Drug-Induced Hepatotoxicity

ISBN-13: 9783642646577 / Angielski / Miękka / 2011 / 681 str.

Ross Cameron; George Feuer; Felix De La Iglesia

Opis

The advances in science and medicine we are now experiencing are unprec- edented and exciting. Life expectancy is prolonged, and quality of life is much improved. We learn of fabulous new discoveries made at the bench or the bedside every week. Many diseases have been totally eliminated, others can be significantly improved by new therapeutic formulations. Much of the success can be attributed to a better understanding of disease processes and the specific targeting of new and more effective medications. As is the case in many areas of successful human endeavour, there can be a downside. In the case of drugs and chemicals it is their adverse effects which are of concern. Of course, every effort is made to devise medications that are safe, and the need to elucidate and understand mechanisms are crucial, yet adverse effects remain a problem. They can be unpredictable and diverse. Drugs have been shown to induce virtually the whole gamut of human liver pathology from acute fulminant hepatitis to chronic active hepatitis to cirrho- sis and even malignancy. Hence the possibility of adverse drug effects must be considered in the differential diagnosis of many patients with liver disease. This is well recognized and is very important; indeed, removal of the offending agent can often lead to reversal of the adverse effect. This is an area of hepatology where we can really make a difference.

Spis treści

1: Orientation in Liver Toxicity by Drugs.- A. Introduction.- B. Agents and Processes.- C. Responses to Injury as Multitier or Multigrid Patterns.- I. Quantitative Versus Qualitative Changes.- II. Patterns of Liver Toxicity.- 1. Tier One: Patterns of Interactions of Agents with Liver.- 2. Tier Two: Patterns of Biological Responses to Cell Injury.- 3. Tier Three: Cellular and Intracellular Responses.- 4. Tier Four: Cellular and Tissue Physiology.- D. Conclusion.- References.- 2: Clinical Studies and Role of Necrosis in Hepatotoxicity (With 7 Figures).- A. Zonal Necrosis as a Response to Acetaminophen.- I. Zonality: Specific Hepatocytes Die as a Group.- II. Ethanol Plus Acetaminophen: Extension of Zone of Necrosis.- III. Constitutive Bases of Zonal Responses.- 1. Perivenous Localization of Acetaminophen-Metabolizing enzyme CYP 2E1.- IV. Zonal Hepatocellular Necrosis: Historical Perspective.- B. Regeneration in Response to Zonal Necrosis of Acetaminophen Overdose.- I. Regeneration of Periportal and Mid-zonal Hepatocytes to Restore the Perivenous Zone.- C. Clinical Implications of “Adaptive” Perivenous Necrosis.- References.- 3: Subcellular Biochemical and Pathological Correlates in Experimental Models of Hepatotoxicity (With 5 Figures).- A. Introduction.- B. Organization of the Liver Cell.- C. Liver Cell Injury.- D. Subcellular Organelle Pathology.- I. Endoplasmic Reticulum.- 1. Membrane Structure.- 2. Cytochrome P450 System.- 3. Proliferation and Induction.- 4. Structure-Activity Relationships.- 5. Membrane-Bound Phospholipids.- II. Golgi Apparatus.- III. Intracellular Membrane Dynamics.- IV. Mitochondria.- V. Lysosomes.- VI. Peroxisomes.- E. Biochemical Pathology of Subcellular Changes.- I. Cell Respiration.- II. Protein Metabolism.- III. Lipid Metabolism.- IV. Bile Secretion.- F. Latent Hepatotoxicity Models.- G. Conclusions.- References.- 4: Molecular Biology of Hepatic Drag Reactions (With 6 Figures).- A. Introduction.- B. General Considerations.- C. DNA Damage.- I. Drugs and DNA Metabolism.- II. DNA Replication and Repair Pathways.- D. Inhibition of DNA Replication.- I. Inhibition of DNA Polymerases.- II. Inhibition of DNA Ligase.- III. Chain Termination.- IV. Inhibition of DNA Repair.- V. Alterations in Purine/Pyrimidine Metabolism.- VI. Alterations in DNA Processing Post Synthesis.- E. Damage to RNA.- F. Interference with Protein Synthesis.- G. Apoptosis.- H. Future Developments.- I. Summary and Conclusions.- References.- 5: In Vitro Models of Liver Toxicity (With 4 Figures).- A. Introduction.- I. Metabolism of Foreign Compounds Can Cause Zone-Specific Hepatotoxicity.- II. Advantages and Disadvantages of Whole Cell Models.- B. Techniques Used to Study Zone-Specific Hepatotoxicity in the Isolated Perfused Liver.- I. Metabolite Measurements in Tissue and Perfusate.- II. Microlight Guides.- III. Miniature Oxygen Electrodes.- IV. Trypan Blue Exclusion.- C. Applying In Vitro Models to the Study of Liver Toxicology.- I. Monooxygenation in Periportal and Pericentral Zones of the Liver Lobule.- II. Conjugation Reactions in Periportal and Pericentral Regions of the Liver Lobule.- 1. Sulfation.- 2. Glucuronidation.- III. Oxygen as a Determinant of Zone-Specific Hepatotoxicity.- D. Conclusions.- References.- 6: Cytochromes P450 and Liver Injury (With 4 Figures).- A. Drug Biotransformation, Cytochromes P450 and the Liver.- I. Drug Biotransformation by the Liver.- II. General Drug Biotransformation Processes.- III. Phase I Reactions.- IV. Introduction to the Cytochromes P450.- B. Cytochromes P450 and Drug Biotransformation.- I. Human Hepatic Cytochromes P450.- II. Sources of Variability in P450 Expression and Activity.- 1. P450 Genetics and Polymorphisms.- 2. P450 Induction.- 3. P450 Inhibition.- 4. Liver Disease: Effects on Drug Biotransformation.- II. Reaction Mechanism.- III. Drug Biotransformation and Drug Toxicity.- 1. Cytochrome P450 and Bioactivation.- 2. Activation/Detoxification Balance.- 3. “Probe Drugs” for Determining P450 Activities in Humans In Vivo.- C. Mechanisms of P450-Mediated Liver Injury.- I. Reactive Metabolites.- 1. Noncovalent Interactions.- 2. Covalent Adduct Formation.- II. P450s as Targets of Immune Effectors.- D. Specific Drugs/P450s and Liver Injury.- I. Acetaminophen.- II. Halothane.- III. Tienilic Acid.- IV. Dihydralazine.- V. Diclofenac.- E. Conclusions.- References.- 7: Mechanisms of Drug-Induced Cholestasis.- A. Definition of Cholestasis.- B. Mechanisms of Canalicular Bile Formation.- I. Transport of Bile Acids.- II. Transport of Inorganic Ions and Glutathione.- III. Other Mechanisms.- C. Mechanisms of Cholestasis.- I. Alterations in Basolateral Membrane Function.- II. Alterations in Canalicular Membrane Function.- III. Alterations in Intracellular Events.- 1. Binding to Intracellular Proteins and Conjugation Enzymes.- 2. Cytoskeleton.- IV. Permeability Changes in the Biliary Tree.- 1. Altered Permeability of the Junctional Complex.- 2. Altered Permeability of the Canalicular Membrane.- 3. Alterations in Membrane Proteins.- 4. Alterations in Membrane Composition and Function.- D. Drugs and Other Chemicals Inducing Cholestasis.- I. a-Naphthylisothiocyanate.- II. Androgenic and Estrogenic Steroids.- III. Bile Acids.- IV. Chlorpromazine and Other Phenothiazines.- V. Cyclosporine.- VI. Miscellaneous Cholestatic Agents.- References.- 8: Fatty Liver and Drugs (With 1 Figure).- A. General Mechanisms for Fatty Liver.- B. Drugs Provoking Fatty Liver.- I. Drugs Provoking Fatty Liver by Increasing FFA Supply to the Liver.- II. Drugs Provoking Fatty Liver by Intrahepatic Mechanisms.- 1. Drugs Increasing Intrahepatic FFA Synthesis.- 2. Drugs Provoking Fatty Liver by Decreasing Fatty Acid Oxidation.- 3. Drugs Blocking Lipoprotein Secretion.- III. Drugs Decreasing Fat Infiltration in the Liver.- References.- 9: Choline Deficiency: An Important Model for the Study of Hepatotoxicity (With 2 Figures).- A. Introduction.- B. Hepatotoxicity by Dietary Manipulation - Not by Addition but by Depletion.- C. Absence of Choline in an Otherwise Complete Diet — An Excellent Model for the Study of Liver Cell Death and Liver Cancer.- I. Choline Deficiency Model and Cell Death.- II. Choline Deficiency and Liver Cancer.- D. Lipotrope Deficiency Versus Choline Deficiency.- E. Step by Step Development of Liver Aberration.- F. Hypothesis of Choline Deficiency Induced Hepatocarcinoma.- G. Conclusions.- References.- 10: Immune Mechanisms and Liver Toxicity (With 3 Figures).- A. Introduction and Overview of Drug-Mediated Hepatotoxicity.- B. Functional Aspects of the Immune System.- I. Immune Repertoire.- II. Major Histocompatibility Complex.- III. Afferent Limb of the Immune Response.- IV. Efferent Limb of the Immune Response.- V. Regulation and Dysregulation of Immune Responses.- C. Genetic Determinants of Adverse Drug Reactions.- D. Liver in Relation to Adverse Drug Reactions.- I. Intrahepatic Metabolism of Drugs by Microsomal Enzymes.- 1. Cytochrome P450 Oxidases (CYP450).- 2. UDP Glucuronosyl Transferases.- 3. Carboxyl Esterases.- II. Intrahepatic Immune Processes.- 1. Initiation of Immune-Mediated Drug Reactions in the Liver.- 2. Regulatory and Dysregulation of Intrahepatic Immune Reactions.- III. Infrequency of Hepatic Hypersensitivity Drug Reactions.- IV. Immunopathology of Hepatic Hypersensitivity Drug Reactions.- V. Drug-Altered Neoantigen - The Halothane Paradigm.- 1. Halothane Hepatitis.- 2. Immunological Investigations of Halothane Hepatitis.- 3. Detection of Antibodies to TFA Conjugates.- VI. Native Liver Antigens - The Liver-Kidney Microsomal (LKM) System.- 1. Hepatitis with Anti-LKM-2.- 2. Identification of LKM as Cytochrome P450 Species.- 3. Antibodies to CYP 1A2 in Drug-induced Hepatitis.- 4. Inhibition of Enzyme Function by Anti-LKM.- 5. Origins of Anti-LKM Reactivity.- VII. Drug-induced Hepatitis with Reactions to Autoantigens.- E. Experimental Models of Drug-induced Immune-Mediated Disease.- F. Laboratory Investigation of Immune-Mediated Hepatic Drug Reactions.- I. General Laboratory Investigations.- II. Drug-Specific Immunological Investigations.- 1. Detection of T-Cell-Mediated Reactions.- III. Pharmacological Idiosyncrasy.- References.- 11: Hepatic Encephalopathy.- A. Introduction.- I. Clinical Manifestations of Hepatic Encephalopathy.- II. Neuropathological Changes in Hepatic Encephalopathy.- 1. Anatomy.- 2. Electrophysiology.- B. Involvement of Neurotoxins in the Pathogenesis of Hepatic Encephalopathy.- I. Ammonia.- 1. Glial Interactions.- 2. Electrophysiological Changes.- 3. Changes in Oxidative Metabolism.- 4. Summary.- II. Synergistic Neurotoxins.- C. Neurotransmitter Involvement in the Pathogenesis of Hepatic Encephalopathy.- I. y-Aminobutyric Acid.- 1. Electrophysiology.- 2. Neurochemistry and Pharmacology.- 3. Behavior.- 4. Summary.- II. Excitatory Amino Acids.- III. Aromatic Amino Acids and Monoamine Neurotransmitters.- D. Conclusions.- References.- 12: Liver Drug Reactions and Pregnancy.- A. The Liver in Normal Pregnancy.- I. Liver Histology.- II. Liver Perfusion and Function.- B. Effects of Pregnancy on the Risk of Experiencing a Drug-Induced Hepatic Injury.- I. Specific Pre-Marketing Risk/Benefit Evaluation of Drugs.- II. Risk of Exposure to Hepatotoxic Drugs.- III. Pharmacokinetics.- 1. Absorption.- 2. Distribution.- 3. Hemodynamics and Drug Clearance.- 4. Maternal-Placental-Fetal Unit.- IV. Liver Vulnerability.- C. Liver Drug Reactions Occurring Düring Pregnancy.- I. Antibiotics.- II. Antiemetics.- III. Anesthetics and Analgesics.- IV. Anticonvulsants.- V. Other Agents.- D. Clinical Presentation and Diagnostic Approach to Hepatic Injury in Pregnancy.- E. Treatment.- F. Prevention.- References.- 13: Pediatric Hepatic Drug Reactions.- A. Classification of Drug Hepatotoxicity.- B. Specific Drugs Causing Hepatotoxicity in Children.- I. Acetaminophen.- II. Phenytoin.- III. Valproic Acid.- IV. Isoniazid.- V. Halothane.- VI. Carbamazepine.- VII. Phenobarbital.- VIII. Antineoplastic Drugs.- IX. Pemoline.- X. Sulfonamides.- XI. Aspirin.- XII. Propylthiouracil.- XIII. Erythromycin.- XIV. Methotrexate.- XV. Estrogens: Oral Contraceptive Pill.- XVI. Ketoconazole.- XVII. Haloperidol.- XVIII. Amiodarone.- XIX. Nitrofurantoin.- XX. Retinoids.- XXI. Azathioprine.- XXII. Cocaine.- References.- 14: Reye’s Syndrome.- A. Introduction.- B. Clinical Features.- C. Laboratory Features.- D. Diagnostic Criteria for Population Surveys.- E. Liver Morphology.- F. Brain Morphology.- G. Liver Histology and Electron Microscopy in Reye’s Syndrome.- H. Pathophysiology.- I. Aspirin and Reye’s Syndrome.- J. Animal Models.- K. Reye’s Syndrome in Adults.- L. Treatment.- M. Sequelae.- References.- 15: Drug Hepatotoxicity in the Elderly (With 7 Figures).- A. Introduction.- B. Clinical Information.- I. Idiosyncratic Hepatotoxicity: The Swedish Experience.- II. Dose-Dependent Hepatotoxicity.- C. Age-Related Alterations in Hepatic Detoxifying Functions: Discrepancies Between Human and Animal Data.- I. Phase I Drug Metabolism.- II. Phase II Metabolism.- 1. Glucuronidation and Sulfation: Acetaminophen Conjugation.- 2. Glutathione S-Transferases.- III. Oxidant and Antioxidant Variables.- 1. Lipid Peroxidation.- 2. Glutathione.- 3. Antioxidant Enzymes.- D. Morbidity and Frailty as Major Factors for Lowered Drug Clearances in the Elderly: A Possible Role in Hepatotoxicity.- E. Adverse Drug Reactions in the Liver in Old Animals: Mini Review.- I. Hepatocyte Susceptibility to Chlorpromazine and Erythromycin Estolate.- II. Acetaminophen Hepatotoxicity: An Example of Variability of the Results in Studies Using Rodents.- III. Ethanol Metabolism in the Liver and Its Hepatotoxicity: Another Controversy.- IV. Hepatotoxicities by Other Toxicants.- F. Conclusions and Suggestions for Future Studies.- References.- 16: Effect of Liver Disease on Drug Metabolism and Pharmacokinetics (With 6 Figures).- A. Introduction.- B. Function and Structure of the Liver.- C. Types and Severity of Liver Disease.- I. Changes in Hepatic Function.- II. Changes in Hepatic Vasculature.- III. Changes in Renal Function.- IV. Ascites.- D. Pharmacodynamic Factors.- E. Pharmacokinetic Factors.- I. Linear Pharmacokinetic Models.- 1. One-Compartment Model, Intravenous Dosing.- 2. First-Order Absorption and Elimination.- 3. Repeated Dosing with Linear Pharmacokinetics.- II. Nonlinear Pharmacokinetic Models.- III. Impact of Liver Disease.- 1. Distribution Volume.- 2. Elimination Half-Life.- 3. Protein Binding.- 4. Presystemic Clearance.- F. Markers of Liver Disease Relevant to Drug Metabolism and Pharmacokinetics.- G. Examples of Effects of Liver Disease on the Pharmacokinetics of Some Drug Therapeutic Classes.- I. Cardiovascular Agents.- II. Drugs Acting on the Central Nervous System.- III. Antimicrobial Agents.- IV. Other Drugs.- H. Conclusions.- References.- 17: Liver Reactions to Tacrine (With 2 Figures).- A. Introduction.- B. Clinical Experience.- C. Metabolism of Tacrine in Humans.- D. Preclinical Toxicology.- E. Metabolism of Tacrine in Animals.- F. Cytotoxicity Studies.- G. In Vitro Metabolism Studies.- H. Conclusions.- References.- 18: Mechanisms of Hypertransaminemia (With 7 Figures).- A. Introduction.- B. Overview of Liver Transaminase Monitoring.- I. Significance of the Different Tests Used to Monitor Liver Function.- II. Spectrum of Drug-induced Hepatotoxicity and Hypertransaminemia.- III. Clinical Correlates of Transaminase Measurement.- 1. Sensitivity and Specificity of Hypertransaminemia.- 2. Correlation Between Severity of Hepatic Injury and Degree of Hypertransaminemia.- 3. Clinical Significance of Minor Degrees of Hypertransaminemia.- C. Classification of the Causes of Hypertransaminemia.- D. Mechanisms of Acute Hepatic Injury Leading to Hypertransaminemia.- I. Role of Drug Metabolism.- II. Evidence for the Formation of Chemically Reactive Metabolites.- III. Acute Chemical Hepatotoxicity.- 1. Acetaminophen Hepatotoxicity.- 2. Carbon Tetrachloride Hepatotoxicity.- IV. Acute Idiosyncratic Hepatotoxicity.- 1. Metabolie Idiosyncrasy Causing Hypertransaminemia.- 2. Immune-Mediated Drug-induced Hypertransaminemia.- E. Mechanisms of Chronic Hepatic Injury Causing Hypertransaminemia.- I. Chronic Chemical Hypertransaminemia.- II. Chronic Idiosyncratic Drug-induced.- Hypertransaminemia.- F. Diagnosis of Drug-induced Hypertransaminemia.- I. Distinction Between Drug- and Non-Drug-Induced Etiologies.- II. Distinction Between Direct and Immune-Mediated Acute Idiosyncratic Toxicity.- G. Conclusions.- References.- 19: Diagnostic Tools and Clinical Pathology.- A. General Features and Clinical Evaluation of Drug-induced Liver Diseases.- B. General Mechanisms of Drug Reactions.- I. Toxic Reactions.- II. Idiosyncratic Reactions.- III. Tumor Formation.- IV. Vascular Reactions :.- V. Interactions.- C. General Biochemical and Histological Types of Drug Reactions.- I. Hepatocellular Reactions.- II. Cholestatic Reactions.- III. Mixed Hepatocellular-Cholestatic.- IV. Tumors.- V. Vascular Lesions.- D. Clinical Evaluation and Diagnosis of Hepatic Drug Reactions.- I. History.- II. Laboratory Findings.- III. Histopathological Findings.- E. Some Specific Illustrative Drug Reactions.- I. Unsuspected Acetaminophen Overdose Caused by Consumption of Nyquil.- II. Suspected Fatal Isoniazid Toxicity Disproven by Autopsy Examination.- III. Toxicity Due to Health Food (“Hot StufF”).- F. Summary of the Clinical Approach to Drug Toxicity.- References.- 20: Antimicrobial Drugs (With 7 Figures).- A. Antibiotics.- I. Aminoglycosides.- II. Cephalosporins.- III. Chloramphenicol.- IV. Clindamycin.- V. Colimycin.- VI. Erythromycin.- VII. Fusidic Acid.- VIII. Roxithromycin.- IX. Tetracyclines.- X. Troleandomycin.- XI. Penicillin.- B. Synthetic Antimicrobials.- I. Organic Arsenicals.- II. Quinolones.- III. Sulfonamides.- IV. Sulfamethoxazole-Trimethoprim.- V. Sulfasalazine.- VI. Sulfones.- VII. Nitrofurantoin.- VIII. Furazolidone.- C. Antituberculous Drugs.- I. p-Aminosalicylic Acid.- II. Isoniazid.- III. Rifampin.- D. Antifungal Agents.- I. Griseofulvin.- II. Ketoconazole.- III. Other Imidazoles.- IV. Flucytosine.- E. Antiviral Agents.- F. Antiprotozoal Agents.- I. Anthelmintics.- References.- 21: Hepatotoxicity of Cardiovascular Drugs (With 9 Figures).- A. Introduction.- B. a-Methyldopa.- I. Hepatitis.- II. Fatty Change.- III. Hepatic Necrosis.- IV. Cholestasis.- V. Cirrhosis.- C. Amiodarone.- I. Alcoholic-Type Hepatitis.- II. Phospholipid Fatty Liver.- III. Reye’s Syndrome-Like Disease.- D. Aprindine.- I. Hepatitis.- E. Hydralazine and Dihydralazine.- I. Hepatitis.- F. Papaverine.- I. Hepatitis.- G. Procainamide.- I. Hepatitis.- II. Cholestasis.- H. Quinidine.- I. Hepatitis.- II. Granulomatous Hepatitis.- I. Lipid-Regulating Agents.- I. Classes of Lipid-Regulating Agents.- II. Hyperlipoproteinemia and Liver Structure.- III. Nicotinic Acid.- IV. Fibrates.- V. Statins.- J. Miscellaneous Cardiovascular Drugs.- K. Modulation of Hepatotoxicity.- L. Conclusions.- References.- 22: Analgesie Hepatopathy.- A. Introduction.- B. Acetaminophen.- I. Epidemiology.- 1. Incidence of Hepatotoxicity.- 2. Hepatotoxicity in Alcoholics.- 3. Hepatotoxicity in Therapeutic Settings.- II. Pathogenesis.- 1. Hepatotoxic Dose and Blood Level.- 2. Mechanism.- 3. Factors Influencing Hepatotoxicity.- III. Clinical Manifestations and Laboratory Findings.- 1. Clinical Course.- 2. Pathology.- 3. Prognosis.- IV. Treatment.- 1. General Management.- 2. Specific Therapy.- 3. Fulminant Hepatic Failure.- V. Prevention.- C. Nonsteroidal Antiinflammatory Drugs.- I. Epidemiology.- II. Pathogenesis.- III. Clinical Manifestations and Laboratory Findings.- 1. General Observations.- 2. Specific NSAIDs.- IV. Treatment.- V. Prevention.- D. Narcotic Analgesics.- References.- 23: Steroids and Other Hormones (With 7 Figures).- A. Gonadal Steroids and Their Derivatives.- B. Anabolic Steroids.- I. Cholestasis.- 1. Structural Characteristics of Icterogenic Steroids.- 2. Incidence.- 3. Clinical Features.- 4. Biochemical Features.- 5. Histopathology.- 6. Prognosis.- 7. Mechanism.- II. Peliosis Hepatis.- III. Neoplasms.- 1. Nodular Regenerative Hyperplasia.- 2. Hepatocellular Adenoma.- 3. Hepatic Carcinoma.- 4. Other Neoplasms.- C. Female Sex Hormones and the Contraceptive Steroids.- I. Estrogenic Hormones and Related Drugs.- II. Progestational Steroids.- III. Adverse Effects of Contraceptive Steroids on the Liver.- IV. Syndrome of Contraceptive Steroid Jaundice.- 1. Clinical Features.- 2. Biochemical Features.- 3. Histologie Characteristics.- 4. Prognosis.- 5. Susceptibility.- V. Tumors Associated with Oral Contraceptives.- 1. Hepatocellular Adenoma.- 2. Focal Nodular Hyperplasia.- 3. Hepatocellular Carcinoma.- VI. Vascular Lesions.- 1. Effect on Hemangiomas and Related Lesions.- 2. Sinusoidal Dilatation.- 3. Peliosis Hepatis.- 4. Hepatic Vein Thrombosis.- 5. Rupture of the Liver.- 6. Other Vascular Changes.- VII. Disturbed Porphyrin Metabolism.- VIII. Mechanisms of Injury by Contraceptive Steroids.- IX. Cholelithiasis.- D. Drugs Related to Sex Hormones.- I. Antiestrogens.- 1. Clomiphene.- 2. Cyclofenil.- 3. Tamoxifen.- II. Antihypophysial Drugs.- 1. Danazol.- 2. Octreotide.- E. Glucocorticoids.- F. Oral Hypoglycemic Agents.- I. Sulfonylureas.- II. Clinical Syndrome.- III. Prognosis.- IV. Biguanide.- V. Other Oral Hypoglycemic Agents.- G. Antithyroid Drugs.- I. Form of Injury.- II. Clinical Features.- III. Prognosis.- IV. Mechanism.- V. Comment.- References.- 24: Hepatotoxicity of Immunomodulating Agents.- A. Introduction.- B. Immunostimulatory Agents.- I. Classification.- 1. Immune-System-Derived Biologicals.- 2. Immunostimulatory Pharmaceutical Agents.- II. Hepatotoxicity of Specific Immunostimulatory Agents.- 1. Interleukin-2.- 2. Interferons.- C. Immunosuppressive Agents.- I. Classification.- 1. Antilymphocyte Products.- 2. Immunophilin-Binding Agents.- 3. Cytotoxic Agents.- 4. Sterols.- 5. Immunosuppressive Antibiotics.- 6. Arachidonic Acid Metabolites.- II. Hepatotoxic Effects of Specific Immunosuppressive Agents.- 1. Methotrexate.- 2. Corticosteroids.- 3. Azathioprine.- 4. Cyclosporine.- 5. FK-506.- D. Conclusion.- References.- 25: Alcohol-Induced Liver Injury.- A. Epidemiology.- B. Liver Dysfunction in Alcoholic Liver Disease.- I. Hemodynamic Alterations.- II. Liver Failure.- C. Alcoholic Liver Injury: Morphological Studies.- I. Hepatocytes.- II. Inflammation.- III. Collagen Deposition.- IV. Nonparenchymal Cells (EM Studies).- 1. Ito Cells.- 2. Endothelial Cells.- 3. Kupffer Cells :.- D. Clustering.- I. Fatty Liver.- II. Alcoholic Hepatitis.- III. Alcoholic Cirrhosis.- E. Pathogenesis of Alcohol-Induced Liver Injury.- I. Liquid Diet Model.- II. Cytochrome P450 2E1.- III. Acetaldehyde Adducts.- IV. Hepatocyte Ballooning and Hepatomegaly.- V. Hepatic Oxygen Consumption.- VI. Liver Hypoxia.- VII. Intragastric Infusion Model.- VIII. Modulation of Alcohol-Induced Liver Injury.- IX. Glutathione.- X. Micropig Model of Alcoholic Liver Injury.- XI. Baboon Model of Alcoholic Liver Injury.- References.- 26: Antiepileptic Drugs (With 10 Figures).- A. Phenytoin.- I. Type of Hepatic Injury.- II. Clinical Manifestations.- III. Biochemical Features.- IV. Histopathology.- V. Prognosis.- VI. Mechanism.- VII. Other Hydantoins.- 1. Mephenytoin.- 2. Acetylurea Derivatives.- 3. Oxazolidinediones.- 4. Barbiturates and Primidone.- B. Carbamazepine.- I. Susceptibility.- II. Clinical Features.- III. Biochemical Features.- IV. Histopathology.- V. Prognosis.- VI. Mechanism.- C. Valproic Acid.- I. Incidence of Injury.- II. Susceptibility.- III. Clinical Features.- IV. Biochemical Features.- V. Histopathology.- VI. Prognosis.- VII. Mechanism of Injury.- VIII. Prevention.- References.