For professionals:

Metabolism of drug and toxic agent in the liver

• Induced by drugs and/or environmental chemical compounds.
  • There are 800 million chemical compounds.

  • Increasing with the rate of 7,000/week.

  • 63,000 kinds of chemical compounds are in common use.

  • 11,000 of them are food ingredients and drugs.

  • 55,000 of chemical compound: potential environmental pollusion.

• Main site of drug metabolism is in the liver, because the liver is abundant with enzymes and the substances absorbed from the intestines reach the liver directly.

• Biotrnasformation :
  • Mixed function oxidase (MFO) -- Cytochrome P- 450

  • Detoxication of toxic metabolites produced in the liver.

  • Heavy drinkers have more isoenzyme of cytochrome P- 450 production.

  • Metabolites of CCl₄, acetoaminophen, and isoniazide are hepatotoxic.

Drug induced and toxic liver diseases:

• Incidence:
  • Differ by the method used for estimation.

  • Account for about 2% of hospitalized patients with jaundice.

  • More in elderly individuals.

  • Account for 25% of acute liver failure patients.

  • Account for 25% of chronic active hepatitis patients.

• Classification:
  • Predictable --- dose related

  • Unpredictable --- dose unrelated, idiosyncrasy

• Predictable:
  • Reproducile in animals and damages particular site of hepatic lobules. It is a kind of direct hepatotoxicity.

  • Frequently induced by drug metabolites, and not caused by the toxicity of the drug itself.

• Unpredictable:
  • Induce masssive liver cell necrosis and cholestatic inflammatory reaction.

  • Unreproducible in animals.

  • Usually, related to the immune reaction of liver cells.

• Drug-induced liver disease occurs unrelated to the pre-existing liver diseases.

• Symptoms are non-specific, such as with the fever like that of viral origin.

• Because of these facts, on aggravation of symptoms, it is very difficult to differentiate between the deterioration or complication of the underlying liver disease and drug induced liver disease.

• New drugs are often not known about their liver toxicity, thus they should be used under careful observation.

• Rechallenge test to prove the causing drug is highly reliable, but it should not be recommended because of danger and immorality.

• Predictable drugs: Acetoaminophen, Paraquat, Tetracycline, Anabolic hormone

• Unpredictable drugs: Erythromycine, INAH, Halothane, Chlorpromazine

Type					Drugs	
1) Impaired liver function
	1.1 Microsomal enzyme induction	Phenitoin, Warfarin
	1.2 Hyperbilirubinemia		Flavasdic acid, Novobiocin, Rifampcin

2) acute hepatocyte necrosis
	2.1 Focal necrosis		Isoniazid, Cloxacilin, Halothane
	2.2 Bridging necrosis		Isoniazid, Alphamethyldopa, Phosphorus
	2.3 Zonal necrosis		Paracetamol, Halothane, Phosphorus
	2.4 Massive necrosais		Halothane, Valproic acid, NSAID

3)Fatty liver 
	3.1 Acute fatty change		Tetracycline, Valproic acid, NSAID,
					Corticosteroid, L-asparaginase
	3.2 Steatohepatitis		Perhexiline maleate, Amidodarone

4) Granulomatou change			Hydralazine, Allopurinol, Carmabazepine

5) Acute cholestatic type
	5.1 Without hepatitis		OCS, Anabolic androgen
	5.2 With hepatitis		Chlorpromazine, Erythromycin, 									Flucloxacillin
	5.3 With bile duct injury	Flucloxacillin, Chlorpromazine, 4,4'-
                                         diaminodiphenylmethane

6) Cholestatic type
	6.1 Vanishing bile duct 
		syndrome		Chlorpromazine, Flucloxacillin, 									Amitriptyline
	6.2 Sclerosing cholangitis	Intra-arterial 5-fluorodeoxyuridine

7) Chronic parenchymal injury
	7.1Chronic active hepatitis	Alpha-methyldopa, Nitrofurantoin, 									Dantrolene
	7.2 Fibrosis and necrosis	Methotrexate, Hypervitaminosis A

8) Vascular change
	8.1 Sinusoid widening		OCS
	8.2 Peliosis hepatis		Anabolic androgen
	8.3 Non-cirrhotic
           portal hypertension	        Vinyl chloride, Hypervitaninosis A, 									Azathioprine
	8.4 Hepatic venous 
           outflow obstruction	        6-thioguanine, OCS, Pyrrolizidine 									alkaloid
	8.5 Nodular regenerative
            hyperplasia	                Azathioprine, Actinomycin D
	8.6 Other vascular lesions	OCS

9) Liver tumor
	9.1 Hemangioma			OCS
	9.2 Focal nodualr hyperplsia	OCS
	9.3 Hepatic adenoma		OCS, Androgen
	9.4 Hepatocellualr carcinoma	OCS, Androgen
	9.5 Rare carcinoma 
              	Hepatoblastoma,		OCS
		Chlangiocarcinoma,
		Carcinosarcome				
	9.6 Hemoangiosarcoma		Arsenioc, Vinyl chloride, Thorium dioxide
	9.7 Epithelioid 
		hemoangioendothelioma	OCS