1

content

(Gastrointestinal

11.1 Peptic ulcer and GERD

11.2 Constipation and Diarrhea
11.3 Hemorrhoid
11.4
Intra
abdominal
infection,Cholelithiasis,Pancretitis
11.5 IBD and IBS
11.6 Hepatic disease
11.7 Drug induced hepatotoxicity
: ..
..
..
..
..
..

Pharmacy Khon Kaen University

73

11
Peptic ulcer and GERD
.1

hydrochloric acid (HCl)

(Proteolytic pepsin enzyme)
Hydrolysis

Parietal (Oxyntic) cell acid secretory unit

gastric mucosa hydrogen ion pump
H+/K+ ATPase system H3O+
K+

mediator
receptor basolateral
membrane
o Histamine agonism of H2 receptors (cellular)
o Gastrin activity at G receptors (blood)
o Acetylchloline (Ach) at M2 muscarinic receptors
(neuronal)

Gastrointestinal disorder

74

Peptic ulcer Disease

upper GI tract
(erosive action)

Duodenal ulcer (DU) 25-55

:
(-2)

Gastric ulcer (GU) 55-65

:

N/V
DU : GU = 4:1 5 %
GU
DU

25-55
,

antacid

GU

55-65

Antacid

1. H. pyroli-associated PUD -

- DU > GU
- GI tract
2. NSAID-induced PUD -

- GU > DU
- GI tract
3. Stress-relate mucosal damage(SRMD)

Pharmacy Khon Kaen University

75
- GU > DU

- GI tract

( Mucosal defense)
HCl
2.5 L/d parietal cell
pepsin chief cell
pepsinogen bicarbonate
mucus
mucosa
prostaglandin PGI2 PGE2
mucus bicarbonate
/pepsin
(mucosal damaging mechanism) mucus/bicarbonate
(mucosal protecting mechanism)
mucosa

Treatment Goal
peptic ulcer
, ,
complication hemorrhage, perforation, obstruction
(recurrent)

1. Antacid (Al(OH)3 + Mg(OH) 2 simethicone )

neutralize
- Na
- Mg
-
Drug interactions : Adsorption or chelation : Tetracycline
Digoxin
Absorption : Ketoconazole , Digoxin
Elimination : pH
Quinidine
reabsorption
2
2. Antisecretory drug
2.1 H2 antagonist (Cimetidine, Ranitidine)

76

Gastrointestinal disorder

Competitive inhibition histamine

receptor H2 receptor selective H2
receptor H1 receptor receptor

(gastric acid
secretion) histamine, gastrin,
muscarinic agonist
(basal or fasting)
(nocturnal acid secretion)
gastrin pepsin
duodenal ulcers
Maintenance
Drug
Initial therapy
therapy
200 mg
QID
Cimetidine
400 mg
400 mg HS
Tagamet
BID
800 mg
HS
150 mg
Ranitidine
BID
150 mg HS
Zantac
300 mg
HS
20 mg
Famotidine
BID
20 mg HS
Pepecidine
40 mg HS
150 mg
Nizatidine
BID
150 mg HS
Axid
300 mg
HS

SAR

heterocyclic ring
nitrogen group 4-carbon
chain
optimal antagonist
activity

Terminal nitrogen containing

functional group
polar
nonbasic substituent
maximal antagonist activity

Pharmacy Khon Kaen University

NH

77

C H3

HN
N
H 3C

HN

Methyl group
imidazole ring
selectivity
H2 receptor

Cimetidine: cyano-imino
functional group
Thioether linkage
S-atom side chain
electron withdrawing group

imidazole ring N -H
tautomer maximal H2antagonist activity

heterocylclic ring Ranitidine, Nizatidine Famotidine

imidazole ring recepter
imidazole ring
potency selectivity H2 receptor
ADR : Gynecomastia () , Galactorrhea
cimetidine
Drug Interaction
Cimetidine CYP450-dependent metabolic process

therapeutic index phenytoin,
theophylline, some benzodiazepine, warfarin, quinidine

CYP450 cimetidine
imidazole ring ligand
porphyrin iron CYP450

Gastrointestinal disorder

78

heterocyclic ring imidazole

2.2 Proton
+

Pump Inhibitor

- H /K ATPase (
(H3O+) K+ )
parietal cell
parietal cell
- PPIs
pyridinylmethylsulfinyl benzimidazole skeleton
H
N

O
N

S
N

pyridinyl methylsulfinyl benzimidazole

SAR
- pyridine benzimidazole ring

lipophilic character

Pantoprazole Omeprazole
Lansoprazole
H+/K+-ATPase

Rabeprazole

- prodrug active

sulfenamide intermediate
acidic canaliculi parietal cells
- active sulfenamide intermediate

proton pump (irreversible)

Pharmacy Khon Kaen University

79

covalent disulfide bond cysteine residues

H+/K+ATPase

W
eakbase
pKa~4

OCH 3
H 3C

CH 3

N
S
N

O
NH
OCH 3

H 3CO
H 3C

PPIs;O
m
eprazole
(prodrug)

CH 3

H+/K +ATPase

N
N

NH

H 3CO

OCH 3
H 3C

OCH3
CH 3

H 3C

N
N

Parietal
cell

CH 3

H+
O

N
H
N

NH

S
O
NH

H 3CO

H 3CO

PPIs pKa ~ 4.0

physiological pH (7.4)
ionization
free base
lipophilicity
cell
membrane parietal
cell

Active
Sulfenamide
metabolite

Lumen of
stomach

canaliculi parietal
cell
protonate ionized species

canaliculi
Canaliculus
Strongly acidic condition
(pH 2)

active sulfenamide
intermediate H+/K+ATPase
parietal cell

HCl

H+/K+ATPase irreversible
(long duration of action)

H+/K+ATPase

delay-release, enteric-coated
granular dosage forms
Acceptable
Maintenance
Drug
Regimens for
therapy
initial therapy
Omeprazole(220-40 mg OD
20-40 mg OD
16yr) Losec
Lansoprazole(115-30 mg OD
15-30 mg OD

Gastrointestinal disorder

80
11yr)
Prevacid
Rabeprazole
Pariet
Pantoprazole
Controloc
Esomeprazole
Nexium

20 mg OD

20 mg OD

40 mg OD

40 mg OD

20-40 mg OD

20.40

g OD

Therapeutic Application of PPIs

PPIs (short term)

H2 blockers DU Erosive
esophagitis Esophagitis
H2-blockers
PPIs antimicrobial activity H. pylori
GU antimicrobial

Selectivity and Side Effect of PPIs

PPIs side effect
(selectivity of action)
Target enzyme (H+/K+ATPase) parietal cells
Canaliculi parietal cell
pH (pH 1-2)
target site
protonated (ionized) species

active metabolite
target site target
site
neutral pH

Drug-Drug Interaction of PPIs

- Omeprazole , Esomeprazole CYP2C19

Diazepam , Phenytoin , Warfarin

- Omeprazole oxidative metabolism (
Esomeprazole)
benzodiazepines, phenytoin, warfarin
- Lansoprazole theophylline
efficacy
- Pantoprazole Rabeprazole drug
interaction

Pharmacy Khon Kaen University

81

PPIs
bioavailability pH
Azole antifungals ( Ketoconazole) ,
Ampicillin , Iron salts , Digoxin cyanocobalamine

3. Sucralfate ,
Bismuth compound
Sucralfate : Al salt of sulfated disaccharide
OR

OR
O

RO
RO

H
OR O

R=
-SO3[Al2(OH)

OR
((HO)5Al)O3SO

O
RO

OSO3(Al(OH)5)
O

((HO)5Al)O3SO
((HO)5Al)O3SO

OSO3(Al(OH)5)
OSO3(Al(OH)5)
O
OSO3(Al(OH)5)
OSO3(Al(OH)5)

H
OR

Sucralfate

- Anion sulfate ester bind to positively charged molecules to

form a gelatinous layer at the ulcer site insoluble
adherent complexes proteinasceous exudates
protective barrier
acid, pepsin bile
salt
- prostaglandin (
mucus ), bicarbonate,
epidermal and fibroblast growth factors
- Adsorb pepsin , bile salt
Dosage : 1g QID or 2g BID (
1 .
)
ADR :
:

Al3+
( Tetracycline ,
Phenytoin , Digoxin Cimetidine)
GI
2 ( antacid
)

4. +
Misoprostol

82

Gastrointestinal disorder

Prostaglandin Antisecretory effects gastric acid

(Cytoprotective effect)
adenylcyclase activity parietal cell
gastric acid
mucus bicarbonate adjacent
superficial cells.
Therapeutic applications :
- NSAIDs
gastric ulceration and bleeding
- duodenal ulcers (unlabelled uses)
duodenal ulcer H2
antagonists
: smooth muscle contraction effect
(drug misuse)
diarrhea,
abdominal pain
( Misoprostal

)

PU H. pylori

Pharmacy Khon Kaen University

Regimen
Monotherapy
Bismuth , H2RA , PPI ,
Antibiotics
One antimicrobial plus
an secretory agent
Clarithromycin + PPI
Two antimicrobials plus
an secretory agent
Metronidazole + amoxicillin
+ H2RA
Metronidazole + amoxicillin
+ PPI
Metronidazole +
Clarithromycin + PPI
Three antimicrobials plus
an secretory agent
Bismuth + Metronidazole +
Tetracycline + PPI
( Triple therapy
)

83
Eradication rate(%)
0-10
70-90

55-90
90-95
90-95

>95

ADR
Taste disturbance
:
Clarithromycin
Disulfuram-like action :
day )

Metronidazole ,
Metronidazole ( dose > 1g /

Triple therapy = 2 antibiotic+ PPI or H2 antagonist

Ranitidine 400 mg bid
Tetracycline 500 mg
qid
Clarithromycin 500 mg bid
Metronidazole
400-500 mg tid-qid
Amoxycillin 1000 mg bid
1. metronidazole + tetracycline (or amoxycillin)+ PPI
2.

amoxycillin + clarithro + PP

Gastroesophageal Reflux
disease(GERD)

Gastrointestinal disorder

84

(heartburn)

1.
2.
3.
4.
5.

LES LES pressure

Esophageal clearance
refluxate
Mucosal resistance
Delayed gastric emptying

Therapeutic approach

Phase I
Lifestyle modification + antacid/Low dose H2
receptor antagonist

Phase IIa
or

A. Std. dose H2 receptor antagonist 8-12 wks

B. Mucosal protective agent (sucrafate 1 g bid)

and/or
C. Prokinetic agent(metoclopramide 10 mg tid)

Phase IIb
A. Titration of H2 receptor antagonist to 1.52 time of std. dose or
B. PPI (omeprazone 20 mg qd,8 wks) and/or
C. Prokinetic agent(metoclopramide 10 mg tid)

Pharmacy Khon Kaen University

Phase III

85

Surgery

Lifestyle modification
15 . 6-8

86

Gastrointestinal disorder

1.Omeprazole
2.Antacid
3. Prokinetic drugs GI

metoclopramide D2 antagonist
5HT3
antagonist
EPS
Domperidone
-Cisapride 5HT3 antagonist EPS

NSAIDs
PPI > H2RA or Sucralfate
NSAIDs ,
selective cox-2
inhbitor , misoprostal (200 mcg QID)
H2RA DU NSAIDs
GU
PPI DU GU

Reference
.
anti-ulcer agents .

. 1. 2547.
. .
. PEPTIC DISEASES.
. .2539
.
Gastrointestinal Motility. 2543.
. .

Pharmacy Khon Kaen University

87

11.
Constipation and Diarrhea
2
( Constipation )
3

Type of constipation
1. Acute constipation ()

anal fissure
2. Chronic constipation ()

functional

Cause of constipation

( )

-
- Amitriptylene , Fluoxetine ,
Imipramine
- Phenytoin , Carbamazepine
-
- Diltiazem , Nifedipine
-

Gastrointestinal disorder

88

Diverticulosis , Irritable Bowel Syndrome,

Refer
2 wk
-

Bulk-forming
Laxatives

cellulose,
polysaccharides

Psyllium
hydrophilic
mucilloid
(Metamucill,
powd)

Polycarbophil
(Fibercon ,
tablet )

Lubricant or
emollient
laxative

Mineral oil

- :

-


irritable bowel syndrome
-

- < 6

stool
softener (Docusate)
-

HTN
-
mineral

Pharmacy Khon Kaen University

Stool softeners
or Wetting
agents

Docusate Na :
Cusate , Liqd

Osmotic
laxatives

Saline (Mg/MOM,
SO42-, PO43-)
Ex. Magnesium
hydroxide: milk of
magnesia (MOM) ,
susp

hyper Mg
CVD
Na overload

Lactulose

89

oil

- *
lipid granuloma ,
lipid pneumonitis*

- surfactant
Na+/K+ ATPase
cAMP

-
pressure

-
-

8-6 .

3 .
-

- disaccharide

Gastrointestinal disorder

90

Glycerin

Stimulant
laxatives
:

(myenteric
plexus)

Bisacodyl
(Dulcolax,
Emulax)
Sennosides
(Senokot)
Phenolphthalein
(Regulim)
NaCl (Unison
enema)
Caster oil

Anthraquinone
(Cascara, Rhubarb,
Senna, Aloe)

Phenolphthalein

Bisacodyl

Castor oil

lactic acid

-
hepatic encephalopathy
-
, DM
-

-
-

Na+/K+ ATPase
-

- melanosis
coli
-

- /
, < 6
-*

* (
)

Pharmacy Khon Kaen University

o
o
o
o
o

91

-
Na+/K+ ATPase

<5 glycerin suppo stimulant

< 2 Enema
senna mineral oil
bulk-forming, glycerin suppo
bulk-forming

Gastrointestinal disorder

92

""

( Diarrhea )
Definition
/ 1
24 (
vascular collapse)
3 /

colon

refer
1. >380 / /
2.
3.

(
)
4.
2 wk
5. > 5%
6. 3 , > 60
7.

1. ( lactase)
, ,
2. Phenolphthalein ,Sorbitol ,Lactulose
3. Penicillin ,Cephalosporin ,Clindamycin
,Tetracycline , MOM , Cisapride

Pharmacy Khon Kaen University

93

4. Infect bacteria

Salmonella , Shigella , E.coli

(traveler diarrhea)
virus
Rotavirus , Norwalk virus
parasite

Giardia lambia ,E.histolitica

5. Toxin bacteria S.aureus , Clostridium
6. Disease Crohn disease ,
, IBS

( )

-
-
1. non-inflammatory:
: Cholera , ETEC , Staph , Campylobacter
2. inflammatory:

: Salmonella , Shigella , E.histolytica

1.

ORS (oral rehydration therapy) : 1 1

(250 ml)
Fluid and electrolyte replacement (WHO)
NaCl ()
90 mEq ( 0.6 )
KCl
20 mEq ( 1/4 ) 1
)
NaHCO3 (baking soda)
30 mEq (

Glucose
20 g
( 2
6
)
osmolarity = 333
- ORS

- 24 .
(rice base oral
solution)

2.

94

Gastrointestinal disorder
diphenoxylate ( Lomotil )
atropine (
3)
8 ,
< 6

loperamide (Imodium)

diphenoxylate
2 1
8
diphenoxylate
Lomotil
2 tab 3-
2.5 mg +

4

atropine 25

mg

Racecadotril
Hidrase 1x3 tab
enkephalinase
(100)
c
inhibitor
Loperamide
Imodiu
2 cap
8
GI
m

cap/day
motility
1 cap

4-6 .
, ,

3.

( absorbent ) Kaolin , Attapulgite ,

Polycarbophil
-
-
- Polycarbophil

2
Kaolin -Pectin
kaopectal 1-2

1x3 pc

attapulgite
Entox-P
2-3 tab
16
tab/day

Pharmacy Khon Kaen University

activated
charcoal

Ultracarbon

95

3-4 tab 3-4

/

4. antimicrobial

48

6 24

( )
Shigella, cholera, Campylobacter /
travelers diarrhea / < 12 wk / immune

1. Staphylococcus
1 6

1 - 2

toxin
2. Streptococcus
Staphylococcus

1 - 2
3. Salmonella


2 - 5 10 - 14

4. Shigella ()
1-2

5. Amoeba ()

96

Gastrointestinal disorder

20-50

6. (Vibrio cholerae)






7.










5

infectious diarrhea

Drug of choice
Duration
E.coli
3-5
Quinone Norfloxacin
400 .
Ciprofloxacin 500 . bid
3
Cholera
Doxycycline 300 .
3

Fluoroquinolones 3

Ciprofloxacin 1

Campylobacter
Azithromycin
3
Shigella

Quinolone or
Trimetoprimsulfamethoxazole DS q
12 h 3 5

Pharmacy Khon Kaen University

Salmonella

97

5
Quinolone
Fluoroquinolones 5
Trimetoprimsulfamethoxazole DS q
12 h
Ceftriaxone 2 g. IV QD
Cefotaxime
2 g IV tid 5
Ciprofloxacin 500 . bid
3-14
G. lambia
Tinidazole 4 x 500 mg.
single dose
(2g)
E. histolytica
Tinidazole 4x 500 mg.
3
(2g)
C. difficile
Metronidazole 500 mg
7-10
tid
5.
()
6.Probiotics agent

Lactocacillus (L. acidophilus, L. bulgaricus, L.

rhamnosus strain GG), Saccharomyces
pH

colonize

acute pediatric diarrhea (rotavirus),

travelers diarrhea, antibibotic-associated diarrhea,
Clostridium difficile diarrhea

Antibiotic-associated colitis:
- C.dificile

Gastrointestinal disorder

98

Drug of choice Metronidazole 250 mg

QID 500 mg TID 7
Metronidazole
Vancomycin 125-500 mg QID 7

1.

2.


3.
()

1 1
(3 750 .)
2 1

4.

. . :
, 2546
Comprehensive Pharmacy Review : GI drug .
24

11
.3

(Hemorrhoids)

Hemorrhoids vessels ,
supporting tissue mucous membrane

(anorectal area)

Pharmacy Khon Kaen University

99

3
1. Internal hemorrhoid
anorectal line
(- , //) ,
( 1st, 2nd, 3rd,4th )
cushion 3 anal
canal connective tissue hemorrhoid
anus

2.

External hemorrhoids
anorectal line ()
2 1. Thromboses hemorrhoids =
hemorrhoidal vein
2. Cutaneous hemorrhoids = fibrous
connective tissue
3. Mixed hemorrhoids 3
Prolapsed H. = +
Without prolapsed H. =
Strangulated H. = Prolapsed sphincter

gangrene

(Etiology)
-

10
0

Gastrointestinal disorder

-
-


, (lifestyle) , ,,

1.
2.
3.
4.
5.


6.
7.

1.

2.

3. 2

4.
5. 7

1.

2.
3.

4.
5.
6.

Pharmacy Khon Kaen University

10
1
7.

8. 10 15 2 3

9.

10.

1. Non Pharmacological treatment

sitz bath 43.3-46.1 C 15

2-3

2. prolapsed
Nonsurgical
Sclerotherapy = phenol > atrophy >

Rubber band ligation = >

> >
Cryotherapy = Liq.N2 > >

3. ()
1. benzocaine,lidocaine,tetracaine

: sensory nerve
ending
perianal area ( ) ; rectum nerve


:

2. Vasoconstrictor Epinephrine , nor epinephrine

-adrenergic

Gastrointestinal disorder

10
2

o S/E , Cardiac arrhythmia

o Contraindication >> DM , HT, hyperthyroidism ,

, MAOI , TCA
3. Protectant aluminium hydroxide gel

,lanolin ,kaolin
burning
4. Astringent
>> >>
mucous
Calamine , Zn oxide
5. Keratolytic ( )

Aluminum chlorhydroallantoinate

(Alcoxa) , Resorcinol

6. Bulk forming agents ( )

Methylcellulose , Docusate salt , Psyllium

7. Hydrocortisone

onset

( Topical treatment )

steroid

Proctocedyl suppository :
- Hydrocortisone
- Aesculin
- Cinchocaine HCl
- Framycetin sulfate
Scheriproct suppository :
- Cinchocaine hydrochloride
- Prednisolone
caproate
- Clemizole undecylate
Doproct :
- Hydrocortisone acetate
- Zn oxide
- Benzocaine
*** hepatic
portal vein first pass metabolism

( Oral preparation )

Pharmacy Khon Kaen University

-

10
3

1. Micronized purified flavonoid fraction (Diosmin,

Hesperidin) : Daflon 500 , Heroid 500
- Inflammatory mediator
- : 12 32
2. Aescin: Reparil
- Vasoconstriction

- 23 13
3. Rutin , Essaven : Rutin + Aescin
-
- 2 3
14 1 3

Comprehensive Pharmacy Review : hemorrhoids .

24
. .
: , 2545.

11.
4

Intra-abdominal infection

(Intra-abdominal
infections)
(Peritonitis)
,

Primary peritonitis

(spontaneous bacterial
peritonitis : SBP)

10
4

Gastrointestinal disorder
1. : nephritic syndrome

: (alcoholic cirrhosis) , congestive

heart failure (CHF) , , SLE , lymphedema
, metastatic malignant disease
2.
- Bacteria : E.coli , Klebsiella pneumonia, Streptococcus
pneumonia, Streptococcus , Enterococci
- : Mycobacterium tuberculosis, Neisseria
gonorrhoeae ,Chlamydia trachomatis

primary peritonitis
1. : child-pugh class C.
2. AF total protein level < 1 g/dl / AF C3 level < 13
mg/dl.
3.
4.
5.

Bacterial over growth

6.

Iatrogenic factors :

7.

spontaneous bacterial peritonitis

acute febrile illness (

)

rebound tenderness
bowel sound

1. Empiric antibiotic
- Ampicillin + Aminoglycoside
- Cephalosporin gen 3 ( Cefotaxime , Ceftriaxone )
- Penicillin ( Ticacillin
Piperacillin ) , Carbapenem , Beta-lactam / Betalactamase inhibitor antibiotic ( PiperacillinTazobactam , Amoxicillin-Clavulanic acid)
- Quinolone Levofloxacin, Moxifloxacin

Pharmacy Khon Kaen University

10
5

2.
Pseudomonas aeruginosa

>> Aminoglycoside + Anti-pseudomonal Penicillin /

Cephalosporin ( Imipenem , Meropenem )
>> Quinolone ( Ciprofloxacin ) + Anti-pseudomonal
Penicillin / Cephalosporin / Carbapenem
Polymicrobial , anaerobes ( Bacteroides )

>> Beta-lactam / Beta-lactamase inhibitor , Metronidazole ,

Clindamycin

primary peritonitis
(selective decontamination ) Norfloxacin 400
mg/day Co-trimoxazole 2 /
primary peritonitis

Secondary peritonitis

, peptic
pelvic inflammatory disease

mixed organism
- endogenous organism obligate anaerobe :
B.fragaris, Bifidobacterium spp.
- facultative organism E.coli.
- streptococci , enterococcus ,
Eubacteriumm, Klebsiella spp, Proteus spp ,
Enterobacter , C.perfringens , Candida , Enterobacter ,
Serratia , Acinetobacter , P.aeruginosa

-
material
- : N/V

E.coli , Klebsiella/Enterobacter spp, Proteus spp , Enterococci
obligate anaerobe (
5 ) B.fragilis, P.melaninogenica ,

Gastrointestinal disorder

10
6

Peptostreptococcus , Fusobacterium , Eubacterium ,

Clostridium spp.
S.aureus , P.aeruginosa Candida
bacteremia

monotherapy :
- anaerobe >> Chloramphenical, Clindamycin,
Metronidazole
- gram (-) facultative >> Aminoglycoside , Quinolone , Cef
gen 3 gram(-) anaerobe
Cefoxitin, Ceftrizoxime
- anaerobe gram (-) facultative >> Piperacillin (
P.aeruginosa ) beta-lactam / beta-lactamase inhibitors
Amoxicillin / Clavulanic acid , Piperacillin /
Tazobactam , Carbapenem (Imipenem, Meropenem) (
P.aeruginosa)
Tertiary peritonitis
peritonitis sepsis
secondary peritonitis pathogen
low grade pathogen peritoneal
exudates.

( Cholelithiasis )

cholesterol ,
billirubin
cholesterol
micelles
vesicles cholesterol

cholesterol
1.
2.
3.

(cholesterol stones) cholesterol 50 %

()
(mixed stones) cholesterol 20-50 %
(pigmented stones) cholesterol 10 %

1.

Pharmacy Khon Kaen University

10
7

2.

3.
4. fibric acid derivatives , ,
, octreotide Ceftriaxone
5.
6.
7.
8. Hyperalimentation

9. Ileal disease Crohns disease ,

, , ,
,
10. Primary biliary cirrhosis ,
duodenal diverticula , truncal vagotomy ,
Hyperparathyroidism , HDL


clonorchiasis, fascioliasis
ascariasis

1.

(asymptomatic
gallstone)

( prophylactic cholecystectomy)

1.
: ,
porcelain gallbladder (calcification of gall bladder wall)
2.

2.5

10
8

Gastrointestinal disorder
(anomalous
pancreaticobiliary ductal junction) choledochal cysts
Carolis disease
3.

4.
5.

sickle cell anemia

6.

(morbid obesity, BMI

40) cholesterol

7.

8.

2.

cystic duct
biliary colic
visceral pain

,

4

(biliary colic)


bilirubin, AST, ALT, alkaline phosphatase, amylase

Pharmacy Khon Kaen University

10
9
( open cholescystectomy )
( laparoscopic cholescystectomy )

3.

(
CBD stone) , (biliary sludge) , gall bladder
dysmotility , sphincter of oddi dysfunction

reflux esophagitis , peptic ulcer , pancreatitis , renal colic ,
colonic disorder diverticulitis , colonic cancer ,
radiculopathy angina pectoris


peptic ulcer disease hollow
viscus organ
irritable bowel syndrome

4.

- Biliary colic (70-80%) , Perforation of gallbladder (12%) ,
Acute cholecystitis (10%)
Mirizzis syndrome , Emphysematous
cholecystitis , Hydrop of gallbladder , Small bowel obstruction
, Gastric outlet obstruction , Acute biliary pancreatitis , acute
suppurative / obstructive cholansitis

1.
2.

11
0

Gastrointestinal disorder

2.1

cholesterol
cholesterol

1. Chenodeoxycholic acid 12-24

,
cholesterol ,
2. Ursodeoxycholic acid 10-15
1
chenodeoxycholic acid

: ,

2.2 Contact dissolution



methyl tertbutyl ether (MTBE) penthyl ethers (
MTBE)
EDTA
N-acetylcysteine (NAC )

( transhepatic approach )
nasobiliary tube
2.3 Extracorporeal Shock-Wave Lithotripsy
ESWL

ESWL
5
mm.

1. aerobic exercise

Pharmacy Khon Kaen University

11
1

1.5 kg / week

2.

ursodeoxycholic acid

3.

colonic
transit time

4.

40-75
2-3 /

Gallstones diagnosed
Asymptomatic
complication

Symptomatic or

Observe
candidate

Operative

Laparoscopic or open

If

cholesterol
Cholecystectomy
stones
<5 mm,

Single

stone,
Patent cystic duct

5-20 mm, patent

Oral bile acid

ESWL +/- oral

cystic duct

bile acid

11
2

Gastrointestinal disorder

Pancreatitis
Exocrine pancreas
1. pancreatic enzymes carbohydrate , fat
protein
2. bicarbonate pH
pancreatic enzymes

pancreatic juice
3 phase
. Cephalic phase , ,
pancreatic juice vagus nerve
. Gastic phase stomach antral
distention gastrin
pancreatic juice
. Intestinal phase
(chyme) stomach duodenum
pancreatic juice
- low pH gas acid secretin
crypt cell pancreatic
juice carbonate 130 -140 mEq/L
( < 50 mEq/L) pH duodenum
pancreatic enzymes
- fat , protein amino acid
phenylalanine , valine methionine
cholecystokinin (CCK) intestinal crypt cell
pancreatic juice high enzymes low
bicarbonate
Enzymes inactive form
(proenzymes) trypsinogen , chymotrypsinogen ,
proelastase active form amylase lipase
Gut Hormones inhibit pancreatic secretion VIP,
glucagon somatostatin

Pharmacy Khon Kaen University

11
3

Acute Pancreatitis
pancreas
autodigestion pancreas pancreatic enzymes
Mechanism of pancreatic auto -digestion pancreatic
enzymes pancreas
A. enzymes fat
- Lipase
- Esterase
- Pro. Phospholipase A.
- Colipase
B. enzymes carbohydrate
- Amylase
C. enzymes Protein
- Trypsinogen
- Carboxypeptidase
- Chymotrypsin
- Prekallikrein
- Proelastase
D. Trypsin inhibitor : Trypsin
auto-digestion acute pancreatitis pancreas
inactive enzymes lumen
duodenum active form

Acute pancreatitis
Alcohol Alcohol protein plugs
pancreatic duct alcohol pancreatic
enzymes pancreatitis
(Obstructive Hypersecretion Hypothesis)
2. Biliary tract disease : cholelithiasis
3.Post ERCP
4.Drugs
. Definite group pancreatitis

Azathioprine , Sulfonamides , Thiazide , Furosemide
, Estrogen, tetracycline Na valproate
. Probable group
pancreatitis

Ethracrynic acid, Procainamide, chlorthalidone LAsparaginase
5. Infections
- Virus mumps, hepatitis B virus, coxsackie , echovirus
- Mycoplasma
1.

Gastrointestinal disorder

11
4

- Parasite Ascaris common bile duct

pancreatic duct.
6. Vascular disease
- Vasculitis SLE , periarteritis nodosa
- Thromboembolism Thrombotic thrombocytopenic
purpura
7. Metabolic
- Hypertriglyceridemia
- Renal failure
- Hypercalcaemia
- Acute fatty liver in
pregnancy
8. Post traumatic
- Blunt abdominal
- Post operative
9. Other
- hereditary pancreatitis
- penetrating peptic ulcer
- pancreatic divisum
Bile-reflux bile
reflux pancreatic duct pancreatitis
common bile duct
stone , ascaris, duodenal diverticulum , pancreatic divisum

Clinical manifestation
1.
2.
3.

1.
2.
3.
4.
5.
6.

Abdominal pain
Jaundice
Discoloration of skin echymosis
( Cullens sign ) left flank (Grey Turners
sign ) pancreatitis

Aim medical management

Relieve pain
fluid, metabolic electrolyte imbalance
Suppression of pancreatic secretion
Prevention of secondary infection
complication shock, respiratory renal
failure pulmonary edema
Neutralize toxic substances

1. Relief of pain Pentazocine ( morphine

sphincter of Oddi spasm )

Pharmacy Khon Kaen University

11
5

2.

Metabolic imbalance hyperglycemia,

hypocalcaemia metabolic acidosis
3. Suppression pancreatic secretion
- NPO
- NG tube suction
- H2-antagonist, anticholinergic, glucagon,
somatostatin
4. Prevention secondary infection
early detection treatment infection
prophylactic antibiotic

5. complication
6. Neutralize toxic substance anti
kallikrein (Trasylol)
medical treatment
complication 5-7
complication
Pseudocyst formation.

acute pancreatitis
- ,
hypertriglyceridemia hyperparathryrodism

Chronic Pancreatitis
pancreatitis
pancreas
exocrine endocrine function chronic
pancreatitis Abdominal pain
malabsorption
chronic pancreatitis
1. Alcoholic induced pancreatitis
pancreatitis chronic
2. Non alcoholic tropical pancreatitis
toxic substance

3. Post - acute pancreatitis

Acute pancreatitis pancreatic tissue
exocrine endocrine function

4. Metabolic hyperlipidemia , hyperparathyroidism ,

uremia recurrent pancreatitis

Gastrointestinal disorder

11
6

Pancreas divisum Acute pancreatitis

ERCP
recurrent attack chronic pancreatitis

6. Obstructive pancreatitis carcinoma pancreas

7.Idiopathic
5.

Clinical manifestation
1. Pain acute pancreatitis
peptic ulcer pancreatic
tissue

2. Diabetic Mellitus

3. Malabsorption pancreatic secretion

enzymes bicarbonate ( bicarbonate secretion
neutralize duodenum pancreatic enzyme
)
Pancreatic enzymes protein , fat
carbohydrate pancreatic secretion
maldigestion malabsorption
steatorrhea

1. Pain
- non-narcotic analgesic
narcotic analgesic
- caeliac ganglion block pain

- main pancreatic duct obstruction

pancreatic duct stone pain
exocrine function
2. Diabetic mellitus pancreatic diabetes
ketosis , angiopathy hypoglycemic
insulin
- hypoglycemic
drug insulin
3. Malabsorption pancreatic insufficiency
- pancreatic enzymes replacement

- H2-antagonist sodium bicarbonate

pancreatic enzymes

Pharmacy Khon Kaen University

11
7

4.

complication
obstructive jaundice , Pseudocyst
abscess
5.
Medical control pain
nerve block obstruction pancreatic
duct pancreas
complication Pseudocyst , abscess ,
obstructive jaundice carcinoma of pancreas

11.
5

Inflammatory Bowel Diseases &

Irritable Bowel Syndrome

Inflammatory Bowel Diseases (IBD)

Crohns disease
(CD) Ulcerative Colitis (UC) 2040
Pathogenesis

1. Infection theory product

pathogenic

2. Immunological theory
Ab (Autoimmune
reaction)

Crohns disease


terminal ileum () 2 3

Gastrointestinal disorder

11
8

Nutritional deficiency

3 The Vienna
classification of Crohn's disease
1. Stricturing

2. Penetrating

3. Inflammatory
2

Complications
-

fistula ( UC)
systemic arthritis , iritis , skin
lesions , liver disease

Sign and Symptom

1. Gastrointestinal symptoms
- (Cramp-like)

- (Diarrhea)
(Ileitis)
()

-

(Bile duct)
2. Systemic symptoms
- 38.5 C
-

3. Extra intestinal symptoms
-
(Photophobia),

Pharmacy Khon Kaen University

11
9
(Sclera)

Physical Examination
-
-

Laboratory test
-

WBC ESR
CT, Ultrasound, X-ray

Ulcerative Colitis (UC)

mucosa submucosa




(Remission)
Crohns disease

Primary lesion crypts of mucosa (crypts of
Lieberkuhn) (abscess)
colonic cancer

4
1. Mild disease : 4

2. Moderate disease : 4
(Anemia)
38 39 C
3. Severe disease : 6 /

4.
Fulminant :

Complications
Local complications (in colon) :
Minor complications : ,

12
0

Gastrointestinal disorder
Major complications (toxic megacolon) :

, tachycardia , , WBC count

() ,

Others : Hepatobiliary complication , dermatological

complication , arthritis , iritis

Sign and Symptom

-
50
- , , (Anemia) ,
, ,
, , , , Blurred vision ,
Photophobia
-

Physical Examination
-

Laboratory test
WBC ESR
Hb / Hct

Albumin case

Pharmacy Khon Kaen University

12
1

Goal of Therapy ()
-

systemic
/ ,

Treatment

Non-pharmacological treatment
1. Nutrition Support
-
moderate severe
- lactase
(
lactose )
- severe
peripheral
2. Surgery
- Ulcerative Colitis :
colon (colectomy)
anus
- Crohns disease :

Pharmacological treatment
- IBD (

Autoimmune)

1. Sulfasalazine

(common use)

- 2
Sulfapyridine 5-ASA (Mesalamine)
- 5-ASA Prostaglandin
Leukotriene
- IBD
- Mesalamine
Lumen

12
2

Gastrointestinal disorder
- (enema)
- ADR : GI disturbance, , , folic
, , ,

2. Glucocorticoids
- moderate severe case
- , cytokines mediator
- ADR : Hyperglycemia, Hypertension, Osteoporosis, Acne,
Fluid retention (edema), Cushing syndrome, Buffalo
hump ( Long term)
3. Immunosuppressant : Azathiopine, Mercaptopurine,
Cyclosporine, Methotrexate
- Steroid
- (2-3 ,
6 )
- Mesalamine / Steroid
- Severe ADR : Lymphoma , Pancreatitis , Nephrotoxicity
- Cyclosporine Acute,
Severe Ulcerative colitis Continuous infusion
- Methotrexate Crohns
Disease

4. Antimicrobials
- Methonidazole ( anaerobic bacteria)
Crohns Disease perineal area
fistula
-
- ADR : , metallic taste , Disulfiram-like
reaction
- Ciprofloxacin Gram negative bacteria

5. Anti-TNF
- Infliximab, Eternacept
- IgG1 chimeric monoclonal Ab TNF

- Steroid fistulizing
disease
- Severe case
- ADR : Infusion reaction, Serum sickness, Sepsis, TB

Pharmacy Khon Kaen University

12
3

Treatment approach for Crohns disease

1. Mild - Moderate
- Ilecolonic colonic : Sulfasalazine Mesalamine 3 4 g/d
- Perianal () : Sulfasalazine oral Mesalamine
/ Metronidazole 10 20 mg/kg/d (
anus)
- Small bowel : Oral Mesalamine 3 - 4 g/d Metronidazole
2. Moderate Severe
- Mild - Moderate Prednisolone
40 60 g/d
- fistulizing disease Infiximab (
Steroid )
1. Prednisolone
2 3
2. Azathiopine, Mercaptopurine
Methotrexate
3. Severe Fulminant
- Hydrocortisone 100 mg IV q 6 8 hr.
- 7 -----> Cyclosporine IV 4 mg/kg/d

Treatment approach for Ulcerative colitis

1. Mild - Moderate
- Sulfasalazine 4 6 g/d oral Mesalamine 2 4.8 g/d
2 g/d
2. Moderate Severe
- Sulfasalazine 4 6 g/d oral Mesalamine 3 6 g/d +
Prednisolone 40 60 g/d
Prednisolone Sulfasalazine 2
3 Sulfasalazine Mesalamine 2 g/d
3. Severe Fulminant
- Hydrocortisone IV 100 mg q 6 8 hr.
Prednisolone Sulfasalazine Mesalamine
Steroid 1 2 ----->
Maintenance dose Sulfasalazine
- Hydrocortisone 5 7
Cyclosporine IV 4 mg/kg/d

Evaluation of therapeutic outcome

- ,

12
4

Gastrointestinal disorder
- Sign Symptoms
-
-
-
-
- Crohns Disease Activity Index
(CDAI), Standardized assessment

tools for Ulcerative colitis

Irritable Bowel Syndrome (IBS)

Irritable Bowel Syndrome (IBS)

(3 :1)
IBS 3

1. (constipationpredominant IBS; IBS-C)
2. (diarrheapredominant IBS; IBS-D)
3. (pain-predominant
IBS)

Pharmacy Khon Kaen University

12
5

Pathogenesis

1.
5-HT3 , 5-HT4
(hypermotility) diarrhea-predominant IBS (IBSD) (hypomotility)
constipation-predominant IBS (IBS-C)
2 (alternating IBS; IBS-A)
2.
(heightened visceral perception)
IBS-D, IBS-C pain-predominant IBS
3. (post-infective IBS) acute
bacterial gastroenteritis

IBS 2 - 3
IBS
4
4.
lactose

5. (psychological factor)
IBS

(depressant)

Diagnosis

-
-

- USA and Canada Guideline

40-50

IBS

Alarm symptom

refer

-
GI bleeding
-
(anemia)

12
6

Gastrointestinal disorder

Alarm symptom
50
IBS

Treatment
Non-pharmacological treatment
1. Reassurance :
()
2. Psychotherapy :

3. Dietary management :

IBS-C
fiber

Pharmacological treatment
1.
-

2.

3.

IBS-C
Fiber therapy (first line)
Psyllium-based product Fibrogel, Metamucil,

- 1 1 (
) 1
()
Standard laxative (second line)
- Osmotic laxative MOM, lactulose
4 6 wk
- Stimulant laxative
laxative
dependence

Tegaserod (third line)
- CP IBS
- specific 5 HT4 partial agonist ----->

- Regimen : 1 x 2 AC ( PC bioavailability
)

Pharmacy Khon Kaen University

12
7

- ADR : , ,
-

cardiotoxicity (IHD ----> chest pain ----> )

IBS-D
1. Loperamide (Imodium) (first line)

opioid agonist

SE anticholinergic

2. Diphenoxylate with atropine (Lomotil) (second
line)
3
Atropine

Atropine
SE anticholinergic

3. Cholestylamine (Quastan) (third line)

4. Alosetron
FDA approved DP-IBS
high potent 5-HT3 receptor antagonist --->
colonic transit time

- ADR : ,
- 2002
2002

Pain-predominant IBS ()
1. Antispasmodics
- Hyoscyamine (Buscopan) (first line)
- Dicyclomine (second line)
- Smooth muscle relaxant
-
- ( prn q 4 6 hr.)
-
Anticholinergic
2. Antidepressants

12
8

Gastrointestinal disorder

- TCA

-
-
- Third line : Amitryptyline low dose
( Antispasmodics)
ADR : anticholinergic , ,

Therapies for the Symptoms of Irritable Bowel Syndrome

Drug
Symptom(s
Adverse Reactions
)
Antispasmodic agents
Dicyclomine
Pain
Urinary retention, constipation,
blurred vision,
dry mouth, tachycardia
Hyoscyamine
Pain
Dry mouth, urinary hesitancy,
blurred vision,
tachycardia, headache
Antidiarrhea agents

Pharmacy Khon Kaen University

12
9
Loperamide
Diarrhea Abdominal pain, N/V, drowsiness,
dizziness,
dry mouth, fatigue
Diphenoxylate plus Diarrhea Dizziness, drowsiness, euphoria,
atropine
malaise,
sedation, toxic megacolon
Cholestyramine resin Diarrhea Constipation, abdominal
discomfort/pain, flatulence, N/V
Osmotic laxatives
Lactulose
Constipation
Flatulence, cramping, diarrhea,
bloating,
epigastric pain
Polyethylene glycol
Constipation
Nausea, abdominal fullness,
solution
bloating,
abdominal cramps, vomiting
Stimulant laxatives
Senna compounds
Constipation
Bisacodyl
Constipation
Antidepressants
Amitriptyline (TCA)
Pain
Sedation, arrhythmia, seizure,
hypotension, anticholinergic
effects, CNS effects
Nortriptyline (TCA)
Pain
Sedation, cardiovascular effects,
anticholinergic effects, weight
gain, seizure
Desipramine (TCA)
Pain
N/V, cardiovascular effects,
anticholinergic
effects, sedation, seizures
Citalopram (SSRI)
Pain
Serotoninergic neuroenteric modulators
Alosetron (5-HT3
Diarrhea, Constipation, acute ischemic
antagonist)
pain
colitis, nausea
Cilansetron (5-HT3
Diarrhea,
antagonist)
pain
Tegaserod (5-HT4
Constipation
Headache, dizziness, orthostatic
agonist)
,
hypotension,
pain
diarrhea, abdominal pain, N/V
Cisapride (5-HT4 agonist)
Constipation
,
pain

13
0
1.
2.
3.
4.
5.
6.

Gastrointestinal disorder

Dose Loperamide : 1 tab = 2 mg dose 2 tab (4 mg)

dose 1 tab (2 mg)
Dose Diphenoxylate with atropine : 2.5 5 mg
unformed stool
Antiflatulant : Simethicone (AirX) 2 4 tab qid pc

fiber gas
()
Lactose --->
2 wk
(), (fatty
acid), (caffeine)

. . [1 screen].
Available from: URL:http://www.thaidsc.
worldmedic.com/main/disease.html. Accessed Nov 18, 2008.
.
107.25 MHz
(IBS). 2547 [1 screen]. Available from:
URL:http://www.pha.nu.ac.th/paisach/files/ibs.doc. Accessed
Nov 18, 2008.
.
1 IBS,IBD.

Pharmacy Khon Kaen University

11.
6

13
1

Hepatic disease
(Hepatitis)

2
[acute hepatitis]
23 2

HAV, HDV
[chronic hepatitis]
6 HBV, HCV
chronic persistent

chronic active hepatitis

A, B, C, D, E,
G
1.
2. halothane, isoniazid,
methyldopa, phenytoin, valproic acid, sulfonamide drugs
acetaminophen

3. ,

13
2

Gastrointestinal disorder

1. SGOT[AST],

SGPT [ALT] 40 IU/L 1.52

3
2.
- Ig M Anti HAV
- HBsAg
Anti HBs
HBeAg HBV-DNA

- Anti-HCV
HCV-RNA

polymerase chain reaction (PCR)
3.

4.

: A, B, C, D, E, G
1.

fecal-oral route ,

carrier state

3-7

1-3


28 (15-50 )

SGOT ,SGPT
IgM HbAg , IgM
anti-HAV

1.
2.

Pharmacy Khon Kaen University

13
3

2
1. Immune globulin


2 Hepatitis A vaccine
2

2.
-

- 3 0
6 12
2.

B
parenteral (), sexual ,perinatal (
), mucous membrane ()
>>>
(cirrhosis) >>>
carrier state HBsAg positive
6

45-90 180
-
-

-
-
-

HBV HbsAg
HBeAg
HBV-DNA HBeAg
(seroconversion) HbeAb
HBV DNA

polymerase chain reaction (PCR)

13
4

Gastrointestinal disorder

1.

2. 90% 10

3. HbAg +

carrier
4. 5-10% Chronic hepatitis

Chronic hepatitis B
1.
2.
: skin rash, arthralgia, nephrotic
syndrome, polyarteritis nodosa, oral lichen planus


1.
steroid
2.

3.
( , 2540)
4. : Interferon, lamivudine (

)
1. Interferon alfa
- 5-10 million IU SC 3 / 16-24
4.5-5 mu SC 16
- response rate 20-40%
- SE : Flu-like effect, Chill, myalgia, nausea
: Hematologic-neutropenia, thrombocytopenia, anemia
: Neuropsychiatric-depression, psychosis
: Autoimmune-thyroid dysfunction
: chronic fatigue, weight loss etc.
2. Pegylated Interferon
- renal clearance, T1/2
- blood level

Pharmacy Khon Kaen University

13
5

- side effect
- antiviral activity
3. Lamivudine
- irreversible inhibit reverse transcriptase
- oral 100 mg
3
- mutation,
resistance

3.

C
parenteral () , sexual , perinatal (
)
85% chronic infection
1 5% hepatocellular carcinoma

-
Anti-HCV
HCV-RNA
2-8
-
6 HCV -RNA

5-10
6-7
25

ALT
40-60

20-30

13
6

Gastrointestinal disorder

- alpha interferon
- alpha interferon and ribavirin
-

-
-
-
-
-

HAV
- RNA virus
-
infectious hepatitis
-

- lab AST > ALT 2.5

1.

2. electrolyte
3.
4.

prednisolone 30 mg/day
Vaccine

HBV
- DNA virus
- serum
hepatitis
-

- lab ALT
HBs Ag,
HBeAg, HBcAg


4-15


( angioneuotic edema)
antiviral
1. Interferon alpha SC
IM
2. Lamivudine
3. Adefovir dipivoxil (Hepsera)

Pharmacy Khon Kaen University

HAVRIX , VAGTA

13
7

Vaccine
ENGERIX-B, H-B-VAX, Hevac B
pastuer, Hepavax-B,
Heppacine B

Interferon Alpha

Lamivudine

1.
2. 6

3.

1. ADR INF
2. INF
lamivudine

1.
2. ADR
3.

1.
2. HBV DNA
3. HBs Ag

(Cirrhosis)

(fibrosis)
regenerating nodules
(chronic hepatitis)

1. Alcoholic cirrhosis

2. Chronic hepatitis B , D

3. Chronic hepatitis C

4. Autoimmune hepatitis

Gastrointestinal disorder

13
8

5. Inherited diseases
hemochromatosis, Wilson's disease,
galactosemia
6. Nonalcoholic steatohepatitis (NASH)


7.






8.

9. Schistosome

portal
hypertension

1. compensated

compensated cirrhosis 10
58 decompesated cirrhosis
(median time to death)
9 1.6
2. decompensated

(ascites)

portal hypertension

1.

Pharmacy Khon Kaen University

13
9

-
- ()
,
,
-
()
-
(
)
(gynecomastia)

)
- (
)
(
)
40-60


2. (
)
- (ascites) ,
(edema)
-
( , )
-
(esophageal varices)

-
(Hepatic
encephalopathy)
-
(Hepatorenal syndrome)

Lab finding
1. ALT and AST

2. ALP (alkaline phosphatase)

3. BUN hepatic
encephalopathy

14
0

Gastrointestinal disorder

(treatment)
Treatment goals
- Identify and eliminate the
causes
- Prevent symptoms and maintain a
reasonable quality of life
- Treat complication mortality

1.

2.
nutrition replacement
3.

NH3
4.
glucose
5.

6.

1.
2.
3.

Hypokalemic - Hypochloremic metabolic alkalosis

KCl
Prerenal azotemia Cr BUN
diuretic
diuretic
ascite ()
ascites intrahepatic resistance
portal hypertension, local production nitric oxide
splanchnic arterial vasodilation
cirrhosis
effective blood volume
vasoconstrictors anti-natriuretic factors

1. sodium
2. diuretic K sparing
spironolactone
3. paracentesis

1.

Pharmacy Khon Kaen University

14
1

1.

umbilical hernia
2.
1 1.5
3.
spironolactone (Aldactone) , triamterene (Dyrenium)
furosemide (Lasix)
spironolactone
100 mg + furosemide 40 mg
maximum dose
spironolactone 400 mg furosemide 60 mg, daily
90%

4.
encephalopathy electrolyte imbalance
4. Esophageal varices

2. Hct 30 35%
coagulopathy fresh blood fresh
packed red cell fresh frozen plasma

3. NG tube
4. vasoconstrict vasopressin (0.2-0.4 IU/min IV
infusion), terlipressin, somatosttin, octreotide
splanchnic arterioles

5. screotherapy
6. balloon
7. beta-blocker propanolol, nadolol (
beta blocker isosorbide-5-mononitrate)
8.
5. Hepatic encephalopathy



HE

14
2

Gastrointestinal disorder

- albumin

- gamma aminobutyric acid (GABA)

GABA/central BZ receptor
- branched chain amino acid
(BCAA), AAA false
neurotransmitters
4 Grade
Grade 1 : mild tremor, altered handwriting, anxiety,
insomnia, mild confusion
Grade 2 : dysarthria, ataxia, asterixis, lethargy,
disorientation
Grade 3 : seizure, muscle twitching, delirium, bizarre
behavior
Grade 4 : posturing, coma

1. fetor hepaticus
2. flapping tremor
3. drownsiness and confusion

1. intake
2. vegetable protein aromatic protein
3. lactulose initial 30-60 ml 1-2 h 1530 ml 2-4 2-4 /
lactulose

lactic acid acetic acid formic acid colon
NH3 gaseous
distension () , flatulence () ,
4. Neomycin, Metronidazole, Vancomycin Rifaximin
protein NH3
HE 2

5. Flumazenil benzodiazepine antagonist specific

GABA receptor HE
benzodiazepine overdose
6.

Barbitone, Phenobarbiton, Lorazepam,

Chlordiazepoxide
()

Pharmacy Khon Kaen University

14
3

1.


-

-


-
(

30
)
2
6 (1,500 cc)
-
2.
(alphafetoprotein) 6

3.
5-10

2-5

1.
alc

2.

3.

1.

2.

14
4

Gastrointestinal disorder

1.


2.
3.

,,Common Consultation in GI
and Liver Diseases (: ,2546),
,, A
TEXTBOOK OF INFECTIOUS DISEASES, (:

,2548)
, ,
( : ),
,,
3 (: ,2548)

11.
6

Drug induced Hepatic

Disease

1. 2
1.1 Type A : Predictable ADR , Intrinsic
hepatotoxicity , Direct toxic effect

ADR

- Paracetamol , Tetracycline ,
Metrothexate Alcohol
metabolised

Pharmacy Khon Kaen University

14
5

- Carbon tetrachloride

- Anabolic steroids Contraceptives

1.2 Type B : Unpredictable ADR , Idiosyncratic

hepatotoxicity



ADR

-
1-5
, , Eosinophillia
Methyldopa , Phenytoin , Chlorpromazine ,
Erythromycin Sulfonamides
-
1 12
eosinophillia

(Rechallenge)

metabolite

2.

2.1
3

(Steatosis)
2.2

3
methyldopa, INH, phenytoin,
trazodone, nitrofurantoin

3.

Gastrointestinal disorder

14
6

3.1 Toxic Cirrhosis mild hepatitis

progress
cirrhosis MTX psoriasis,
arthritis active metabolite
interval A high
dose hepatomegaly,
ascites, portal HTN
3.2 Liver vascular disorder
- lesions hepatic venules, sinusoid
portal vein centralized necrosis
cirrhosis
cytotoxic drug, sex
hormones, pyrrolizidine alkaloids
- Peliosis hepatitis androgen
6 , tamoxifen, azathioprine, danazol

Mechanism of drug induced Hepatic

Disease
1.

Hepatocellular toxic metabolite

Hepatitis involve hepatocyte

1 INH, nitrofurantoin,
ketoconazole, halothane, methyldopa (methyldopa
hepten specific cell protein
autoimmune reaction)

Hepatocellular necrosis
halothane (idiosyncrasy), ketoconazole, INH,
phenelzine (generalized) paracetamol (localized)
paracetamol glutathione Marker of hepatocellular
necrosis ALT , AST
hepatocellular necrosis ALT
hepatocellular necrosis AST / ALT < 1
aminotranferase(AST)

aminotransferase
AST
Aminotranferase (AST)
10 acute liver injury
100

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2.

14
7

Metabolic process involvement

Cholestatic jaundice : affect bilirubin metabolism

organic anion salicylate,

sulfonamides albumin
competitive free bilirubin BBB
kernicterus
sulfonamides, erythromycin, testosterone, captopril, OC
toclopidine
steatonecrosis :

1. fatty acid Hepatocytes

fatty acid mitochondria
oxidation
2. alcohol alcohol
acetaldehyde fatty acid
hepatocyte break open inflame,
necrosis
alcohol completely reversible
3. tetracycline iv dose > 1.5 g/day
cirrhosis mortality
rate 70 80 %
4. valproate metabolite CYT P450
-4-valproic acid potent
microvesicular fat accumulation
Hepatocellular cholestasis :

hepatocellular cholestatic damage

chlorpromazine precipitate bile salts
total bile flow
TPN > 1 week serum albumin conc
3. Hypersensitivity : hepatocellular
cholestatic damage allupurinol
sulfonamide, penicillins, erythromycin
fever, rash, eosinophilia, hemolytic anemia
recover
4. Neoplastic disease : androgens,

estrogens, hormones polyvinyl Cl (angiosarcoma)

carcinoma sarcoma
rare instances

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8

Gastrointestinal disorder

1. : metabolised
methotrexate
niacin
(cirrhosis) , (ascites)
(hepatic encephalopathy)
2. : ADR
- > halothane ,
isoniazid , sulfonamides methyldopa
- >
flucloxacillin azathiopine
3.
-

Isoniazid , Halothane Nitrofurantoin

- 3 sodium valproate
enzyme inducers

aspirin

Reyesyndrome
steatosis

aspirin
juvenile arthritis
4. :
sodium valproate , phenytoin
5. :

- sodium valproate

- rifampicin isoniazid

6.
- tetracycline

- fibrosis
methotrexate

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9

- AIDS
Cotrimoxazole

Assessment
patients history
clinical tests

hepatic lesion biopsy

enzyme

ALT AST sensitive indicators

necrosis
R = magnitude of ALT elevation
compared to normal limit
magnitude of AP elevation
compared to normal limit

ALT = 400 u/l

(normal 0 35)
AP = 500 u/l (normal 35
130)
R =
400 / 35
=
2.97
500 / 130
Hepatocellular injury : ALT / normal limit > 2 times
R > 5 necrosis
Cholestatic injury : AP / normal limit > 2 times R
< 2 Hepatocellular
Mixed : ALT AP / normal limit > 2 times R = 2
5
jaundice / ALT or AST > 2 times
of normal limit / AP > 1.5 times
necessary drugs
Clinical available test hepatic function
serum proteins (albumin, transferin)
hepatic function serum proteins concentration

Ultrasound CT scans monitor

fibrosis vascular lesion hepatocellular
carcinoma

15
0

Gastrointestinal disorder
Hepatobiliary scaning lebeled Tc-99m

obstruction damage

Type of liver injury

- Acute : 3
- Chronic : 3 enzyme

elevation
- Severe : jaundice, PT not improve > 50%
vitamin K, hepatic encephalopathy
- Fulminant : normal severe

Signs and symptoms

Highly variable : LFTs

fulminant failure
Acute or Chronic
Other symptoms : fever, rash, arthralgia, nausea,
jaundice, abdominal complaints, lymphoagenopathy,
hepatomegaly and/or eosinophilia
Increased LFTs : AST, ALT, AP, bilirubin
Severe diseases : ascites, encephalopathy, esophageal
varices, death

An approach to evaluate a suspected

hepatotoxic reaction

1. sex, age, occupation, herbal drink, vitamin or

micronutrients, pregnant, other diseases, concomitant

drugs
2. onset of reaction
3.

4. reaction
5.
6. Rechallenge

7. biopsy results, MRI, CT, U/S pattern

enzyme elevation

Monitoring

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15
1
Monitor serum transaminases (AST, ALT) 4
characteristics of reaction
MTX monitor 4

biopsy 12 1

Example of drug induced hepatic disease

1. Isoniazid ( INH )

- 3-5 mg / kg / day
300 mg / day
- 1-2

acetylation

: aminotranferases
5

Isoniazid

rifampicin


cytochrome
P 450 dilantin

aminotranferases 3-5
monitor AST/ALT
35 , alcohol

Isoniazid

Gastrointestinal disorder

15
2

2. Rifampicin

Rifampicin
unconjucated hyperbilirubinemia

1 2

aminotranferases

- Rifampicin 10
mg / kg / day
- 600 mg / day
- Rifampicin

- , , ,

- Rifampicin
0 Isoniazid
2.7
Isoniazid 1.1

3.

Pyrazinamide
- 20-25 mg / kg / day
-

-
25-35 mg / kg / 3 day/wk
-
(
2 % 20 - 40 mg / kg / day
60 mg / kg / day
60 %)

4.

Ketoconazole

Ketoconazole

Ketoconazole
H-antagonist , antacid , anticholionergic

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15
3
propantheline oxyphencyclimine
didanosine alkaline buffer
ketoconazole cimetidine
ranitidine AUC ketoconazole 95%

Ketoconazole 2
Ketoconazole
gastric achlorhydria
84%
CSF
oxidation hydroxylation

2-4 %
ketoconazole aminotransferase
ALT AST alkaline phosphatase

drug induced hepatitis
ketoconazole 1-2

ketoconazole
systemic azole antifungal
liver function test
2-4

5. NSAIDs
- nontoxic
- Diclofenac (not hypersen) , Indomethacin :

hepatocellular
Sulindac : cholestatic mixed type
hypersensitivity
piroxicam, naproxen, ibuprofen,
nabumetone, tolmetin
- 6

- Symptomatic liver damage : rare 0.001 0.05 %

- Asymptomatic minor elevation of transaminases
15%

6. Paracetamol : overdose

15
4
-

7.

Gastrointestinal disorder
-
fulminant viral hepatitis
s/s, lab data : acute
(max abnormal LFT ~ 3 )
Toxic hepatitis 5 8 g/d
3 4 g/d
1 140 mg/kg
Early stage : apparent recovery 48 - 72

Recover case : rapid LFT

7 14
Severe : fulminant hepatic failure
jaundice, hyperventilation, cerebral edema, RF 3
6
Reactive metabolite (NAPQI) hepatocyte
covalent
N-acetylcysteine : precursor glutathione
dose 150 mg/kg iv infusion over 15 min >> 50
mg/kg infused over 4 hr >> 100 mg/kg infused over the
next 16 hr
severe liver damage 8
15

Phenytoin

- acute hepatocellular necrosis

cholestasis
- rashes,
lymphadenopathy, eosinophilia
immune
-
- 80 % : 6

8.

Carbamazepine
- 22 % mild to

moderate liver enzyme

6-8
- hepatic necrosis, cholestasis
-
- Overdose : direct hepatotoxic

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9.

15
5

Valproic acid
- transaminase 0 18 %
- Resolved completely dose 25 50 %
- Centriobular necrosis with or without

bile duct
- Sudden failure of seizure control, malaise, anorexia,
vomiting indicator liver damage
- Death : 3 180

10. Plavix (Clopidogrel) platelet

aggregation inhibitor

- PEAK CONCENTRATION : Peak level of major metabolite

2.6 mcg/mL single 75-mg dose
0.7-0.9 .
: 7-8 .
:
- bilirubinemia, fatty liver hepatitis
infection (rare; < 1%)
- 3 %
- metabolized

moderate-to-severe
mild-to-mederate cirrhosis
: (50%)
(46%)

11. Phenobarbital
: 600
: 2-5 , 40-70 . , 59400 .
:
-
monitor
-

- : mild hepatitis hepatic
injury (rare)
: 12-38%

12. Depakine (Na valproate)

15
6

Gastrointestinal disorder

: 60 mg / kg /day
: 6-17 .
12-18 .
:
-

- hepatitis, elevated liver function tests,

Serious hepatic failure, jaundice, hepatocellular, transient
elevated liver enzymes (SGPT/ALT, SGOT/AST) fatal
cholestatic hepatitis hepatotoxicity
2

fatal hepatotoxicity

: 70%-80%, 7%
2 to 18%

13. Miracid (Omeprazole)

: 360 mg / day
: 0.5-1 .
3 .
:
-
-

- hepatitis, hepatic failure, elevations in

ALT (alanine aminotransferase, or serum glutamic oxalocetic
transaminase (SGOT)), gamma glutamyl transpeptidase,
alkaline phosphatase, and bilirubin, jaundice (rare; <1%
)
: 77% metabolites,

14. Nexium (Esomeprazole Mg)

20
/
: 1.2 1.5 . 20
40 /
:

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7

- mild- tomoderate
20
-
aminotransferases
hepatotoxicity)
: 80% inactive
metabolites 1% parent drug,
20%

15. Motens (Lacidipine)

:
2 mg OD 4 mg/day

: 12 to 19 hours
:
- meatabolized 100%

- Transient and
generally clinically insignificant elevations in alanine
aminotransferase (ALT; SGPT), aspartate aminotransferase
(AST; SGOT), alkaline phosphatase, and serum bilirubin
( 1% ), cholestatic jaundice
: 30%, 70%

16. Hydrochlorothiazide

: 10-12 . uncompensated
congestive heart failure 28.9 .
:
- hypersensitivity type of
CHOLESTATIC JAUNDICE (rare)
- hepatotoxicity (rare)
:
50-70%

17. Renitec (Enalapril maleate)

: 40 mg / day , 0.58 mg
/ kg /day ( 40 mg / day)
: Enalapril prodrug
metabolized enalaprilat.
Enalapril 1.3 .
enalaprilat 5.9-35 .

15
8

Gastrointestinal disorder

:
- metabolized 70%
-
sudden onset of
cholestatic jaundice fulminant hepatitis
(rare; <0.1%)
- mild and
transient transaminases, lactic
dehydrogenase, alkaline phosphatase serum bilirubin
0.7%

- enalapril-induced
liver failure
: 61%
enalaprilat 43% unchanged enalapril 18%

enalaprilat 27 % enalapril 6 %

Drug dosing in patients with hepatic diseases

creatinine clearance Cockcroft-Gault equation

"Chlid-Pugh score"
5 serum bilirubin,
serum albumin, ascites, encephalopathy, prothrombin time

3

The Child-Pugh Score

Points
1
2
3
Encephalopat none
minimal
advanced
hy
(coma)
Ascites
absent
controlle refractory

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Total
bilirubin
(mg/dL)
Albumin
(g/dL)
Prothrombin
time (sec)

total score 5-8

total score 9-11
total score 12-15

less than
2
greater
than 3.5
less than
4

15
9
d
2-3
2.8-3.5
4-6

greater than
3
less than
2.8
greater than
6

grade A
grade B
grade C

hepatic metabolism/
excretion 20% parent drug
hepatic dysfunction
Child-Pugh score caspofungin
Child-Pugh core 5-6 mild
hepatic insufficiency
score 7-9 moderate hepatic
insufficiency loading dose 70 mg
maintenance dose 35 mg/day

LFTs (Liver function test)
baseline

Statins
MTX
Leflunomide
Sulfasalazine

Amiodarone
Cyproterone
Dantrolene
Rosiglitazone

Nevirapine
Rifampin
Na valproate
Methyldopa

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0

Gastrointestinal disorder

antiTB

FDA (
http://www.fda.gov/medwatch/safety.htm)
Regulatory actions due to DILI (1995-2006)
Withdrawals
Second Line
Warnings
bromfenac
felbamate
acetaminophen
troglitazone
tolcapone
leflunomide
pemoline
trovafloxacin
nefazodone
nevirapine
pyrazinamide/rifam
pin
terbinafine
valproic acid
zifirlukast
atomoxetine
interferon 1b 1b
and 1a
saquinavir
infliximab
bosentan
telithromycin
(kava, lipokinex)

,
Hepatitis (Drug induced Hepatic Disease)
3, 4

.. .. .
Interpretation of viral hepatitis profiles and Interpretation
and approach to abnormal LFT.
.
. 12 -13 2549
MICROMEDEX(R) Healthcare Series Vol. 121. Accessed
September 14, 2004.

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