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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
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
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
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Submucosa
Muscle layer
Phospholipid Phospholipase Arachidonic acid Lipoxygenase Increase of LTs LTC4 LTB4 H+ dependent pathway
Cyclooxygenase
Decrease of PGs
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
HCl
HCl
A 8
H. Pylori adhesion To mucosa
Increasing of Mucus synthesia
Stress
B
Enhancement of Prostaglandin synthesis
Pepsin
H2O2
1
Inflammatory 3 X cytokines
5 4
Free radical
neutrophil X
2 X 7 macrophage
Ischemia - Reperfusion 20
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
O2
Lipid Radical L
Lipid Peroxide
LOOH Membrane & Protein
T. Yoshikawa, Reactive Oxygen. Free Radical 1990
Lipid LH
Damage
Choi S.R, Lee S.Aa, Kim Y.J, Ok J.Y, Lee H.J, Hahm K.B, 2008
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ENDOSCOPICAL APPEARANCES
Lesions: Hyperemia, erosion &
ulcer
Bleeding: active/not, oozing,
spurting
Lesions in stomach,
Duodenal ulcer
Peptic ulcer
Ulcer
HISTOPATHOLOGICAL ABNORMALITIES
Subepithelial hemorrhage
Epithelial thinning & separation Mucus thinning & disappearance
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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
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
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.
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
Imunopatogenesis
C3a, C5a
IMUNOCOM
LPS
Kortikosteroid
APC
SUPER ANTIGEN CD 4+ MHC II TCR
LPS bp
C7a
CD 14
TLR 4
TLR2
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
Dorren 2005
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
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
53