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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
Thank YouThank You