Frank A. Barile

Barile's Clinical Toxicology (eBook, PDF)

Principles and Mechanisms

• Format: PDF

Produktbeschreibung

This book examines the complex interactions associated with clinical toxicological events as a result of therapeutic drug administration or chemical exposure. Special emphasis is placed on signs and symptoms of diseases and pathology caused by toxins and clinical drugs.

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Produktdetails

• Verlag: Taylor & Francis
• Seitenzahl: 622
• Erscheinungstermin: 24. April 2019
• Englisch
• ISBN-13: 9781498765381
• Artikelnr.: 56840214

Autorenporträt

Frank A. Barile, PhD, is Professor in the Toxicology Division and past chairman

of the Department of Pharmaceutical Sciences, St. John's University College of

Pharmacy and Health Sciences, New York.

Dr. Barile received his BS in Pharmacy, MS in Pharmacology, and PhD in

Toxicology at St. John's University. After doing a postdoctoral fellowship in

Pulmonary Pediatrics at the Albert Einstein College of Medicine, Bronx, NY, he

moved to the Department of Pathology, Columbia University-St. Luke's Roosevelt

Hospital, NY, as a research associate. In these positions, he investigated the role of

pulmonary toxicants in collagen metabolism in cultured lung cells. In 1984, he was

appointed assistant professor in the Department of Health Sciences at City University

of NY. Sixteen years later, he rejoined St. John's University in the Department of

Pharmaceutical Sciences in the College of Pharmacy.

Dr. Barile holds memberships in several professional associations, including the

U.S. Society of Toxicology, the American Association of University Professors, the

American Association for the Advancement of Science, the American Society of

Hospital Pharmacists, New York City Pharmacists Society, New York Academy of

Sciences, and New York State Council of Health System Pharmacists. He is past

president of the In Vitro and Alternative Methods Specialty Section of the U.S.

Society of Toxicology and a former member of the Scientific Advisory Committee

for Alternative Toxicological Methods, the National Institute of Environmental

Health Sciences, U.S. National Institutes of Health (NIH). He is former editor of

Toxicology in Vitro and Journal of Pharmacological & Toxicological Methods, published

by Elsevier Ltd.

Dr. Barile is the recipient of Public Health Service research grants from the

National Institute of General Medical Sciences, the National Institutes of Health,

and grants from private foundations dedicated to alternatives to animal testing.

He has authored approximately 100 original research manuscripts, review articles,

research abstracts, and conference proceedings in peer-reviewed toxicology and biomedical

journals. He has also published several books and related chapters in the

field. He contributed original in vitro toxicology data to the international Multicenter

Evaluation for In Vitro Cytotoxicity program. He lectures regularly to pharmacy and

toxicology undergraduate and graduate students in clinical and basic pharmaceutical

and toxicological sciences and was awarded "Professor of the Year" for the College

of Pharmacy by the St. John's University Student Government Association (2003).

Dr. Barile has served on several U.S. government advisory committees, including:

Toxicology Assessment Peer Review Committee, U.S. Environmental Protection

Agency; National Institutes of Health Review Panel, Study Section Reviewer (2013);

Scientific Advisory Committee on Alternative Toxicological Methods (SACATM,

2005-2009); National Toxicology Program (NTP) Interagency Center for the

Evaluation of Alternative Toxicological Methods, Support Contract Reviewer (2014);

U.S. Food and Drug Administration (U.S. FDA), National Center for Toxicology

Research, Systems Biology Subcommittee (2016); National Institute for Occupational

Safety and Health (NIOSH) and Oak Ridge Associated Universities, SK Profiles

Review Group (2014); U.S. Food and Drug Administration advisory committee on

alternative toxicological methods (2013); and has served as vice president of the

Dermal Toxicology Specialty Section for the Society of Toxicology (2013-2014).

Dr. Barile received the Faculty Recognition Award, American Association of

University Professors Faculty Association Award, St. John's University, in 2003,

2004-2005, 2013-2014, and 2015-2016 and received the prestigious Public Health

Service Medallion from the director of the National Institute of Environmental

Health Sciences, Dr. Linda Birnbaum, for contributions to the Scientific Advisory

Committee for Alternative Toxicological Methods (2009).

Dr. Barile continues original research on the cytotoxic effects of therapeutic

drugs, environmental chemicals, and controlled substances on cultured mammalian

embryonic stem cells and human induced pluripotent stem cells and has dedicated

his professional life to the advancement of in vitro alternative methods to reduce,

replace and refine animal toxicology testing.

Inhaltsangabe

Contents

Preface...................................................................................................................xxxi

Acknowledgments............................................................................................... xxxiii

Author...................................................................................................................xxxv

Contributors........................................................................................................xxxvii



Section I Introduction to Basic

Toxicological Principles



Chapter 1 Introduction...........................................................................................3

1.1 Introduction................................................................................3

1.2 Basic Definitions.........................................................................4

1.2.1 Toxicology.....................................................................4

1.2.2 Clinical Toxicology.......................................................4

1.3 Types of Toxicology...................................................................5

1.3.1 General Toxicology.......................................................5

1.3.2 Mechanistic Toxicology................................................5

1.3.3 Regulatory Toxicology..................................................5

1.3.4 Descriptive Toxicology..................................................6

1.4 Types of Toxicologist..................................................................7

1.4.1 Forensic Toxicologist.....................................................7

1.4.2 Clinical Toxicologist.....................................................8

1.4.3 Research Toxicologist....................................................8

1.4.4 Regulatory Toxicologist................................................8

References.............................................................................................8

Suggested Readings...............................................................................8

Review Articles.....................................................................................9

Chapter 2 Risk Assessment and Regulatory Toxicology..................................... 11

2.1 Risk Assessment....................................................................... 11

2.1.1 Introduction................................................................. 11

2.1.2 Hazard Identification/Risk Assessment (HIRA)......... 11

2.1.3 Dose-Response Evaluation......................................... 11

2.1.4 Exposure Assessment and Assessment Modeling....... 12

2.1.5 Risk Characterization.................................................. 14

2.2 Regulatory Toxicology............................................................. 16

2.2.1 Nuclear Regulatory Commission (NRC).................... 16

2.2.2 Environmental Protection Agency (EPA)................... 17

2.2.3 The Food and Drug Administration (FDA)................ 18

2.2.4 Drug Enforcement Administration (DEA).................. 19

2.2.5 Consumer Products Safety Commission (CPSC)........20

2.2.6 Occupational Safety and Health Administrations

(OSHA)........................................................................22

References...........................................................................................23

Suggested Readings.............................................................................23

Review Articles...................................................................................23

Chapter 3 Therapeutic Monitoring of Adverse Drug Reactions (ADRs).............27

3.1 Adverse Drug Reactions (ADRs) in Clinical Practice.............27

3.1.1 The Joint Commission (TJC)......................................27

3.1.2 Growing Medication Safety Concerns........................28

3.1.3 National Patient Safety Goals (NPSG).......................28

3.2 Factors that Contribute to Adverse Drug Reactions (ADRs)...29

3.2.1 Inadequate Monitoring of Prescribed Drugs..............29

3.2.2 Improper Adherence to Prescribed Directions........... 32

3.2.3 Over-Prescribing and Overuse of Medications........... 32

3.2.4 Drug-Drug and Drug-Disease Interactions............... 32

3.2.5 Allergic Reactions....................................................... 32

3.2.6 Medication Warnings.................................................. 33

3.2.7 Medication Errors....................................................... 33

3.2.8 Adverse Drug Reactions (ADRS)............................... 33

3.3 Treatment of ADRs and Poisoning in Patients......................... 35

3.3.1 History......................................................................... 35

3.3.2 Poison Control Centers (PCCs)................................... 35

3.3.3 Clinical Management of ADRs...................................36

3.3.4 Clinical Management of Toxicologic Emergencies.....36

3.4 Drug Identification and Methods of Detection......................... 41

References...........................................................................................44

Suggested Readings.............................................................................44

Review Articles................................................................................... 45

Chapter 4 Classification of Toxins in Humans.................................................... 47

4.1 Introduction.............................................................................. 47

4.2 Target Organ Classification...................................................... 47

4.2.1 Agents Affecting the Hematopoietic System.............. 47

4.2.2 Immunotoxic Agents...................................................48

4.2.3 Hepatotoxic Agents.....................................................48

4.2.4 Nephrotoxic Agents.....................................................49

4.2.5 Pulmonary Toxic Agents............................................. 52

4.2.6 Agents Affecting the Nervous System........................54

4.2.7 Agents Affecting the Cardiovascular (CV) System.... 55

4.2.8 Dermatotoxic Agents................................................... 55

4.2.9 Agents Affecting the Reproductive System................ 59

4.2.10 Agents Affecting the Endocrine System..................... 59

4.3 Classification According to use in the Public Domain.............60

4.3.1 Insecticides, Herbicides, Fungicides, and

Rodenticides (Pesticides).............................................60

4.3.2 Food and Color Additives........................................... 61

4.3.3 Therapeutic Drugs.......................................................63

4.3.4 By-Products of Combustion........................................63

4.4 Classification According to Source..........................................63

4.4.1 Botanical.....................................................................63

4.4.2 Environmental.............................................................63

4.5 Classification According to Effects..........................................64

4.5.1 Pathologic....................................................................64

4.5.2 Teratogenic, Mutagenic, and Carcinogenic.................64

4.6 Classification According to Physical State...............................64

4.6.1 Solids...........................................................................64

4.6.2 Liquids.........................................................................64

4.6.3 Gases...........................................................................65

4.7 Classification According to Biochemical Properties................65

4.7.1 Chemical Structure.....................................................65

4.7.2 Mechanism of Action or Toxicity................................65

References...........................................................................................65

Suggested Readings.............................................................................65

Review Articles...................................................................................65

Chapter 5 Exposure..............................................................................................69

5.1 Introduction..............................................................................69

5.2 Route of Exposure....................................................................69

5.2.1 Oral..............................................................................69

5.2.2 Intranasal..................................................................... 70

5.2.3 Inhalation.................................................................... 71

5.2.4 Parenteral.................................................................... 71

5.3 Duration and Frequency........................................................... 72

5.3.1 Acute Exposure........................................................... 72

5.3.2 Chronic Exposure........................................................ 73

5.3.3 Single- or Repeated-Dose Exposure........................... 73

5.4 Accumulation........................................................................... 73

5.4.1 According to Physiological Compartment.................. 74

5.4.2 According to Chemical Properties.............................. 74

5.4.3 According to Other Biological Factors........................ 74

References........................................................................................... 76

Suggested Readings............................................................................. 76

Review Articles................................................................................... 76

Chapter 6 Effects.................................................................................................. 79

6.1 General Classification............................................................... 79

6.1.1 Introduction to Principles of Immunology.................. 79

6.1.2 Chemical Allergies...................................................... 79

6.1.3 Idiosyncratic Reactions...............................................86

6.1.4 Immediate versus Delayed Effects..............................86

6.1.5 Reversible versus Irreversible Reactions.....................86

6.1.6 Local versus Systemic Effects.....................................86

6.1.7 Target Therapeutic Effects..........................................87

6.2 Chemical Interactions...............................................................87

6.2.1 Potentiation..................................................................87

6.2.2 Additive.......................................................................87

6.2.3 Synergistic...................................................................88

6.2.4 Antagonistic................................................................88

References...........................................................................................88

Suggested Readings.............................................................................88

Review Aricles.....................................................................................89

Chapter 7 Dose-Response................................................................................... 91

7.1 General Assumptions............................................................... 91

7.1.1 Types of Dose-Response Relationships...................... 91

7.1.2 Concentration-Effect and Presence at the

Receptor Site...............................................................93

7.1.3 Criteria for Measurement............................................93

7.2 LD50 (Lethal Dose 50%)...........................................................93

7.2.1 Definition.....................................................................93

7.2.2 Experimental Protocol................................................93

7.2.3 Factors That Influence the LD50..................................94

7.3 ED50 (Effective Dose 50%), TD50 (Toxic Dose 50%), and

TI (Therapeutic Index).............................................................95

7.3.1 Relationship to LD50....................................................95

7.3.2 Assumptions Using the TI...........................................95

7.4 IC50 (Inhibitory Concentration 50%)........................................96

7.4.1 Definition.....................................................................96

7.4.2 Experimental Determination.......................................97

7.4.3 For In Vitro Systems....................................................97

References...........................................................................................97

Suggested Readings.............................................................................97

Review Articles...................................................................................98

Chapter 8 Descriptive Animal Toxicity Tests......................................................99

8.1 Correlation with Human Exposure...........................................99

8.1.1 Human Risk Assessment.............................................99

8.1.2 Predictive Toxicology and Extrapolation to

Human Toxicity...........................................................99

8.2 Species Differentiation.............................................................99

8.2.1 Selection of a Suitable Animal Species......................99

8.2.2 Cost-Effectiveness..................................................... 100

8.2.3 Institutional Animal Care and Use Committee

(IACUC).................................................................... 100

8.3 Descriptive Tests..................................................................... 101

8.3.1 Required LD50 and Two Routes............................... 101

8.3.2 Chronic and Subchronic Exposure............................ 101

8.3.3 Types of Tests............................................................ 101

References......................................................................................... 102

Suggested Readings........................................................................... 102

Review Aricles................................................................................... 103

Chapter 9 In Vitro Alternatives to Animal Toxicity.......................................... 105

9.1 In Vitro Methods.................................................................... 105

9.1.1 Cell Culture Methods................................................ 105

9.1.2 Organ System Cytotoxicity....................................... 105

9.1.3 Applications to Clinical Toxicology.......................... 106

9.1.4 Relationship to Animal Experiments........................ 107

9.2 Correlation with Human Exposure......................................... 107

9.2.1 Risk Assessment........................................................ 107

9.2.2 Extrapolation to Human Toxicity.............................. 107

9.2.3 Predictive Toxicology................................................ 108

References......................................................................................... 108

Suggested Readings........................................................................... 108

Review Articles................................................................................. 108

Chapter 10 Toxicokinetics................................................................................... 111

10.1 Toxicokinetics......................................................................... 111

10.1.1 Relationship to Pharmacokinetics............................. 111

10.1.2 One-Compartment Model......................................... 111

10.1.3 Two-Compartment Model......................................... 112

10.1.4 Application to Clinical Toxicology........................... 112

10.2 Absorption.............................................................................. 112

10.2.1 Ionic and Nonionic Principles................................... 112

10.2.2 Henderson-Hasselbalch Equation and Degree of

Ionization................................................................... 114

10.2.3 Route of Administration and Solubility.................... 118

10.2.4 Absorption in Nasal and Respiratory Mucosa.......... 119

10.2.5 Transport of Molecules............................................. 120

10.3 Distribution............................................................................. 121

10.3.1 Fluid Compartments.................................................. 121

10.3.2 Ionic and Nonionic Principles................................... 122

10.3.3 Plasma Protein Binding............................................. 123

10.3.4 Lipids......................................................................... 125

10.3.5 Liver and Kidney....................................................... 125

10.3.6 Blood-Brain Barrier.................................................. 125

10.3.7 Placenta..................................................................... 125

10.3.8 Other Factors Affecting Distribution........................ 126

10.4 Biotransformation (Metabolism)............................................ 126

10.4.1 Principles of Detoxification....................................... 126

10.4.2 Phase I Reactions...................................................... 127

10.4.3 Phase II Reactions..................................................... 128

10.5 Elimination............................................................................. 131

10.5.1 Urinary...................................................................... 131

10.5.1.1 First-Order Elimination............................. 132

10.5.1.2 Zero-Order Elimination............................. 134

10.5.2 Fecal.......................................................................... 135

10.5.3 Pulmonary................................................................. 135

10.5.4 Mammary Glands..................................................... 136

10.5.5 Secretions.................................................................. 136

References......................................................................................... 136

Suggested Readings........................................................................... 136

Review Articles................................................................................. 137

Chapter 11 Chemical- and Drug-Receptor Interactions..................................... 139



Zacharoula Konsoula



11.1 Types of Chemical and Drug Receptors................................. 139

11.1.1 Ion Channels.............................................................. 139

11.1.2 G-Protein-Coupled Receptors................................... 142

11.1.3 Kinases and Enzyme-Coupled Receptors................. 143

11.1.4 Intracellular Receptors.............................................. 145

11.2 Signal Transduction................................................................ 148

References......................................................................................... 150

Suggested Readings........................................................................... 150

Review Articles................................................................................. 150

Chapter 12 Toxicogenomics................................................................................. 151



Anirudh J. Chintalapati, Zacharoula Konsoula, and Frank A. Barile



12.1 Introduction............................................................................ 151

12.2 Human Genomic Variation..................................................... 151

12.2.1 Genomic Variation in Target Molecules................... 152

12.2.2 Genomic Variation in Drug Metabolism................... 154

12.3 Gene Structure and Function.................................................. 154

12.3.1 DNA Alterations and Genotoxic Effects................... 155

12.3.2 DNA Repair Mechanisms......................................... 157

12.3.3 Experimental Monitoring for Genetic Toxicity......... 159

12.3.4 Clinical Monitoring for Genetic Toxicity.................. 159

12.4 Epigenetic Toxicology............................................................ 160

12.4.1 Mechanisms of Epigenetic Toxicity.......................... 161

12.4.1.1 DNA Methylation...................................... 161

12.4.1.2 Posttranslational Modifications of

Histone Proteins......................................... 162

12.4.1.3 Noncoding RNA........................................ 162

12.4.2 Epigenetics and Disease............................................ 163

Referenes........................................................................................... 163

Suggested Readings........................................................................... 163

Review Articles................................................................................. 164



Section II Toxicity of Therapeutic Agents



Chapter 13 Sedative/Hypnotics............................................................................ 167



Frank A. Barile and Anirudh J. Chintalapati



13.1 Barbiturates............................................................................ 167

13.1.1 History and Classification......................................... 167

13.1.2 Epidemiology............................................................ 167

13.1.3 Medicinal Chemistry................................................. 167

13.1.4 Pharmacology and Clinical Use................................ 168

13.1.5 Toxicokinetics and Metabolism................................ 168

13.1.6 Mechanism of Toxicity.............................................. 169

13.1.7 Signs and Symptoms of Acute Toxicity.................... 169

13.1.8 Emergency Guidelines.............................................. 171

13.1.9 Clinical Management of Acute Overdose................. 171

13.1.10 Tolerance and Withdrawal......................................... 172

13.1.11 Methods of Detection................................................ 172

13.2 Benzodiazepines (BZ)............................................................ 172

13.2.1 Epidemiology............................................................ 172

13.2.2 Medicinal Chemistry................................................. 173

13.2.3 Pharmacology and Mechanism of Toxicity............... 173

13.2.4 Toxicokinetics........................................................... 173

13.2.5 Signs and Symptoms of Acute Toxicity.................... 174

13.2.6 Emergency Guidelines.............................................. 174

13.2.7 Clinical Management of Acute Overdose................. 174

13.2.8 Tolerance and Withdrawal......................................... 174

13.2.9 Methods of Detection................................................ 174

13.3 Miscellaneous Sedative/Hypnotics........................................ 176

13.3.1 Chloral Hydrate......................................................... 176

13.3.2 Meprobamate (Miltown®, Equanil®)......................... 176

13.3.3 Zolpidem tartrate (Ambien®)..................................... 177

13.3.4 Buspirone (Buspar®).................................................. 177

13.3.5 Flunitrazepam (Rohypnol®)...................................... 177

13.3.6 Gamma-hydroxybutyrate (GHB)............................... 178

13.3.7 Ethchlorvynol (Placidyl®), Methaqualone

(Quaalude®), Glutethimide (Doriden®),

Methyprylon (Noludar®)............................................ 178

13.4 Methods of Detection and Laboratory Tests for S/H............. 179

References......................................................................................... 179

Suggested Readings........................................................................... 180

Review Articles................................................................................. 181

Chapter 14 Opioids and Related Agents.............................................................. 183

14.1 Opioids.................................................................................... 183

14.1.1 U.S. Public Health and Historical Use...................... 183

14.1.2 Neonatal Abstinence Syndrome (NAS).................... 185

14.1.3 Classification............................................................. 186

14.1.4 Medicinal Chemistry................................................. 189

14.1.5 Mechanism of Toxicity.............................................. 189

14.1.6 Brain Chemistry........................................................ 191

14.1.7 Toxicokinetics........................................................... 191

14.1.8 Mechanism of Toxicity.............................................. 191

14.1.9 Signs and Symptoms of Clinical Toxicity................. 192

14.1.10 Clinical Management of Acute Overdose................. 192

14.1.11 Tolerance and Withdrawal......................................... 193

14.1.12 Clinical Management of Addiction........................... 195

14.2 Specific Opioid Derivatives.................................................... 195

14.2.1 Codeine..................................................................... 195

14.2.2 Diphenoxylate............................................................ 196

14.2.3 Fentanyl..................................................................... 196

14.2.4 Meperidine................................................................ 196

14.2.5 Pentazocine............................................................... 197

14.2.6 Propoxyphene............................................................ 197

14.2.7 Hydrocodone/Oxycodone.......................................... 197

14.2.8 Tramadol................................................................... 198

14.2.9 Clonidine................................................................... 199

14.3 Methods of Detection............................................................. 199

References.........................................................................................200

Suggested Readings...........................................................................200

Review Articles................................................................................. 201

Chapter 15 Sympathomimetics............................................................................203

15.1 Amphetamines and Amphetamine-like Agents.....................203

15.1.1 Incidence...................................................................203

15.1.2 Classification.............................................................203

15.1.3 Medicinal Chemistry.................................................204

15.1.4 Pharmacology and Clinical Use................................204

15.1.5 Toxicokinetics...........................................................206

15.1.6 Effects and Mechanism of Toxicity...........................206

15.1.7 Chronic Methamphetamine Use...............................208

15.1.8 Tolerance and Withdrawal.........................................208

15.1.9 Clinical Management of Amphetamine Addiction...208

15.1.10 Methods of Detection................................................209

15.2 Cocaine...................................................................................209

15.2.1 Incidence and Occurrence.........................................209

15.2.2 Medicinal Chemistry................................................. 210

15.2.3 Pharmacology and Clinical Use................................ 210

15.2.4 Toxicokinetics........................................................... 211

15.2.5 Signs and Symptoms of Acute Toxicity.................... 212

15.2.6 Clinical Management of Acute Overdose................. 212

15.2.7 Tolerance and Withdrawal......................................... 213

15.2.8 Clinical Management of Cocaine Addiction............. 213

15.2.9 Methods of Detection................................................ 213

15.3 Xanthine Derivatives.............................................................. 213

15.3.1 Source and Medicinal Chemistry.............................. 213

15.3.2 Occurrence................................................................ 214

15.3.3 Pharmacology and Clinical Use................................ 214

15.3.4 Toxicokinetics........................................................... 216

15.3.5 Signs and Symptoms and Clinical Management

of Caffeine Toxicity................................................... 216

15.3.6 Signs and Symptoms and Clinical Management

of Theophylline Toxicity........................................... 217

15.3.7 Tolerance and Withdrawal......................................... 217

15.4 Other Specific Sympathomimetic Agents.............................. 217

15.4.1 Strychnine................................................................. 217

15.4.2 Nicotine..................................................................... 218

15.4.3 Ephedrine.................................................................. 219

15.4.4 Phenylpropranolamine..............................................220

15.4.5 Pseudoephedrine.......................................................220

References.........................................................................................220

Suggested Readings...........................................................................220

Review Articles................................................................................. 221

Chapter 16 Hallucinogenic Agents......................................................................225

16.1 History and Description.........................................................225

16.2 Ergot Alkaloids.......................................................................225

16.2.1 Incidence and Occurrence.........................................225

16.2.2 Medicinal Chemistry.................................................226

16.2.3 Pharmacology and Clinical Use................................226

16.2.4 Signs and Symptoms of Acute Toxicity....................227

16.2.5 Clinical Management of Acute Overdose.................227

16.3 Lysergic Acid Diethylamide (LSD)........................................228

16.3.1 Incidence and Occurrence.........................................228

16.3.2 Mechanism of Toxicity..............................................228

16.3.3 Hallucinogenic Effects..............................................228

16.3.4 Toxicokinetics...........................................................229

16.3.5 Signs and Symptoms of Acute Toxicity....................229

16.3.6 Clinical Management of Acute Overdose.................229

16.3.7 Tolerance and Withdrawal.........................................230

16.3.8 Methods of Detection................................................230

16.4 Tryptamine Derivatives..........................................................230

16.4.1 Incidence and Occurrence.........................................230

16.4.2 Mechanism of Toxicity..............................................230

16.4.3 Signs and Symptoms of Acute Toxicity.................... 231

16.4.4 Clinical Management of Acute Overdose................. 231

16.4.5 Tolerance and Withdrawal......................................... 231

16.4.6 Methods of Detection................................................ 231

16.5 Phenethylamine Derivatives................................................... 232

16.5.1 Incidence and Occurrence......................................... 232

16.5.2 Medicinal Chemistry................................................. 232

16.5.3 Mescaline.................................................................. 232

16.5.4 DOM (2,5-dimethoxy-4-methylamphetamine,

STP) and MDA (3,4-methylenedioxyamphetamine)...............................234

16.5.5 MDMA (3,4-methylenedioxymethamphetamine,

ecstasy)......................................................................234

16.5.6 Methods of Detection................................................ 235

16.6 Phencyclidine (1-Phenylcyclohexyl Piperidine; PCP)............ 235

16.6.1 Incidence and Occurrence......................................... 235

16.6.2 Toxicokinetics........................................................... 235

16.6.3 Signs and Symptoms of Acute Toxicity....................236

16.6.4 Clinical Management of Acute Overdose.................236

16.6.5 Tolerance and Withdrawal......................................... 237

16.6.6 Methods of Detection................................................ 237

16.7 Marijuana............................................................................... 237

16.7.1 Incidence and Occurrence......................................... 237

16.7.2 Medicinal Chemistry.................................................240

16.7.3 Receptor Pharmacology and Toxicology..................240

16.7.4 Clinical Use and Effects............................................ 241

16.7.5 Toxicokinetics...........................................................242

16.7.6 Acute Toxicity and Clinical Management.................242

16.7.7 Tolerance, Withdrawal, and Chronic Effects............242

16.7.8 Clinical Management of Chronic Addiction............. 243

16.7.9 Methods of Detection................................................ 243

16.8 Miscellaneous Hallucinogenic Agents................................... 243

16.8.1 Ketamine (Special K, Vitamin K)............................. 243

16.8.2 Gamma-hydroxybutyrate (GHB; Xyrem®)................245

16.8.3 NBOMe.....................................................................246

References.........................................................................................246

Suggested Readings...........................................................................246

Review Articles................................................................................. 247

Chapter 17 Anticholinergic and Neuroleptic Drugs............................................ 251

17.1 Introduction to Drugs Possessing Anticholinergic Effects........251

17.2 Antihistamine, Gastrointestinal, and Antiparkinson Drugs.......251

17.2.1 Incidence................................................................... 251

17.2.2 Medicinal Chemistry, Pharmacology, and

Clinical Use............................................................... 253

17.2.3 Signs and Symptoms of Acute Toxicity.................... 253

17.2.4 Clinical Management of Acute Overdose.................254

17.2.5 Methods of Detection................................................254

17.3 Tricyclic Antidepressants (TCA)............................................ 255

17.3.1 Incidence................................................................... 255

17.3.2 Medicinal Chemistry................................................. 255

17.3.3 Pharmacology and Clinical Use................................ 255

17.3.4 Toxicokinetics........................................................... 255

17.3.5 Mechanism of Toxicity..............................................256

17.3.6 Signs and Symptoms of Acute Toxicity....................256

17.3.7 Clinical Management of Acute Overdose.................256

17.3.8 Tolerance and Withdrawal......................................... 259

17.3.9 Methods of Detection................................................ 259

17.4 Phenothiazine, Phenylbutylpiperidine, and Thioxanthine

Antipsychotics........................................................................ 259

17.4.1 Classification and Indications................................... 259

17.4.2 Pharmacology and Clinical Use................................260

17.4.3 Toxicokinetics...........................................................260

17.4.4 Mechanism and Signs and Symptoms of Acute

Toxicity......................................................................260

17.4.5 Clinical Management of Acute Overdose................. 262

17.4.6 Tolerance and Withdrawal......................................... 262

17.4.7 Methods of Detection................................................ 262

17.5 Selective Serotonin Reuptake Inhibitors (SSRIS).................. 262

17.5.1 Classification and Clinical Use................................. 262

17.5.2 Pharmacology and Receptor Activity.......................263

17.5.3 Toxicokinetics...........................................................264

17.5.4 Side Effects and Adverse Reactions..........................265

17.5.5 Signs and Symptoms of Acute Toxicity....................266

17.5.6 Clinical Management of Acute Overdose (O.D.)......266

17.5.7 Tolerance and Withdrawal......................................... 267

17.5.8 Methods of Detection................................................ 267

References......................................................................................... 267

Suggested Readings........................................................................... 267

Review Articles.................................................................................268

Chapter 18 Acetaminophen, Salicylates, and Nonsteroidal Anti-

Inflammatory Drugs (NSAIDs)........................................................ 271

18.1 History and Description......................................................... 271

18.2 Acetaminophen (N-Acetyl-Para-Aminophenol,

APAP, Paracetamol)............................................................... 271

18.2.1 Incidence................................................................... 271

18.2.2 Medicinal Chemistry and Pharmacology................. 272

18.2.3 Clinical Use............................................................... 272

18.2.4 Metabolism and Mechanism of Toxicity................... 272

18.2.5 Signs and Symptoms of Acute Toxicity.................... 274

18.2.6 Clinical Management of Acute Overdose................. 274

18.3 Salicylates and Acetylsalicylic Acid (ASPIRIN, ASA).......... 276

18.3.1 Incidence and Clinical Use....................................... 276

18.3.2 Toxicokinetics...........................................................277

18.3.3 Mechanism of Toxicity..............................................277

18.3.4 Signs and Symptoms of Acute Toxicity.................... 278

18.3.5 Clinical Management of Toxicity.............................. 279

18.4 Nonsteroidal Anti-Inflammatory Agents (NSAIDS)............. 281

18.4.1 History and Description............................................ 281

18.4.2 Classification, Pharmacology, and Clinical Use.......282

18.4.3 Signs and Symptoms of Acute Toxicity....................282

18.4.4 Clinical Management of Acute Overdose.................282

18.5 Methods of Detection.............................................................284

References.........................................................................................284

Suggested Readings...........................................................................284

Review Articles.................................................................................285

Chapter 19 Anabolic-Androgenic Steroids.........................................................287

19.1 The Endocrine System...........................................................287

19.2 Neuroendocrine Physiology...................................................287

19.2.1 Description................................................................287

19.3 Anabolic-Androgenic Steroids (AAS)...................................288

19.3.1 Definition and Incidence...........................................288

19.3.2 Pharmacology and Clinical Use................................289

19.3.3 Adverse reactions......................................................289

19.3.4 Addiction and Withdrawal Syndrome.......................293

19.3.5 Treatment of the Consequences of Chronic

Steroid Use................................................................293

19.4 Estrogen and Progestins.........................................................293

19.4.1 Physiology.................................................................293

19.4.2 Pharmacology and Clinical Use................................294

19.4.3 Clinical Toxicity of Prolonged Estrogen and/or

Progestin Administration..........................................294

References.........................................................................................297

Suggested Readings...........................................................................297

Review Articles.................................................................................297

Chapter 20 Cardiovascular Toxicology................................................................299

20.1 Epidemiology..........................................................................299

20.2 Cardiovascular (CV) Physiology............................................299

20.2.1 CV Functions.............................................................299

20.2.2 Cardiac Circulation...................................................300

20.2.3 Electrophysiology......................................................300

20.2.4 The Conducting System............................................ 301

20.2.5 Electrocardiography..................................................302

20.3 Digitalis Glycosides................................................................303

20.3.1 Medicinal Chemistry.................................................303

20.3.2 Pharmacology and Clinical Use................................304

20.3.3 Toxicokinetics...........................................................304

20.3.4 Clinical Manifestations of Toxicity...........................305

20.3.5 Mechanisms of Toxicity............................................305

20.3.6 Clinical Management of Intoxication........................306

20.3.7 Methods of Detection................................................307

20.4 Beta-Adrenergic Receptor Antagonists..................................307

20.4.1 beta-Adrenergic Receptor System..................................307

20.4.2 Pharmacology and Clinical Use................................307

20.4.3 Clinical Manifestations of Toxicity...........................308

20.4.4 Clinical Management of Intoxication........................308

20.5 Calcium Channel Antagonists (Ca2+ Channel Blockers)........309

20.5.1 Pharmacology and Clinical Use................................309

20.5.2 Clinical Manifestations of Toxicity........................... 310

20.5.3 Clinical Management of Intoxication........................ 310

20.6 Other CV Drugs..................................................................... 310

20.6.1 Angiotensin-Converting Enzyme (ACE)

Inhibitors................................................................... 311

20.6.2 Direct Vasodilators.................................................... 312

20.6.3 Antiarrhythmic Drugs............................................... 313

References......................................................................................... 314

Suggested Readings........................................................................... 314

Review Articles................................................................................. 315

Chapter 21 Antineoplastic Agents....................................................................... 317

21.1 Description............................................................................. 317

21.2 Review of the Cell Cycle........................................................ 317

21.3 Antimetabolites...................................................................... 318

21.3.1 Pharmacology and Clinical Use................................ 318

21.3.2 Acute Toxicity........................................................... 319

21.3.3 Clinical Management of Acute Overdose................. 319

21.4 Alkylating Agents................................................................... 320

21.4.1 Pharmacology and Clinical Use................................ 320

21.4.2 Acute Toxicity........................................................... 320

21.4.3 Clinical Management of ADRs................................. 321

21.5 Miscellaneous Chemotherapeutic Drugs............................... 321

21.5.1 Natural Products........................................................ 321

21.5.2 Hormones and Antagonists....................................... 323

21.5.3 Platinum Coordination Complexes...........................324

21.5.4 Substituted Urea........................................................324

References......................................................................................... 325

Suggested Readings........................................................................... 325

Review Articles................................................................................. 325

Chapter 22 Vitamins............................................................................................ 329

22.1 Introduction............................................................................ 329

22.2 Fat-Soluble Vitamins.............................................................. 331

22.2.1 Vitamin A and Retinoic Acid Derivatives................ 331

22.2.2 Vitamin D.................................................................. 332

22.2.3 Vitamin E.................................................................. 335

22.2.4 Vitamin K.................................................................. 335

22.3 Water-Soluble Vitamins.......................................................... 336

22.3.1 Thiamine................................................................... 336

22.3.2 Riboflavin.................................................................. 336

22.3.3 Niacin........................................................................ 336

22.3.4 Folic Acid.................................................................. 338

22.3.5 Cyanocobalamin (Vitamin B12)................................. 338

22.3.6 Ascorbic Acid (Vitamin C)....................................... 338

22.3.7 Pyridoxine (Vitamin B6)........................................... 339

22.3.8 Pantothenic Acid (Vitamin B5)................................. 339

References.........................................................................................340

Suggested Readings...........................................................................340

Review Articles.................................................................................340

Chapter 23 Herbal Remedies............................................................................... 343

23.1 Introduction............................................................................ 343

23.2 Nomenclature and Classification............................................344

23.2.1 Nomenclature............................................................344

23.2.2 Therapeutic Category................................................ 345

23.3 Indications.............................................................................. 345

23.4 Other Therapeutic and Toxicologic Information on

Herbal Products...................................................................... 345

References......................................................................................... 356

Suggested Readings........................................................................... 356

Review Articles................................................................................. 357



Section III Toxicity of Nontherapeutic Agents



Chapter 24 Alcohols and Aldehydes.................................................................... 361

24.1 Ethanol.................................................................................... 361

24.1.1 Incidence and Occurrence......................................... 361

24.1.2 Chemical Characteristics.......................................... 361

24.1.3 Toxicokinetics........................................................... 362

24.1.4 Calculation of Blood Alcohol Concentrations

(BAC)........................................................................ 363

24.1.5 Mechanisms of Toxicity............................................364

24.1.6 Clinical Manifestations of Acute Toxicity................366

24.1.7 Management of Acute Intoxication...........................368

24.1.8 Clinical Manifestations of Chronic Toxicity.............368

24.1.9 Management of Chronic Intoxication....................... 370

24.1.10 Fetal Alcohol Syndrome (FAS)................................. 371

24.1.11 Tolerance, Dependence, and Withdrawal.................. 371

24.1.12 Methods of Detection................................................ 372

24.2 Methanol................................................................................. 373

24.2.1 Incidence and Occurrence......................................... 373

24.2.2 Toxicokinetics........................................................... 373

24.2.3 Mechanism of Toxicity.............................................. 373

24.2.4 Clinical Manifestations of Acute Intoxication.......... 374

24.2.5 Management of Acute Intoxication........................... 374

24.3 Isopropanol............................................................................. 374

24.3.1 Toxicokinetics........................................................... 375

24.3.2 Mechanisms of Toxicity............................................ 375

24.3.3 Clinical Manifestations of Acute Toxicity................ 375

24.3.4 Management of Acute Intoxication........................... 375

24.4 Formaldehyde......................................................................... 375

24.4.1 Incidence and Occurrence......................................... 376

24.4.2 Toxicokinetics........................................................... 376

24.4.3 Mechanisms of Toxicity............................................ 377

24.4.4 Clinical Manifestations of Acute Intoxication.......... 377

24.4.5 Management of Acute Intoxication........................... 377

References......................................................................................... 377

Suggested Readings........................................................................... 377

Review Articles................................................................................. 378

Chapter 25 Gases................................................................................................. 381

25.1 Introduction............................................................................ 381

25.2 Pulmonary Irritants................................................................ 381

25.3 Simple Asphyxiants................................................................ 382

25.3.1 Introduction............................................................... 382

25.3.2 Gaseous Agents......................................................... 382

25.4 Toxic Products of Combustion (TCP).................................... 387

25.4.1 Introduction............................................................... 387

25.4.2 Clinical Toxicity........................................................ 387

25.5 Lacrimating Agents (Tear Gas).............................................. 389

25.5.1 Introduction............................................................... 389

25.5.2 Chemical Agents....................................................... 389

25.6 Chemical Asphyxiants............................................................ 389

25.7 Carbon Monoxide (CO).......................................................... 389

25.7.1 Incidence................................................................... 389

25.7.2 Chemical Characteristics and Sources of Exposure.....391

25.7.3 Toxicokinetics........................................................... 391

25.7.4 Mechanism of Toxicity.............................................. 391

25.7.5 Signs and Symptoms of Acute Toxicity.................... 392

25.7.6 Treatment of Acute Poisoning................................... 393

25.8 Cyanide................................................................................... 394

25.8.1 Chemical Characteristics, Occurrence, and Uses..... 394

25.8.2 Mechanism of Toxicity.............................................. 394

25.8.3 Toxicokinetics........................................................... 394

25.8.4 Signs and Symptoms of Acute Toxicity.................... 395

25.8.5 Treatment of Acute Poisoning................................... 395

25.9 Methods Of Detection............................................................397

References.........................................................................................397

Suggested Readings...........................................................................397

Review Articles................................................................................. 398

Chapter 26 Metals................................................................................................ 401



Anirudh J. Chintalapati and Frank A. Barile



26.1 Introduction............................................................................ 401

26.1.1 Background............................................................... 401

26.1.2 Exposure and Applications....................................... 401

26.1.3 Physiological Role of Metals.....................................402

26.2 Chelation Therapy..................................................................402

26.2.1 Description................................................................402

26.2.2 Dimercaprol...............................................................404

26.2.3 Ethylenediaminetetraacetic Acid (EDTA)................404

26.2.4 Penicillamine.............................................................405

26.2.5 Deferoxamine............................................................406

26.2.6 Succimer....................................................................406

26.2.7 Unithiol......................................................................407

26.3 Antimony................................................................................407

26.3.1 Physical and Chemical Properties.............................407

26.3.2 Occurrence and Uses.................................................407

26.3.3 Mechanism of Toxicity..............................................408

26.3.4 Toxicokinetics...........................................................408

26.3.5 Signs and Symptoms of Acute Poisoning.................408

26.3.6 Treatment of Acute Poisoning...................................408

26.4 Arsenic (As)............................................................................409

26.4.1 Physical and Chemical Properties.............................409

26.4.2 Occurrence and Uses.................................................409

26.4.3 Mechanisms of Toxicity............................................409

26.4.4 Toxicokinetics...........................................................409

26.4.5 Signs and Symptoms of Acute Toxicity.................... 410

26.4.6 Signs and Symptoms of Chronic Toxicity................. 410

26.4.7 Treatment of Acute Poisoning................................... 410

26.4.8 Treatment of Chronic Poisoning............................... 411

26.4.9 Carcinogenesis.......................................................... 411

26.5 Asbestos.................................................................................. 411

26.5.1 Physical and Chemical Properties............................. 411

26.5.2 Occurrence and Uses................................................. 411

26.5.3 Mechanism of Toxicity.............................................. 412

26.5.4 Toxicokinetics........................................................... 412

26.5.5 Signs and Symptoms of Acute Toxicity.................... 412

26.5.6 Signs and Symptoms of Chronic Toxicity................. 412

26.5.7 Treatment of Acute Poisoning................................... 413

26.5.8 Treatment of Chronic Poisoning............................... 413

26.6 Cadmium................................................................................ 413

26.6.1 Physical and Chemical Properties............................. 413

26.6.2 Occurrence and Uses................................................. 413

26.6.3 Mechanism of Toxicity.............................................. 414

26.6.4 Toxicokinetics........................................................... 414

26.6.5 Signs and Symptoms of Acute Toxicity.................... 414

26.6.6 Signs and Symptoms of Chronic Toxicity................. 415

26.6.7 Treatment of Acute Poisoning................................... 415

26.6.8 Treatment of Chronic Poisoning............................... 415

26.7 Cobalt..................................................................................... 415

26.7.1 Physical and Chemical Properties............................. 415

26.7.2 Occurrence and Uses................................................. 415

26.7.3 Mechanism of Toxicity.............................................. 416

26.7.4 Toxicokinetics........................................................... 416

26.7.5 Signs and Symptoms of Acute Toxicity.................... 416

26.7.6 Signs and Symptoms of Chronic Toxicity................. 416

26.7.7 Treatment of Acute Poisoning................................... 417

26.7.8 Treatment of Chronic Poisoning............................... 417

26.8 Copper.................................................................................... 417

26.8.1 Physical and Chemical Properties............................. 417

26.8.2 Occurrence and Uses................................................. 417

26.8.3 Mechanism of Toxicity.............................................. 418

26.8.4 Toxicokinetics........................................................... 418

26.8.5 Signs and Symptoms of Acute Toxicity.................... 419

26.8.6 Signs and Symptoms of Chronic Toxicity................. 419

26.8.7 Treatment of Acute Poisoning................................... 419

26.8.8 Treatment of Chronic Poisoning............................... 419

26.9 Iron (Fe2+, Fe3+)....................................................................... 420

26.9.1 Physical and Chemical Properties............................. 420

26.9.2 Occurrence and Uses................................................. 420

26.9.3 Mechanism of Toxicity.............................................. 420

26.9.4 Toxicokinetics...............................................

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"The stated audience is undergraduate and graduate students, which is appropriate. The book will be a good starting point for understanding basic information on a large number of chemical toxicities."

-Udayan Apte, PhD, DABT (University of Kansas Medical Center)
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