Drug-Induced Hepatotoxicity

by Cameron, R. G.; Feuer, George; De LA Iglesia, F. A.; Anuras, S.

• ISBN13: 9783540602019
• ISBN10: 3540602011
• Format: Hardcover
• Copyright: 1996-05-01
• Publisher: Springer Nature

Summary

This book discusses drug-induced hepatotoxicity in its entirety from details of molecular mechanisms to clinical case presentations. Special features of drug-induced hepatotoxicity during pregnancy, in pediatric practice, and in the elderly are described. It is complemented by a complete index of all drugs and a comprehensive table of contents allows ready access to all of the knowledge concerning each drug and each class of drugs. Special features include chapters on Reye's syndrome, in vitro models of liver toxicity, hepatic encephalopathy, and alcohol-induced liver injury. The reader will benefit from the scholarly approach to the subject, from the detailed discussions of mechanims and from the attention to details of hepatic responses to each drug.

Table of Contents

CHAPTER 1 Orientation in Liver Toxicity by Drugs With 1 Figure	1	(24)
E. FARBER
A. Introduction	1	(1)
B. Agents and Processes	1	(1)
C. Responses to Injury as Multitier or Multigrid Patterns	2	(19)
I. Quantitative Versus Qualitative Changes	3	(1)
II. Patterns of Liver Toxicity	4	(17)
1. Tier One: Patterns of Interactions of Agents with Liver	4	(4)
2. Tier Two: Patterns of Biological Responses to Cell Injury	8	(2)
3. Tier Three: Cellular and Intracellular Responses	10	(9)
4. Tier Four: Cellular and Tissue Physiology	19	(2)
D. Conclusion	21	(1)
References	21	(4)
CHAPTER 2 Clinical Studies and Role of Necrosis in Hepatotoxicity With 7 Figures	25	(18)
R. G. CAMERON
L. M. BLENDIS
A. Zonal Necrosis as a Response to Acetaminophen	25	(8)
I. Zonality: Specific Hepatocytes Die as a Group	25	(3)
II. Ethanol Plus Acetaminophen: Extension of Zone of Necrosis	28	(2)
III. Constitutive Bases of Zonal Responses	30	(3)
1. Perivenous Localization of Acetaminophen-Metabolizing enzyme CYP 2E1	32	(1)
IV. Zonal Hepatocellular Necrosis: Historical Perspective	33	(1)
B. Regeneration in Response to Zonal Necrosis of Acetaminophen Overdose	33	(5)
I. Regeneration of Periportal and Mid-zonal Hepatocytes to Restore the Perivenous Zone	33	(5)
C. Clinical Implications of "Adaptive" Perivenous Necrosis	38	(1)
References	39	(4)
CHAPTER 3 Subcellular Biochemical and Pathological Correlates in Experimental Models of Hepatotoxicity With 5 Figures	43	(32)
G. FEUER
F. A. DE LA IGLESIA
A. Introduction	43	(1)
B. Organization of the Liver Cell	44	(1)
C. Liver Cell Injury	45	(1)
D. Subcellular Organelle Pathology	46	(13)
I. Endoplasmic Reticulum	46	(6)
1. Membrane Structure	46	(2)
2. Cytochrome P450 System	48	(1)
3. Proliferation and Induction	48	(2)
4. Structure-Activity Relationships	50	(1)
5. Membrane-Bound Phospholipids	51	(1)
II. Golgi Apparatus	52	(2)
III. Intracellular Membrane Dynamics	54	(1)
IV. Mitochondria	55	(1)
V. Lysosomes	56	(1)
VI. Peroxisomes	57	(2)
E. Biochemical Pathology of Subcellular Changes	59	(4)
I. Cell Respiration	59	(1)
II. Protein Metabolism	60	(1)
III. Lipid Metabolism	61	(1)
IV. Bile Secretion	62	(1)
F. Latent Hepatotoxicity Models	63	(1)
G. Conclusions	64	(1)
References	65	(10)
CHAPTER 4 Molecular Biology of Hepatic Drug Reactions With 6 Figures	75	(24)
R. W. SALLIE
E. A. JONES
A. Introduction	75	(1)
B. General Considerations	75	(2)
C. DNA Damage	77	(2)
I. Drugs and DNA Metabolism	77	(1)
II. DNA Replication and Repair Pathways	78	(1)
D. Inhibition of DNA Replication	79	(5)
I. Inhibition of DNA Polymerases	79	(1)
II. Inhibition of DNA Ligase	80	(1)
III. Chain Termination	81	(1)
IV. Inhibition of DNA Repair	81	(2)
V. Alterations in Purine/Pyrimidine Metabolism	83	(1)
VI. Alterations in DNA Processing Post Synthesis	83	(1)
E. Damage to RNA	84	(1)
F. Interference with Protein Synthesis	85	(1)
G. Apoptosis	86	(6)
H. Future Developments	92	(1)
I. Summary and Conclusions	93	(1)
References	94	(5)
CHAPTER 5 In Vitro Models of Liver Toxicity With 4 Figures	99	(20)
R. G. THURMAN
P. E. GANEY
S. A. BELINSKY
J. G. CONWAY
M. Z. BADR
A. Introduction	99	(2)
I. Metabolism of Foreign Compounds Can Cause Zone-Specific Hepatotoxicity	99	(1)
II. Advantages and Disadvantages of Whole Cell Models	100	(1)
B. Techniques Used to Study Zone-Specific Hepatotoxicity in the Isolated Perfused Liver	101	(5)
I. Metabolite Measurements in Tissue and Perfusate	103	(1)
II. Microlight Guides	104	(1)
III. Miniature Oxygen Electrodes	105	(1)
IV. Trypan Blue Exclusion	106	(1)
C. Applying In Vitro Models to the Study of Liver Toxicology	106	(7)
I. Monooxygenation in Periportal and Pericentral Zones of the Liver Lobule	106	(1)
II. Conjugation Reactions in Periportal and Pericentral Regions of the Liver Lobule	107	(4)
1. Sulfation	107	(2)
2. Glucuronidation	109	(2)
III. Oxygen as a Determinant of Zone-Specific Hepatotoxicity	111	(2)
D. Conclusions	113	(1)
References	113	(6)
CHAPTER 6 Cytochromes P450 and Liver Injury With 4 Figures	119	(36)
J. S. LEEDER
A. B. OKEY
A. Drug Biotransformation, Cytochromes P450 and the Liver	119	(2)
I. Drug Biotransformation by the Liver	119	(1)
II. General Drug Biotransformation Processes	119	(1)
III. Phase I Reactions	120	(1)
IV. Introduction to the Cytochromes P450	120	(1)
B. Cytochromes P450 and Drug Biotransformation	121	(14)
I. Human Hepatic Cytochromes P450	121	(4)
II. Sources of Variability in P450 Expression and Activity	125	(5)
1. P450 Genetics and Polymorphisms	126	(1)
2. P450 Induction	127	(2)
3. P450 Inhibition	129	(1)
4. Liver Disease: Effects on Drug Biotransformation	130	(1)
II. Reaction Mechanism	130	(2)
III. Drug Biotransformation and Drug Toxicity	132	(3)
1. Cytochrome P450 and Bioactivation	132	(1)
2. Activation/Detoxification Balance	132	(2)
3. "Probe Drugs" for Determining P450 Activities in Humans In Vivo	134	(1)
C. Mechanisms of P450-Mediated Liver Injury	135	(4)
I. Reactive Metabolites	135	(3)
1. Noncovalent Interactions	136	(1)
2. Covalent Adduct Formation	137	(1)
II. P450s as Targets of Immune Effectors	138	(1)
D. Specific Drugs/P450s and Liver Injury	139	(5)
I. Acetaminophen	139	(2)
II. Halothane	141	(1)
III. Tienilic Acid	142	(1)
IV. Dihydralazine	143	(1)
V. Diclofenac	144	(1)
E. Conclusions	144	(11)
References	145	(10)
CHAPTER 7 Mechanisms of Drug-Induced Cholestasis	155	(30)
J. B. WATKINS III
C. D. KLAASSEN
A. Definition of Cholestasis	155	(1)
B. Mechanisms of Canalicular Bile Formation	156	(2)
I. Transport of Bile Acids	156	(1)
II. Transport of Inorganic Ions and Glutathione	157	(1)
III. Other Mechanisms	157	(1)
C. Mechanisms of Cholestasis	158	(7)
I. Alterations in Basolateral Membrane Function	158	(1)
II. Alterations in Canalicular Membrane Function	158	(1)
III. Alterations in Intracellular Events	159	(1)
1. Binding to Intracellular Proteins and Conjugation Enzymes	159	(1)
2. Cytoskeleton	159	(1)
IV. Permeability Changes in the Biliary Tree	160	(5)
1. Altered Permeability of the Junctional Complex	161	(1)
2. Altered Permeability of the Canalicular Membrane	161	(1)
3. Alterations in Membrane Proteins	162	(2)
4. Alterations in Membrane Composition and Function	164	(1)
D. Drugs and Other Chemicals Inducing Cholestasis	165	(6)
I. a-Naphthylisothiocyanate	165	(1)
II. Androgenic and Estrogenic Steroids	166	(2)
III. Bile Acids	168	(1)
IV. Chlorpromazine and Other Phenothiazines	169	(1)
V. Cyclosporine	170	(1)
VI. Miscellaneous Cholestatic Agents	170	(1)
References	171	(14)
CHAPTER 8 Fatty Liver and Drugs With 1 Figure	185	(26)
M. U. DIANZANI
A. General Mechanisms for Fatty Liver	185	(2)
B. Drugs Provoking Fatty Liver	187	(15)
I. Drugs Provoking Fatty Liver by Increasing FFA Supply to the Liver	187	(1)
II. Drugs Provoking Fatty Liver by Intrahepatic Mechanisms	188	(12)
1. Drugs Increasing Intrahepatic FFA Synthesis	188	(4)
2. Drugs Provoking Fatty Liver by Decreasing Fatty Acid Oxidation	192	(1)
3. Drugs Blocking Lipoprotein Secretion	192	(8)
III. Drugs Decreasing Fat Infiltration in the Liver	200	(2)
References	202	(9)
CHAPTER 9 Choline Deficiency: An Important Model for the Study of Hepatotoxicity With 2 Figures	211	(10)
A. K. GHOSHAL
A. Introduction	211	(1)
B. Hepatotoxicity by Dietary Manipulation - Not by Addition but by Depletion	212	(1)
C. Absence of Choline in an Otherwise Complete Diet - An Excellent Model for the Study of Liver Cell Death and Liver Cancer	213	(4)
I. Choline Deficiency Model and Cell Death	215	(1)
II. Choline Deficiency and Liver Cancer	216	(1)
D. Lipotrope Deficiency Versus Choline Deficiency	217	(1)
E. Step by Step Development of Liver Aberration	217	(1)
F. Hypothesis of Choline Deficiency Induced Hepatocarcinoma	218	(1)
G. Conclusions	218	(1)
References	218	(3)
CHAPTER 10 Immune Mechanisms and Liver Toxicity With 3 Figures	221	(28)
I. R. MACKAY
A. Introduction and Overview of Drug-Mediated Hepatotoxicity	221	(1)
B. Functional Aspects of the Immune System	222	(5)
I. Immune Repertoire	222	(1)
II. Major Histocompatibility Complex	223	(1)
III. Afferent Limb of the Immune Response	224	(1)
IV. Efferent Limb of the Immune Response	225	(1)
V. Regulation and Dysregulation of Immune Responses	226	(1)
C. Genetic Determinants of Adverse Drug Reactions	227	(1)
D. Liver in Relation to Adverse Drug Reactions	228	(11)
I. Intrahepatic Metabolism of Drugs by Microsomal Enzymes	228	(1)
1. Cytochrome P450 Oxidases (CYP450)	228	(1)
2. UDP Glucuronosyl Transferases	228	(1)
3. Carboxyl Esterases	228	(1)
II. Intrahepatic Immune Processes	229	(1)
1. Initiation of Immune-Mediated Drug Reactions in the Liver	229	(1)
2. Regulatory and Dysregulation of Intrahepatic Immune Reactions	229	(1)
III. Infrequency of Hepatic Hypersensitivity Drug Reactions	230	(1)
IV. Immunopathology of Hepatic Hypersensitivity Drug Reactions	230	(2)
V. Drug-Altered Neoantigen - The Halothane Paradigm	232	(2)
1. Halothane Hepatitis	232	(1)
2. Immunological Investigations of Halothane Hepatitis	233	(1)
3. Detection of Antibodies to TFA Conjugates	233	(1)
VI. Native Liver Antigens - The Liver-Kidney Microsomal (LKM) System	234	(4)
1. Hepatitis with Anti-LKM-2	235	(1)
2. Identification of LKM as Cytochrome P450 Species	235	(1)
3. Antibodies to CYP 1A2 in Drug-Induced Hepatitis	236	(1)
4. Inhibition of Enzyme Function by Anti-LKM	237	(1)
5. Origins of Anti-LKM Reactivity	237	(1)
VII. Drug-Induced Hepatitis with Reactions to Autoantigens	238	(1)
E. Experimental Models of Drug-Induced Immune-Mediated Disease	239	(1)
F. Laboratory Investigation of Immune-Mediated Hepatic Drug Reactions	240	(2)
I. General Laboratory Investigations	240	(1)
II. Drug-Specific Immunological Investigations	240	(1)
1. Detection of T-Cell-Mediated Reactions	241	(1)
III. Pharmacological Idiosyncrasy	242	(1)
References	242	(7)
CHAPTER 11 Hepatic Encephalopathy	249	(24)
A. S. BASILE
A. Introduction	249	(3)
I. Clinical Manifestations of Hepatic Encephalopathy	249	(2)
II. Neuropathological Changes in Hepatic Encephalopathy	251	(1)
1. Anatomy	251	(1)
2. Electrophysiology	251	(1)
B. Involvement of Neurotoxins in the Pathogenesis of Hepatic Encephalopathy	252	(6)
I. Ammonia	253	(4)
1. Glial Interactions	253	(1)
2. Electrophysiological Changes	254	(2)
3. Changes in Oxidative Metabolism	256	(1)
4. Summary	256	(1)
II. Synergistic Neurotoxins	257	(1)
C. Neurotransmitter Involvement in the Pathogenesis of Hepatic Encephalopathy	258	(7)
I. y-Aminobutyric Acid	258	(3)
1. Electrophysiology	258	(1)
2. Neurochemistry and Pharmacology	258	(2)
3. Behavior	260	(1)
4. Summary	260	(1)
II. Excitatory Amino Acids	261	(2)
III. Aromatic Amino Acids and Monoamine Neurotransmitters	263	(2)
D. Conclusions	265	(1)
References	265	(8)
CHAPTER 12 Liver Drug Reactions and Pregnancy	273	(20)
F. TREVISANI
D. H. VAN THIEL
A. The Liver in Normal Pregnancy	273	(3)
I. Liver Histology	273	(1)
II. Liver Perfusion and Function	274	(2)
B. Effects of Pregnancy on the Risk of Experiencing a Drug-Induced Hepatic Injury	276	(6)
I. Specific Pre-Marketing Risk/Benefit Evaluation of Drugs	276	(1)
II. Risk of Exposure to Hepatotoxic Drugs	276	(2)
III. Pharmacokinetics	278	(2)
1. Absorption	278	(1)
2. Distribution	278	(1)
3. Hemodynamics and Drug Clearance	279	(1)
4. Maternal-Placental-Fetal Unit	279	(1)
IV. Liver Vulnerability	280	(2)
C. Liver Drug Reactions Occurring During Pregnancy	282	(3)
I. Antibiotics	282	(1)
II. Antiemetics	283	(1)
III. Anesthetics and Analgesics	283	(1)
IV. Anticonvulsants	284	(1)
V. Other Agents	284	(1)
D. Clinical Presentation and Diagnostic Approach to Hepatic Injury in Pregnancy	285	(1)
E. Treatment	286	(1)
F. Prevention	287	(1)
References	288	(5)
CHAPTER 13 Pediatric Hepatic Drug Reactions	293	(30)
E. A. ROBERTS
A. Classification of Drug Hepatotoxicity	293	(1)
B. Specific Drugs Causing Hepatotoxicity in Children	294	(18)
I. Acetaminophen	294	(2)
II. Phenytoin	296	(1)
III. Valproic Acid	297	(4)
IV. Isoniazid	301	(1)
V. Halothane	302	(1)
VI. Carbamazepine	303	(1)
VII. Phenobarbital	304	(1)
VIII. Antineoplastic Drugs	304	(2)
IX. Pemoline	306	(1)
X. Sulfonamides	306	(1)
XI. Aspirin	307	(1)
XII. Propylthiouracil	307	(1)
XIII. Erythromycin	308	(1)
XIV. Methotrexate	308	(2)
XV. Estrogens: Oral Contraceptive Pill	310	(1)
XVI. Ketoconazole	310	(1)
XVII. Haloperidol	310	(1)
XVIII. Amiodarone	310	(1)
XIX. Nitrofurantoin	311	(1)
XX. Retinoids	311	(1)
XXI. Azathioprine	311	(1)
XXII. Cocaine	312	(1)
References	312	(11)
CHAPTER 14 Reye's Syndrome	323	(18)
R. R. VARMA
A. Introduction	323	(1)
B. Clinical Features	324	(2)
C. Laboratory Features	326	(1)
D. Diagnostic Criteria for Population Surveys	327	(1)
E. Liver Morphology	328	(1)
F. Brain Morphology	328	(1)
G. Liver Histology and Electron Microscopy in Reye's Syndrome	329	(1)
H. Pathophysiology	330	(2)
I. Aspirin and Reye's Syndrome	332	(2)
J. Animal Models	334	(1)
K. Reye's Syndrome in Adults	335	(1)
L. Treatment	335	(1)
M. Sequelae	336	(1)
References	337	(4)
CHAPTER 15 Drug Hepatotoxicity in the Elderly With 7 Figures	341
K. KITANI
A. Introduction	341	(1)
B. Clinical Information	341	(2)
I. Idiosyncratic Hepatotoxicity: The Swedish Experience	341	(2)
II. Dose-Dependent Hepatotoxicity	343	(1)
C. Age-Related Alterations in Hepatic Detoxifying Functions: Discrepancies Between Human and Animal Data	343	(10)
I. Phase I Drug Metabolism	344	(2)
II. Phase II Metabolism	346	(4)
1. Glucuronidation and Sulfation: Acetaminophen Conjugation	346	(1)
2. Glutathione S-Transferases	347	(3)
III. Oxidant and Antioxidant Variables	350	(3)
1. Lipid Peroxidation	351	(1)
2. Glutathione	351	(1)
3. Antioxidant Enzymes	351	(2)
D. Morbidity and Frailty as Major Factors for Lowered Drug Clearances in the Elderly: A Possible Role in Hepatotoxicity	353	(1)
E. Adverse Drug Reactions in the Liver in Old Animals: Mini Review	354	(7)
I. Hepatocyte Susceptibility to Chlorpromazine and Erythromycin Estolate	355	(1)
II. Acetaminophen Hepatotoxicity: An Example of Variability of the Results in Studies Using Rodents	355	(3)
III. Ethanol Metabolism in the Liver and Its Hepatotoxicity: Another Controversy	358	(3)
IV. Hepatotoxicities by Other Toxicants	361	(1)
F. Conclusions and Suggestions for Future Studies	361	(1)
References	362	(5)
CHAPTER 16 Effect of Liver Disease on Drug Metabolism and Pharmacokinetics With 6 Figures	367	(28)
P. G. WELLING
W. F. POOL
A. Introduction	367	(1)
B. Function and Structure of the Liver	368	(1)
C. Types and Severity of Liver Disease	369	(1)
I. Changes in Hepatic Function	369	(1)
II. Changes in Hepatic Vasculature	369	(1)
III. Changes in Renal Function	370	(1)
IV. Ascites	370	(1)
D. Pharmacodynamic Factors	370	(1)
E. Pharmacokinetic Factors	371	(10)
I. Linear Pharmacokinetic Models	371	(5)
1. One-Compartment Model, Intravenous Dosing	371	(2)
2. First-Order Absorption and Elimination	373	(1)
3. Repeated Dosing with Linear Pharmacokinetics	374	(2)
II. Nonlinear Pharmacokinetic Models	376	(1)
III. Impact of Liver Disease	377	(4)
1. Distribution Volume	379	(1)
2. Elimination Half-Life	379	(1)
3. Protein Binding	380	(1)
4. Presystemic Clearance	380	(1)
F. Markers of Liver Disease Relevant to Drug Metabolism and Pharmacokinetics	381	(1)
G. Examples of Effects of Liver Disease on the Pharmacokinetics of Some Drug Therapeutic Classes	382	(5)
I. Cardiovascular Agents	383	(1)
II. Drugs Acting on the Central Nervous System	384	(1)
III. Antimicrobial Agents	385	(1)
IV. Other Drugs	386	(1)
H. Conclusions	387	(1)
References	388	(7)
CHAPTER 17 Liver Reactions to Tacrine With 2 Figures	395	(16)
T. F. WOOLF
W. F. POOL
R. M. WALKER
D. K. MONTEITH
A. Introduction	395	(1)
B. Clinical Experience	395	(2)
C. Metabolism of Tacrine in Humans	397	(2)
D. Preclinical Toxicology	399	(2)
E. Metabolism of Tacrine in Animals	401	(1)
F. Cytotoxicity Studies	402	(1)
G. In Vitro Metabolism Studies	403	(2)
H. Conclusions	405	(1)
References	406	(5)
CHAPTER 18 Mechanisms of Hypertransaminemia With 7 Figures	411	(30)
M. PIRMOHAMED
B. K. PARK
A. Introduction	411	(1)
B. Overview of Liver Transaminase Monitoring	411	(8)
I. Significance of the Different Tests Used to Monitor Liver Function	411	(2)
II. Spectrum of Drug-Induced Hepatotoxicity and Hypertransaminemia	413	(1)
III. Clinical Correlates of Transaminase Measurement	414	(5)
1. Sensitivity and Specificity of Hypertransaminemia	414	(1)
2. Correlation Between Severity of Hepatic Injury and Degree of Hypertransaminemia	415	(1)
3. Clinical Significance of Minor Degrees of Hypertransaminemia	416	(3)
C. Classification of the Causes of Hypertransaminemia	419	(1)
D. Mechanisms of Acute Hepatic Injury Leading to Hypertransaminemia	419	(1)
I. Role of Drug Metabolism	419	(2)
II. Evidence for the Formation of Chemically Reactive Metabolites	421	(1)
III. Acute Chemical Hepatotoxicity	422	(3)
1. Acetaminophen Hepatotoxicity	422	(2)
2. Carbon Tetrachloride Hepatotoxicity	424	(1)
IV. Acute Idiosyncratic Hepatotoxicity	425	(6)
1. Metabolic Idiosyncrasy Causing Hypertransaminemia	425	(1)
2. Immune-Mediated Drug-Induced Hypertransaminemia	426	(5)
E. Mechanisms of Chronic Hepatic Injury Causing Hypertransaminemia	431	(2)
I. Chronic Chemical Hypertransaminemia	431	(1)
II. Chronic Idiosyncratic Drug-Induced Hypertransaminemia	432	(1)
F. Diagnosis of Drug-Induced Hypertransaminemia	433	(1)
I. Distinction Between Drug- and Non-Drug-Induced Etiologies	433	(1)
II. Distinction Between Direct and Immune-Mediated Acute Idiosyncratic Toxicity	433	(1)
G. Conclusions	434	(1)
References	435	(6)
CHAPTER 19 Diagnostic Tools and Clinical Pathology	441	(16)
D. C. SNOVER
A. General Features and Clinical Evaluation of Drug-Induced Liver Diseases	441	(1)
B. General Mechanisms of Drug Reactions	442	(3)
I. Toxic Reactions	442	(1)
II. Idiosyncratic Reactions	443	(1)
III. Tumor Formation	443	(1)
IV. Vascular Reactions	444	(1)
V. Interactions	445	(1)
C. General Biochemical and Histological Types of Drug Reactions	445	(4)
I. Hepatocellular Reactions	445	(2)
II. Cholestatic Reactions	447	(1)
III. Mixed Hepatocellular-Cholestatic	448	(1)
IV. Tumors	448	(1)
V. Vascular Lesions	448	(1)
D. Clinical Evaluation and Diagnosis of Hepatic Drug Reactions	449	(2)
I. History	450	(1)
II. Laboratory Findings	450	(1)
III. Histopathological Findings	451	(1)
E. Some Specific Illustrative Drug Reactions	451	(2)
I. Unsuspected Acetaminophen Overdose Caused by Consumption of Nyquil	451	(1)
II. Suspected Fatal Isoniazid Toxicity Disproven by Autopsy Examination	452	(1)
III. Toxicity Due to Health Food ("Hot Stuff")	452	(1)
F. Summary of the Clinical Approach to Drug Toxicity	453	(1)
References	453	(4)
CHAPTER 20 Antimicrobial Drugs With 7 Figures	457	(20)
H. J. ZIMMERMAN
K. G. ISHAK
A. Antibiotics	457	(6)
I. Aminoglycosides	457	(1)
II. Cephalosporins	457	(1)
III. Chloramphenicol	457	(1)
IV. Clindamycin	458	(1)
V. Colimycin	458	(1)
VI. Erythromycin	459	(1)
VII. Fusidic Acid	460	(1)
VIII. Roxithromycin	460	(1)
IX. Tetracyclines	461	(1)
X. Troleandomycin	461	(1)
XI. Penicillin	462	(1)
B. Synthetic Antimicrobials	463	(6)
I. Organic Arsenicals	463	(4)
II. Quinolones	467	(1)
III. Sulfonamides	468	(1)
IV. Sulfamethoxazole-Trimethoprim	468	(1)
V. Sulfasalazine	468	(1)
VI. Sulfones	468	(1)
VII. Nitrofurantoin	469	(1)
VIII. Furazolidone	469	(1)
C. Antituberculous Drugs	469	(2)
I. p-Aminosalicylic Acid	469	(1)
II. Isoniazid	470	(1)
III. Rifampin	470	(1)
D. Antifungal Agents	471	(1)
I. Griseofulvin	471	(1)
II. Ketoconazole	471	(1)
III. Other Imidazoles	471	(1)
IV. Flucytosine	471	(1)
E. Antiviral Agents	472	(1)
F. Antiprotozoal Agents	472	(1)
I. Anthelmintics	472	(1)
References	473	(4)
CHAPTER 21 Hepatotoxicity of Cardiovascular Drugs With 9 Figures	477	(38)
R. G. CAMERON
F. A. DE LA IGLESIA
G. FEUER
A. Introduction	477	(1)
B. XXX-Methyldopa	478	(5)
I. Hepatitis	479	(2)
II. Fatty Change	481	(1)
III. Hepatic Necrosis	482	(1)
IV. Cholestasis	482	(1)
V. Cirrhosis	483	(1)
C. Amiodarone	483	(5)
I. Alcoholic-Type Hepatitis	484	(3)
II. Phospholipid Fatty Liver	487	(1)
III. Reye's Syndrome-Like Disease	488	(1)
D. Aprindine	488	(1)
I. Hepatitis	488	(1)
E. Hydralazine and Dihydralazine	489	(2)
I. Hepatitis	490	(1)
F. Papaverine	491	(1)
I. Hepatitis	492	(1)
G. Procainamide	492	(1)
I. Hepatitis	492	(1)
II. Cholestasis	493	(1)
H. Quinidine	493	(2)
I. Hepatitis	494	(1)
II. Granulomatous Hepatitis	494	(1)
I. Lipid-Regulating Agents	495	(6)
I. Classes of Lipid-Regulating Agents	495	(1)
II. Hyperlipoproteinemia and Liver Structure	496	(2)
III. Nicotinic Acid	498	(1)
IV. Fibrates	498	(2)
V. Statins	500	(1)
J. Miscellaneous Cardiovascular Drugs	501	(1)
K. Modulation of Hepatotoxicity	502	(1)
L. Conclusions	502	(2)
References	504	(11)
CHAPTER 22 Analgesic Hepatopathy	515	(28)
M. J. ZUCKERMAN
S. ANURAS
A. Introduction	515	(1)
B. Acetaminophen	515	(11)
I. Epidemiology	515	(3)
1. Incidence of Hepatotoxicity	515	(3)
2. Hepatotoxicity in Alcoholics	516	(1)
3. Hepatotoxicity in Therapeutic Settings	517	(1)
II. Pathogenesis	518	(1)
1. Hepatotoxic Dose and Blood Level	518	(1)
2. Mechanism	518	(1)
3. Factors Influencing Hepatotoxicity	519	(1)
III. Clinical Manifestations and Laboratory Findings	519	(3)
1. Clinical Course	519	(1)
2. Pathology	520	(1)
3. Prognosis	521	(1)
IV. Treatment	522	(4)
1. General Management	522	(1)
2. Specific Therapy	523	(1)
3. Fulminant Hepatic Failure	524	(1)
V. Prevention	525	(1)
C. Nonsteroidal Antiinflammatory Drugs	526	(10)
I. Epidemiology	526	(3)
II. Pathogenesis	529	(2)
III. Clinical Manifestations and Laboratory Findings	531	(3)
1. General Observations	531	(1)
2. Specific NSAIDs	532	(2)
IV. Treatment	534	(1)
V. Prevention	535	(1)
D. Narcotic Analgesics	536	(1)
References	537	(6)
CHAPTER 23 Steroids and Other Hormones With 7 Figures	543	(38)
H. J. ZIMMERMAN
K. G. ISHAK
A. Gonadal Steroids and Their Derivatives	543	(1)
B. Anabolic Steroids	543	(8)
I. Cholestasis	544	(4)
1. Structural Characteristics of Icterogenic Steroids	544	(1)
2. Incidence	544	(1)
3. Clinical Features	545	(1)
4. Biochemical Features	546	(1)
5. Histopathology	546	(1)
6. Prognosis	546	(1)
7. Mechanism	547	(1)
II. Peliosis Hepatis	548	(1)
III. Neoplasms	549	(2)
1. Nodular Regenerative Hyperplasia	549	(1)
2. Hepatocellular Adenoma	549	(1)
3. Hepatic Carcinoma	550	(1)
4. Other Neoplasms	550	(1)
C. Female Sex Hormones and the Contraceptive Steroids	551	(14)
I. Estrogenic Hormones and Related Drugs	551	(1)
II. Progestational Steroids	552	(1)
III. Adverse Effects of Contraceptive Steroids on the Liver	553	(1)
IV. Syndrome of Contraceptive Steroid Jaundice	554	(1)
1. Clinical Features	554	(1)
2. Biochemical Features	554	(1)
3. Histologic Characteristics	554	(1)
4. Prognosis	554	(1)
5. Susceptibility	554	(1)
V. Tumors Associated with Oral Contraceptives	555	(5)
1. Hepatocellular Adenoma	555	(3)
2. Focal Nodular Hyperplasia	558	(1)
3. Hepatocellular Carcinoma	558	(2)
VI. Vascular Lesions	560	(3)
1. Effect on Hemangiomas and Related Lesions	560	(1)
2. Sinusoidal Dilatation	560	(1)
3. Peliosis Hepatis	560	(1)
4. Hepatic Vein Thrombosis	561	(1)
5. Rupture of the Liver	562	(1)
6. Other Vascular Changes	563	(1)
VII. Disturbed Porphyrin Metabolism	563	(1)
VIII. Mechanisms of Injury by Contraceptive Steroids	563	(1)
IX. Cholelithiasis	564	(1)
D. Drugs Related to Sex Hormones	565	(1)
I. Antiestrogens	565	(1)
1. Clomiphene	565	(1)
2. Cyclofenil	565	(1)
3. Tamoxifen	565	(1)
II. Antihypophysial Drugs	565	(1)
1. Danazol	565	(1)
2. Octreotide	566	(1)
E. Glucocorticoids	566	(1)
F. Oral Hypoglycemic Agents	566	(3)
I. Sulfonylureas	566	(1)
II. Clinical Syndrome	567	(1)
III. Prognosis	568	(1)
IV. Biguanide	569	(1)
V. Other Oral Hypoglycemic Agents	569	(1)
G. Antithyroid Drugs	569	(2)
I. Form of Injury	570	(1)
II. Clinical Features	570	(1)
III. Prognosis	570	(1)
IV. Mechanism	571	(1)
V. Comment	571	(1)
References	571	(10)
CHAPTER 24 Hepatotoxicity of Immunomodulating Agents	581	(30)
R. J. FINGEROTE
G. A. LEVY
A. Introduction	581	(1)
B. Immunostimulatory Agents	582	(6)
I. Classification	582	(1)
1. Immune-System-Derived Biologicals	583	(1)
2. Immunostimulatory Pharmaceutical Agents	583	(1)
II. Hepatotoxicity of Specific Immunostimulatory Agents	583	(5)
1. Interleukin-2	583	(2)
2. Interferons	585	(3)
C. Immunosuppressive Agents	588	(14)
I. Classification	588	(3)
1. Antilymphocyte Products	589	(1)
2. Immunophilin-Binding Agents	589	(1)
3. Cytotoxic Agents	589	(1)
4. Sterols	590	(1)
5. Immunosuppressive Antibiotics	590	(1)
6. Arachidonic Acid Metabolites	590	(1)
II. Hepatotoxic Effects of Specific Immunosuppressive Agents	591	(11)
1. Methotrexate	591	(3)
2. Corticosteroids	594	(1)
3. Azathioprine	595	(3)
4. Cyclosporine	598	(3)
5. FK-506	601	(1)
D. Conclusion	602	(1)
References	602	(9)
CHAPTER 25 Alcohol-Induced Liver Injury	611	(26)
Y. ISRAEL
E. RUBIN
A. Epidemiology	611	(1)
B. Liver Dysfunction in Alcoholic Liver Disease	612	(3)
I. Hemodynamic Alterations	612	(1)
II. Liver Failure	613	(2)
C. Alcoholic Liver Injury: Morphological Studies	615	(2)
I. Hepatocytes	615	(1)
II. Inflammation	616	(1)
III. Collagen Deposition	616	(1)
IV. Nonparenchymal Cells (EM Studies)	616	(1)
1. Ito Cells	616	(1)
2. Endothelial Cells	616	(1)
3. Kupffer Cells	616	(1)
D. Clustering	617	(1)
I. Fatty Liver	617	(1)
II. Alcoholic Hepatitis	617	(1)
III. Alcoholic Cirrhosis	617	(1)
E. Pathogenesis of Alcohol-Induced Liver Injury	617	(11)
I. Liquid Diet Model	617	(1)
II. Cytochrome P450 2E1	618	(1)
III. Acetaldehyde Adducts	619	(1)
IV. Hepatocyte Ballooning and Hepatomegaly	620	(1)
V. Hepatic Oxygen Consumption	621	(1)
VI. Liver Hypoxia	622	(1)
VII. Intragastric Infusion Model	623	(1)
VIII. Modulation of Alcohol-Induced Liver Injury	624	(2)
IX. Glutathione	626	(1)
X. Micropig Model of Alcoholic Liver Injury	627	(1)
XI. Baboon Model of Alcoholic Liver Injury	627	(1)
References	628	(9)
CHAPTER 26 Antiepileptic Drugs With 10 Figures	637	(26)
H. J. ZIMMERMAN
K. G. ISHAK
A. Phenytoin	637	(9)
I. Type of Hepatic Injury	637	(1)
II. Clinical Manifestations	638	(2)
III. Biochemical Features	640	(1)
IV. Histopathology	640	(1)
V. Prognosis	641	(2)
VI. Mechanism	643	(2)
VII. Other Hydantoins	645	(1)
1. Mephenytoin	645	(1)
2. Acetylurea Derivatives	645	(1)
3. Oxazolidinediones	646	(1)
4. Barbiturates and Primidone	646	(1)
B. Carbamazepine	646	(3)
I. Susceptibility	646	(1)
II. Clinical Features	647	(1)
III. Biochemical Features	647	(1)
IV. Histopathology	648	(1)
V. Prognosis	648	(1)
VI. Mechanism	648	(1)
C. Valproic Acid	649	(8)
I. Incidence of Injury	649	(1)
II. Susceptibility	650	(1)
III. Clinical Features	650	(2)
IV. Biochemical Features	652	(1)
V. Histopathology	652	(2)
VI. Prognosis	654	(1)
VII. Mechanism of Injury	654	(3)
VIII. Prevention	657	(1)
References	657	(6)
Subject Index	663