FARMAKOLOGI

ENTEROHEPATAL

NOOR WIJAYAHADI

Functions
**Plays an essential role in the
metabolism of CHO, fat, protein, and
drugs.**

Other Functions
1) Storage of vitamins and trace elements
2) Conversion of beta-carotene, folate,
and vitamin D to their active form
3) Bile formation and excretion
4) Sodium and water homeostasis

Anabolic functions
1) Control of blood glucose:
glycogenesis, glycogenolysis,
glycolysis, gluconeogenesis.
2) Protein and amino acid metabolism:
synthesis of a number of proteins;
albumin, transferrin, prealbumin,
retinol-binding protein, coagulation...

3) Lipid metabolism: synthesis of

triacylglycerols, lipoproteins,
cholesterol, LCAT, and bile acids.

Catabolic functions
1) Oxidation of fatty acids: energy source
2) Detoxification of ammonium and drugs
3) Phagocytosis of bacteria and endotoxin
from the GI tract
4) Conjugation and excretion of bilirubin
5) Catabolism of aldosterone

Nutrient storage
1)
2)
3)
4)
5)

Glycogen
Fat-soluble vitamins
Vitamin B12
Magnesium
Metals: zinc, iron, copper

Conversion
1)
2)
3)
4)

Carotene vitamin A
Folate 5-methyltetrahydrofolate
Pyridoxine pyridoxal-5-Phosphate
Vitamin D 25-hydroxyvitamin D

Homeostatic function
1) Water and sodium homeostasis
2) Maintenance of normal plasma volume

Diseases of the liver

Hepatitis
Inflammation of the liver.
Caused by virus, bacteria, toxins,
obstruction, parasites, or
chemicals.
Viral hepatitis: caused by viruses
A, B, C, D, or E; may have up to 10
more viruses.

Common Symptoms
Jaundice
Dark urine
Anorexia
Fatigue
Headache
Nausea
Vomiting

Hepatomegaly
Splenomegaly
Bilirubin,
alkaline
phosphate,
and serum AST
are all
elevated.

Hepatitis A Virus
Hepatitis A:
Highly contagious.
Resolves within weeks.
Does not become chronic.
80% of cases in children remain
asymptomatic.
In adults,1/3 of cases develop
jaundice.
Lowest in 40 years!

Contamination:
Drinking water
Food (especially seafood)
Sewage
No special treatment
occasionally hospitalized.
Rarely get acute liver failure.

Hepatitis B Virus
Transmitted through
Blood or blood-derived fluids
Improperly sterilized medical
instruments, dental drills
Tattooing needles
Other skin-puncturing
instruments that has comes in
contact in contaminated blood.

Treatment
Acute hepatitis: similar to HAV.
Chronic hepatitis: several antiviral
drugs available.
Regularly monitoring, see if
disease is progressing, identify
liver damage or cancer.

Hepatitis C (HCV)
Exposed to blood or bodily fluids from
an infected persons.
Sharing needles
Recipient of blood clotting factor
before 1987.
Hemodialysis patients, infants born to
infected mothers
Cannot be prevented by vaccination.

Symptoms of acute viral

hepatitis
Four-seven days:
Anorexia
Nausea
Vomiting
Up to 30 days:
Abdominal tenderness
Jaundice
Leukopenia

Other symptoms:
Fatigue
Malaise
Changes in smell or taste sensation
Headache
Photophobia
Diarrhea

During acute illness:

Protein/energy requirements depends
on the degree of catabolism.
Anorexia/vomiting: smaller meals,
more frequent.
TEN or TPN should be considered.
Fluid balance needs to be monitored
carefully; patients with severe
hepatitis may not excrete a water
load.

Chronic hepatitis
Chronic hepatitis is defined as the
persistence of liver injury, without
improvement, for longer than six
months.
Carries the risk of cirrhosis, liver
cancer, liver failure.

Symptoms
Asymptomatic
Portal hypertension
Bleeding from esophageal varices
Elevated bilirubin and hepatocellular
enzymes
Weight loss
Increased energy expenditure

Acute liver failure

Acute liver failure is often caused by
drug toxicity or viral hepatitis.
Symptoms:
Massive liver cell necrosis
Cardiopulmonary dysfunction
Marked coagulation disorders
Renal failure
Cerebral edema

People with previously existing liver

disease suddenly develop rapidly
progressive liver failure.
Even if patients are in good nutritional
status of the start, they tend to develop
protein-energy malnutrition within 7-10
days.

Impaired liver function results in a

increase in aromatic amino acids and a
decrease in branched-chain amino
acids.
So, patients who require hemodialysis
for the treatment of renal failure must
be careful to replace amino acids.

Once the patient has recovered,

start to restore nutritional status
by using basic healthy eating
principles.
Note: high mortality rate lately
rate has been improved.
Patients with liver failure also has a
wide variety of complications

They include:
1. Encephalopathy: a nonspecific
term describing a syndrome
affecting the brain.
Generally, it refers to involvement of
large parts of the brain (or the
whole organ), instead of
identifiable changes confined to
parts of the brain.

2. Cerebral edema: accumulation of

excessive fluid in the substance of
the brain. The brain is especially
susceptible to injury from edema,
because it is located within a
confined space and cannot expand.
Also known as brain edema, brain
swelling, swelling of the brain, and
wet brain.

3. Renal failure: the condition where

the kidneys fail to function
properly.
Renal failure is described as a
decrease in the glomerular
filtration rate. This manifests in an
elevated serum creatinine.
Either acute renal failure and chronic
renal failure.

4. Hypoglycemia: a medical term

referring to a pathologic state
produced by a lower than normal
amount of glucose in the blood. The
term hypoglycemia literally means
"low blood sugar".

5. Metabolic acidosis: a state in which

the blood pH is low (under 7.35)
due to increased production of H+
by the body or the inability of the
body to form bicarbonate (HCO3-)
in the kidney.

6. Sepsis: a serious medical

condition caused by a severe
infection.
The more critical subsets of sepsis
include severe sepsis (sepsis with
acute organ dysfunction) and
septic shock (sepsis with
refractory arterial hypotension).

7. Coagulopathy: a medical term for a

defect in the bodies mechanism for
blood clotting.
While there are several possible
causes they generally result in
excessive bleeding and a lack of
clotting.

All patients should be managed in an

intensive care unit and they may
need to perform a liver transplant.
Why? Thats the only treatment that
greatly improve patient outcome
greater than 80% one-year survival
rate.

Alcoholic liver disease

Can be classified into three types:
a)Fatty infiltration of the liver
(steatosis): 80% of heavy drinkers.
b)Alcoholic hepatitis: 10-35%.
c)Fibrosis* and or cirrhosis*: 10%.

 Fibrosis: formation or development

of excess fibrous connective tissue
in an organ or tissue as a reparative
or reactive process.

 Cirrhosis: chronic disease of the liver;

liver tissue is replaced by connective
tissue, resulting in loss of liver function.
Caused by damage from toxins
(including alcohol), metabolic problems,
chronic viral hepatitis or other causes.
Is irreversible, but treatment of disease
will slow down or halt the damage.

Cirrhosis depends on both the

amount and duration of alcohol
intake.
How much? Controversial
associated with the daily
consumption of more than 40 g
absolute alcohol over many years.
Women absorb about 30% more
alcohol than men for the same
amount consumed. So

More susceptible to:

hepatic damage
More likely to relapse after treatment
More likely to progress to cirrhosis

 Alcoholic liver damage is increased

in those drinking of empty stomach
for drinking multiple different
alcoholic beverages.
Less damage, however, when
drinking beer, compared with drinks
with a high concentration of alcohol.

Pathogenesis and complications of

alcoholic liver disease
a) Alcohol dehydrogenase is contained in
the lining of the stomach and in the
liver. Catalyzes the oxidation of ethanol
to acetaldehyde
Even more toxic than ethanol, is
responsible for many of the hangover
symptoms.
Quickly converted to NADH. acetic acid
and other harmless molecules.

High levels of alcohol may not allow the

processing of NADH to keep up.
Can lead to a number of metabolic
consequences (esp. low food intake).
Build-up of intermediates:
acetaldehyde from the alcohol
dehydrogenase reaction is extremely
toxic and may cause several kinds of
damage.

Such as
Free radical production lipid
peroxidation
Increased production of cytokines
Binding to phospholipids
Interference with mitochondrial
electron transport
Inhibition with nuclear repair
Interference with microtubule
function

b) Redox alteration:
Decreased NADP shifts redox state
of hepatocytes, increased fatty acid
synthesis and inhibition of oxidation.
Decreased pyruvate glucose: may
cause hypoglycemia
Increase conversion to lactate: risk of
developing acidosis

c) Oxidant stress: formation of several

free radicals species, can cause
oxidative damage to the liver.
Injury to hepatocytes by lipid
peroxidation
Worse if excess drinking leads to a
depletion of antioxidants: vitamin A,
E, and glutathione.

d) Hypoxia: ethanol consumption has

been associated with a
hypermetabolic state in liver and
increased oxygen consumption by
hepatocytes.
This causes hypoxia (lack of oxygen),
leading to depletion of ATP and
liver damage.

Non-alcoholic fatty liver disease

Wide spectrum of liver damage:
a) Steatosis: defined as a liver that
contains 5-40% of the livers
weight in triglycerides.
Hepatomegaly
Can be reversible
Not involve other hurdles
May still cause liver damage

Other symptoms:
Nausea
Vomiting

b) Non-alcoholic steatohepatitis (NASH):

Resembling alcoholic hepatitis, but
not due to alcohol
Overweight women
Associated with insulin resistance*
Very common, mild
May advance to cirrhosis and endstage liver disease

Treatment
Similar to Type II diabetes:
Correction of insulin resistance amount
central obesity,
Treatment of dyslipidemia*
Physical activity.

Dyslipidemia
Disorders of lipoprotein metabolism,
including lipoprotein overproduction or
deficiency.

Why do we get NAFLD?

Occurs when there is a imbalance
between lipogenic (fat producing) and
lipotrophic (decreasing the deposit of
fat) factors; insulin resistance plays
an important role.

Steatosis occurs when:

in free fatty acids of the stores in
the liver,
in liver synthesis of fatty acids,
in -oxidation of free fatty acids
because of mitochondrial damage,
triglycerides production from fatty
acids in the liver,
triglyceride removal from the liver.

Insulin resistance is associated with:

in fatty acids in the liver, which
circulating levels of fatty acids,
Hyperinsulinemia, which glycolysis
and triglyceride production.

After a while, the fatty acids in the

liver causes an cytochrome P-450,

This then production of free radicals

and lipid peroxidation of liver cells,

Eventually causes NASH and

cirrhosis.

Conditions associated with

development of NAFLD
1) Kwashiorkor:
Shortage of lipotrophic factors
(substances that have the ability
to remove and prevent fatty
deposits in the body)
Treatment: protein feeding

2) Obesity:
Fatty infiltration of the liver due to
lipolysis from the fat cells, get free
fatty acids to the liver.
Treatment: weight loss

3) Jejuno-ileal bypass:
Caused already by obesity, but worsened
by an increase in -oxidation,
decrease in lipotrophic factors, and
(possibly) bacterial overgrowth in the
liver.
Treatment: partly by repair (healing);
partly by gradual weight loss.

4) Total parenteral nutrition:

Patients who are on TPN for a long time
may develop hepatitis, cirrhosis, and
gallstones.

Treatment: balance carbohydratelipid source of energy. CHO should

not exceed 4 mg/ml per minute; not
greater than 30-40% of total
energy; and the energy:nitrogen
should be 150 cal:1 gram nitrogen.

Other causes of fatty liver disease

Drugs
Hepatotoxins
Metabolic or genetic factors
HIV
IBD
Diverticulosis with bacterial
overgrowth

Liver cirrhosis: end stage of a number of

different chronic liver disease
Characterized by:
Hepatocellular damage and necrosis of
hepatocytes
Fibrosis
Predispose to cancer

Early stages:
Asymptomatic, or
Clinical evidence of cirrhosis
complications decline in the
functioning of the liver.
Mean survival time: 1-5 years

Treatment is always aimed at

eliminating the underlying cause
Abstinence from alcohol
Adequate protein intake
Moderate weight reduction
Discontinuation in TPN
Control of serum glucose and lipid
levels

Assessment of nutritional status

Dietary intake
History of weight loss
Detection of edema and ascites
Assessment of somatic protein
reserves and body fat
Micronutrient deficiencies

PEM is more frequent than energy

malnutritioncommon
complications in liver cirrhosis.
In alcoholic liver cirrhosis, ascites
and hepatic encephalopathy are
more common than in patients with
non-alcoholic liver cirrhosis.

Nutritional abnormalities are present

in all patients with moderate or
severe alcoholic hepatitis.
Biochemical indices: creatinine-height
index, hemoglobin, cholesterol,
complement C4: theyre all low.

Malnutrition is multifactorial:
a. decreased dietary intake
b. increased nutrient losses
c. Alterations in substrate utilization and
energy expenditure

Nutritional
recommendations
for patients with
liver disease

Energy
Adequate energy intake is essential for
liver regeneration and prevent protein
catabolism.
Determining energy expenditure by
equations not very useful
Any of these requires increased EE:
Ascites
Malabsorption
Infections

Note: overfeeding of the

malnourished patients should be
avoidedmay cause
hyperglycemia, lipogenesis, CO2
production.

Protein
Estimated protein intake to maintain
nitrogen balance in liver
cirrhosis:1.0-1.2 g/kg/day.
Patients will tolerate a (relatively) high
protein intake so unless they show
signs of impending coma, proteins
should not be restricted.
Otherwisemay contribute to
protein catabolism, ammonia,
infection.

Patient with hepatic encephalopathy (the

occurrence of confusion, altered level
of consciousness and coma as a result
of liver failure)should be treated with
other methods such as lactulose before
starting protein restriction.

Lactulose: a synthetic sugar (fructose

and galactose) used in the treatment of
constipation and liver disease.
In treating hepatic encephalopathy,
lactulose helps "draw out" ammonia
(NH3) from the body.

Protein: start out at 0.5-0.6 g/kg per day;

advance by 0.25-0.5 g/kg per day until
target level is reached OR until
encephalopathy occurs.
Quality of protein is also important for
encephalopathy: increased intake of
vegetable protein in patients who are
unable to tolerate protein > 1 g/kg/day.

Why vegetable protein?

On the plus side:
Higher fiber intake (accelerates GI
transit time)
More favorable composition of amino
acids
Reduction in pH of the intestinal lumen
by promoting fermentation by intestinal
bacteria
Higher energy-to-nitrogen ratio

On the minus side:

May be poorly tolerated in some
individuals because of bloating, early
satiety, and flatulence so start
gradually!
In patients with protein intolerance,
BCAA can be given: 0.25 g/kg per day
promote nitrogen balance.

Carbohydrate
CHO: 50-60 % of energy intake.
Bedtime snack: may help prevent
breakdown protein.
Small, frequent meals for hypoglycemia.
Patients with insulin resistance or
diabetes should follow dietary
guidelines for diabetics.

Fat
Important energy source: make foods
more appetizing.
Only restricted when steatorrhea is
present.
Medium-chain triglycerides (MCT) can
replace some of the fats.

*Medium-chain triglycerides contain only

8-12 carbons:changes their physical
characteristics.
Much more water soluble; can be
absorbed across the small intestine
wall into the blood stream, not into
the lacteals.

Mainly, they are transported direct to the

liver via the portal vein.
They do not bind to fatty acid-binding
proteins, are not reesterified to
triglycerides, and are not packaged in
chylomicrons.

TPN: 50-60% CHO and 50-35% fat for

patients who cant tolerate protein.
IV fats should not exceed 1 g/kg/day.
Caution: should be used over 24-hour.

Sodium and fluid

We talked about ascites so sodium
restriction: 500-2000 mg/day,
depending on severity.
Fluid restriction: not necessary unless
sodium levels fall to below 120 mmol/l
AND weight continues to rise as a
result of fluid retention.

Vitamins
May be required in many patients with
advanced liver disease: thiamin, folate,
vitamin B6, and riboflavin are common.
In hypoglycemic alcoholic patient, thiamin
should be given before the glucose
load because the glucose may deplete
borderline thiamin and precipitates
Wernicke-Korsakoff syndrome and
Wernickes encephalopathy. *.

*Wernicke-Korsakoff syndrome: manifestation

of thiamin deficiency usually seen in individuals
suffering from alcohol.
*Wernickes encephalopathy: condition
characterized by confusion, involuntary eye
movement, unequal size of the pupils, ataxia,
and sluggishness.
*Nutrition Therapy & Pathophysiology, 2nd ed,
2011

Fat-soluble vitamin deficiency has been

reported in steatorrhea.
a) Vitamin K deficiency: increased
bleeding time increased GI
bleeding.
b) Liver ability to convert vitamin D to
active form is impaired: may
contribute to hepatic osteodystrophy.
Doesnt respond well to supplements.

Minerals
Deficiencies are known to occur in
patients:
Calcium steatorrhea
Potassium increased aldosterone
Potassium, calcium, magnesium, zinc:
diuretics

Nutritional support
Oral route is preferred choice, but
nausea, vomiting, early satiety, and
encephalopathy prevent sufficient
intake.
Frequent small meals: increased feeding
tolerance (reduced gastric emptying,
slow transit time, reduce gastric
accommodation, relaxation).
Otherwise enteral suppl., TEN or TPN.

Problems to enteral feeding:

GI bleeding
Intestinal obstruction
Pancreatitis
Patients with tense ascites
May not be able to tolerate required
volume of enteral feeding.

Nitrogen support by TPN is reserved for

patients who either have a
nonfunctional GI tract, or cant be fed
any other way.
Normally, either standard amino acids
solution or BCAA solutions.

CHO and fat are also added: standard

solutions of glucose (2 g/kg per day)
and TG (< 3 mmol/L).
Patient with fluid overload to be treated
with concentrated TPN.

Hepatitis
After entry in the hepatocyte, the DNA of the hepatitis
virus is uncoated and brought to the nucleus.
There the DNA is transcribed and the resulting mRNA
is transported to the cytoplasm.
The viral genetic material is replicated by reverse
transcriptase and viral proteins are synthesized.
The viral DNA and proteins are assembled and
enveloped before exocytosis.
The resulting viremia can lead to either an acute viral
hepatitis (with or without fulminant hepatic necrosis) or
a chronic necro-inflammatory process.
The individuals immune response determines the level
injury from the viremia.

Interferons
Interferons (IFN-a 2a and IFN-a 2b) are compounds
that are produced via recombinant DNA technologies
in manipulated E. coli strains.
Interferons "mark" infected cells by binding to
receptors on the cell membrane of virus-infected cells
initiate the synthesis of antiviral proteins that work
via complex actions inside the cell to prevent viral
replication and activate the immune system.
The proportion of patients that will respond to
interferon therapy seems to depend on which hepatitis
infection is present (B, C, or D).
Frequently patients will experience fever, chills,
headaches, and myalgias with the initiation of therapy.
paracetamol is often co-administered with
interferon-a treatment.

Lamivudine for hepatitis B

Lamivudine is a drug with nucleoside reverse
transcriptase inhibitor (NRTI)-like properties.
It is an enantiomer of the NRTI drug zalcitabine (an
anti-retroviral agent).
1) competes for the reverse transcriptase activity
with the normal substrate
2) when incorporated in the viral DNA it terminates
chain elongation.
This effect has been shown clinically to have
inhibitory activity against hepatitis B.
The most frequently reported adverse effects are
headache, fatigue, nausea, and insomnia. Dosages
should be adjusted in patients with decreased
renal function

Ribavirin for hepatitis C

Ribavirin is a small purine nucleoside analog that
inhibits the replication of a variety of DNA and RNA
viruses.
the mechanism is not fully understood, it seems to
inhibit nucleic acid syntheis, perhaps via inhibition of
viral messanger RNA synthesis.
chronic therapy is associated with dose related
effects of anemia and bone marrow suppression
Common side effects include headache, tiredness,
muscle pain, fever and CNS disturbances such as
depression, insomnia, and anxiety.

Liver failure
The clinical presentation arise from many factors:
hepatitis, alcoholic liver disease, etc.
The end-result is cirrhosis and a fatty liver, which leads to
intrahepatic obstruction and decreased liver function.
Unfortunately there is no other treatment of liver failure
than transplantation. Instead, most patients receive
treatment for complications that arise as a result of liver
disease.
The complications of liver failure:
1. Increased pressure in the portal vein
2. Oesophageal varices.
3. Ascites portal hypertension, decrease in production
of albumin in the liver, decreased clearance by the liver
and hyperaldosteronism.
4. Encephalopathy: high circulating levels of ammonia
result from an increased ammonia uptake in the GI tract
and decreased conversion of ammonia in the liver

Ascites and treatment

Ascites is an abnormal accumulation of fluid
in the abdominal cavity.
The treatment :
1. Decreasing water and salt intake
2. Increasing the water and salt excretion by
the kidneys with the diuretic spironolactone
3. Paracentesis and albumin therapy.
4. Bypassing liver obstruction by placing a
TIPS (transjugular intrahepatic
portosystemic shunt), decreasing portal
hypertension

Encephalopathy
metabolic disorder arising in the CNS in patients with liver
failure.
associated with increased circulating levels of ammonia
(NH3)
Patients present with altered mental status, asterixis with
flapping tremor, confusion, disturbed day-night rhythm
and decreased motor ability.
The cause of hepatic encephalopathy is not known but is
probably multifactorial:
1. Increased uptake of ammonia from the GI tract.
a. Increased dietary protein intake
b. Resulting from absorption of blood from bleeding
oesophageal varices
2. Decreased conversion of ammonia into urea in the liver.
Normally, ammonia is converted into urea by the liver and
then excreted by the kidneys.
3. High circulating ammonia levels interfere in the CNS with
normal metabolic pathways resulting in encephalopathy

Treatment of encephalopathy
Treatment is aimed at decreasing the intake and
uptake of ammonia.
Different opportunities:
1. Lowering ammonia uptake by decreasing the
protein intake via the diet. (less meat, cheese etc.)
2. The laxative lactulose is broken down in the GI
lumen to form lactic and acetic acids, thereby
decreasing the pH in the colonic lumen. The resulting
increased presence of hydrogen ions binds the
ammonia and forms NH4+, which is not absorbed
from the colonic lumen.
NH3 + H+ = NH4+
3. Neomycin is an aminoglycoside antibiotic, which is
not broken down and barely absorbed by the GI tract.
Neomycin will eradicate the bacteria in the gastric
lumen that break down proteins to produce ammonia.

Esophageal varices
Therapy: 1. treatment of acute variceal
bleeding, 2. prevention of recurrent bleeding.
The acute treatment requires restoration of the
systemic circulation (if impaired), use of drugs
that reduce variceal pressure and flow
(vasopressin, somatostatin, octreotide) and
endoscopic sclerotherapy.
Preventing recurrent bleeding can be obtained
by repeated endoscopic sclerotherapy or band
ligation and/or the treatment with beta-blockers
that will reduce portal vein pressure.

Gallbladder
2 major functions:
bile storage
bile modification.

The bile produced by the liver is concentrated and

stored in the bladder.
Without food in the stomach the sphincter of Oddi
is closed and the bile remains in the gallbladder.
Upon arrival of food (containing lipids) in the
duodenum (1), the cells in the wall of the
duodenum release cholecystokinin (CCK) (2,3). Via
the circulation (4) CCK reaches the gallbladder
and stimulates contraction of the bladder (5). CCK
also relaxes the sphincter of Oddi (6), which
results in secretion of bile in the duodenum.
Bile salts break fat droplets; this is called
emulsification (7)

Cholelithiasis
When bile becomes too concentrated,
crystals can be formed.
Bile salts and phospholipids keep
cholesterol in a micelle solution.
shortage of bile salts or a surplus of
cholesterol, gall stones can be formed.
In cholelithiasis the crystals/stones are
small enough to pass through the bile duct.
If the crystals and stones become too large,
they can damage the wall of the gallbladder
and block the bile duct.

Cholecystectomy
Surgical treatment is the best option in case of
severe damage or inflammation of the gallbladder
by gallstones.
Surgical removal of the gallbladder (1,
cholecystectomy by laparoscopy) has no severe
impact on the digestive process. Bile production
continues, however, it is no longer concentrated
and its release in the duodenum is not closely tied
to food arrival in the stomach. The circulation of
bile salts is quicker and more fat is excreted via
the digestive tract.
Another non-pharmacological option to treat
gallstones is the non-invasive method lithotripsy
(2). In this case the gallstones are shattered by
focused sound waves.

Bile salts
In people with a functioning gallbladder, bile salts
(which act by desaturating cholesterol in the bile)
taken by mouth may dissolve gallstones
containing cholesterol. However, the process may
take 2 years or longer, and stones may return after
the therapy is ended
Medical dissolution, using urodeoxycholic acid is
successful in 40% of cases. This bile salt is used
for the dissolution of gall stones and for various
liver disorders. It suppresses hepatic cholesterol
synthesis and secretion.
For the treatment of liver disorders other
properties of urodeoxycholic acid are useful: it
reduces the toxic bile acids in bile, and it has
immunomodulating effects on the hepatocellular
membranes.

Pancreatitis

Depending on the cause and severity of the

pancreatitis, the pancreatic enzymes can affect
their own environment.
When proteases cannot be released into the
duodenum, they can cause damage and
destruction of the pancreatic tissue itself
(autolysis).
The decreased function of the pancreas can cause
fatty diarrhea and increased glucose levels (like in
diabetes).
Pancreatitis is accompanied by severe abdominal
pain.
An inflammation of the pancreas can have various
causes. In acute pancreatitis, gallstones and
alcohol account for 70 % of cases.

Pancreatitis

Many drugs may give rise to pancreatitis:

- diuretics like furosemide and
hydrochlorothiazide
- antimicrobial drugs: tetracyclines,
sulphonamides, rifampicin, and metronidazole
- immunosuppressants: corticosteroids,
azathioprine and mercaptopurine
- oestrogens
- selective serotonin reuptake inhibitors (SSRIs)
- 5-acetylsalicylic acid agents (mesalazine and
olsalazine)
- miscellaneous: indomethacin, enalapril,
methyldopa, simvastatin, sodium valproate

Pancreatic enzymes
Pancreatin is a mixture of:
1. fat dissolving enzyme, lipase, which catalyzes
the hydrolysis of fats into glycerol and fatty acids
2. protein enzymes such as protease, that convert
protein into peptides and amino acids
3. enzymes like amylase that break down starch
and complex sugar molecules into smaller
carbohydrates like dextrins and glucose
Pancreatin tablets are prescribed for patients who
are unable to digest food properly because of an
insufficient amount of natural pancreatic
secretions

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organ hepar
hepar misalnya
misalnya pada
pada
sirosis
sirosis ..

Efek sakit parenchym hati

terhadap half -life berbagai obat
Half-life
memanjang
Amobarbital
Carbenicillin
Klorampenikol
Diazepam
Hexobarbital
Isoniazid
Lidocain
Meperidine
Meprobamate
Fenobarbital
Prednisone
Rifampin
Fenilbutazon*
Pentobarbital*
Tolbutamide*

Half-life tetap
Asam salisilat
Chlorpromazine
Dicumarol
Fenitoin
Fenilbutazone*
Pentobarbital*
Tolbutamide*
* Half-life
memanjang
atau tetap

AAlliirraann Dar
Daraahh ddii H
Haattii
Obat
Obat dengan
dengan angka
angka first-pass
first-pass atau
atau ratio-ekstraks
ratio-ekstraksii
tinggi
tinggi (hepar
(hepar melakukan
melakukan metabolisme
metabolisme besarbesarbesaran
besaran bahkan
bahkan lebih
lebih dari
dari jumlah
jumlah obat
obat bebas
bebas dlm
dlm
plasma
plasma dan
dan eritrosit)
eritrosit) a.l.:
a.l.: propranolol,me
propranolol,meperidine
peridine
dan
dan lidocain,
lidocain, akan
akan mengalami
mengalami perubahan
perubahan
kadar
kadar plasma
plasma yg
yg cukup
cukup bermakna
bermakna dgn
dgn
adanya
adanya perfusi
perfusi organ
organ yang
yang menurun
menurun
(aliran
(aliran darah
darah lewat
lewat hepar
hepar berkurang).S
berkurang).Sebaliknya
ebaliknya
tidak
tidak demikian
demikian halnya
halnya dgn
dgn obat
obat yg
yg ratio
ratio ekstraksiekstraksinya
nya rendah.a.l.
rendah.a.l. antipyrine,
antipyrine, ratio-ekstraks
ratio-ekstraksinya
inya 0.1.
0.1.
(Lidocain
(Lidocain 0.9).
0.9).
Obat
Obat semacam
semacam lidocain
lidocain ini
ini disebut
disebut
liver
liver blood-fow
blood-fow dependen
dependentt..

EEffeekk ttookksik
sik oobbaatt tteerrhad
hadaapp hhaattii
Toksisitas
Toksisitas obat
obat dpt
dpt terjadi
terjadi o.k
o.k over-dosis
over-dosis hiperhipersensitivitas,atau
sensitivitas,atau berhubungan
berhubungan dengan
dengan
metabolit
metabolit nya.
nya. Beberapa
Beberapa obat
obat penting
penting
berpotensi
berpotensi toksik
toksik thd
thd hepar.
hepar.
Hepatitis
Hepatitis akut:paracetamol
akut:paracetamol
(Acetaminophen)
(Acetaminophen) ,tetrasiklin,Isoniazid,salisilat,
,tetrasiklin,Isoniazid,salisilat,
ethanol,ferrosulfas
ethanol,ferrosulfas (dosis
(dosis besar).
besar).
Cirrhosis:
Cirrhosis: MTX,arsen,ethanol.
MTX,arsen,ethanol.
Cholestasis:Estrogen.
Cholestasis:Estrogen.
Neoplasma:kontrasepsi
Neoplasma:kontrasepsi oral
oral

Efek
Efek toksik
toksik obat
obat terhadap
terhadap
hati
hati
Selain
Selain karena
karena over-dosis,toksisitas
over-dosis,toksisitas dapat
dapat
terjadi
terjadi karena
karena hipersensitivitas.
hipersensitivitas.Secara
Secara
klinis
klinis maupun
maupun histologis
histologis manifestasinya
manifestasinya
dpt
dpt berupa
berupa penyakit
penyakit
hepatoseluler,cholestasis
hepatoseluler,cholestasis atau
atau gabungan
gabungan
keduanya.Secara
keduanya.Secara klinis
klinis bisa
bisa berupa
berupa
hepatitis
hepatitis akut
akut atau
atau kronik
kronik aktip.
aktip.
Mekanisme
Mekanisme reaksi
reaksi tersebut
tersebut tidak
tidak diketahui
diketahui
dengan
dengan pasti.
pasti.

Interaksi farmakodinamis obat

Pada keadaan sakit hepar, furosemide atau
thiazide menimbulkan kehilangan kalium
dan alkalosis
yang memicu timbulnya
ensefalopati hepatik.Demikian juga
morphin,sedatip analgetik dan tranquilizer.
Hipoglikemik drug memicu koma
hipoglikemikum .
Kemampuan memproduksi faktor
penjendalan berkurang pada penyakit hepar,