Farmakoterapi Obat sistem hepato-bilier

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LIVERLIVERLiver blood flow a portal vein (80) nutrients amp xenobiotics from GIT

b hepatic artery (20) oxygen metabolite amp circulating xenobiotics

potentially suffer from intoxication

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LIVER

Physiological role

Nutrients metabolism carbohydrates lipids and proteins

Synthesis and secretes bilewater ions lipids (bile salts) and bile pigments

(bilirubin)

Synthesis protein enzymesalbumin cytochrome P450s transaminase

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LIVERLIVER

Nutrient metabolism

a Carbohydrate metabolism synthesis glycogen from glucose and reverse

b Lipid metabolismtriglyceride FFA HDL LDL VLDL

c Protein metabolismenzymes albumin amino acid

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LIVER

xenobiotic metabolism

a enhance excretionby change any substance become polar hydrophilic

b inactivate detoxicationit is often (but not always) achieved sometime activation

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Parasetamol

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

conjugation

(sulphate or glucuronate)

renal excretion renal excretion

7 ndash 10 90 ndash 93

NABQI hepatotoxic

glutathione

oxidation

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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 Hepatitis1 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

bull Acid bile chelator bull Bind to acid bile in the intestine lumen block acid bile reabsorption

serum bilirubin pruritusbull Unpleasant tastebull May causes diarrhea and abdominal

discomfortbull If pruritus is not controlled by

cholestyramine antihistamine is recommended

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Corticosteroids

bull May have a benefit in cholestasis secondary to hepatitis-A viral infection(not for other type of viral hepatitis)

bull May suppress RES decrease self protection toward infection

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Chronic active hepatitis

bull Autoimmune hepatitis characterized by histopathological feature chronic hepatitis presence of autoantibody

bull 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

bull A pathological features caused by irreversible chronic injury of the hepatic parenchyma

bull Extensive fibrosisin association with regenerative nodules

bull As a final common pathwayof many types of chronic liver injury

bull Clinical featuresreflect the severity of hepatic damage rather than the etiology of underlying liver diseases

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Clinical features of Clinical features of

Liver cirrhosisbull Loss of functioning hepatocellular mass

jaundice edema coagulopathy metabolic abnormalities

bull Fibrosis and distorted vasculature portal hypertension and its sequelae(gastroesophagel varices and splenomegaly)

bull Ascites and hepatic encephalopathy resulted from both hepatocellularinsufficiency 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 hepatitishepatocyte degeneration and necrosis ballooned cells infiltrate alcoholic hyaline

3 Alcoholic cirrhosisdestruction of hepatocytes and fibroblast collagenization

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Liver cirrhosis

bull 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 cirrhosisbull 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

bull Edema and ascites- mobilise intraperitoneal fluid decrease Na+ dietary intake

(1 ndash 15 gday 40 ndash 60 mmolday)

- diuretics (furosemide or spironolacton if needed)

avoid dehydration if diuretic is used

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bull 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

Liver cirrhosis

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HEPATOTOXICITY

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Manifestation of HEPATOTOXICITY

Fatty liver2 Hepatitic reactions 3 Obstructive jaundice cholestatic jaundice

4 Liver necrosis5 Liver cirrhosis6 Liver cancer

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1 Fatty Liver1 Fatty Liveruptake FFA + glycerol triglyceride +

phospholipidscholesterolprotein

VLDL- triglyceride- chlolesterol- phospholipid- protein

Increase in- FA synthesis- triglyceride synthesis

Defect of - lipid metebolism- protein synthesis

Fatty liver

ethionine CCl4

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Drug induced Fatty LiverDrug induced Fatty Liver

1 Carbontetrachloride (CCl4)2 Tetracycline3 Ethionine 4 Ethanol chronic5 Phalotidine alkaloids

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2 Hepatitic Reactionxenobiotics

haptens

hepatocytes hypersensitive reactions

hepatitic reaction

symptoms

reactive metabolite

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3 Intrahepatic cholestasis(non dose dependent)

1 Carbimazole methylthiouracil (antithyroiddrugs)

2 Benzodiazepines (anxiolytics anticonvulsant)

3 Clavulanic acid (b-lactamase inhibitor)

4 Imidazole (ie ketokonazole antimycotics)

5 Sulphonylurea (oarl antidiabetics tolbutamideglibenclamide chlopropamide)

6 Tricyclic antidepressants (imipramine amitryptiline desipramine iprindole)

7 Phenothiazines (ie 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 4 Drug Drug toxin inducedtoxin inducedLIVER NECROSIS

1 Aflatoxin2 INH3 Carbontetrachloride4 Paracetamol5 Chloroform 6 Tetracycline7 Dinitrophenol8 Ethionine9 Halothane10 Ibuprofen11 Indomethacin12 Amanita phaloides

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Liver NecrosisLiver NecrosisParasetamol

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

conjugation(sulphate or glucuronate)

renal excretion renal excretion

7 ndash 10 90 ndash 93

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NABQI (n(n--acetylbenzoquinoneimineacetylbenzoquinoneimine))

NABQI

binding (covalent) to celluler hepatic proteins

damage endoplasmic reticulumswelling mitochondriadestruction of nucleus

mesruption of plasma membrane

cell necrosis

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Acute hepatocellular damage (non dose dependent)(non dose dependent)1 INH pyrazinamide rifampicin

(antituberculosis)2 Carbamazepine (muscle realxant

anticonvulsant)3 Halothane (inhalant general anesthetics)4 Imidazole (ie ketokonazole antimycotics)5 Ibuprofen indomethacin (NSAIDs)6 Methyldopa (antihypertensive)7 MAO inhibitor (ie desipramine

antidepresant)8 Barbiturate (hypnotics anticonvulsant)7 Sulfonamide (sulfamethoxazol

chemotherapeutics)Create PDF files without this message by purchasing novaPDF printer (httpwwwnovapdfcom)

1 Alcohol (beverage)2 Amiodarone (cardiac stimulant)3 Azatrioprine (antiviral)4 Chlorambucil (alkylating agent ndash for CLL)5 Hydrocarbons (glue glue sniffing)6 Overdose iron salt (antianemics)a7 Methotrexate (antimetabolite antifolic acid ndash for cancer)8 Acetaminophen (analgesics ndash antipyretics)7 Tetracycline (intravenous large dose)

Acute hepatocellular damage ( dose dependent)( dose dependent)

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CHOLELITHIASIS(Gallbladder stone)

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bull Previous cholecystitis bull Rapid weight loss during treatment of overweight morbid-obesity cholesterol is the main substance forms the stone

bull Ursodiol decrease cholesterol secretion into the bile decrease intestine cholesterol absorption increase bile flow cholesterol stone disolve

bull Opioid analgesics analgesia increase duct smooth muscle tonemasking effect stone captures duct rupture spasmolytics (hyoscin papaverin)

bull Antibiotics antiinflammatory drugs

CHOLELITHIASIS

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Navarro V J et al N Engl J Med 2006354731-739

Drug Induced Liver Injury andIts Patterns

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Navarro V J et al N Engl J Med 2006354731-739

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

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Navarro V J et al N Engl J Med 2006354731-739

Diagnosis of Drug-Related Hepatotoxicity

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Navarro V J et al N Engl J Med 2006354731-739

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

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TerimaTerima kasihkasihhelliphelliphelliphellip

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