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The drug therapy of

gastrointestinal, hepatic,
and billiary disorder


azalia arif - fkui
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Hematemesis vomiting of blood or altered
blood indicates bleeding proximal to
ligament of Trietz

Melena altered blood per rectum (>100 mL
blood required for one melenic stool),
usually indicates bleeding of Treitz, but may
be as distal as ascending colon;
pseudomelena may be caused by ingestion
of iron, bismuth, licorice, beets, blueberries,
charcoal

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Hematochezia bright red or maroon rectal
bleeding, usually implies bleeding beyond
ligament of Trietz but may due to rapid
upper intestinal bleeding (>1000mL)
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Ascites and edema

accumulation of fluid within the peritoneal
cavity. Small amounts may be
asymptomatic; increasing amounts cause
abdominal distention and discomfort,
anorexia, nausea, flank pain and respiratory
distress

retention of sodium and water occurs in
chronic liver disease for variety of reasons

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Pathogenesis

contributing factors :
- portal hypertension
- hypoalbuminemia
- increase hepatic lymph formation
- renal sodium retention secondary to
hyperaldosteronism, increase sympathetic
nervous activity (renin-angiotensin
production)


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Initiating events may be peripheral arterial
vasodilation triggered by endotoxin and
cytokines and mediated by nitric oxide;
result in decrease effective plasma
volume and activation of compensatory
mechanisms to retain renal Na and preserve
intravascular volume.

In severe ascites, plasma atrial natriuretic
factor levels are high but insufficient to
cause natriuresis
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Management of hepatic oedema and ascites
Low diet salt and diuretics

salt usually moderate restriction (to 80
mmol/day
advising patient not to add salt to thei
food

diuretics
spironolactone (100-400 mg/day), is
still a drug of choice
an aldosterone antagonist
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if spironolactone not fully effective, can
be combined with furosemide
care should be taken not produce too
brisk diuresis

precipitating acute electrolyte
disturbances

hepatic encephalopathy
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Therapy should be monitored by :
- daily weighing
- weight loss should be not > 0.5 kg/day
with ascites alone and
> 1.0 kg/day if there is peripheral oedema

If hypokalemia does not respond to
spironolactone add K supplement

In resistant ascites large-volume
paracentesis is required
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Spironolactone
antagonist aldosterone (aldosterone causes Na
retention), directly increases Na+ excretion and
decreases K
+
secretion in distal convulated tubule
indikasi : use with thiazides for edema, cirrhosis
hepatis, and nephrotic syndrome
S.E : hyperkalemia, Na and water depletion

given orally, excreted unchanged in kidney, can
be used in patients with hepatic insufficiency
C.I : anuria, substantial renal insufficiency,
hyperkalemia. Avoid in diabetics
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Furosemide
inhibits chloride reabsorption in thick
ascending loop of Henle. High loss of K
+
in
urine
indications : prefered diuretics in patients
with low GFR and hypertensive
emergencies. Also edema, pulmonary
edema, and to mobilize large volume of
fluid.

S.E : hyponatremia, hypokalemia,
hyperglycemia, hyperuricemia,
hypocalcemia, ototoxicity, hypomagnesemia,
hypochloremic alkalosis, hypovolemia
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Hepatic encephalopathy
a state of disordered CNS function associated with
severe acute or chronic liver disease; may be
acute and reversible or chronic and progressive

Precipitant
- GI bleeding (100 mL= 14-20 gr of protein)
- azotemia
- constipation
- high-protein meal
- hypokalemic alkalosis
- CNS depressant drugs (benzodiazepin and barbiturate)
- hypoxia, sepsis
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Treatment
Remove precipitant
Reduced blood anemia by decreasing protein intake
Enema /cathartics to clear gut
Lactulosa (converts NH3 to NH4
+
, produces diarrhea,
alters bowel flora) 30-60 mL
In refractory cases : add neomycin 0,5-1 gr bid
Flumazenil, benzodiazepine antagonist, may have a
role in management of hepatic encephalopathy
precipitated by benzodiazepine use
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Neomycin
aminoglycoside antibiotics
bactericidal inhibitors of protein synthesis
clinical use : to reduce g.i.t flora
preoperatively
to reduce amonia-producing
bacteria in patients with hepatic
coma

S.E : nephrotoxic, topical dermatitis

phkinetics : topical, not well absorbed
systemically
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Flumazenil

- antagonist benzodiazepin

- action blocks many of the action of
benzodiazepin

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Acute bleeding from gastro-oesophageal varices

acute variceal bleeding is a medical
emergency
blood losses should be placed immediately

the diagnosis should be confirmed as soon
as possible endoscopy
octreotide reduces bleeding from varices

sclerotherapy is the treatment of choice
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Terlipressin is given in a single IV dose of 2 mg,
repeated every 4-6 hour until
bleeding stop or

Vasopressin is given by IV infusion over 20 min in
a dose of 20 i.u in 100 mL of 5%
dextrose

Propranolol is effective in preventing primary
bleeding from varices
the dose of propranolol for this
conditionis 40-160 mg b.d
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Portal hypertension
an increase in portal vein pressure due to
anatomic or functional obstruction to blood
flow in the portal venous system

normal vein pressure is 5-10 mmHg

Indicators of portal hypertension are :
- intraoperative portal vein pressure > 30 cm
saline
- intrasplenic pressure of > 17 mmHg
- wedged hepatic vein pressure of > 4 mmHg
above IVC (inferior vena cava)
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Consequencies
1. increased collateral circulation between high-pressure
portal venous system and low pressure systemic venous
system

2. increased lymphatic flow

3. incresed plasma volume

4. ascites

5. splenomegaly, possible hypersplenism

6. protosystemic shunting (including hepatic encephalopathy)
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Treatment
control of acute bleeding
IV vasopressin up to 0.1-0.4 U/min until
bleeding is controlled for 12-24 hour (50-80%
success rate) than stop or taper;
add nitroglycerin up to 0.6 mg SL, can be
given IV or transdermal patch to prevent
coronary or renal vasoconstriction
maintain systolic BP > 90 mmHg
octreotide 50-259 mcg bolus + 50-250 mcg IV
infusion as effective as vasopressin with
fewer serious complication
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Vasopressin
- antidiuretic hormone polypeptide
- potent arterial vasoconstrictor
- IV in continous infusion splanchnic arterial
vasoconstriction

lead to reduced splanchnic arterial
perfusion and lowered portal
venous pressure
- prior to advent octreotide vasopressin
commonly use to treat acute variceal
hemorrhage
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- adverse effects :
- hypertension
- myocardial ischemia / infarction
- mesenteric infarction
- nausea, vomitus, abd. cramps, diarrhea

may be reduced by coadministered of
nitroglycerin

- antidiuretic effects water retention

hyponatremia, fluid retention
pulmonary edema
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Nitroglycerin
actions : reduces cardiac preload by reducing
venous tone blood pooling in the
periphery
indications : antianginal
S.E : hypotension and rebound tachycardia,
bradycardia , cerebral ischemia,
contact dermatitis, aggravation of
peripheral edema
phkinetics : SL, transdermal, topical,
interactions : alcohol, antihypertensive
agents, and vasodilators
increase risk of orthostatic
hypotension
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Propranolol
- block 1 and 2 adrenergic receptors
- indication : cardiosuppression in acute MI
and unstable angina
- S.E : transient hypertension due to
antagonism of 2 receptors (which
dilate large arteries) and reflex
response to decreased c.o,
bronchospasm
- PO, good CNS penetration more severe S.E
- C.I : severe diabetes, bradycardia, partial
heart block, heart failure, asthma,
emphysema

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Octreotide
- analog somastatin

- 45x more potent than somatostatin in
inhibiting GH release
- also useful for the acute control of bleeding
from esophageal varices, given for 3-5 days
- in patient with cirrhosis & portal
hypertension, IV somatostatin or octreotide
(50 mcg/day) reduces portal blood flow &
variceal pressurs mech of action ???

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Octreotide
- action may be mediated through inhibition
of glucagon release and other gut peptides

alter mesenteric blood flow
- very costly
- adverse effects : nausea, vomiting,
abdominal cramps, sinus tachycardia (25%),
conduction disturbances (10%)
- billiary sludge and gallstone may occur after
6 months of use 20-30% pats

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Chronic active hepatitis
- chronic viral hepatitis (h v types B and C),
involves a chronic immune inflammatory
response asymptomatic cirrhosis with
complication hepatocellular carcinoma
Treatment interferon-
- chronic hepatitis B, interferon may eliminate
could be combined with lamivudin
- in chronic hepatitis C, interferon plus
ribavirin give response to 50% of patients
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Drug treatment in gallstone

mostly cholesterol stones
pathogenesis is not clearly understood
chenodeoxycholic acid (10-15 mg/kg/day) and
ursodeoxycholic acid (8-10 mg/kg/day)
with long term treatment (3 months or
more) dissolve stones


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Drug and the liver
many drugs can cause hepatic damage (table)

Paracetamol
- liver damage associated with paracetamol overdose
is due to the formation of hepatotoxic
metabolite N-acetyl-p-benzoquinoneeimine


accumulate and bind to liver cell
irreversible damage
- liver damage can be prevented by providing
acetylcysteine
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Isoniazid (INH)
- long term treatment with INH can cause
liver damage ( 15%)
- a small number chronic active hepatitis
- liver damage cause by metabolite
- INH acetylisoniazid

acetylhydarzine reactive metabolite

bind to liver protein cause liver
damage
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Drug that can cause intrahepatic cholestasis
(table)
chlorpromazine hypersensitivity reaction

it starts with week 1-4; fever, chills, itching,
nausea and vomiting due to conjugation of
the drug metabolite with liver cell proteins

cholestatic jaundice oral contraseptive,
estrogen and corticosteroids

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Hepatoprotective
many plants have hepatoprotective effects

1. Milk thistle (Silybum marianum)
- alkaloids from the seed (silymarin,
silychristin and silydianin)
- inhibit the entrance of toxins and block
toxin-binding site through alteration of the
liver cells outer membrane
- silymarin increases gluthatione production
by the liver, intestines and stomach
Gluthation is used for detoxification cells in
the liver
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- silybinin decreases hepatic and mitochondrial
glutathione oxidation induced by iron
overload and is a mild chelator of iron

- silymarin stimulate RNA polymerase I in the
cell nucleus of the hepatocytes

increase of ribosomal protein synthesis and
the regenerative activity of the liver


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Licorice (Glycyrrhiza glabra)
antiviral/antifungal effects
- glycyrrhizin supresses the secretion of
hepatitis B virus (HBV) surface antigen
(HbsAg) in patients with HBV
- the compound is thought to bind to
hepatocytes at a concentration able to modify
the expression of HBV-related antigens on the
hepatocytes ans suppress sialylation of HbsAg
- glycyrrhizin stimulates interferon gamma
produced by T-cells for an antiviral effect
against influenza virus infection

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- C.I : - chronic hepatitis
- cholestatic diseases of the liver
- severe renal insuficiency
- diabetes
- arrhythmia
- hypertension
- hypertonia
- hypokalemia and pregnancy
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Curcuma (Curcuma xanthorrhizia)
- root contains curcuminoids curcumin
- approve by Commission E :
- liver and gall bladder complains
- loss of appetite
- in Indonesia it has long been used for liver
and gallbladder complaints
- it should not be administered if there is a bile
duct blockage.
colic can occur when the patient suffers
from gallstones

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