopy

HISTOPATHOLOGICAL ABNORMALITIES
Subepithelial hemorrhage
Epithelial thinning & separation Mucus thinning & disappearance

Mucosal erosion & ulcer

32

Management
Summary of International consensus on nonvariceal upper GI bleeding (American College Of Physician, 2010):
Resuscitation, risk assessment, and preendoscopy management
Resuscitation should be initiated immediately Prognostic scales are recommended for early stratification of patients into lowand high-risk categories for rebleeding and mortalityi, including: The Blatchford score (Hb level, BUN level, pulse, systolic blood pressure, the presence of syncope or melena, and evidence of hepatic disease or cardiac failure and accurately identifies patients at low risk or high risk for clinical intervention) and The Rockall score (endoscopic variables to predict rebleeding or mortality) Consider placement of a NGT in selected patients because the findings may have prognostic value Blood transfusions should be administered to a patient with a hemoglobin level 7.0 g/dL In patients receiving anticoagulants, correction of coagulopathy is recommended but should not delay endoscopy Prokinetic agents should not be used routinely before endoscopy to increase the diagnostic yield Preendoscopic PPI therapy may be considered to downstage the endoscopic lesion and decrease the need for endoscopic intervention but should not delay endoscopy

Postdischarge, ASA, and NSAIDs

In patients with previous ulcer bleeding who require an NSAID, it should be recognized that treatment with a traditional NSAID plus PPI or a COX-2 inhibitor alone is still associated with a clinically important risk for recurrent ulcer bleeding In patients with previous ulcer bleeding who require an NSAID, the combination of a PPI and a COX-2 inhibitor is recommended to reduce the risk for recurrent bleeding from that of COX-2 inhibitors alone In patients who receive low-dose ASA and develop acute ulcer bleeding, ASA therapy should be restarted as soon as the risk for cardiovascular complication is thought to outweigh the risk for bleeding In patients with previous ulcer bleeding who require cardiovascular prophylaxis, it should be recognized that clopidogrel alone has a higher risk for rebleeding than ASA combined with a PPI

Helicobacter pylori

Suerbaum & Micheti, NEJM 2002;347:1175-1186

Helicobacter pylori eradication(KSHPI)

Tripel therapy(1 or 2 wks):

1. PPI+Amoksisilin+Klaritromisin 2. PPI+Metronidazol+Klaritromisin 3. PPI+Metronidazol+Tetrasiklin (alergi klaritromisin) Quadrupel therapy(1 or 2 weeks): 1. Failure with 3 drugs: Bismuth+PPI+Amoksisilin+Klaritromisin Bismuth+PPI+Metronidazol+Klaritromisin 2. Area with high resistency clarithromycin: PPI+Bismuth+Tetrasiklin+Metronidazol PPI 2 x/hr; Omeprazol/Esomeprazol 20 mg, Lansoprazol 30 mg, Pantoprazol 40 mg, Rabeprazol 10 mg. Amoksisilin: 2 x 1000 mg/hr, Klaritromisin 2 x 500 mg/hr, Metronidazol 3 x 500 mg/hr, Tetrasiklin 4 x 250 mg/hr, Bismuth 4 x 120 mg/hr.

Rebamipide
{2-(4-chlorobenzoylamino)-3-[2(1H)-

quinolinon-4-yl]propionic acid Gastroprotective agent : accelerate ulcer healing without affecting gastric acid secretion.

Haruma & Ito, Aliment Pharmacol Ther, 2003;18(Suppl):153-159

Arakawa T et al., Dig Dis Sci , 2005;50: S3-S11

Arakawa T et al., Dig Dis Sci , 2005;50: S3-S11

Arakawa T et al., Dig Dis Sci , 2005;50: S3-S11

Cytoprotector Drug(2):
o Sucralfate consists of a combination of sucrose octasulfate and aluminum hydroxide. o The beneficial effects are through local action on the mucosa. o The mode of action is multifactorial o In the acid secretion of the stomach, sucralfate dissociates to aluminum hydroxide ions and sucrose octasulfate
Terry C. Gerros

Cytoprotector Drug(3):
o Sucrose octasulfate polymerizes to a viscous substance that adheres to the mucosa, protects against back diffusion of hydrogen ions, and promotes ulcer healing. o The electrostatic charges, sucralfate preferentially adheres to ulcerated tissue o Inactivates pepsin and absorbs bile acids. o The agent is cytoprotective in that it enhances mucosal defense mechanisms by increasing the synthesis of prostaglandins, mucus, and bicarbonate
Terry C. Gerros

Cytoprotector Drug(4):
o Sucralfate also binds to uninjured mucosa and is believed to exert a similar "barrier" effect on regenerated and normal mucosa o Animal data show that the action of sucralfate is sustained because of its viscous adhesiveness, slow reaction with acid, and high affinity for defective mucosa.

Sucralfate actions(1):
o Sucralfate action as anti acid and promote defensive factors
o Incresed mucus and bicarbomate

production o Covered mucosal lesions & prevention acid influenced to the lesions o Longterm effect promote sub epithel component to resolve the mucosal lesions

Sucralfate action(2) :
Al sucrose octasulfate Al(OH) Sucrose-octasulfate

H + binding

Electrical resistance mucosa

PG & mucus gastric mucosa Secondary effect in esophagus

Mucosal defense mechanism

Sloan,USA

Imunopatogenesis
C3a, C5a
IMUNOCOM

LPS

Kortikosteroid

APC
SUPER ANTIGEN CD 4+ MHC II TCR

LPS bp

C7a

CD 14

TLR 4
TLR2

IFN -g TH - 1 TH - 2 CSF N Compl. IL-2

IL - 10 IL - 4 IL - 5 IL - 6

B cell Ig

SEPSIS

IL 8
IL 6

IL -1

MOD
PAI-1

TNF -a
PGE
2

CD 8+

NK

NO

ICAM -1

SHOCK SEPTIC (Guntur, 2000)

47

Dorren 2005

Kemampuan Memprediksi HCRP Terhadap Morbiditas dan Mortalitas Kejadian Kardiovaskuler

IL-6
Sel Hepar

HCRP
Disfungsi endothel eNOS mRNA NO BCL-2 Apoptosis Endothel
(Szmitko PE, 2003)

NFk aktif

ET-1

VCAM MCP-1

AT-1R

ekspresi Sitokin ICAM

ROS VSM proliferasi Restenosis

Thymus gland decrease / (-) at age 75 thymosin /

No alteration on killing function, chemotactic and phagocytic function of netrophyl, monocyte and macrophag except if there is a chronic disease (DM,RA etc) NK cells activity are not reported to decrease due to aging Nave T-cells production # impaired Tcell mediated lymph. response # T-memory although the capacity to be active # T proliferation as a response to mitogen # Il-2 secretion antibody resp. to new antigen T cell may not but the function might be responsible to decreasing cap. to attack intracellullar pathogen Delayed skin hypersensitivity might decrease in aging
52

Immunosenescence
function of macrophages expression of TLRs Innate Immunity function of mitogen-activated protein kinases production of TNF-alpha and IL-6 production of IL-10 bactericidal activity nave cells memory cells CD45Ro+ T-Cells function of mitogen-activated protein kinases

type 1 cytokine response (IL-2, TNF-alpha) type 2 cytokine response (IL-4, IL-10)
number of B-Cells and plasma cells B-cells polyspecific immunoglobulins with low affinity produced by B1-cells response to neoantigens

Guntur, Geriatri Semarang 2011

53