drug induced hepatitis (2)

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DRUG INDUCED HEPATITISDr.M.Sharmila Assistant Professor M7 (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 HEPATOTOXICITYDamage 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 (enzymedrug) 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 (enzymeinducing effects) Starvation (Depletion of hepatic glutathione) Environmental factors Genetic effects

DIAGNOSISBy 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 Ferrous sulphate Sodium valproate,Tetracyclines

Zone 1 necrosis Microvesicular fat


Amiodarone,Synthetic oestrogens,NifedipineMethotrexate,Other cytotoxic agents,Arsenic,Vitamin A,Retinoids

TYPES OF LIVER DAMAGEVASCULARSinusoidal dilatation Contraceptive drugs,Anabolic steroids,Azathioprin Oral contraceptives,Anabolic steroids, e.g. Danazol,Azathioprin Pyrrolizidine alkaloids (Senecio in bush tea),Cytotoxics cyclophosphamide

Pelioses hepatis


TYPES OF LIVER DAMAGEAcute 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 DAMAGECanalicular cholestasis Sex hormones, Ciclosporin A

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

TYPES OF LIVER DAMAGEBiliary sludge Sclerosing cholangitis Ceftriaxone Hepatic arterial infusion of 5-fluorouracil Pills with high hormone content (adenomas) Contraceptive pill,Danazol

Hepatic tumours

Hepatocellular carcinoma

TYPES OF LIVER DAMAGEGeneral Sulphonamides hypersensitivity

Sulfasalazine, Co-trimoxazole,Fansidar Flucloxacillin,Ampicillin, Amoxicillin,Co-amoxiclav Salicylates,Diclofenac Allopurinol

Penicillins NSAIDs

Antithyroid Quinine

Propylthiouracil, Carbimazole Quinidine

DiltiazemAnticonvulsants 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 BuddChiari 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 firstpass 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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