DRUGS AND LIVER

dr. Agung Wiwiek Indrayani,

M.Kes
Faculty of Medicine
Dept of Pharmacology
Udayana University
LIVER AND ITS FUNCTION
DRUGS AND THE LIVER
Pharmacokinetic Changes
Systemic circulation

Liver

Portal System

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Pharmacodynamic Changes
Toxic effect of drugs or chemical
substance in the liver
CHOLESTATIC JAUNDICE
(ASA, Erythromycin Estolat, Penicillin,
Sulfonamid, Methyl Testosteron, Chlorpropamid,
Chlorpromazine)

HEPATOCELLULAR REACTION
predictable type
unpredictable type

CARCINOGENESIS
( Nitrosamin, Aflatoxin )
 Predictable Type
Dose related, > treshold dose, can repeate in animal testing
have relation with bilirubin metabolism
- Novobiocin, Derivat testosteron

Have relation with cell liver

- Carbon tetrachloride, tetracycline,
paracetamol, chloroform, anticancer drugs
Unpredictable Type

Not dose related, just happen in view people ,

cannot repeat in animal testing
HEPATITIS LIKE REACTION
- MAO INHIB, HALOTHANE,CHLOROFOM
CHOLESTATIC INJURY
- PHENOTHIAZINE ( CPZ), CHOLRPROPAMIDE,
THIOURACIL

GENERALIZED DRUG ALLERGIES

- PENICILLIN , SULPHONAMIDE, PAS, PHENYTOIN,
IMIPRAMINE
DRUG INDUCED LIVER INJURY
* TYPE A (Augmented) if increase of the dose
- CENTRIZONAL NECROSIS ( paracetamol ,
carbon tetrachloride )

- HEPATOCELLULER NECROSIS
( salicylate > 2 g/day )

- FATTY LIVER AND HEPATIC FAILURE

( tetracycline > 2 g/day oral )

- HEPATITIS
( Alkohol >>, Amiodarone > 600 mg/hari)
* TYPE B ( BIZARRE) in theraupeutic dose
- ACUTE HEPATOCELLULAR NECROSIS
( Halothane, Carbamazepine, Phenytoin, SOD
Valproate, Phenobarbitone, MAO, INH,
Indomethacine, Ibuprofen, Isoniazid,
Nitrofurantoin, Methyl-Dopa, Hydralazine)

- CHOLESTATIC HEPATITIS
( Chlorpromazine, OAD, Carbimazole,
Erythromycin, Gold )
* TYPE C ( CONTINUED USE)
- CHRONIC ACTIVE HEPATITIS
( Methyldopa, Isoniazid, Dantrolene,
Nitrofurantoin )
- HEPATIC FIBROSIS OR CIRRHOSIS
( Alcohol, MTX, Amiodarone )

* TYPE D ( DELAYED EFFECTS)

- BENIGN LIVER TUMOR
( Anabolic steroids, oral contraceptives > 5
years )
- Hepatocelluler carcinoma
Interfere with billirubin metabolism
Sulfonamide in new born

Novobiocin inhibit billirubin conyugation

Testosteron derivative interfere with billirubin

excretion
Generalized drug allergies
May occur with a wide range of drug
* Penicillin
* Sulfonamide
* PAS
* Phenytoin
 PRESCRIBING IN LIVER DISEASE

Impaired synthetic function:

* hypoalbuminemia, Coagulation impaired
Hepatic encephalopathy
Fluid retention/ renal impairment
Be careful with the drug that has:
* high hepatic extraction
* high albumin binding
* low therapeutic ratio
* CNS depressant effect
Analgesics

Opiate : can precipitate hepatic encephalopathy

Codein : constipation, can precipitate hepatic
encephalopathy
Aspirin & NSAID:
* impaired renal function (fluid retention)
* precipitate GI bleeding
CNS depressant
Sedative, antidepressant, antiepilepsy should be
avoided
Chlormethiazole has a high hepatic extraction
Cardiovascular drugs
Non selective blocker (Propranolol or Nadolol)
Propranolol extensively extracted by the liver
Gastrointestinal drugs
Antacid that contain large quantities of sodium
can precipitate edema, ascites
Diuretic
Spironolacton
Frusemide
Spironolacton + Frusemide
Adjustment dose in Hepar Impairment
1. Adjustment of the initial dose
2. Adjustment of the maintenance dose
3. Special cautions
Dosage in liver disease

Depend on BSP retention

BSP retention < 5% (No Liver Damage)
BSP retention 5-25% (Mild Liver Damage)
maintenance dose decreased 25-50%
BSP retention 25-75% (Severe Liver Damage)
maintenance dose decreased 50-80%
BSP retention >75% (Very Severe Liver Damage)
maintenance dose decreased 80%
Drugs Used For The Dissolution of
Gallstones
Cholesterol is solubilized in aqueous bile by the
combined effects of bile acids and lecithin
mixed micelle
Cholesterol gallstones impaired bile salt
secretion
Oral therapy chenodiol & ursodiol
dissolving cholesterol stones
Chenodiol
inhibits the rate limiting enzyme of the
conversion of bile salts to cholesterol, HMG-Co
A reductase thus causing an increase in bile salt
excretion and a decrease in cholesterol secretion
diarrhea, increased serum aminotransferase

Ursodiol
causes the transprot of cholesterol in a liquid
crystal form and stabilize the canalicular
membranes of hepatocytes
fewer side effects, more expensive
 Other drugs
* Methyl tert butyl ether
dissolve cholesterol stones in gallbladder
and bile ducts when it is infused via a catheter
directly into the gallbladder or bile duct lumen
*Monoctanoin
(glyceryl-1 monoctanoate)
via catheter to dissolve retained bile
duct stones