drug induced hepatitis (2)

DRUG INDUCED HEPATITIS

Dr.M.SharmilaAssistant ProfessorM7 (Prof CR unit)Institute of Internal Medicine

DRUG METABOLISM

The liver is the major site of drug metabolism

Drugs are converted from fat-soluble to water-soluble substances that can be excreted in the urine or bile

Mediated by a group of mixed-function enzymes

DETOXIFICATION Conjugation with glucuronide and

sulphate Microsomal enzymes produce toxic

derivatives that are immediately detoxified by conjugation with glutathione

Saturation of the former and glutathione depletion in drug overdose produce hepatic damage

DRUG HEPATOTOXICITY

Damage to the liver by drugs is usually classified as

Predictable (or dose-related) Non-predictable (not dose-related)

MECHANISMS Disruption of intracellular calcium homeostasis Disruption of bile canalicular transport

mechanisms Formation of non-functioning adducts (enzyme-

drug) Presentation on the surface of the hepatocyte as

new immunogens (attacked by T cells) Induction of apoptosis Inhibition of mitochondrial function, which

prevents fatty acid metabolism, and accumulation of both lactate and reactive oxygen species

TYPES OF LIVER INJURY

Hepatitic Cholestatic Immunological [skin rashes, fever and

arthralgia (serum-sickness syndrome)]

Eosinophilia and circulating immune complexes and antibodies may be detected

CONTRIBUTING FACTORS

Chronic alcohol abusers (enzyme-inducing effects)

Starvation (Depletion of hepatic glutathione)

Environmental factors Genetic effects

DIAGNOSIS By exclusion of other causes. Most reactions occur within 3 months Monitoring liver biochemistry is advisable Suspected drug should be stopped

immediately Liver biopsy is of limited help in confirming

the diagnosis, but occasionally hepatic eosinophilia or granulomas may be seen

Diagnostic challenge with subtherapeutic doses of the drug is sometimes required to confirm the diagnosis

TYPES OF LIVER DAMAGEZone 3 necrosis Carbon tetrachloride,Amanita

mushrooms,Paracetamol, Salicylates,Piroxicam,Cocaine

Zone 1 necrosis Ferrous sulphate

Microvesicular fat Sodium valproate,Tetracyclines

Steatohepatitis Amiodarone,Synthetic oestrogens,Nifedipine

Fibrosis Methotrexate,Other cytotoxic agents,Arsenic,Vitamin A,Retinoids

TYPES OF LIVER DAMAGEVASCULAR    

Sinusoidal dilatation Contraceptive drugs,Anabolic steroids,Azathioprin

Pelioses hepatis Oral contraceptives,Anabolic steroids, e.g. Danazol,Azathioprin

Veno-occlusive Pyrrolizidine alkaloids (Senecio in bush tea),Cytotoxics - cyclophosphamide

TYPES OF LIVER DAMAGE

Acute hepatitis Isoniazid,Rifampicin, Methyldopa,Atenolol, Enalapril,Verapamil, Ketoconazole,Cytotoxic drugs,Clonazepam, Disulfiram,Niacin,Volatile liquid anaesthetics e.g.   Halothane

Chronic hepatitis Methyldopa,Nitrofurantoin, Fenofibrate,Isoniazid

TYPES OF LIVER DAMAGE

Canalicular cholestasis

Sex hormones, Ciclosporin A

Hepatocanalicular cholestasis

Chlorpromazine, Haloperidol, Erythromycin, Cimetidine/ranitidine, Nitrofurantoin, Imipramine, Azathioprine, Oral hypoglycaemics, Dextropropoxyphene

TYPES OF LIVER DAMAGE

Biliary sludge Ceftriaxone

Sclerosing cholangitis Hepatic arterial infusion of 5-fluorouracil

Hepatic tumours Pills with high hormone content (adenomas)

Hepatocellular carcinoma

Contraceptive pill,Danazol

TYPES OF LIVER DAMAGEGeneral hypersensitivity    

Sulphonamides Sulfasalazine, Co-trimoxazole,Fansidar

Penicillins Flucloxacillin,Ampicillin, Amoxicillin,Co-amoxiclav

NSAIDs Salicylates,Diclofenac

Allopurinol

Antithyroid Propylthiouracil, Carbimazole

Quinine Quinidine

Diltiazem

Anticonvulsants Phenytoin

PARACETAMOL

The toxic metabolite is N acetyl p benzoquinone

It binds irreversibly to liver cell membranes

In high doses paracetamol produces liver cell necrosis

HALOTHANE Produces a hepatitis in patients having

repeated exposures Mechanism is thought to be a hypersensitivity

reaction Unexplained fever occurs about 10 days later Jaundice, typically with a hepatitic picture Most patients recover spontaneously High mortality in severe cases No chronic sequelae Risk is smaller with enflurane and isoflurane

STEROIDS Cholestasis is caused by natural and synthetic

oestrogens as well as methyltestosterone Interfere with canalicular biliary flow and cause a

pure cholestasis

Contraceptive pill is associated with gallstones, hepatic adenomas (rarely HCCs), the Budd-Chiari syndrome and peliosis hepatis

Peliosis hepatis also occurs with anabolic steroids, consists of dilatation of the hepatic sinusoids to form blood-filled lakes

ANTI TUBERCULOUS DRUGS Isoniazid -Damage is due to the metabolites -Elevated aminotransferases -Hepatic necrosis with jaundice -Related to acetylator status Rifampicin -hepatitis, usually within 3 weeks in patients on

high doses. Pyrazinamide -abnormal liver biochemical tests, liver cell

necrosis

OTHER DRUGS Phenothiazines -(e.g. chlorpromazine) can produce a

cholestatic picture -Hypersensitivity reaction-Occurs within 4 weeks -Associated with fever,eosinophilia -Recovers on stopping the drug Amiodarone -steatohepatitis and liver failure

DRUG PRESCRIPTION Removal of many drugs depends on liver blood

flow and the integrity of the hepatocyte. Effect of drugs is prolonged by cholestasis Portosystemic shunting diminishes the first-

pass extraction of drugs With hypoproteinaemia there is decreased

protein binding of some drugs Bilirubin competes with many drugs for the

binding sites on serum albumin Drugs with a central depressant action to be

given cautiously in patients with portosystemic encephalopathy

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