Factors influencing drug-induced<unk>  * Age * Ethnicity and race * Gender * Nutritional status * Underlying liver disease * Renal function * Pregnancy * Duration and dosage of drug * Enzyme induction * Drug-to-drug interaction Drugs continue to be taken off the market due to late discovery of<unk> . Due to its unique metabolism and close relationship with the gastrointestinal tract, the liver is susceptible to injury from drugs and other substances. 75% of blood coming to the liver arrives directly from gastrointestinal organs and the spleen via portal veins that bring drugs and xenobiotics in near-undiluted form. Several mechanisms are responsible for either inducing hepatic injury or worsening the damage process. Many chemicals damage mitochondria, an intracellular organelle that produces energy. Its dysfunction releases excessive amount of oxidants that, in turn, injure hepatic cells. Activation of some enzymes in the cytochrome P-450 system such as CYP2E1 also lead to oxidative stress. Injury to hepatocyte and bile duct cells lead to accumulation of bile acid inside the liver. This promotes further liver damage. Non-parenchymal cells such as Kupffer cells, collagen-producing stellate cells, and leukocytes (i.e. neutrophil and monocyte) also have a role in the mechanism. Drug metabolism in liver Drug metabolism in liver: transferases are: glutathione, sulfate, acetate, glucoronic acid. P-450 is cytochrome P-450. Different pathways are shown for Drugs A, B and C. The human body subjects most, but not all, compounds to various chemical processes (i.e. metabolism) to make them suitable for elimination. This involves chemical transformations to (a) reduce fat solubility and (b) to change biological activity. Although almost all tissues in the body have some ability to metabolize chemicals, smooth endoplasmic reticulum in the liver is the principal "metabolic clearing house" for both endogenous chemicals (e.g., cholesterol, steroid hormones, fatty acids, proteins) and exogenous substances (e.g., drugs, alcohol). The central role played by liver in the clearance and transformation of chemicals makes it susceptible to drug-induced injury. Drug metabolism is usually divided into two phases: phase 1 and phase 2. Phase 1 reaction is generally speaking to prepare a drug for phase 2. However, many compounds can be metabolized by phase 2 directly or be excreted without any phase 2 reactions occurring. Phase 1 reaction involves oxidation, reduction, hydrolysis, hydration and many other rare chemical reactions. These processes tend to increase water solubility of the drug and can generate metabolites that are more chemically active and/or potentially toxic. Most of phase 2 reactions take place in cytosol and involve conjugation with endogenous compounds via transferase enzymes. Phase 1 are typically more suitable for elimination. A group of enzymes located in the endoplasmic reticulum, known as cytochrome P-450, is the most important family of metabolizing enzymes in the liver. Cytochrome P-450 is not a single enzyme, but rather consists of a closely related family of 50 isoforms; six of them metabolize 90% of drugs. There is a tremendous diversity of individual P-450 gene products, and this heterogeneity allows the liver to perform oxidation on a vast array of chemicals (including most drugs) in phase 1. Three important characteristics of the P-450 system have roles in drug-induced toxicity: :1. Genetic diversity: Each of the P-450 proteins is unique and accounts (to some extent) for the variation in drug metabolism between individuals. Genetic variations (polymorphism) in P-450 metabolism should be considered when patients exhibit unusual sensitivity or resistance to drug effects at normal doses. Such polymorphism is also responsible for variable drug response among patients of differing ethnic backgrounds. :2. Change in enzyme activity: Potent inducers Potent inhibitors Substrates Rifampicin, Carbamazepine, Phenobarbital, Phenytoin, St John's wort, Amiodarone, Cimetidine, Ciprofloxacin, Fluconazole, Fluoxetine, Erythromycin, Isoniazid, Diltiazem Caffeine, Clozapine, Omeprazole, Losartan,Theophylline Many substances can influence the P-450 enzyme mechanism. Drugs interact with the enzyme family in several ways. Drugs that modify cytochrome P-450 enzyme are referred to as either inhibitors or inducers. Enzyme inhibitors block the metabolic activity of one or several P-450 enzymes. This effect usually occurs immediately. On the other hand, inducers increase P-450 activity by increasing enzyme production, or, in the case of CYP2E1, preventing degradation in the proteasome. There is usually a delay before enzyme activity increases. :3. Competitive inhibition: Some drugs may share the same P-450 specificity and thus competitively block their biotransformation. This may lead to accumulation of drugs metabolized by the enzyme. This type of drug interaction may also reduce the rate of generation of toxic metabolites. Patterns of injury + Patterns of drug-induced liver disease Type of injury: Hepatocellular Cholestatic Mixed ALT ≥ Twofold rise Normal ≥ Twofold rise ALP Normal ≥ Twofold rise ≥ Twofold rise ALT: ALP ratio High, ≥5 Low, ≤2 2–5 Examples AcetaminophenAllopurinolAmiodaroneHAARTNSAID Anabolic steroidChlorpromazineClopidogrelErythromycinHormonal contraception Amitriptyline,EnalaprilCarbamazepineSulfonamidePhenytoin Chemicals produce a wide variety of clinical and pathological hepatic injury. Biochemical markers (e.g. alanine transferase, alkaline phosphatase and bilirubin) are often used to indicate liver damage. Liver injury is defined as a rise in either (a) ALT level more than three times of upper limit of normal (ULN), (b) ALP level more than twice ULN, or (c) total bilirubin level more than twice ULN when associated with increased ALT or ALP. Liver damage is further characterized into hepatocellular (predominantly initial Alanine transferase elevation) and cholestatic (initial alkaline phosphatase rise) types. However they are not mutually exclusive and mixed types of injuries are often encountered. Specific histo-pathological patterns of liver injury from drug-induced damage are discussed below. Zonal Necrosis This is the most common type of drug-induced liver cell necrosis where the injury is largely confined to a particular zone of the liver lobule. It may manifest as a very high level of ALT and severe disturbance of liver function leading to acute liver failure. :Causes include: :Paracetamol, carbon tetrachloride Hepatitis In this pattern, hepatocellular necrosis is associated with infiltration of inflammatory cells. There can be three types of drug-induced hepatitis. (A) viral hepatitis is the most common, where histological features are similar to acute viral hepatitis. (B) in focal or non-specific hepatitis, scattered foci of cell necrosis may accompany lymphocytic infiltration. (C) chronic hepatitis is very similar to autoimmune hepatitis clinically, serologically, and histologically. :Causes: :(a) Viral hepatitis: Halothane, isoniazid, phenytoin :(b) Focal hepatitis: Aspirin :(c) Chronic hepatitis: Methyldopa, diclofenac Cholestasis Liver injury leads to impairment of bile flow and cases are predominated by itching and jaundice. Histology may show inflammation (cholestatic hepatitis) or it can be bland (without any parenchymal inflammation). On rare occasions, it can produce features similar to primary biliary cirrhosis due to progressive destruction of small bile ducts (vanishing duct syndrome). :Causes: :(a) Bland: Oral contraceptive pills, anabolic steroid, androgens :(b) Inflammatory: Allopurinol, co-amoxiclav, carbamazepine :(c) Ductal: Chlorpromazine, flucloxacillin Steatosis<unk>  may manifest as triglyceride accumulation, which leads to either small-droplet (microvesicular) or large-droplet (macrovesicular) fatty liver. There is a separate type of steatosis by which phospholipid accumulation leads to a pattern similar to the diseases with inherited phospholipid metabolism defects (e.g., Tay–Sachs disease) :Causes: :(a) Microvesicular: Aspirin (Reye's syndrome), ketoprofen, tetracycline (especially if expired) :(b) Macrovesicular: Acetaminophen, methotrexate :(c) Phospholipidosis: Amiodarone, total parenteral nutrition :(d) Antiviral: nucleoside analogues :(e) Corticosteroid :(f) Hormonal: Tamoxifen Granuloma Drug-induced hepatic granulomas are usually associated with granulomas in other tissues and patients typically have features of systemic vasculitis and hypersensitivity. More than 50 drugs have been implicated. : Causes: :Allopurinol, phenytoin, isoniazid, quinine, penicillin, quinidine Vascular lesions These result from injury to the vascular endothelium. :Causes: :Venoocclusive disease: Chemotherapeutic agents, bush tea :Peliosis hepatis: Anabolic steroids :Hepatic vein thrombosis: Oral contraceptives Neoplasm Neoplasms have been described with prolonged exposure to some medications or toxins. Hepatocellular carcinoma, angiosarcoma, and liver adenomas are the ones usually reported. :Causes: :Vinyl chloride, combined oral contraceptive pill, anabolic steroid, arsenic, thorotrast
Hepatotoxicity
Cardiotoxicity
Phototoxicity
Lipotoxicity
Nephrotoxicity
Neurotoxicity
Pulmonary toxicity
Bone marrow suppression