Farmakoterapi Obat

sistem hepato-bilier

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 LIVER
Liver blood flow :
a. portal vein (80%)
 nutrients & xenobiotics from GIT

b. hepatic artery (20%)

 oxygen, metabolite & circulating xenobiotics

potentially suffer from intoxication

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 LIVER
Physiological role
* Nutrients metabolism
carbohydrates, lipids and proteins

* Synthesis and secretes bile

water, ions, lipids (bile salts), and bile pigments
(bilirubin).

* Synthesis protein enzymes

albumin, cytochrome P450s, transaminase
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 LIVER
 Nutrient metabolism :
a. Carbohydrate metabolism
synthesis glycogen from glucose and reverse

b. Lipid metabolism
triglyceride, FFA, HDL, LDL, VLDL

c. Protein metabolism
enzymes, albumin, amino acid

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 LIVER
xenobiotic metabolism :
a. enhance excretion
by change any substance become polar,
hydrophilic.

b. inactivate  detoxication
it is often (but not always) achieved,
sometime activation.

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 Parasetamol
7 – 10%
oxidation 90 – 93%

NABQI conjugation
(N-cetylbenzoquinoneimine) (sulphate or glucuronate)
glutathione
conjugation
(sulphate or glucuronate)

renal excretion renal excretion

NABQI : hepatotoxic

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 Liver Diseases - Disorders
1. Acute hepatitis (acute viral hepatitis, alcoholic
hepatitis)
2. Chronic hepatitis (chronic persistent hepatitis,
chronic active hepatitis  autoimmune type)
3. Liver cirrhosis (compensated and non-
compensated cirrhosis, liver cirrhosis
encephalopathy, cirrhosis edema and ascites,
bleeding from esophageal varices, and cirrhosis
renal failure)

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 Liver Diseases - Disorders

4. Special liver cirrhosis

(hemochromatosis, Wilson disease,
primary biliary cirrhosis)
5. Gallstones

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 Drugs in Hepatitis
1. Acute hepatitis
 Symptomatic teraphy
 cholestyramine,  reduce pruritus but may cause
hepatotoxicity  use this drug as it really needed
 corticosteroids  no benefit
 active immunization  hepatitis-B vaccine
 passive immunization  immune serum globulin
(HBIG)  effective?  side effects?

2. Chronic hepatitis
 corticosteroids or other immunosuppressant  avoid

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 Cholestyramine
• Acid bile chelator
• Bind to acid bile in the intestine lumen
 block acid bile reabsorption
serum bilirubin  pruritus
• Unpleasant taste
• May causes diarrhea and abdominal
discomfort
• If pruritus is not controlled by
cholestyramine  antihistamine is
recommended

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 Corticosteroids

• May have a benefit in cholestasis

 secondary to hepatitis-A viral infection
(not for other type of viral hepatitis)

• May suppress RES

 decrease self protection toward
infection

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 Chronic active hepatitis
• Autoimmune hepatitis
 characterized by histopathological
feature : chronic hepatitis, presence of
autoantibody
• Interferon-a
 inhibit viral replication (+ 40% of
chronic hepatitis-B)
 may cause influenza like symptom,
bone marrow suppression, depression,
irritable
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 LIVER CIRRHOSIS

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 Liver cirrhosis
• A pathological features
 caused by irreversible chronic injury of the hepatic
parenchyma

• Extensive fibrosis
in association with regenerative nodules

• As a final common pathway

of many types of chronic liver injury,

• Clinical features
reflect the severity of hepatic damage rather than the
etiology of underlying liver diseases

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 Clinical features of
Liver cirrhosis
• Loss of functioning hepatocellular mass 
jaundice, edema, coagulopathy, metabolic
abnormalities,
• Fibrosis and distorted vasculature
 portal hypertension and its sequelae
(gastroesophagel varices and splenomegaly)
• Ascites and hepatic encephalopathy
 resulted from both hepatocellular
insufficiency and portal hypertension

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 Alcohol induced hepatic lesion
1. Alcoholic fatty liver
accumulation of fat in the liver
 result from an impairment of fatty acid oxidation,
increase uptake and esterification to form
triglyceride and diminished lipoprotein biosynthesis

2. Alcoholic hepatitis
hepatocyte degeneration and necrosis  ballooned
cells, infiltrate  alcoholic hyaline
3. Alcoholic cirrhosis
destruction of hepatocytes and fibroblast 
collagenization

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 Liver cirrhosis
• compensated cirrhosis
- regularly reviewed for sign of hepatocellular
failure  serum analysis for LFT
- long term care includes control of ascites
- avoid drugs that induce coma
 do not give unnecessarily drugs

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 Liver cirrhosis
• decompensated cirrhosis
- diet should be as nutritious as possible.
 high protein diet
(provided that there is no evidence of precoma or
coma)
- oral vitamin K if there is high prothrombin time
 avoid unnecessarily drugs

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 Liver cirrhosis
• Edema and ascites
- mobilise intraperitoneal fluid
 decrease Na+ dietary intake
(1 – 1,5 g/day : 40 – 60 mmol/day)
- diuretics (furosemide, or spironolacton if needed)
 avoid dehydration if diuretic is
used

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 Liver cirrhosis
• Hepatic encephalopathy
- oral lactulose
 acidifying the colonic contents
(reducing absorption of ammonia and possible
toxins)
the dose is increased until desired effect is
obtained
- neomycin (reduce urease producing intestinal
bacteria)
 avoid unnecessarily drugs

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 HEPATOTOXICITY

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 Manifestation of
HEPATOTOXICITY

. Fatty liver
2. Hepatitic reactions
3. Obstructive jaundice
 cholestatic jaundice
4. Liver necrosis
5. Liver cirrhosis
6. Liver cancer

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 1. Fatty Liver
phospholipids
uptake FFA + glycerol triglyceride + cholesterol
protein
ethionine, CCl4
Defect of :
- lipid metebolism
- protein synthesis

Increase in
- FA synthesis
- triglyceride synthesis VLDL
- triglyceride
- chlolesterol
- phospholipid
Fatty liver - protein

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 Drug induced Fatty Liver

1. Carbontetrachloride (CCl4)
2. Tetracycline
3. Ethionine
4. Ethanol chronic
5. Phalotidine alkaloids

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 2. Hepatitic Reaction
xenobiotics
reactive metabolite

haptens

hepatocytes hypersensitive reactions

hepatitic reaction

symptoms

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 3. Intrahepatic cholestasis
(non dose dependent)

1. Carbimazole, methylthiouracil (antithyroid

drugs)
2. Benzodiazepines (anxiolytics, anticonvulsant)
3. Clavulanic acid (b-lactamase inhibitor)
4. Imidazole (i.e. ketokonazole  antimycotics)
5. Sulphonylurea (oarl antidiabetics  tolbutamide,
glibenclamide, chlopropamide)
6. Tricyclic antidepressants (imipramine,
amitryptiline, desipramine, iprindole)
7. Phenothiazines (i.e. chlorpromazine 
antipsychotics)

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 3. Intrahepatic cholestasis
(dose dependent)

1. Anabolic steroids (methyltestosterone,

norethindrolone)
2. Azatrioprine (antiviral)
3. Mercaptopurine (antimetabolite
 for acute leukemia)
4. Oestrogen (contraceptive agents)

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 4. Drug / toxin induced
LIVER NECROSIS
1. Aflatoxin
2. INH
3. Carbontetrachloride
4. Paracetamol
5. Chloroform
6. Tetracycline
7. Dinitrophenol
8. Ethionine
9. Halothane
10. Ibuprofen
11. Indomethacin
12. Amanita phaloides
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 Liver Necrosis
Parasetamol
7 – 10% 90 – 93%

NABQI conjugation
(N-cetylbenzoquinoneimine) (sulphate or glucuronate)

conjugation
(sulphate or glucuronate)

renal excretion renal excretion

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 NABQI (n--acetylbenzoquinoneimine
(n acetylbenzoquinoneimine))

NABQI

binding (covalent) to celluler hepatic proteins

damage endoplasmic reticulum

swelling mitochondria
destruction of nucleus
mesruption of plasma membrane

cell necrosis

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 Acute hepatocellular damage
(non dose dependent)
1. INH, pyrazinamide, rifampicin
(antituberculosis)
2. Carbamazepine (muscle realxant,
anticonvulsant)
3. Halothane (inhalant general anesthetics)
4. Imidazole (i.e. ketokonazole  antimycotics)
5. Ibuprofen, indomethacin (NSAIDs)
6. Methyldopa (antihypertensive)
7. MAO inhibitor (i.e. desipramine 
antidepresant)
8. Barbiturate (hypnotics, anticonvulsant)
7. Sulfonamide (sulfamethoxazol 
chemotherapeutics)
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 Acute hepatocellular damage
( dose dependent)

1. Alcohol (beverage)
2. Amiodarone (cardiac stimulant)
3. Azatrioprine (antiviral)
4. Chlorambucil (alkylating agent – for CLL)
5. Hydrocarbons (glue  glue sniffing)
6. Overdose iron salt (antianemics)a
7. Methotrexate (antimetabolite, antifolic acid
– for cancer)
8. Acetaminophen (analgesics – antipyretics)
7. Tetracycline (intravenous large dose)

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 CHOLELITHIASIS
(Gallbladder stone)

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 CHOLELITHIASIS
• Previous cholecystitis
• Rapid weight loss
 during treatment of overweight, morbid-obesity
 cholesterol is the main substance forms the stone
• Ursodiol
 decrease cholesterol secretion into the bile
 decrease intestine cholesterol absorption
 increase bile flow  cholesterol stone disolve
• Opioid analgesics
 analgesia, increase duct smooth muscle tone
 masking effect  stone captures  duct rupture
 spasmolytics (hyoscin, papaverin)
• Antibiotics, antiinflammatory drugs

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 Drug Induced Liver Injury and
Its Patterns

Navarro, V. J. et al. N Engl J Med 2006;354:731-739

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 Key Guidelines in the Recognition and Prevention of Hepatotoxicity in
Clinical Practice

Navarro, V. J. et al. N Engl J Med 2006;354:731-739

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 Diagnosis of Drug-Related Hepatotoxicity

Navarro, V. J. et al. N Engl J Med 2006;354:731-739

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 Key Elements of and Caveats in Assessing Cause in the Diagnosis of
Drug-Related Hepatotoxicity

Navarro, V. J. et al. N Engl J Med 2006;354:731-739

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 Terima kasih
kasih……
……

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